Drugs and the Environment:
Stewardship & Sustainability
Christian G. Daughton, PhD
Environmental Chemistry Branch
Environmental Sciences Division
National Exposure Research Laboratory
Office of Research and Development
U.S. Environmental Protection Agency
944 East Harmon
Las Vegas, NV 89119
12 September 2010
a report prepared for:
NERL-ESD Annual Performance Measure: APM 200
NERL-LV-ESD 10/081, EPA/600/R-10/106
This document can be cited as:
Daughton CG "Drugs and the Environment: Stewardship & Sustainability," National Exposure
Research Laboratory, Environmental Sciences Division, US EPA, Las Vegas, Nevada,
report NERL-LV-ESD 10/081, EPA/600/R-10/106, 12 September 2010, 196 pp;
available: http://www.epa.gov/nerlesdl/bios/daughton/APM200-2010.pdf
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Stockpilings
improper storage
Imprudent disposal
Residues recycled
from en\1ronment
Poisonings
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CG Daughton
Drugs and the Environment:
Stewardship & Sustainability
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TABLE OF CONTENTS
Table of Contents 3
ABSTRACT 7
INTRODUCTION 8
Terminology and What Exactly Is Drug Wastage? 14
MAJOR FINDINGS and INSIGHTS 15
Overview 16
(1) The need for prudent drug disposal is not a new issue 16
(2) Drug disposal is a deceptively complex issue and one refractory to simple solutions 16
CAUSES of LEFTOVER MEDICATIONS 16
(3) The causes of accumulation of leftover drugs are numerous, complex, and not amenable to
simple solutions 16
(4) A comprehensive approach for reducing the incidence of leftovers will require a full and
accurate understanding of the entire cradle-to-grave life cycles of medications 17
DISPOSAL: SCIENCE ISSUES & CONCERNS 17
(5) Evidence for drug disposal acting as a major origin of ambient aquatic residues of APIs does
not exist, except for some select cases 17
(6) Drug disposal may serve as the major source of APIs in landfills (even when not receiving
biosolids) 18
(7) Disposal to trash poses unknowns with regard to the environmental fate of APIs 19
(8) Disposal to trash poses additional hazards 19
(9) Concerns regarding individual privacy during disposal can increase the risks for poisoning or
injury 19
UNDER-RECOGNIZED CONCERNS or DRUG-USE PRACTICES 19
(10) Gray water and septic systems are under-recognized potential problems with regard to drug
disposal 19
(11) Disposal of certain select delivery devices to sewers may serve as a major source of
particular API residues in the environment 20
(12) Pharmacokinetics, dosage form, and patient compliance are the main factors dictating
whether disposal can be a significant contributor to ambient environmental levels of APIs 20
(13) Certain drug-use practices can essentially serve as indirect, unintended, hidden forms of
disposal 20
(14) Biologies pose little concern with regard to disposal to sewers, but do pose some concern
with regard to disposal to trash 21
(15) Drug donations are a major problem for humanitarian relief efforts 21
DISPOSAL GUIDANCE 22
(16) Guidelines for prudent disposal need to avoid a singular focus on protecting the environment
22
(17) Current drug disposal guidance may be flawed and increase risks for humans 22
(18) Drugs possessing the potential for single-dose lethality require special consideration in
disposal guidance 23
(19) Protecting the environment with optimal disposal guidelines can conflict with ensuring
human safety 23
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(20) Prudent drug disposal requires balancing the protection of the environment with ensuring
access to timely medical care 24
FORMAL COLLECTION PROGRAMS 24
(21) The potential effectiveness of drug-collection programs for curbing imprudent disposal is
unknown 24
(22) Formal collection programs for unwanted drugs may have significant hidden costs 24
(23) The statistical representativeness of data from drug collection or take-back programs is
unknown 24
(24) Data from drug collection programs cannot be inter-compared; standardization is needed... 25
(25) Prudent drug disposal requires attention not just to the API, but also to the packaging 27
(26) Drug collection programs (e.g., take-backs) may not be an effective approach for reducing
the diversion of the primary drugs of concern - controlled substances 27
(27) Patchwork of take-backs in the US adds to the existing confusion regarding drug disposal. 27
(28) Sustainable approaches to drug disposal require clear and useful measures of success 28
DRIVERS for ASSES SING MEDICATION WASTE 28
(29) Connection to Healthcare: Viewing leftover drugs as measures of success or opportunities for
improvement, rather than simply as waste 28
(30) Focus on Source Reduction: An overwrought focus on drug disposal may distract from a
sustainable solution yielding a wide range of collateral benefits 29
(31) Adopting Healthier Lifestyles: Reducing the incidence of leftover drugs may in some
instances also serve to reduce the entry of APIs to sewers via excretion and bathing 30
(32) Counter to current perception, excretion of APIs can be reduced - without jeopardizing the
quality of healthcare 30
(33) Several trends hold potential for exacerbating the need for prudent drug disposal 30
(34) Manufacturer promotions such as Direct-to-Consumer (DTC) advertising and drug sampling
increase the incidence of leftovers 32
(35) Certain trends such as large-scale drug diversion may be exacerbating the need for drug
disposal 33
MESS AGING & COMMUNICATION 33
(36) Current science can only justify a focus on drug disposal on the basis of the collateral
benefits for healthcare and protecting human safety - not for protecting the environment.. 33
(37) Possible unexpected paradox: Drug take-back events may potentially worsen the drug
disposal problem, as well as diversion and poisonings, by encouraging stockpiling 34
(38) Public outreach efforts designed to promote prudent disposal should try to ensure that certain,
select groups are reached 35
(39) Public outreach efforts and mechanisms for prudent drug disposal should try to accommodate
consumers with unusual needs 35
(40) Unknowns surrounding the connection of expired drugs with toxicity 36
(41) Non-compliance can be targeted as a means to better involve the patient in effecting change
36
(42) Centralized coordination needed for all issues related to stewardship and disposal -
minimizing waste of resources that leads to duplication of effort, rediscovery, and
reinvention 36
SCOPE AND OBJECTIVES 37
PROJECT COMPONENTS 41
HISTORICAL PERSPECTIVE 47
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BACKGROUND AND RATIONALE 51
Overviews of the Drug Disposal Issue 56
Specific Areas of Research Relevant to Understanding the Origins of Leftover Drugs, the Significance of Drug
Disposal, and the Importance of Stewardship 57
Non-compliance/Non-adherence 57
Introduction 57
The "healthy-adherer" or "healthy-user" effect 60
Some of the many causes of (and means of controlling) non-compliance 62
Shared decision-making and "brown-bag medication review." 65
Dispensed quantities - the roles of stat andPRN 66
Asynchronous repeat prescribing (misalignment) and inequivalence 69
Role of the prescriber and rational prescribing 70
Costs of non-compliance (and hospital wastage) 72
Technology, personalized medicine, and other approaches for improving compliance 73
Leftover drugs as contributors to human poisonings 75
Data from poison control centers and coroner reports 78
Factors that can exacerbate poisonings - the roles of packaging (especially child-resistant closures -
CRCs), drug design, and consumer behavior 79
Child-resistant closures (CRCs) 81
Single-dose lethality and fatal medication errors (FMEs) at home 82
Transdermal and topical drug delivery systems (TDDS) 83
Leftover drugs as contributors to animal poisonings 86
Unintentional or "indirect" disposal of drugs resulting from use in veterinary practices 87
Drug disposal guidance increasing the hazard of leftover drugs 88
Guidelines for altering, manipulating, or treating drugs prior to their disposal by consumers are
ill-advised 89
Pre-treatment of drugs prior to disposal by healthcare facilities and pharmacies 92
Occupational hazards of drug waste and relevance to consumers 94
Pre-treatment of leftover drugs prior to disposal by collection events 95
Pre-treatment of drugs by encapsulation prior to disposal 95
Take-Backs; DUMP, DOOP, and RUM campaigns; home and hospital inventories 96
Mail-backs 99
Role of the CSA 100
Role of expiry and shelf-life 101
Roles of packaging and medication devices 104
Role pharmaceutical promotions: sampling, detailing, DTC and drug data mining 107
Roles of counterfeiting, importation, and Internet pharmacies 109
Role of donations - and recycling, reusing, reissuing Ill
Drug diversion and sharing (possibly made worse by current disposal guidance) 113
Drug disposal for reducing diversion and abuse 117
Drug disposal as a contributor to ambient environmental levels 117
Drug disposal as a contributor to higher episodic spikes of APIs to the environment 120
Proper disposal is not the only approach for reducing ambient environmental levels of APIs 121
Disposal of drugs to landfills 121
Incineration 124
Sustainability/Stewardship/EPR 125
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Eco-labeling 129
Biologies 130
Legislative Activities 131
Enforcement activities 132
Antibiotics and selection for antibiotic resistance 133
CONCLUDING ANALYSIS 134
SUGGESTED FOR FUTURE CONSIDERATION 136
GLOSSARY 138
Illustrations pertinent to drug disposal and stewardship (prepared during this proj ect) 140
BIBLIOGRAPHY 153
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ABSTRACT
This report represents the first-ever comprehensive examination of the broad scope of issues surrounding
the topic of disposal of unwanted, unneeded, leftover medications from consumer use and the countless
ways in which the introduction of active pharmaceutical ingredients (APIs) to the environment can be
reduced. The report presents a synthesis of thought resulting from the body of work performed on this
topic over the last decade by the US Environmental Protection Agency's Office of Research and
Development (ORD) at the National Exposure Research Laboratory in Las Vegas, Nevada.
After distilling and synthesizing the published literature, it becomes clear that a holistic solution to the
problem of consumer drug disposal will require the coordinated efforts of numerous stakeholders,
agencies, and disciplines. A truly sustainable solution has the potential to not just reduce the entry of APIs
to the environment via direct disposal of drugs to sewers (by flushing down drains) and landfills (by
discarding in trash). More significant outcomes are possible from a holistic, sustainable approach that
targets the many factors that contribute to the incidence of leftover drugs. Instead of limiting the focus to
mechanisms for disposing of leftover drugs, a sustainable approach could also reduce: environmental
loadings of APIs as a result of actions that also minimize their excretion; the incidence of drug diversion
and abuse; the incidence of morbidity and mortality resulting from unintended poisonings (for humans,
companion animals, and wildlife); and healthcare costs. Perhaps most importantly, a system that
minimizes drug wastage may lead to improved therapeutic outcomes and general health, as well as to
improvements in other aspects of the system of healthcare such as the way in which drug donations are
handled.
It is clear that the most practical and effective potential solutions to the related issues of leftover
medications and pharmaceutical residues in the environment reside with the prescribing and dispensing
communities and allied industries such as manufacturers and insurers. Countless improvements to these
practices could be made, resulting in lower drug usage, fewer leftovers, improved therapeutic outcomes,
and lower healthcare costs. This is where efforts need to be focused in changing the behaviors and
practices of those involved with medical care. While patient expectations play a large role as well (such as
with non-compliance to medication regimens, or with misguided expectations that a successful visit to a
doctor is measured in part by whether a prescription is obtained), these expectations need to be changed
by the medical care community. The responsibility of manufacturers not only can target issues such as
patient non-compliance and excessive or unnecessary drug usage, but it can extend beyond the point of
drug usage to deal with leftover medications.
A fully integrated, sustainable approach to optimal drug use and generation and disposition of wastes can
only be achieved by the close and integrated collaboration of healthcare professionals, environmental
scientists, regulators, and numerous other organizations and stakeholders.
This report seeks to summarize the many facets and nuances surrounding the drug disposal issue in a way
suited for informing development of future guidance or regulation. A comprehensive examination of the
many dimensions of drug wastage is critically important because policy or regulation not sufficiently
grounded with a holistic, systems-level understanding of the overall issue could result in: increased
healthcare costs (e.g., increased dispensing costs), poor therapeutic outcomes (e.g., from degraded patient
compliance), increased costs to society from policies that exacerbate drug diversion and accidental
poisonings, and at best nominal improvement for the environment (if disposal proves to be of little
consequence to overall environmental residues of APIs).
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INTRODUCTION
A single quotation from Richard Asher (regarded as one of the preeminent medical thinkers of
the 20th century) in 1972 serves to capture the bare essence of the life cycle of pharmaceutical
products:
"If you give a man a pill there are only two things he can do with it:
he can swallow it or he can throw it away" (as quoted by Taylor 1978).
From this simple beginning stems the vast, inter-related complexities that surround the
controversies and consequences involved with the pharmaceuticals we use - and those we fail to
use. But Asher's quip omits some of the other, less-obvious detours along a pill's journey. These
include: refusing to take the pill, ignoring its usage instructions, giving it to someone else, failing
to store it safely (resulting in its theft or deterioration), or simply forgetting about it (until it
expires). All of these contribute to the innumerable issues involved with drug ingredients as
environmental contaminants and with the unintended problems resulting from their use, non-use,
misuse, and abuse. The unintended problems and their possible solutions are the subject of this
report.
The focus of this report is on the many issues surrounding the disposal of consumer-generated
drug waste. Parallel problems derive from the use of pharmaceuticals by healthcare facilities, as
well as by veterinary practices and other professions using pharmaceuticals, such as agriculture.
But the issues facing healthcare facilities regarding drug wastage often differ from those for
consumer drug waste in a number of ways. For example, the types of drugs used most frequently
can differ dramatically; a complex array of regulations govern how drug waste should be
handled; and the geographic distribution of healthcare facilities is more limited (making their
contributions of drug ingredients to the environment less ubiquitous but also less disperse).
Despite the differences with consumer-generated waste, this report discusses some of the aspects
of healthcare waste when they are pertinent to consumer use.
A cursory examination of this report quickly reveals the extraordinary complexity of the topic -
one with myriad interconnections and feedback loops. Changes designed to improve one aspect
can adversely impact others. Countless factors contribute to the accumulation of leftover drugs,
which later require disposal. Available options for consumer disposal have yet to prove
satisfactory with respect to environmental impact or cost. The extent to which drugs become
waste (and the eventual entry of their active ingredients to the environment) is intertwined with
the effectiveness of healthcare. Indeed, drug waste is a direct measure of the efficiency and
success of the overall healthcare system. Effective solutions will require a concerted
transdisciplinary, holistic, systems-level approach - one that integrates the needs, ideas, and
expertise of all stakeholders - including environmental regulators, healthcare professionals,
dispensers, manufacturers, healthcare insurers, and a broad spectrum of technical disciplines and
federal/state agencies. These groups represent a wide spectrum of professions that have never
before had reason to communicate or collaborate with one another.
Current approaches for protecting the environment from drug residues are sometimes at odds
with protection of human health and safety. Some causes and potential solutions are surprising
and counterintuitive - and frequently, deceptively complex. A sustainable solution will instead
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need to treat the environment and the patient as an integral whole. The ultimate objective will be
redesigning parts of the healthcare system to minimize the accumulation of leftover medications,
thereby reducing or eliminating the need to dispose of waste. The concepts underlying the "green
pharmacy" (Daughton 2003a; b) and pharmEcovigilance (Daughton and Ruhoy 2008a) would
need to play major roles.
Active ingredients in pharmaceuticals (as well as illicit drugs) are now widely established as
ubiquitous contaminants in the environment. Beyond the expected occurrence of permissible
residues of certain agricultural drugs in food products, their unintended presence has been
documented in a wide spectrum of environmental compartments and matrices long known to
carry legacy pollutants, including: sewage, surface waters, ground waters, sediments, drinking
waters, marine environments, sewage sludge and biosolids, tissues of crops and native vegetation
(when biosolids or treated wastewater are used for irrigation or as soil amendments), tissues of
aquatic organisms, and even air.
The active ingredients from medications and other pharmaceutical preparations can pose risks
beyond those associated with their intended uses in therapy, diagnosis, or prophylaxis. These
unintended risks comprise two major categories: (1) introduction to the environment as trace
contaminants by the combined actions and activities of myriad individuals, resulting in chronic
ultra-low-level exposure for wildlife and humans (e.g., via recycling in drinking water and fish),
and (2) their involvement in exposure to wildlife and humans at acute doses, primarily from
special situations involving imprudent disposal and from either accidental or purposeful
ingestion by individuals for whom the medications were never intended (i.e., drug diversion).
Each of these two major categories comprises several sources or origins. Active pharmaceutical
ingredients (APIs) enter the environment by way of: (1) the excretion of unmetabolized APIs (as
well as reversible products of metabolism such as conjugates), (2) release from the skin during
bathing (from medications applied topically to the skin and from residues excreted through the
skin via sweat) (Daughton and Ruhoy 2009a), (3) disposal to sewerage or trash of unwanted,
unused, leftover medications, and (4) animal carcasses containing high levels of certain drugs
(these tainted carcasses can contain levels of certain APIs that are acutely toxic to animal
scavengers) (Daughton 2007). The many pathways by which drugs and their APIs are distributed
into the environment and by which they can eventually come into contact with wildlife or result
in unexpected, unintended exposures for humans are summarized in two illustrations (also
included at the end of this report):
Daughton CG. "Unintentional, Unanticipated Exposure to Drugs [illustration published in: Daughton CG and Ruhoy IS
"The Afterlife of Drugs and the Role of PharmEcovigilance," Drug Safety, 2008, 31(12):1069-1082]," illustration,
US EPA, Las Vegas, NV, 8 December 2007 (rev 4 June 2008) 2007.
Daughton CG. "The Environmental Life Cycle of Pharmaceuticals [illustration published in: Daughton, C.G.
"Pharmaceuticals as Environmental Pollutants: the Ramifications for Human Exposure," In: International
Encyclopedia of Public Health, Kris Heggenhougen and Stella Quah (Eds.), Vol. 5, San Diego: Academic Press;
2008, pp. 66-102]," US EPA, Las Vegas, NV, December 2006; available:
http://www.epa.gov/nerlesdl/bios/daughton/drug-lifecycle.pdf.
A number of parallels exist regarding these sources with respect to the use of human
pharmaceuticals and veterinary pharmaceuticals (especially with regard to confined animal
feeding operations, CAFOs); for CAFOs, however, the classes of APIs are primarily limited to
steroids, antibiotics, antiparasitics, and anti-inflammatories.
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The study of the presence and potential impacts of drugs in the environment encompasses a
dizzying spectrum of issues and covers an expansive array of disciplines. It is a transdisciplinary
problem requiring collaboration across the fields of not just engineering and science, but also
criminology, sociology, psychology, healthcare, pharmacology, pharmacy, health insuring, and
politics. The interconnections are so strong that it is extremely difficult to tease any individual
aspect apart and discuss or study it in isolation from the others. Articulating an easily understood
but comprehensive perspective on this complex, multi-faceted topic has so far eluded all and will
certainly not be attempted here. But one outcome from the length and depth of this report may be
a better appreciation for the fact that there are no easy solutions to the drug wastage problem.
The focus of this report is instead devoted to just one aspect - the entry of drugs to the
environment not as a result of their intended usage (such as from excretion of unmetabolized
residues), but rather as a result of their wastage and subsequent disposal. Of the many aspects of
active pharmaceutical ingredients (APIs) used in medications and occurring as environmental
contaminants, drug disposal continues to capture the attention of the public, the press, the water
industry, regulators, and the Congress, which has held several hearings over the last couple of
years. In the US, the primary federal agency involvement has been among the Executive Office
of the President Office of National Drug Control Policy (ONDCP), the Department of Justice
(namely the Drug Enforcement Administration, DEA), the Food and Drug Administration
(FDA), and the Environmental Protection Agency (EPA); and the U.S. Postal Service (USPS)
has become a recent participant.
With the growing emphasis on recycling and stewardship, numerous options have evolved for
the consumer to dispose or even recycle a wide spectrum of items, including pesticides,
household cleaners, batteries, electronics (and supplies such as printer cartridges), household
appliances, oils, fluorescent lamps (and other mercury-containing items), paper, plastics, cans,
glass, packaging materials, and aluminum; for more information see:
http://www.epa.gov/epawaste/index.htm. One of the last major classes of consumer items for
which a formal, uniform mechanism for disposal or recycling is lacking is that of
Pharmaceuticals. Pharmaceutical products, however, occupy a unique place in the world of
recycling - as they have practically no reuse or reclamation value. Instead, pharmaceutical waste
currently represents an economic liability. The real value in drug waste is in the data and
information that can be mined from these wastes - potentially useful, for example, in expanding
our knowledge of drug effectiveness and the extent of patient non-compliance, both of which
play major roles in drug wastage.
But even the specific topic of drug disposal by itself is impossible to cover in a comprehensive
manner. While the topic of disposal of unwanted drugs has garnered increasing attention from
the public, the pharmaceutical and pharmacy industries, healthcare communities, regulators, and
state and federal agencies, comparatively few questions are being asked as to "why is there a
medication disposal issue to begin with?" In essence, what factors coalesce to drive the
accumulation of leftover medications, creating a consequent need for their disposal? Just about
every dimension of the countless factors that feed into the issue of leftover drugs and disposal is
complex and surrounded with controversy. This is one of the reasons this problem has proved so
intractable and why the focus has been on the comparatively easy part of the problem to solve
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(what to do with leftover drugs) as opposed to solving the problems that drive the need for their
disposal.
Only recently has an organization involved with pharmaceutical care begun to ask these
important questions. The American Society of Consultant Pharmacists (2009a) has stated:
"Strategies that focus on appropriate disposal of medications do not address the
underlying problem that resulted in the waste in the first place. For that reason, strategies
that reduce the amount of pharmaceutical waste may be more important and effective in
the long run than changing the method used to dispose of unwanted medications.
Understanding factors and policies that contribute to pharmaceutical waste is an important
first step."
"The first priority should be to reduce the amount of pharmaceutical waste generated,
rather than dealing with the pharmaceutical waste once it has been generated. Reducing
the amount of pharmaceutical waste addresses the root cause of the problem as well as
reducing overall health care costs."
In a resolution adopted by the U.S. Pharmacopeia Convention 4 years prior (USP 2005),
the aim had been solely on developing better disposal programs, not on minimizing
waste: "to work with appropriate constituencies to continue developing programs to
promote safe medication use and disposal"
As a result of our at EPA's Office of Research and Development (ORD) on sustainable
pharmacy ("green pharmacy"), we began to formally advocate this approach in 2008 - one aimed
at sustainability and pollution prevention (Ruhoy and Daughton 2008). The work reported here
results from in-house research performed at ORD's National Exposure Research Program, Las
Vegas, beginning in 2003, but primarily since 2006. Major portions of this work resulted from a
collaboration with an MD who was being mentored in pursuit of her PhD, which was awarded in
2008 (Ruhoy 2008). As such, valuable insights and perspectives were gained regarding the roles
of physicians. This is critical given that most of what occurs within the topic of drug disposal
exists at the interface between the environment and health care. This body of work establishes
the myriad aspects of how and why drugs become waste materials, how they enter the
environment, what the ramifications and consequences can be, and how the wastage can be
prevented or minimized. Concerted interest in environmental stewardship and drug disposal first
began to emerge after 2003 with development of the concept of the Green Pharmacy (Daughton
2003a; b). The first books dedicated to the topic of a green and sustainable pharmacy began to
emerge only in 2009 (Bengtsson et al. 2009; Kummerer and Hempel 2010; Ruden et al. 2010).
The primary focus of this report is on consumer drug use. Analogous problems exist with
institutional drug use, but different solutions are often required - largely because of different
regulations governing waste handling. An overview of the drug disposal problem in the
institutional setting is provided by the American Society of Consultant Pharmacists (2009a). The
US EPA has collected substantial data and information regarding the origins and incidence of
unused drugs in the healthcare and veterinary sectors (USEPA 2008a; b; 2009), as well as
identified best practices for the management and control of unused drugs in the healthcare sector
(Lucy and Wu 2009). The EPA is in the process of finalizing guidance for "Best Management
Practices for Unused Pharmaceuticals at Health Care Facilities" (USEPA 201 Ob; c).
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For brevity, this report will use the acronym APIs ("active pharmaceutical ingredients") as
shorthand for the chemical substances formulated in pharmaceuticals and illicit drugs and which
are responsible for the desired or intended therapeutic or lifestyle outcomes. Also note that there
are a number of different terms commonly used in discussions of pharmaceuticals, most with
subtle differences in meaning; these must be taken into consideration when performing searches
of the published literature. In this report, however, these names will often be used
interchangeably. In addition to drugs and pharmaceuticals, terms include medication, medicine,
medicament, medicinal, and therapeutant; also included in the realm of discussion are diagnostic
agents (such as X-ray contrast agents). Generally excluded from this discussion are vaccines and
biologies, as these substances (whose structures are based on proteins or nucleic acids) generally
do not pose the same types of exposure concerns as ambient residues of synthetic molecules in
the environment; there are, however, some possible exceptions, as seen in a published overview
regarding biologies in the environment (Kiihler et al. 2009).
There are roughly over 1,460 molecularly unique small-molecule APIs registered for use in the
US (Wishart et al. 2008), and perhaps hundreds of distinct ingredients commonly used in illicit
drugs (Daughton 2010b; Daughton 2011); discussion of the environmental aspects of drugs often
must cover both legal and illicit drugs (including counterfeit drugs), as the two groups often have
no distinction in terms of chemical composition (Daughton 2010b; Daughton 2011). These
small-molecule APIs (biologies are excluded from this discussion) are formulated into over
20,000 parenteral, topical, and oral drug products. The types and relative quantities of these
ingredients can vary dramatically across geographic locales - as a function of consumer
preferences and prescribing preferences and customs; as an example, for brick-and-mortar US
pharmacies in 2009, the number of prescriptions dispensed per capita within states varied 3-fold
(from 6 in the west/southwest to 18 in the southeast/northeast), and the total number of
prescriptions filled varied 60-fold (from 5 to 30 million) (Statehealthfacts.org 2010a; b). The
ambient levels of these chemicals can also vary as a function of the natural processes that dictate
their environmental half-lives, such as temperature, pH, solar irradiance, and microbial activity.
These products (both over-the-counter [OTC] and prescription only) might be obtained by the
consumer or end-user from physicians or veterinarians (by way of prescriptions filled at
pharmacies or as free samples), from hospitalization, from stores or Internet pharmacies, from
friends (drug sharing), or from the black market.
"Prescription-only medicines" (sometimes abbreviated PoM in the UK) are also referred to in the
US as "legend" drugs, which include both non-controlled and controlled substances; at one time
the labels for these drugs were required to carry what was called the federal legend: "Caution!
Federal law prohibits dispensing without a prescription," but which has generally been simplified
to "Rx only." Prescription-only drugs are defined in 503(b)(l)[21 USC §353] of the FD&CA
and are essentially those for which adequate directions for self-administration by consumers
cannot be provided on a label (USFDA 2009a). Instead, only a licensed prescriber can provide
the necessary directions - prior to a prescription being filled; this usually means a doctor, nurse
practitioner, physician's assistant, dentist, or veterinarian. Whether a drug is designated as
prescription-only in the US is determined by standards set by the United States Pharmacopeia
(USP) and regulated the FDA.
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The concentrations of APIs currently detectable in the ambient environment vary dramatically -
ranging over roughly 9 orders of magnitude, from sub-parts-per-trillion (ng/L, such as in
drinking water) to more than tens of milligrams per liter or kilogram (such as in manufacturing
waste streams and in sewage biosolids).
The focus of this report is on the pathways by which APIs gain entry to the environment but
which are under direct human control - that is, their release to the environment can be
immediately controlled by any number of countless approaches capable of modifying or
preventing the actions, activities, or behaviors that lead to their escape or release. These pollution
prevention, source control, and environmental stewardship measures can be applied at myriad
places along the life cycle of a drug - spanning the chain extending from drug design,
manufacturing, formulation, distribution, prescribing, dispensing, and consumption, to eventual
disposal of leftovers.
The issue of drug disposal is intimately intertwined with a bewildering array of factors involving
society's relationship with drugs, including: manufacturing (e.g., drug formulation), packaging,
prescribing practices and customs, dispensing practices (including the health insurance industry),
design of drug delivery (especially the need for delivery devices), consumer behavior (numerous
behaviors leading to leftover drugs, a major one being problems with patient
compliance/adherence), drug collection programs (e.g., take-backs), poisoning (human and
animal), diversion, expiry (including stability testing), environmental stewardship, pollution
prevention, and legislation, among many others.
With judicious design and implementation of the most effective measures, a more sustainable
system of healthcare could be designed. A major aspect of the hypothesis behind this work is that
with implementation of measures to reduce the levels of APIs in the environment, significant
collateral benefits could emerge for health care, including improved therapeutic or lifestyle
outcomes and reduced healthcare costs. The environment and human health are intimately
linked. Treating the two as an integral, collective patient holds many advantages with respect to
sustainability. In this sense, and of great significance, efforts to control the presence of APIs in
the environment are intimately linked with progress toward solving many of the intractable
problems long faced by the administration of healthcare.
Traditionally, consumers in the U.S. have used trash receptacles and drains to sewers for
medication disposal. Historically (and only up until the last few years), poison control centers
have recommended that drugs be flushed down the toilet (whether leading to a septic system or
to a municipal waste treatment facility) as the best means of preventing their accidental or
purposeful ingestion by those for whom the medication was not intended, especially children.
Although disposal to the toilet prevents immediate accidental exposure or ingestion, it
unfortunately can add to the overall level of pharmaceutical pollutants in the environment (by
way of treated wastewater or sludge). These ambient levels of APIs then hold the potential to
lead to extremely low-level, chronic human exposure via contact or ingestion of minute residues
in drinking water (as a result of the natural "water cycle") or by ingesting food crops grown on
land treated with sludge or irrigated with treated wastewater. With human exposure aside, it is
important to note that the entry of APIs to the environment is believed to pose more concerns
with respect to exposure by aquatic organisms.
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Terminology and What Exactly Is Drug Wastage?
Discussions of drug disposal are complicated enough, but sometimes it is not even clear as to
what is meant by the various terms used to describe drugs that are subject to disposal. Terms
used in the literature include: unused, unwanted, unneeded, expired, wasted, and leftover. The
distinctions between these can be subtle or ambiguous. "Unused" and "expired", for example, are
not good descriptors as they only comprise subsets of the total spectrum of medications that can
require disposal. "Unused" omits those medications requiring disposal but which have indeed
already been used (such as used medical devices). Just because a medication's container or
package have been opened does not necessarily mean it has been "used." "Unused" can also
mean to the patient that they are literally no longer using the medication (for its intended
purpose), despite the fact that many patients continue using medications on a self-medicating
basis (administering the medication for a condition or duration not originally intended - one of
many forms of non-compliance). The term "expired" omits the preponderance of drugs that are
discarded before expiry - often soon after they are dispensed. The term "leftover" is sufficiently
expansive, as it includes all medications no longer being used for the original prescribed
condition or intended use - or even unintended purpose.
Another term often used to refer to unused consumer pharmaceuticals is "home-generated
Pharmaceuticals" (or home-generated pharmaceutical waste); e.g., see: California Integrated
Waste Management Board (CIWMB) Criteria and Procedures for Model Home-Generated
Pharmaceutical Waste Collection and Disposal Programs (CIWMB -Year Unknown). But this
too is not a rigorous term, as many drugs from consumer use are not kept in the home, but are
dispersed in countless locations throughout society (Ruhoy and Daughton 2008).
Various acronyms are also used to describe drugs subject to disposal. Some include UEMs
(Unused and Expired Medications) and MNU (les Medicaments Non Utilises). Programs
designed to collect leftover medications include "take-backs" (often used in the US), and DUMP
(Dispose Unwanted Medicines Properly) or DOOP (Disposal of Old Pharmaceuticals)
campaigns, which are often used in the EU. All of these terms and acronyms represent but a
portion of those needed to perform comprehensive searches of the literature.
A major obstacle in any discussion of drug wastage is what exactly is meant by "wastage." A
definition of wastage is notoriously difficult - especially since the topic involves countless
variables and perspectives. A simple definition for drug waste is medications dispensed to - or
purchased by - a consumer that are never used for the original intended purpose. But, on closer
examination, this is not as straightforward as it might first appear. A better term might be
"leftover" medications, as this avoids any inference of whether the medications were actually
"wasted" (that is, served no purpose). The term "leftovers" does not infer a reason for why
medications accumulated unused or unwanted. Would a medication intended for emergency
contingency purposes (and now expired) be considered "wasted"? After all, such medications
served their purpose of being available for possible emergencies. How about medications
intended for unscheduled consumption "as the situation arises" or "as needed" (PRN: "pro re
nata," Latin for "in the circumstances" or "as the circumstance arises"). These scenarios show
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that it would not be possible to completely eliminate leftover medications - only to reduce them
to a necessary minimum.
Development of a "justified definition" of wasted medicines was one of the objectives of a study
commissioned by the UK's National Institute for Health Research (Department of Health Policy
Research Programme -Year Unknown). This DHPRP project represents the most ambitious
attempt to date to capture empirical data on the many facets of drug wastage.
One could ask if the basic premise that medications experience undue wastage is even valid. No
one really knows how much drug wastage occurs in commerce (at the consumer level or in the
healthcare setting) in terms of either the total quantity or the cost. In one review of medication
wastage, White (2010) states that traditional estimates for the UK are that 1-10% of the total cost
of medications are wasted; but estimates in the UK are usually based on the quantities of
medications returned to pharmacies by consumers, omitting the quantities that are disposed of at
home, stored indefinitely, or shared with others.
Many statements regarding drug wastage are based on rates of patient compliance, which is an
enormously complex and controversial topic by itself. But non-compliance rates include not just
the frequency with which drugs go unused, but also the frequency with which prescriptions are
NOT filled or with which they are consumed incorrectly. Neither of the latter contributes to any
need for disposal. Failure to fill a prescription may even reduce the need for disposal; so non-
compliance does not necessarily lead to leftover drugs. Few make this distinction in the
literature. One example is a report from White (2009a), who discusses the many nuances and
points of confusion regarding the data on drug wastage.
MAJOR FINDINGS AND INSIGHTS
This project resulted in numerous insights and perspectives. These were used to formulate a wide
array of conclusions, findings, and suggestions for future work. Some of these run counter to the
consensus or popular opinions that have emerged over the years regarding leftover drugs and
disposal. Some even bring into question the validity of new guidance regarding drug disposal.
Most reveal complex interplays - where alterations at a specific point of a drug's life cycle can
have profound and unanticipated ramifications or adverse actions at other points in the cycle.
That alterations at one point in a drug's life cycle can have unintended, unanticipated, or
sometimes unrecognized adverse consequences at another is illustrated by the problems faced
with opiate pain medications. By limiting the quantities that can be dispensed at one time (to
reduce the incidence of leftovers), a patient's continued uninterrupted access to what might be a
critical maintenance medication can be jeopardized. Another long-standing example is controls
and oversight placed on the prescribing of controlled substances to prevent diversion. An
unintended consequence is physician reluctance to prescribe opiates that are critical for
controlling pain.
These insights, conclusions, and recommendations represent major findings from this work.
These major findings, most of which are interrelated, are numbered but are not presented in any
particular order intended to connote importance or priorities. This is because priorities for taking
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action would depend on the immediate and ultimate outcomes that are being sought. Though
they are presented below under various categories, many are applicable to multiple categories.
There are over 40 findings, and nearly all are discussed in more detail in subsequent sections of
this document.
Overview
(1) The need for prudent drug disposal is not a new issue. The accumulation of
unwanted drugs in the home and the need for proper disposal to prevent diversion and
disposal is not a new problem. Leftover, unwanted drugs have been of interest to
healthcare providers and pharmacists since at least the 1960s, when the first studies began
to appear in the peer-reviewed literature. Most of the very same concerns and issues
discussed today have been under study or debate for nearly 50 years. Other than a more
intense concern for potential environmental harm, little has changed. Subjects of
investigation over the decades have included: the storage of unneeded drugs in the home,
the causes for hoarding medications (such as patient non-compliance), the risks
associated with hoarding (such as diversion, abuse, and unintended poisonings), the
monetary cost of wasted drugs, and programs designed to collect unwanted medications.
To illustrate, the following excerpt is from a paper published over 30 years ago
(Goldberg 1977) but which might otherwise seem to be contemporaneous: "The
Department of Health is concerned about the increase in cost of supplying medication to
patients. Comments have been made in the mass media regarding over-prescribing,
patient non-compliance, the high cost of drugs, and the wastage of such medicines." Just
the same, drug disposal continues as a concern, and its audience and stakeholders
continue to expand. But rather than the widening recognition garnered by drug disposal,
what should be surprising is the lack of any real progress toward comprehensive or even
simple solutions. Despite the attention that the accumulation and disposal of drugs has
garnered over the last 4 decades, there are many unanswered questions - as well as many
misconceptions.
(2) Drug disposal is a deceptively complex issue and one refractory to simple
solutions This is borne out by the fact that it has been a point of discussion in the
medical literature for over 40 years and by the very length of this report. The factors
leading to leftover drugs requiring eventual disposal are innumerable, highly complex,
and associated with myriad interconnections, some of which are not at all obvious. The
factors dictating how drugs can be disposed vary across countries and even states within
the US; some of these differences are in part responsible for the relative lack of progress
in the US. The published literature is characterized by an over-wrought focus on drug
collection programs (e.g., take-backs), which represent only one aspect of the overall
issue. These publications tend to rehash the same points but to overlook some of the key
scientific questions.
CA USES ofLEFTO VER MED 1C A TIONS
(3) The causes of accumulation of leftover drugs are numerous, complex, and
not amenable to simple solutions Two of the major factors long assumed to cause
medications to go unused - eventually necessitating disposal - are patient non-compliance
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(failure to take medications as directed) and dispensing of purportedly excessively large
quantities (such as 90-day supplies). The issue of non-compliance is extraordinarily
complex. Efforts to reduce its incidence will not necessarily result in fewer leftovers and
in some instances can jeopardize patient health. If any conclusion can be made regarding
dispensed quantities, it can only be safely surmised that a number of factors must be
considered together with regard to each patient, the type of treatment, and the specific
medication being employed. Across-the-board restrictions on quantities dispensed (either
more or less) can have adverse consequences for therapeutic outcomes, patient health,
and associated costs. Without consideration of the complex interplay between numerous
inter-related factors, an assumed improvement in one area can have unforeseen adverse
consequences in another. This general problem of unforeseen consequences repeats itself
throughout the many facets of the drug disposal issue. This points to the fact that viable
solutions may need to be customizable to the individual patient or situation.
(4) A comprehensive approach for reducing the incidence of leftovers will
require a full and accurate understanding of the entire cradle-to-grave
life cycles of medications. The life-cycles of drugs are extremely complex. This is
shown by the network illustrations covering the origin and fate of pharmaceuticals and
illicit drugs (also appended at the end of this report):
Daughton CG. "Illicit Drags and the Environment [illustration published in: Daughton CG "Illicit Drags:
Contaminants in the Environment and Utility in Forensic Epidemiology," Reviews of Environmental
Contamination and Toxicology, in press, March 2011)]." illustration, US EPA, Las Vegas, NV, 7
December 2009 (rev 17 June 2010) 2009.
Daughton CG. "The Environmental Life Cycle of Pharmaceuticals [illustration published in: Daughton,
C.G. "Pharmaceuticals as Environmental Pollutants: the Ramifications for Human Exposure," In:
International Encyclopedia of Public Health, Kris Heggenhougen and Stella Quah (Eds.), Vol. 5, San
Diego: Academic Press; 2008, pp. 66-102]." published illustration, US EPA, Las Vegas, NV, December
2006.
Although many aspects of the complex network of processes spanning manufacturing to
eventual waste treatment are well understood, some are not. Patient non-compliance, for
example, is a major factor that generates leftovers but whose control is poorly
understood. The many forms of manufacturer promotions (such as advertising and free
samples) have poorly understood impacts on drug purchase and consumption. Even the
distribution and reverse-distribution chains for pharmaceuticals are not fully understood
by those outside the industry because some aspects are proprietary; one of the most
comprehensive overviews of the reverse distribution system is provided by Kumar et al.
(2009).
DISPOSAL: SCIENCE ISSUES & CONCERNS
(5) Evidence for drug disposal acting as a major origin of ambient aquatic
residues of APIs does not exist, except for some select cases. Much of the
ongoing effort in developing drug collection programs to divert leftover drugs away
from sewers and trash, with the intention to protect environment - lacks a body of
supporting data for justification The question as to what fraction of collective or
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individual API residues in the aquatic environment emanates from direct disposal versus
excretion and bathing is currently not answerable. The relative contribution from disposal
versus excretion probably varies dramatically from drug to drug or from class to class
(e.g., antibiotics, analgesics, hormones, controlled substances, etc). It also might vary
according to the type of packaging (e.g., bulk containers versus blister packs; with the
latter probably discouraging disposal to sewers). Little evidence exists to support general
conclusions regarding the potential effectiveness of ceasing drug disposal to sewers (or
landfills) as a means of reducing ambient aquatic levels of APIs (or APIs in biosolids).
Hypothetically, if all disposal of medications to sewers were to cease immediately, it is
possible that there might not be any measurable difference in the current environmental
loadings of APIs in general; some differences might be measurable for a limited number
of particular APIs. This consideration has been overlooked by nearly all assessments to
date of drug disposal, but it represents one of the research needs outlined in 2004
(Daughton 2004). Distinguishing API residues that have originated via disposal from API
residues coming from excretion and bathing by chemical monitoring is currently not
possible, except perhaps for those APIs that should experience the most extensive
metabolism (and therefore are poorly excreted) and whose monitored levels greatly
exceed those based on predictions from usage. To date, only two papers have appeared in
the peer-reviewed literature that delineate the requirements for determining the relative
contributions of APIs to the aquatic environment from disposal to sewers versus
excretion. These papers discuss the variables that must be addressed and the types and
quality of data required for the calculations (Daughton and Ruhoy 2009a; Ruhoy and
Daughton 2007). No study to date has met these requirements.
Even less is known regarding the contributions to the environment as a result of disposal
of illicit drugs (Schedule I) and diverted licit drugs. While progress is being made in
obtaining more reliable data on the types and quantities of illicit drugs in use (Daughton
2011), almost nothing is known regarding the frequency or magnitude of their disposal.
One approach that has been used for assessing recreational drug use is "amnesty bins" at
rave parties (Kenyon et al. 2005).
(6) Drug disposal may serve as the major source of APIs in landfills (even
when not receiving biosolids) While consumer-generated API residues in the
ambient aquatic environment may or may not be reduced by controlling release of APIs
disposed to sewers, disposal is perhaps the major source of APIs in landfills receiving
domestic trash. In contrast to the aquatic environment, disposal of medications via
household trash represents the only source of consumer APIs in those landfills that are
not also receiving biosolids. Paradoxically, comparatively little is known regarding the
magnitude of API disposal to landfills or the fate of APIs in landfills. Even though the
focus of this document is on drug waste resulting from consumer wastage, worth noting
is that hospitals not having a formal pharmaceutical waste program generally dispose of
leftover drugs (including new and used devices and containers) in red sharps containers.
These are then sterilized by microwaving or autoclaving (which does not destroy most
APIs) followed by landfill disposal. This constitutes the other major source of APIs in
landfills.
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(7) Disposal to trash poses unknowns with regard to the environmental fate
of APIs. Current guidance recommending disposal of unwanted medications to domestic
trash destined for landfills poses additional concerns, other than increased risks for
diversion and poisoning. Landfills are not intended for, nor are they capable of, effecting
rapid and significant chemical transformation of synthetic organic chemicals into simpler
structures that are environmentally benign. The drug residues that accumulate in landfills
have the potential to eventually be transported to leachates. When these leachates are
actively collected and diverted through an engineered design to a waste treatment facility
or if portions eventually migrate to groundwater or surface water via defective engineered
barriers, they can eventually contribute to the total environmental load.
(8) Disposal to trash poses additional hazards. Guidance for disposal to trash
usually recommends removal of personal information and/or removal of the identity of
the medication (to discourage diversion). Should a poisoning then occur, emergency
personnel no longer have access to potentially vital information on the drug's identity,
postponing diagnosis and initiation of treatment.
(9) Concerns regarding individual privacy during disposal can increase the
risks for poisoning or injury. General concerns regarding protection of personal
information - sometimes motivated by the Health Insurance Portability and
Accountability Act (HIPAA) - play roles in disposal guidance or regulations. Privacy
concerns pose a conundrum when medications are tossed into the trash. Many labels are
impossible to remove from their containers. Although it is wise to remove personal
information from labels prior to disposal, removing all identifiers from a label, such as
the drug name, dosage, dispensed quantity, and dispensed date could hinder medical
measures needed in the event of an unintended poisoning. Additionally, disposal
guidance that encourages the consumer to deface or obliterate information on the label
may not accomplish its goal, as label print is notoriously difficult to obscure with black
ink, and covering with tape provides only a cosmetic solution, as it could be easily
removed. Some consumers might therefore resort to physically obliterating the label, for
example by attempting its removal with a razor blade, which poses risk for laceration.
Redesign of labels to separate manufacturer data from personal information so that the
portions containing only private data would remain affixed to containers under extreme
storage conditions but could be easily removed when desired would be extremely useful
in solving these problems.
UNDER-RECOGNIZED CONCERNS or DRUG-USE PRACTICES
(10) Graywater and septic systems are under-recognized potential problems
with regard to drug disposal APIs (especially antibiotics and biocides), when
disposed to drains feeding septic systems, may have the potential to disrupt wastewater
treatment more than with centralized waste treatment systems. Furthermore, the
occurrence of APIs in graywaters could pose concern with regard to on-site
reuse/recycling (e.g., such as for land application/irrigation); graywater is household
wastewater originating from all domestic plumbing fixtures except toilets. Surprisingly,
little is known regarding the API content of gray waters, but clearly the composition is a
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direct function of the medications used in each specific household; each household,
therefore, has the ability to control the contaminants entering its own waters or to alter
the reuse of its graywater (e.g., reuse for toilet flushing but not for irrigation). Some of
the only studies that have examined or discussed API occurrence in graywaters include:
Eriksson et al. (2003), Eriksson et al. (2009), Maimon et al. (2010), Kvanli et al. (2008),
Almqvist and Hanaeus (2006), Andersen et al. (2007), and Donner et al. (2010). An
examination of personal care products in graywater was made by Leal (2010).
(11) Disposal of certain select delivery devices to sewers may serve as a major
source of particular API residues in the environment A particular class of
medications for which evidence supports the possible importance of disposal to sewers as
a source of APIs in the environment involves both used and new delivery devices,
especially transdermal devices (e.g., patches). For example, when flushed, new dermal
patches containing methylphenidate can contribute the equivalent amount of API as from
excretion resulting from 3,280 oral doses; patches containing ethynylestradiol can
contribute the equivalent of 214 doses (Daughton and Ruhoy 2009a).
(12) Pharmacokinetics, dosage form, and patient compliance are the main
factors dictating whether disposal can be a significant contributor to
ambient environmental levels of APIs. The biological and chemical processes that
act upon an API once it enters the body, including those effecting absorption,
distribution, metabolism, and excretion are all part of the scope of study called
pharmacokinetics (PK). For those APIs that are extensively excreted unchanged (i.e.,
they undergo little metabolic alteration or tend to be excreted as reversible conjugates) or
for those formulated into medications that have unusually high rates of patient
compliance (which results in proportionately few leftovers), disposal to sewers may only
contribute immeasurably small increments to total environmental loadings. On the other
hand, for those medications containing APIs in transdermal devices and not generally
used in oral or topical dosage forms, their disposal to sewers could serve as the major or
only source of API residues in the environment; examples include rotigotine,
flurandrenolide, and lidocaine. Pharmacokinetics, exclusive dosage forms, and patient
compliance are three critical variables that must be known to assess the potential for
aquatic impact of each individual API disposed to sewers; these have been covered by
Daughton and Ruhoy (2009a), who present a rather comprehensive overview of the many
factors involved with excretion in general and the role played by pharmacokinetics.
(13) Certain drug-use practices can essentially serve as indirect, unintended,
hidden forms of disposal. There are at least two ways in which drugs are used as
intended but which ultimately serve as alternative pathways of unrecognized disposal.
One involves drug-laced carcasses of animals just treated with large doses of certain
drugs. Improper disposal of these carcasses can result in acute (and often fatal) exposures
for scavengers that then consume the carcasses. A second involves the common practice
of application of certain drug preparations directly to the skin. Most of a topically applied
API is not absorbed by the body and is instead washed directly into sewers or waterways
during bathing. APIs in these topical preparations are present at relatively high levels
(e.g., the milligram-per-gram or percent range - known as "high content" preparations),
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so one dose applied to the skin can release as much API to sewers as excretion from
hundreds or thousands of oral doses after metabolism. Even if the disposal problem were
completely solved, the direct introduction of large quantities of certain APIs to sewers
would therefore continue simply as a result of intended use (Daughton and Ruhoy
2009a). This means that other forms of pollution prevention would be required - namely
changes ranging from drug formulation or delivery mechanism, to patient behavior (how
and how much medication is dermally applied). Many topical drugs have traditionally
been applied at very large excessive doses - by covering more of the skin than needed
with larger amounts than prudent. This has been recognized as a clinical problem for
quite some time - and also recognized as a cause of leftovers (Savin 1985).
(14) Biologies pose little concern with regard to disposal to sewers, but do pose
some concern with regard to disposal to trash Biologies comprise a broad and
continually expanding class of pharmaceuticals - with chemical structures based on
proteins, nucleic acids, or sugars - and are used in vaccines, gene therapy, and other
modalities not conducive to conventional "small molecules." These substances are often
unstable in heat, light, and air, and generally unstable in the gut or inefficiently absorbed
from the gut (the entire system of digestive organs). In general, biologies do not pose the
conventional concerns associated with small-molecule pharmaceutical disposal. Those
that do get excreted - and even survive sewage treatment and environmental
transformation or structural denaturing - would probably have considerably lower
potential for resulting in exposure of non-target organisms because of their poor
absorption across the skin or via the gut and propensity for environmental degradation or
denaturing by microorganisms, sunlight, and other physicochemical processes. Although
no published evidence points to concerns that might be associated with disposal to
sewers, disposal to trash may pose unknown risks should someone unintentionally or
unknowingly consume them orally or contact them with their skin, as the possibility of
allergic reactions exists. Whether biologies pose concerns, certain additives may. An
example is the organomercury preservative thimerosal, which is used in certain vaccines
and other biologies (PharmEcology 2010).
(15) Drug donations are a major problem for humanitarian relief efforts. In
general, consumers should always be discouraged from donating pharmaceuticals to
relief efforts; many countries do not welcome donations even from manufacturers.
Humanitarian relief efforts often attract hundreds or thousands of tons of unwanted,
unnecessary, inappropriate, or expired medications. Having to store and manage such
huge inventories (which can amount to thousands of tons of drug waste) diverts resources
from important activities and later imposes enormous costs for disposal or site
remediation. As a consequence, the international guidelines for drug disposal issued by
the World Health Organization (WHO 1999 [revised]) could be integrated into national
drug policies worldwide. Drug donations could be regulated as both a public and
environmental health issue. Alternatively for the US, one or several agencies could issue
clear guidance (patterned after the guidance issued by (WHO 1999 [revised]) to ensure
that pharmaceuticals originating in the US do not become a burden for other countries.
Ultimately, disposal practices should abide by the Basel Convention on the Control of
Transboundary Movements of Hazardous Wastes and their Disposal (Basel Convention
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1989), which is the most comprehensive global environmental agreement on hazardous
and other wastes; it contains language specific for pharmaceutical waste. Its signatories
are expected to minimize waste transported across borders and to minimize the quantity
of waste generated as well as the distance between the location of waste origination and
eventual disposal.
DISPOSAL GUIDANCE
(16) Guidelines for prudent disposal need to avoid a singular focus on
protecting the environment. Guidance recommending the continued disposal of a
limited number of certain medications to sewers is amply justified by the acute risks
posed by disposal to trash. Unintended or purposeful exposure via ingestion or dermal
contact (especially by infants, toddlers, and pets) to these medications can lead to
significant morbidity or mortality. A better balance of concern is required when
developing disposal guidelines. Absent comprehensive disposal options usable by all the
public, highly toxic drugs will probably continue to require disposal to sewers. Redesign
of drug disposal practices to better protect the environment needs to take better note of
the need to protect human safety. A methodology to determine whether continued sewer
disposal of any particular API might be a major contributor of its environment occurrence
was developed by (Daughton and Ruhoy 2009a).
(17) Current drug disposal guidance may be flawed and increase risks for
humans. Current guidance on disposal of drugs to domestic trash poses documented
hazards to the safety of humans, pets, and wildlife. In particular, guidance specifying the
physical destruction of hard dosage forms (e.g., crushing tablets) poses acute risks for
those following the guidance as well as for those who might be incidentally exposed to
any particulates or dusts that might escape within a home or to doses that might be
unknowingly spilled onto floors or other surfaces accessible to infants, toddlers, or pets.
Certain medications are specifically designed to resist mechanical alteration/destruction.
Reclaiming discarded drugs from trash may increase the incidence of diversion and acute
poisonings for humans as well as for wildlife scavengers. Discarded transdermal devices
(e.g., skin patches) pose particular risks, especially for children, who may chew or
swallow them, or apply them to the skin. Some transdermal devices containing synthetic
opioids, for example, hold lethal doses for those who are opiate naive. This points to the
critical importance of continuing the practice of disposal to sewers for certain, select
medications. Drug disposal programs (such as take-back or collection events) can
exacerbate another known hazard simply by encouraging consumers to set aside their
leftover drugs while waiting for sufficient quantities to accumulate - to justify making a
trip to turn them in at a collection event. This behavior could result in the temporary
stockpiling of extremely hazardous, leftover drugs. This could increase the potential for
poisonings - simply because more types and higher quantities of drugs remain on-site
than might ordinarily if disposal were performed immediately.
Exposure to certain leftover drugs is also extremely hazardous for particular sub-
populations, especially those who need to actively avoid them. Examples are drugs under
restricted distribution programs or potential teratogens, such as isotretinoin, thalidomide,
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tamoxifen, methotrexate, and fmasteride, which must be avoided by women of child-
bearing age.
The involvement of drugs as a major cause of human poisonings, especially children,
makes drug disposal a priority for the Agency. Administrator Lisa Jackson, in an all-
employee memo of 16 March 2010 ("EPA's Leadership in Children's Environmental
Health") reiterates that protecting children's environmental health is central to EPA's
work. The memo cited three key areas of focus, one of which is protection of children
through safe chemicals management:
"I named chemical management as one of our top priorities for EPA's future largely
because of the disproportionate effects of chemical exposures on children. We will
establish standards, policies and guidance at home and abroad that help eliminate
harmful prenatal and childhood exposures to pesticides and other toxic chemicals.
We will work with Congress and stakeholders to identify effective approaches for
the protection of children's health in the context of TSCA reform. We will also
encourage green chemistry and safer alternatives to chemicals and products that
present a potential hazard to children."
(18) Drugs possessing the potential for single-dose lethality require special
consideration in disposal guidance. Very real acute poisoning risks are posed by
improper disposal of drugs having single-dose fatal toxicity potential for children;
included as extreme hazards are certain transdermal and other drug delivery devices (e.g.,
medicated patches). Drugs having single-dose lethality are of special concern in the
practice of medicine and pose such a significant hazard for those not intended to receive
them that they warrant special emphasis here. As one of many examples, after 3 days of
use, fentanyl patches can retain up to 84% of their original fentanyl content, a more than
sufficient fatal oral dose for an infant or fatal dermal dose for an opioid-naive adult
(Marquardt et al. 1995).
(19) Protecting the environment with optimal disposal guidelines can conflict
with ensuring human safety. A major dichotomy regarding disposal is that flushing
can directly impact the aquatic (and terrestrial) environment, while discarding in
domestic trash can directly impact human health and safety. Neither is a good option. The
need for prudent drug disposal has been driven by the sometimes opposing needs to
protect the environment (by minimizing the discharge of APIs to sewers) and protect
human health and safety (by reducing diversion and unintended poisonings). These two
needs (primarily the second) were the drivers behind the first federal guidance for drug
disposal, implemented by the ONDCP with assistance from the FDA and EPA in 2007
(ONDCP 2009 [updated October]). But the published evidence is sparse that supports the
claim that leftover, unwanted medications stored in homes and awaiting disposal is a
major contributor to diversion and poisonings. This is because the portion of diversion
and poisonings resulting from unwanted, leftover drugs cannot be teased apart from that
resulting from medications that are in current use as intended. In general, investigations
of poisonings do not report how a victim encountered a medication; there is no way to
discern whether the medication was being actively used by the intended recipient, or
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stored for future use, or stored for eventual disposal, or discarded in trash, or simply
laying around the home long-forgotten.
(20) Prudent drug disposal requires balancing the protection of the
environment with ensuring access to timely medical care. Any plan to
promote what might be called "prudent" drug disposal must strike a difficult balance in
meeting three major objectives: (i) protecting the environment, (ii) maintaining human
safety (e.g., guarding against diversion and unintended poisonings), and (iii) ensuring that
patient access to critical medications is not impeded (in particular, controlled substances
for control of pain). Should one of these objectives become over-emphasized, one or both
of the others can be jeopardized. The best example is the balance needed in preventing
diversion of opiate analgesics while at the same time not discouraging or hindering
physicians in prescribing controlled substances to patients seeking pain control.
FORMAL COLLECTION PROGRAMS
(21) The potential effectiveness of drug-collection programs for curbing
imprudent disposal is unknown Even if nationwide approaches were available for
collecting leftover medications (such as take-back programs), a major unaddressed
question is what portion of the public would routinely make use of them; limitations or
concerns that have been expressed by consumers include inconvenience, insufficient
time, privacy concerns, preferences for alternative routes of disposal (such as flushing),
and skepticism as to the seriousness of the disposal problem. Even in countries with long-
established take-back programs (such as the UK), only a minority of the public makes use
of the service (e.g., see: Bound and Voulvoulis 2005). A few have voiced reservations
regarding the usefulness of collection programs; two examples are Morissette (2006) and
Mackridge (2005).
(22) Formal collection programs for unwanted drugs may have significant
hidden costs. Unexpired medications represent not only unrecoverable purchase costs
for the consumer, but more importantly, they often represent lost opportunities in
achieving the intended therapeutic outcome. Another example of hidden cost is the
collection of unused antibiotics; consumption of partial treatment regimens can
encourage the emergence of antibiotic-resistant pathogens, a cost borne society-wide.
Many other costs are associated with collection programs, including costs associated with
transportation by the consumer and collector, as well as time and effort.
(23) The statistical representativeness of data from drug collection or take-
back programs is unknown. The types, quantities, and rate or frequency of return of
unwanted drugs turned in during drug collection programs cannot be assumed to
represent trends that can be extrapolated. There are currently too many unanswerable
questions. A number of factors must be known to determine how statistically biased the
collected data might be. Are the participants representative of the population at large?
Can the data be used to extrapolate across the broader population and over time? Would
the collection data be representative of return rates sustained over longer periods of time?
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Do drug collection events preferentially attract those who are motivated and who have
stockpiled their unused drugs over long periods of time until they locate an opportunity
for disposal? This last phenomenon could result in a consumer returning relatively large
quantities of drugs that had been accumulated or stockpiled over the course of many
years and yet be misinterpreted as a quantity that would continue to be returned on a
periodic basis. This makes it very difficult for drug collection events to use acquired data
to predict future return rates. Collection events are also prone to biased data as a result of
selecting for those consumers who are willing and able to participate. It is unknown what
percentage of the general population these individuals represent. This is self-selection
bias.
With a few exceptions, the data that have been collected are largely unusable because of
the basis for their measurement. The first study to present a comprehensive summary of
accumulation/disposal data acquired from a well-defined sub-population of a single city
over the span of a year was published in Ruhoy and Daughton (2008, see Table 3). This
study made use of the comprehensive and accurate data residing in coroner records, an
approach pioneered by Ruhoy and Daughton (2007); note, however, that coroner data on
unused drugs can vary across states and is therefore not always an options for study.
Studies collecting data on drugs returned to pharmacies use two basic approaches: (1)
return events that advertise in advance and (2) those that make use of existing returns
programs that are not advertised. The latter unsolicited collections may yield less-biased
data. Their rates of collection and types of collected drugs may be more representative of
what could be obtained in sustained real-world routine collections from the general
population; note, however, that this type of study has only been done in other countries
having on-going collections programs - generally operating through pharmacies.
(24) Data from drug collection programs cannot be inter-compared;
standardization is needed. Data collected from most drug take-back programs
cannot be inter-compared in any way useful for environmental modeling or for assessing
the potential for environmental impact or estimating drug usage/wastage. This is because
of a lack of standardization on exactly what is being measured as well as the actual units
of measure. Drug collection programs attempt to quantify their success by using widely
different approaches for measuring and reporting the quantities of collected drugs. The
most common shortcoming is the failure to report what exactly is being measured and the
units of measurement. For successful comparisons between collection programs, for
scientists to use the data for predictive modeling purposes or for environmental
assessment, it is essential that the units of measurement be defined. A range of
approaches are used by these projects and often are not even specified. The measures
usually employed include the mass of the entire formulated medications themselves (e.g.,
tablets and capsules, including all inert ingredients or excipients), the mass of the
complete formulated medications plus their consumer-use packaging, the mass of
medications plus packaging and shipping containers, or simply the rough volume. With
few exceptions, such as the State of Maine's mail-back program (Kaye et al. 2010), the
mass of each dose (and API) is rarely recorded. These disparate measures will obviously
yield wildly different values (which can vary over many orders of magnitude). In one
study, for example, packaging materials were found to compose more than 90% of the
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total weight of collected materials; and of the remaining 10%, only 1-2% actually
comprised APIs (Macarthur 2000).
The only single measure that has some relevance with regard to ecotoxicology and
human health is the mass of each individual API. But recording inventories on the basis
of each dose collected, followed by performing the required calculations to convert to
API masses is a very time-consuming and laborious task; the first (and still one of the
only) publications to actually calculate the mass of individual APIs that were disposed
was published by Ruhoy and Daughton (2007). A standardized approach would be
extremely useful for measuring, cataloging, and grouping APIs. One approach would be
to use an international standard for categorizing the APIs according to their action on
therapeutic systems, such as the Anatomical Therapeutic Chemical (ATC) Classification
System. An example using this approach is presented in Ruhoy and Daughton (2008, see
Table 3).
A good example of this problem derives from the New Jersey Operation Medicine
Cabinet collection, which may have been the largest collection to date in the US.
Collected were over 9,000 Ibs with a street value of over $35M (DBA 2009a). While the
9,000 Ibs comprised 3.5 million pills, it was not specified whether this was the mass of
the packaged pills or the pills alone. Even if it were the pills alone, the collected quantity
of actual APIs would be nearly 6 orders of magnitude lower. If the average API content
of a pill were assumed to be 100 mg (many medications are 20 mg and below), then the
collected amount of actual APIs would have amounted to 350 kg. While this is certainly a
significant quantity of active ingredients, the reported data (9,000 Ibs) mis-represents the
environmental significance of the collected drugs. Worse yet, if the 9,000 pounds
included packaging, then the collected mass of APIs was much lower yet (by two or more
orders of magnitude).
But it is critical to recognize that even measures of mass will become increasingly less
useful as the potencies of new drug entities increase. Clearly, the total mass of the entire
formulated dosage form imparts little knowledge regarding the mass of the constituent
APIs, when the APIs can range in dose from the low micrograms up to hundreds of
milligrams - 5 orders of magnitude. It is rather pointless to compare the success of one
take-back event versus another on the basis of weight collected, as this cannot impart any
meaning with respect to even the relative masses of the APIs, or more importantly, their
biological potencies.
In the final analysis, the major rationale for performing detailed inventory and
examination of unwanted, leftover medications collected during take-backs is to derive
data regarding prescribing, dispensing, and consuming. These data could prove
invaluable is designing adjustments in the system of healthcare. Improvements would be
aimed at optimizing the interconnections among all three of these aspects of the life cycle
of drugs, so that usage is more efficient - resulting in less cost and better healthcare
endpoints. Studies of returned or collected drugs are important perhaps not so much to
assess their potential contributions to environmental contamination but rather to improve
the delivery and quality of healthcare, including the prevention of accidental poisonings,
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diversion, and adverse drug events. Also worth noting is that inventory of collected drugs
could potentially assist in spotting counterfeit drugs - perhaps offering early warnings of
their introduction into the supply chain.
(25) Prudent drug disposal requires attention not just to the API, but also to
the packaging. Do the packaging materials (especially bottles and dispensers
containing concentrated residuals of APIs) or the ever-increasing numbers of delivery
devices once they have been used (e.g., delivery devices unique to certain drugs such as
pumps, dermal patches, inhalers, syringes) pose a significant source of certain APIs? The
continued development of advanced delivery devices (e.g., with the further integration of
electronics) will complicate disposal yet further. Does packaging constitute a significant
source of other pollutants derived from the packaging itself (e.g., via incineration or
weathering in landfills)? Could these problems be controlled by redesign of the
packaging or by alternative disposal methods? Are the known extractables and leachables
within dispensing devices and containers themselves a significant source of certain
pollutants in the environment (e.g., plasticizers, nitrosamines, and acrylonitrile, deriving
from plastics adhesives, antioxidants, coatings, vulcanizers, accelerants, adhesives)? An
example of one major class of commonly used devices (i.e., Orally Inhaled and Nasal
Drug Products - OINDP), such as inhalers, could eventually pose special challenges as
electronics become integrated with the device. Perhaps the best stewardship model for
electronic OINDPs or other sophisticated delivery devices could be the electronics
industry, where the used product is returned to the manufacturer, who then disassembles
the device and reclaims or detoxifies the constituents. Little data exist on the significance
of either unused or partially used OINDPs in drug collection events; the work of James et
al. (2009) is one of the only examples.
(26) Drug collection programs (e.g., take-backs) may not be an effective
approach for reducing the diversion of the primary drugs of concern -
controlled substances. Very little study has been directed to determining the relative
rates of return during take-backs of controlled substances or drugs of abuse versus those
for non-controlled substances. One study (in Sweden) showed a much lower rate for
drugs of abuse compared with other drugs. This may have been due to the intrinsically
higher rates of hoarding or diversion for non-medical use (Ehrling 2005).
(27) Patchwork of take-backs in the US adds to the existing confusion
regarding drug disposal. The growing number of local, regional, state, and most
recently national efforts designed for collecting leftover drugs is confusing on several
levels. These efforts range from one-time sporadic events to ongoing programs. The
major source of confusion is whether controlled substances are permitted. This is a
function of whether law enforcement or the DEA is formally involved. Without their
formal involvement, controlled substances cannot be collected. The consumer, however,
often does not know how to determine if a drug is a controlled substance. Criticism of the
status quo regarding the handling of leftover drugs has been increasing. One example
comes from Barthwell at al. (2009a):
"The U.S. government, the pharmaceutical industry, medical practitioners, and waste disposal
authorities have yet to develop a consistent message or systematic method for consumers to
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properly dispose of pharmaceutical products. The only advice on disposal currently available to
consumers is to mix old medications with cat litter or coffee grounds to make them unpalatable
before throwing them away. The U.S. Food and Drug Administration, the U.S. Drug Enforcement
Administration (DBA), and the U.S. Environmental Protection Agency - under the coordination of
the Office of National Drug Control Policy - must improve this rudimentary, insufficient
approach."
(28) Sustainable approaches to drug disposal require clear and useful
measures of success. A major unmet need with all approaches for collection of
leftover drugs from the public for disposal (such as by take-backs) is the articulation of
clear measures of success. For any collection program to ever declare success, the
performance goal(s) needs to be clear and measurable. Historically, collection programs
invariably focus solely on collecting and destroying unwanted drugs. At best, the only
measure of "success" has usually been the documentation of the total mass or volumes of
collected products (usually including the packaging or the inert ingredients, which
comprise the bulk of a dose). But these measures do not address outcomes. Few studies
have ever attempted (and none has ever succeeded) in linking drug collection programs to
either reductions in ambient environmental residue levels or to reductions in human
poisonings (either unintentional or purposeful). Furthermore, measuring gross weight and
volumes is not well suited to comparing effectiveness among different programs; it is
useless for predictive modeling, where the content of the individual APIs must be known.
There are three major measures (outcomes) for assessing whether a drug disposal
program is successful: (1) Reduction in accidental and purposeful poisonings (both
humans and domestic pets); (2) reduction in ambient levels of individual APIs in various
environmental compartments (primarily sewage influent, sewage effluent, waters
receiving sewage effluent, sediments, sewage sludge/biosolids, and drinking water); and
(3) improvement in various outcomes from, or activities practiced in, the administration
of healthcare; two examples are improved prescribing practices (by mining data
associated with the types and quantities of collected leftover drugs) and improved
therapeutic outcomes for patients. All three of these measures would face formidable
challenges in their assessment. A necessary conclusion, therefore, is that drug disposal
programs in all likelihood can be implemented usually only as a precautionary action. But
while there is little hope in the near future for assessing their true effectiveness with
respect to environmental impact, the emphasis on drug collections in the US has had
recent impact on pharmacy policy, with the facilitation of shorter-term dispensing for
certain drug classes.
DRIVERS for ASSESSING MEDICATION WASTE
(29) Connection to Healthcare: Viewing leftover drugs as measures of success
or opportunities for improvement, rather than simply as waste. A new
paradigm is proposed for medication usage. This paradigm seeks to solve the disposal
issue while at the same time minimize the use of resources. Leftover, unused medications
should be viewed not as chemical waste but rather as measures of wasted healthcare
resources and as opportunities lost for achieving intended therapeutic treatments.
Leftover medications represent the nexus of numerous facets of the healthcare system and
patients' complex relationships with drugs. The very fact that the issue of drug disposal
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has grown to such proportions amply demonstrates that there may be areas needing
improvement in the healthcare system. Drugs are not always being administered in an
efficient/efficacious manner, patients are ignoring instructions, or the medications are not
efficacious or have too many adverse effects. By redesigning and optimizing the use of
medication, the need for disposal can be minimized. Further, by implementing systems
that can readily inventory the types and quantities of leftover medications in a central
database, alterations can be made to prescribing and dispensing practices that could
reduce the incidence of leftovers while also improve healthcare outcomes. Beyond their
potential to be discarded and enter the environment as contaminants, leftover drugs are
serving as messengers of potentially critical importance to the state of the healthcare
system - and serve as indicators of the many ways in which this system could possibly be
improved. Although the need for waste collection of unused drugs has been justified
primarily as a means for reducing diversion, abuse, poisoning, and environmental
contamination, it has not yet evolved to take advantage of two potential avenues:
reclaiming valuable chemicals (i.e., APIs) for their reuse or re-purposing, and the mining
of extremely valuable information for better targeting the administration and cost-
effectiveness of medical care (e.g., answer questions to improve prescribing, dispensing,
patient compliance/adherence, or to advance evidence-based medicine). Leftover
medications should not be viewed just as nuisance wastes, but rather as tools useful for
gauging the effectiveness and efficiency of medical care. In general, leftover medications
are indicators or measures of two conditions in the administration of healthcare: (1)
prudent and efficacious medication is not being properly used (non-
compliance/adherence), and therefore the targeted therapeutic outcomes are not being
achieved, or (2) unnecessary medication from imprudent or unnecessary prescribing is
not being consumed as the prescriber intended because the patient senses the medication
does not work or is responsible for adverse drug reactions (ADRs).
(30) Focus on Source Reduction: An overwrought focus on drug disposal may
distract from a sustainable solution yielding a wide range of collateral
benefits. A current narrow focus on developing what might initially appear to be better
means of disposing of unwanted drugs may be detracting from the far more important
objective of reducing the occurrence of leftover medications in the first place. Attempting
to control disposal is an inefficient way to tackle the overall problem of APIs in the
environment. The complex chain of actions, activities, behaviors, and customs involved
with all aspects of the life cycle of medication use in health care inevitably leads to
leftover medications. Redesign of key places in the life cycle holds great potential for not
only reducing the incidence of leftovers, but also leading to improvements in the quality
and cost of health care. The potential for collateral benefits of significant cost savings and
improved health may become a major driving force behind the need for comprehensive
environmental stewardship programs directed at drug use. For this reason, a major
conclusion from this report is that the focus of efforts addressing the issue of drug waste
needs to be on solutions for minimizing the generation of waste at the outset rather than
on how to handle it once generated - - up-stream pollution prevention and stewardship
practices as opposed to down-stream mitigation measures. The objective should be
reducing the quantities of medications that go unused rather than figuring out how to
dispose of medications whose accumulation could have been prevented. The ultimate
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objective should be to eliminate the need for avoidable disposal altogether, the need for a
certain degree of disposal will always be needed, such as for the stocks leftover from the
deceased. This can be done only by collaboration among environmental scientists, the
healthcare communities, pharmaceutical and pharmacy industries, and the health
insurance industry. This point of view began to be formalized only in the late 2000s (e.g.,
Daughton and Ruhoy 2008a; 2009b; Summerton et al. 2008).
(31) Adopting Healthier Lifestyles: Reducing the incidence of leftover drugs
may in some instances also serve to reduce the entry of APIs to sewers via
excretion and bathing. A potentially significant collateral benefit from minimizing
the need for disposing of drugs has yet to be recognized. Although minimizing leftovers
by increasing patient compliance may increase the quantities of those APIs excreted
unchanged or discharged to sewers by way of bathing, minimizing leftovers resulting
from unnecessary or imprudent prescribing (e.g., wrong medication) will reduce API
excretion. Of the numerous facets of medical care that can be modified to reduce the
incidence of drug accumulation and subsequent need for disposal, many would entail
modification of dosage regimes, generally resulting in lower amounts over the course of
treatment. Lower overall dosing (e.g., via evidence-based prescribing and personalized
prescribing) will necessarily result in lower excretion. By taking actions to reduce the
need for drug disposal, overall drug usage can decrease. Residues entering sewage from
both disposal and excretion could thereby be reduced simultaneously. The control of
usage is perhaps more capable of reducing overall entry of APIs to the environment, as it
can eliminate the need for disposal plus minimize the residues released by excretion and
bathing. Usage control is much more complex than disposal control as it entails the
involvement of the entire healthcare community, including healthcare insurers.
(32) Counter to current perception, excretion of APIs can be reduced - without
jeopardizing the quality of healthcare. A critical misconception is that control of
API entry to the environment must focus on better control of disposal because excretion
is not a factor that can be controlled. As already pointed out in the prior item (above), the
wherewithal already exists for partly controlling the quantities of APIs excreted. The
suggestion made immediately above regarding optimal, lower doses is clearly a major
way this can be accomplished. Other ways include personalized prescribing (using
pharmacogenomics) to avoid the prescribing of APIs to those who are poor responders -
or to perhaps reduce the dose for those who are poor metabolizers (Daughton and Ruhoy
2010). But another little-recognized approach for reducing excretion would be factoring
pharmacokinetics into the drug selection process before prescribing. For example, within
a given therapeutic class, there may be certain APIs whose metabolism results in much
less excretion of unchanged APIs than others.
(33) Several trends hold potential for exacerbating the need for prudent drug
disposal. In its most recent drug-usage survey "U.S. Prescription Drug Data for 2007-
2008," the CDC reports a continuing upward trend over the last 10 years in the numbers
of prescriptions issued in the month preceding the survey (Gu et al. 2010). Usage rates
increased across all ages, with rates of polypharmacy (5 or more drugs) particularly
increasing for those of age 60 or greater. Those with more than one prescription drug in
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the prior month increased by 10% over the last 10 years, those with more than one drug
increased by 20%, and those with five or more increased by 70%. One-half of the
population used prescription drugs - including 20% of children and 90% of those older
than 60.
Several trends are resulting in a greater variety and larger quantities of pharmaceuticals
being used within the home. The trend that has attracted the most attention is the
continuing rise in prescription drug abuse, especially opiate pain killers. The continuing
escalation in abuse of prescription drugs is reflected by the attention devoted by the
popular press, where new terms have emerged to distinguish "America's new drug crisis"
from previous trends in drug abuse (dominated by illicit drugs) - terms such as "addiction
by prescription" and "pharmageddon" (e.g., Kluger 2010).
But other, less-recognized trends will also play key roles. One is earlier discharge from
hospitals and continuation of care at home. Another is the increasing provision of hospice
care at home. These tend to increase the quantities of leftover drugs needing disposal by
the consumer. Another is the commercialization of ever-more potent drugs (referred to as
"highly potent active pharmaceutical ingredients" HP APIs) and more routine and
widespread use of synthetic opioids, genotoxics, and cytotoxics (such as
chemotherapeutics), with uses expanding not just in homes, but also in veterinary
practices; these drugs pose unique challenges with respect to physical handling (by those
wishing to dispose of them or those who must dispose of resulting medical waste), as
well as the critical importance of preventing access to them in households, especially for
those drugs having single-dose fatality potential. Drug usage in general is forecast to
continue increasing; one driver in Asia is reduction in prices to produce larger sales
volumes (Matsuyama 2010).
Advances in pharmacogenomics have the potential to both: (i) greatly increase the
numbers of low-usage drugs (those specifically tailored to narrowly defined patient
populations, serving to vastly increase the number of therapeutic niches), and (ii) increase
the numbers of high-usage ("block-buster") drugs - by addressing therapeutic targets of
minimal genetic variability across the population to yield drugs of extremely broad
tolerability. By increasing the efficiency of drug discovery (minimizing failures), the
resulting reduced costs will allow more discovery. So the application of
pharmacogenomics could accelerate the development of new drug entities or expanded
use of existing drugs.
Home storage and stockpiling of medications may also increase because of the increasing
interest in self-diagnosis and self-medication (due to greater - but not necessarily better -
availability of information, such as via the Internet) and the more ready access to
medications. One trend that is increasing the incidence of self-medication or self-
administration (and increased purchase of medications) is prescription-OTC switches. A
long-ongoing debate surrounds the switching of certain drugs from prescription only to
OTC. The process by which prescription drugs are switched to nonprescription, over-the-
counter (OTC) status is known as the "Rx-to-OTC switch." In the past, switching has
occurred for drugs used for short-term sporadic treatment, such as certain antihistamines.
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The debate becomes more complicated with medications designed for long-term
maintenance. The statins serve as an excellent example of efforts from industry to gain
FDA approval of Rx-OTC switches (Tinetti 2008). The debate has centered on whether
consumers can properly self-manage long-term conditions. Regardless of the many
factors that enter into this debate, it is very clear that switches will undoubtedly promote
increased purchasing and inevitably the accumulation of yet more unused drugs. Since
the consumer has no boundaries on decisions to self-medicate, Rx-to-OTC switches
greatly expand the spectrum of conditions for which treatment can be attempted, further
escalating drug use. Given the prescription-only APIs or dosage strengths that were
available in the US 25 years ago, now over 700 formulated products incorporating this
same APIs are available OTC. A listing of the nearly 100 APIs that have undergone the
Rx-to-OTC switch since 1976 is available from CHPA (2009).
Designing pollution prevention measures for OTC drugs is much more difficult than for
prescription-only medicines, as control measures cannot be implemented at the level of
physicians and pharmacists. Moreover, while retailers of OTC medications could be seen
as having a major role to play in changing consumer behavior regarding excessive
purchase (e.g., avoiding quantities too large to consume before expiration), their roles as
for-profit businesses could at least give the appearance of a conflict.
Storage in the home also exacerbates self-medication, creating a reinforcing feedback
loop that encourages more stockpiling. The incidence of leftover medications becomes a
factor that serves to amplify its own magnitude. Leftover medications tend to result in yet
more leftovers. The greater the accumulation, the harder it is to keep track of them,
leading to ever-greater difficulty in maintaining compliance. Leftover medications
become an ever-escalating problem, especially as the incidence of polypharmacy grows.
Polypharmacy at one time was driven primarily by the aging population, but it is also
becoming more prevalent in younger populations, as the incidence escalates for chronic
diseases, especially obesity and diabetes (becoming referred to as "diabesity").
A particular aspect of hoarding leftovers and its encouragement of self-medication is the
inappropriate use of antibiotics and its propensity to select for antimicrobial resistance.
The lack of appropriate and fast drug disposal could therefore be a potential contributor
in drug resistance. One self-medication study focused on the use of antimicrobials in
Europe (Grigoryan et al. 2006). The authors estimated the incidence of self-medication
using antimicrobials in 19 European countries to be 1 to 210 per 1,000 population, a very
high rate. Drug storage was a good predictor of future self-medication. The study of
Grigoryan et al. (2006) also hinted toward a possible environmental justice component:
"Substantial variation in the prevalence rates of antimicrobial drug self-medication
among the European regions suggests that cultural ... and socioeconomic factors play a
role, as do disparities in health care systems such as reimbursement policies, access to
health care, and drug dispensing policies."
(34) Manufacturer promotions such as Direct-to-Consumer (DTC) advertising
and drug sampling increase the incidence of leftovers The negative influence
of drug promotions as a factor in the accumulation of leftover drugs could be
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counteracted with a variety of measures largely targeted at reducing the use of drug
sampling (provision of free samples to physicians). Formal "counter-detailing" programs
exist for educating physicians on evidence-based prescribing and the negatives of free
samples. Many of the negative attributes of free samples could be reduced if physicians
employed vouchers, where patients could then obtain the free samples from the
pharmacy. This would greatly reduce the influence of free samples on immediate drug
waste (by avoiding expiration within the physician's office), diversion, and leftovers (as a
portion of patients are known to accept free samples with no intention of ever using them,
and would then choose to not have the voucher filled).
(35) Certain trends such as large-scale drug diversion may be exacerbating the
need for drug disposal. Illegal activities involving prescription drugs, such as drug
diversion and theft, have previously unrecognized connections with the drug disposal
issue. Large-scale diversion of certain drugs due solely to theft (especially hydrocodone,
oxycodone, morphine, methadone, hydromorphone, meperidine, and fentanyl) (see:
Inciardi et al. 2007) probably increases the need for greater manufacturing to replace
these lost inventories and to meet legitimate prescribing needs. This serves not only to
amplify the residues of these APIs ending up in the environment via excretion, but
probably also amplifies the need for disposal - as leftovers and wastage probably occur
for both the diverted supplies and for the replacements. During 2000 through 2003, in just
22 eastern states, roughly 28 million doses of these drugs were reported stolen or "lost";
also see Solomon (2010). Perhaps for no other consumer product does theft make such a
significant contribution to environmental pollution. Since drug counterfeiting sometimes
relies on diverted pharmaceuticals, it too may be directly connected with the need for
greater disposal.
MESSAGING & COMMUNICATION
(36) Current science can only justify a focus on drug disposal on the basis of
the collateral benefits for healthcare and protecting human safety - not
for protecting the environment On the basis of available science, the only
demonstrated benefits from devising alternative drug disposal systems (e.g., to reduce or
eliminate flushing into sewers) that can be currently justified are collateral benefits
involving healthcare (e.g., improvements in therapeutic outcomes and reduced healthcare
costs from measures designed to optimize the use of medications). The design and
implementation of programs for controlling leftover medications (by "proper" disposal or
by pollution prevention measures designed to minimize or eliminate leftovers) can
currently be based only on hypothetical risks. No published data could be found to
support the four major drivers that have been highlighted for the need for prudent drug
disposal, namely, the need to reduce: (1) unintentional poisonings, (2) diversion and
abuse, (3) inappropriate donations, and (4) residues of APIs in the aquatic ambient
environment. It is simply not yet known whether better disposal of leftover drugs would
have any impact in reducing the loadings of APIs in the environment. The major driver
behind development of alternative drug disposal schemes is therefore rooted in benefits to
the healthcare system rather than for the environment. While benefits to healthcare would
certainly constitute a notable outcome, they would require substantial progress in
pollution prevention rather than in handling of the drug waste itself. Focusing limited
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resources on controlling or optimizing the myriad processes upstream of drug waste
therefore holds potential not just for what is currently only a hypothesized possibility of
reducing adverse impacts on the environment, but more importantly for the more
probable improvements that could result in many of the facets of healthcare and human
safety.
(3 7) Possible unexpected paradox: Drug take-back events may potentially
worsen the drug disposal problem, as well as diversion and poisonings, by
encouraging stockpiling. The approach used in nearly all collections activities is
physical transport by the consumer to the drop-off site. This approach incurs added costs
from transportation and consumer time, and requires planning ahead. Some consumers
are unable to conveniently travel and many locales do not have access to collection sites.
Most importantly, however, the use of episodic take-back events may be inadvertently
encouraging and perpetuating one of the major consumer behaviors long-sought for
elimination by drug control programs. Episodic take-backs can facilitate or force the
consumer to amass and store leftover medications - a practice that imposes the same risks
for diversion and unintended poisonings as does hoarding. A continual returns program,
such as mail-backs, can avoid this shortcoming, as shown by the Maine pilot program
(Kayeetal. 2010).
Public outreach has been a major approach for attempting to correct several of the
problems surrounding drug disposal. One of the major objectives of the ONDCP, for
example, has been to draw a tight connection between drug stocks in the home with an
increased incidence of both drug abuse and accidental poisonings. These themes have
been repeated by most of those involved with the drug disposal issue. Although this
approach might seem to be one having clear and positive outcomes, this is an assumption
that has little corroborative evidence. Other than questions as to whether more rapid
disposal will impact these endpoints, a question and concern that emerges from this
approach is whether this type of public relations campaign may actually exacerbate the
problem. By advertising that drugs stored at home are being diverted for recreational
purposes, could this be making diversion and drug experimentation worse? This would be
analogous to the concerns that the reporting of drug abuse by the media may be an
additional cause of drug poisonings rather than just reflecting the news (Dasgupta et al.
2009). This is an important question - one that deserves investigation in case the current
approach to public communication unexpectedly proves counterproductive.
Formal drug disposal programs need to be accompanied with public messages explaining
that the generation of leftover drugs is not necessarily an acceptable practice. But by
having the public focus on "proper disposal," a major existing risk could be greatly
exacerbated depending on how convenient the disposal options are. Some consumers
might be tempted to store their unwanted drugs until the stockpiled quantity is
sufficiently large that it warrants transport to a disposal location. Storage in the home of
larger quantities of more types of drugs simply increases the possibility of access by
those who could be involved with diversion or unintended poisoning.
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Perhaps the most ironic aspect of programs designed for prudent disposal of medications
is that formal disposal programs might unwittingly encourage the replacement of these
medications with new stocks and thereby generate yet more waste - perpetuating the
cycle of excessive, repeated purchase and disposal. By facilitating easy, "cost-free"
disposal of drugs with formal take-back programs, consumers may be inadvertently
encouraged to not hesitate in buying additional large quantities (to achieve false
economies of lower unit-dose pricing), only to again find themselves unable to fully
consume them before expiration. Disposal would then be followed by repurchasing new
supplies. Instead, a larger more holistic message needs to be conveyed to the consumer -
one where leftover drugs are an indirect measure of wasted resources, lost opportunities
to achieve desired therapeutic outcomes, poor purchasing decisions, and further burden
for the environment. Indeed this problem has been alluded to by others: "Easing
regulation of waste disposal [namely, with regard to modifying the Universal Waste
Rule] decreases institutional motivation for waste reduction and pollution prevention"
(Tucker 2009).
The public message needs to be directed at points further up the chain of events that lead
to the acquisition of medications - not a focus on the availability of disposal programs.
Better public awareness of the larger issue (the actions, activities, and behaviors that lead
to the need for disposal) could reduce unrealistic expectations, imprudent use (especially
self-medication), and stockpiling.
The psychology of drug returns indicates that another factor may be at play. A UK study
of consumer drugs returned to pharmacies discovered that many patients were "shocked"
to learn that their returned drugs were going to be destroyed. They had falsely believed
that their unused medications were going to be redistributed to others who were in need.
It could be important to determine if this is a common perception in the US, as it might
alter people's decisions to fill unnecessary scripts or those they had no intention of ever
using (knowing in advance that if they did not actually use the medication, it could not be
made available to someone else) (Bradley 2009).
(38) Public outreach efforts designed to promote prudent disposal should try
to ensure that certain, select groups are reached Evidence exists that a small
portion of consumers overall are responsible for a disproportionately large portion of
drugs that eventually become leftovers. A study by Ekedahl (2006) reported that 25% of
all medicines collected in a Swedish returns program came from just 3% of those making
the returns. If this behavior translates to other countries, then this small, select group of
consumers needs to be influenced by public outreach programs to ensure high rates of
prudent disposal.
(39) Public outreach efforts and mechanisms for prudent drug disposal should
try to accommodate consumers with unusual needs. Unforeseen circumstances
often add complexity to design of prudent and useful disposal programs. Given the
growing incidence of drug abuse and addiction, one particular source of stockpiled drugs
comprises the caches accumulated by addicts who have begun addiction recovery
therapy. These individuals commonly have large stockpiles of drugs - primarily
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comprising controlled substances. Wishing to avoid being discovered by law
enforcement, they cannot discard these substances into the trash or hand over to law
enforcement. The lack of an acceptable means of disposal may result in these drugs
remaining stockpiled indefinitely (increasing the risks of diversion and unintended
poisonings) or flushed down the toilet (Lessenger and Feinberg 2008).
(40) Unknowns surrounding the connection of expired drugs with toxicity One
of the major drivers and justifications for consumers to clear their supplies of medications
is the purported hazard associated with expired drugs. Despite the considerable research
and data developed for drug registration on API stability and expiry, the evidence that
expired drugs pose toxicological concerns is extremely thin. At worst, expired
medications simply lose potency and therefore are not as effective (albeit this can
obviously cause concerns for achieving therapeutically effective doses). As a driver for
take-backs, the public message regarding expiry might instead be based on potency, not
on toxicity. But moreover, the extensive shelf-life research program initiated by the
Department of Defense, and research by independent investigators, has demonstrated that
many medications when stored under controlled conditions (but generally not achievable
by the consumer) can remain effective for years past expiration. This points to the
possibility of improving the accuracy of declared expiration dates, with the potential to
reduce the need for disposal.
(41) Non-compliance can be targeted as a means to better involve the patient
in effecting change Consumers (and many in the healthcare industry) do not fully
understand the intimate inter-connections between non-compliance and a spectrum of
other adverse outcomes, including: sub-optimal therapeutic outcomes, increased
healthcare costs (not just from wasted medications, but also from the increased need for
future treatment because of incomplete or insufficient current treatment), and possible
environmental impacts. With communication targeted at the patient (and physician)
showing that all of these factors are intimately linked, more progress could possibly be
made in reducing drug usage (and therefore excretion) as well as the generation of
leftovers. This could be achieved by a combination of patient education and by the use of
innovative labeling. Drug usage could be optimized if the patient better understood up
front - before a script were issued and filled - that restricting medications to those known
to be effective and by taking their medications as prescribed could reduce future
healthcare costs, better optimize therapeutic outcomes, and protect the environment. With
a better appreciation regarding the many benefits for improved compliance and active
collaboration with the physician (such as alerting the physician when directions are
unclear or when adverse effects occur), the patient could become more motivated to play
an active and productive role in minimizing the impact on the environment by APIs.
(42) Centralized coordination needed for all issues related to stewardship and
disposal - minimizing waste of resources that leads to duplication of
effort, rediscovery, and reinvention While the drug disposal issue only emerged
as a topic of discussion in the US roughly 5 years ago, very substantial investments in
time, money, and effort have been devoted to the topic by a broad array of public and
private organizations and agencies. Because of the sheer number of participants and
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stakeholders, there has been considerable duplication of effort, much of it simply
amounting to rediscovery or reinvention - and much leading to dead ends. The vast
majority of all publications that deal with some aspect of drug disposal simply restate
what prior articles have already stated - especially with regard to guidance for disposal.
This promotes group think and its attendant liability of preventing truly effective
solutions. Moreover, this points to the need for a lead agency (or at least a national
clearinghouse or institute) responsible for setting the agenda and coordinating efforts
along the many fronts of inquiry surrounding the expansive drug disposal issue.
There are many other findings, some of which are dispersed throughout this document. Others
can be derived by reading the supporting documents that compose the foundation for this project.
The overall topic of drug disposal is so deceptively complex - involving many professions,
spanning numerous fields of study, and involving countless processes - that it cannot be covered
in a truly comprehensive manner in a single report. This reiterates the importance of the
background documents and the published literature captured in the electronic database (DDS)
described later in this report.
The refractory problem of drug disposal is remarkable in that a solution that balances human
health and safety while also protecting the environment will require a truly transdisciplinary
collaboration. A holistic solution will involve the concerted efforts of numerous private, public,
and government entities. It must be based on science to have maximum impact and expend
public resources effectively.
Despite the decades of debate and discussion surrounding drug disposal, surprisingly no single
comprehensive resource exists that examines and distills what is known (and what further needs
to be known) and provides a synoptic overview of this multi-faceted topic. While this report too
is not comprehensive, it strives to provide the most in-depth balanced view to date.
SCOPE AND OBJECTIVES
More than any other aspect of the overall topic of pharmaceuticals as environmental
contaminants, disposal of "leftover" consumer drugs has consistently attracted the most attention
from the public, the media, local and state regulators, and the healthcare community. Leftover
drugs are those that have expired or are no longer needed, wanted, or desired (because they are
no longer effectual or have undesired side effects). For all of those who have tackled the issue of
drug disposal over the years, it has always seemed to be one that could be easily solved. With
appearances aside, the singular feature of drug disposal that quickly emerges from all attempts at
solutions is that it is a surprisingly and deceivingly complex, convoluted, and frustrating problem
- one that continually encounters myriad obstacles and pitfalls that thwart all attempts at effective
and efficient solutions.
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If the focus of this report were simply on how to best dispose of leftover drugs, the discussion
would quickly distill down to a narrow focus on regulatory obstacles and on local and state
legislation that attempts to enable various means of collecting leftover medications from the
public (so-called "take-back" or "returns" programs), the design considerations and logistics
involved with implementing take backs, and the limited published literature on leftover drugs
(such as data collected from take-back programs or from in-home inventories). But this would
not address the real issue - one that has far greater potential for achieving broad and sweeping
outcomes. The real issue is one of stewardship and sustainability spanning the complete lifecycle
of Pharmaceuticals. This vastly expands the scope and complexity of the issue.
Therefore, this report's main objectives are to: (i) summarize what is currently known regarding
whether the disposal of consumer medications contributes significant fractions of environmental
residues of APIs (a finding required to justify and design consumer drug take-back programs),
(ii) reveal the numerous factors that dictate why and whether medications eventually require
disposal, (iii) show how these factors can be altered to reduce the accumulation of unused drugs
and their consequent need for disposal, (iv) explain how efforts to control the actions, activities,
and behaviors that contribute to the need for drug disposal could serve to catalyze many
improvements in the nation's healthcare system, and (v) foster advancement of a new concept
(pharmEcovigilance) regarding environmental stewardship of medications - a concept that could
help protect ecological and human health as well as reduce the incidence of poisonings caused by
diversion of medications awaiting disposal. The report provides an integrated overview of the
key elements and findings, along with recommendations.
Some of the key questions addressed in the documents prepared for this report include:
• where do leftover drugs accumulate in society?
• what causes their accumulation?
• what are the current routes of their disposal?
• what portion of drug residues in the environment originate from disposal?
• what are the risks of unwanted drugs for humans, domestic animals, and wildlife?
• how can the accumulation of excess medications by consumers be minimized or eliminated?
• how can these unwanted drugs be best disposed?
• are there potential benefits beyond reduced environmental impact?
A major outcome sought by the final report is to provide a science-based framework for
discussing, justifying, and designing a nationwide approach for dealing with the accumulation
and disposal of unwanted medications. The objective is to minimize exposure of humans and
wildlife to ambient levels of APIs while at the same time ensure collateral improvements in our
system of health care. The problem needs to be examined from two perspectives: not just down-
stream pollution control, involving the most efficient and prudent approaches for disposal, but
more importantly up-stream pollution prevention, aimed at reducing or minimizing the need for
disposal.
Long overlooked in the debate surrounding consumer drug disposal is the larger imperative to
reduce or eliminate the need for disposal in the first place - - by a wide spectrum of approaches
targeted at pollution prevention. Drugs accumulate unused for a wide variety of reasons, each of
which presents opportunities for reducing the need for disposal (Ruhoy and Daughton 2008).
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These reasons range from patient non-compliance (which itself has a plethora of causes),
inefficient oversight of the prescribing process by physicians, imprudent dispensing practices by
the retail pharmacy and insurance industry, and wasteful packaging by manufacturers. A wide
array of causes for accumulation and subsequent disposal are summarized by Ruhoy and
Daughton (2008); many of these are summarized in Figure 3 of that article. Another significant
aspect of medication accumulation is the broad spectrum of locations in society where
medications are stored and where they eventually can accumulate unused (for example, upon
expiration), ranging from zoos and all public buildings (e.g., first aid kits), to schools and cruise
ships; many of these are summarized in Figure 4 of Ruhoy and Daughton (2008). The numbers
and types of places go far beyond the traditional view of the home medicine cabinet.
Perhaps the most important point to understand with respect to the many routes leading to drug
accumulation and disposal is that these represent the most productive avenues for pursuing
pollution prevention. To minimize or eliminate the occurrence of leftover drugs represents a
much more efficient way to deal with the many problems faced by the need for drug disposal. Of
most significance, preventing the need for disposal in the first place not only eliminates the
resources required for environmentally sound drug disposal programs, perhaps more importantly
it serves to conserve and make more efficient use of medications for their intended purposes
(through prudent, evidence-based prescribing), thereby reducing healthcare costs and improving
healthcare outcomes. In the process, reducing drug usage also reduces the first two routes of
entry to the environment - - excretion and bathing (Daughton and Ruhoy 2008b).
With this said, however, the focus in the U.S. has remained on how to best dispose of drugs with
minimal environmental impact, rather than on the need to generate less medication waste. To
date, this has been done in the US with relatively inefficient one-time community collection
events or on-going local programs that vary in their scope and design across geographic locales.
The most visible of consumer-based collection approaches are known as "take-backs" or
"returns," but other means also exist, including mail-backs. A disparate patchwork of these
collection programs exists sporadically across the U.S. The EPA has been evaluating a pilot
demonstration of one approach that may prove to be more sustainable - one that could be
implemented nationwide - designed to make use of the US Postal Service (Gressitt 2005;
University of Maine 2008). A second pilot program involved the return of consumer medications
through a pharmaceutical reverse distributor via UPS (Hendrickson 2010). While consumer take-
back programs are a relatively new concept in the U.S., they have been in place in Europe for
over 30 years. Three of the earliest publications dealing with formal drug take-backs are Bradley
and Williams (1975), Harris et al. (1979), and Sixsmith and Smail (1978).
To shift the emphasis of the discussion away from disposal and toward the many aspects of
stewardship and pollution prevention will require an active dialog between experts from the
various healthcare communities and from the environmental science community. Bridging these
two sectors has never been done. To date, there have been extraordinarily few publications in the
medical or healthcare literature that discuss the fact that medications have afterlives as
environmental pollutants (e.g., Daughton 2002; Daughton and Ruhoy 2008a; Zuccato et al.
2000). An approach that integrates the monitoring of adverse events in medicated humans as
well as adverse events in the environment has been termed pharmEcovigilance (Daughton and
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Ruhoy 2008b). Its main focus is on identifying and reducing those sources of APIs that
contribute to unintended human and ecological exposure.
A pharmEcovigilance program would focus on the numerous points along the expansive network
spanning from manufacturers to patients - - where medications are designed, packaged,
prescribed, dispensed, and consumed, and where numerous processes and procedures could be
redesigned or altered to ensure optimal therapeutic outcomes from minimized drug use. The
ultimate objective and measure of success would be the degree to which medications are fully
consumed (reducing leftovers) while maintaining or improving therapeutic outcomes. This could
be achieved by redesigning a system that can get the right medication to the patient at the
optimal dosage and dosing time, and total quantity appropriate for the situation - and to choose
the most efficacious medication having the smallest environmental footprint and affordable cost
(Daughton 2009). This must be coupled with a system that provides rapid feedback on
therapeutic success, adverse events, and non-compliance. Such a program could lead to a more
efficient, optimized healthcare system, improved therapeutic outcomes and cost. Reduced
environmental impact would then become a natural outcome of better healthcare. While all of
this remains hypothetical, as sufficient data and knowledge to accomplish it are lacking, it
emphasizes that an unbalanced focus on drug disposal alone could miss much greater
opportunities.
PharmEcovigilance would emphasize that human and ecological health are intimately connected.
It would seek to optimize the design of the life cycle of drug manufacturing, sales/distribution,
and usage by ensuring: (1) prescribing the most effective medications in efficacious minimal
doses individualized for each patient, (2) dispensing in quantities and for durations that ensure
patient compliance (full consumption), and (3) minimizing/eliminating the generation of leftover
medications - so the need for disposal is avoided. Its major objectives would be to: (1) minimize
impacts on the environment from APIs as pollutants, (2) minimize exposure of humans via
consumption of APIs "recycled" from the environment (trace residues in drinking waters and
foods), and (3) minimize hazards posed to safety and health from accidental exposure or
diversion or scavenging of unused medications by humans, pets, and wildlife (Daughton 2008;
Daughton and Ruhoy 2008b).
One tenet of pharmEcovigilance is whether an imperative exists to now begin treating human
and ecological health as one and the same. The historical disconnect between human health and
ecological integrity still persists. Social, scientific, engineering, and regulatory systems
traditionally divide and separate what is really one integral system. The health of humans and
ecological integrity and sustainability are intimately intertwined. This becomes evident when the
processes involved with drug disposal are examined in detail.
The many actions that could be considered for prudently reducing drug use (and thereby reduce
the need for disposal) have been summarized in several publications: (Daughton 2003a; b;
Daughton and Ruhoy 2008b; Ruhoy and Daughton 2008). The prudent reduction in overall
medication usage could minimize the need for disposal. To reiterate, in contrast to improving the
drug disposal process, pollution prevention actions might afford the potential for significant
collateral benefits in reducing healthcare costs and improving therapeutic outcomes, as well as
reducing entry of APIs to the environment via excretion and bathing. The major emphasis to
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date, however, has been on improving approaches for drug disposal. The most important thing to
keep in mind with respect to disposal is the many unknowns regarding its benefits and
sustainability. These unknowns will serve as the focus of much of the discussion that follows.
PROJECT COMPONENTS
Pursuit of these objectives resulted in a comprehensive body of work from EPA's ORD
comprising a series of seminal publications in the peer-reviewed archival literature, invited
presentations at scientific conferences, and construction of the world's most complete electronic
database of all forms of published literature that are relevant to the many aspects of leftover
drugs, drug disposal, and environmental stewardship and pollution prevention. These products
serve as the foundation for this report. The report serves to synthesize the data, knowledge, and
insights from these publications and those captured in the contents of the literature database.
Note, however, that only a small portion of the references captured in the DDS bibliographic
database are cited in this report.
The main products in addition to the bibliographic database are 7 peer-reviewed journal articles,
5 book chapters, over 20 invited presentations at scientific and programmatic conferences, a
doctoral dissertation, roughly 10 posters and technical illustrations, and various outreach
activities (particularly, numerous interviews with the mass media, addressing inquiries from the
public, State Attorneys General, Congressional staff, GAO, and EPA program offices). The
major products published from this project are listed below. Digital reprints can be obtained from
daughton.christian@epa.gov, but versions of most of these documents can be directly accessed
and downloaded from:
"Drug Disposal & Stewardship: Ramifications for the Environment and Human Health,"
U.S. Environmental Protection Agency, Las Vegas, Nevada (web page maintained by CG
Daughton); available: http://www.epa.gov/ppcp/projects/disposal.html
Journal Articles:
Daughton CG and Ruhoy IS. "PharniEcovigilance: prescribing to protect the planet and improve healthcare," invited
article for Expert Review of Clinical Pharmacology, targeted for March 2011 (in preparation).
Daughton CG and Ruhoy IS. "Environmental Footprint of Pharmaceuticals: The Significance of Factors Beyond
Direct Excretion to Sewers," Environmental Toxicology & Chemistry (special issue: Pharmaceuticals and Personal
Care Products in the Environment) 2009, 28(12):2495-2521; doi:10.1897/08-382.1; available:
http://www3.interscience.wilev.com/cgi-bin/fulltext/123234136/PDFSTART.
Glassmeyer ST, Hinchey EK, Boehme SE, Daughton CG, Ruhoy IS, Conerly O, Daniels RL, LauerL, McCarthy M,
Nettesheim TG, Sykes K, and Thompson VG. "Disposal Practices for Unwanted Residential Medications in the
United States," Environment International, 2009, 35(3): 566-572; doi: 10.1016/j.envint.2008.10.007.
Daughton CG and Ruhoy IS "The Afterlife of Drugs and the Role of PharniEcovigilance," Drug Safety, 2008,
31(12): 1069-1082; doi: 10.2165/0002018-200831120-00004.
Ruhoy IS and Daughton CG "Beyond the Medicine Cabinet: An Analysis of Where and Why Medications
Accumulate," Environment International, 2008, 34(8): 1157-1169; doi:10.1016/j.envint.2008.05.002; available:
http://www.epa.gov/nerlesdl/bios/daughton/EnvInt2008.pdf.
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Ruhoy IS and Daughton CG "Types and Quantities of Leftover Drags Entering the Environment via Disposal to
Sewage - Revealed by Coroner Records," Science of the Total Environment, 2007, 388(1-3): 137-148; doi
10.1016/j.scitotenv.2007.08.013; available: http://www.epa.gov/nerlesdl/bios/daughton/SOTE2007.pdf.
Daughton CG "Cradle-to-Cradle Stewardship of Drags for Minimizing Their Environmental Disposition while
Promoting Human Health. I. Rationale for and Avenues toward a Green Pharmacy," Environmental Health
Perspectives, 2003, lll(5):757-774; doi: 10.1289/ehp.5947; available:
http://www.epa.gov/nerlesdl/bios/daughton/greenl.pdf.
Daughton CG "Cradle-to-Cradle Stewardship of Drags for Minimizing Their Environmental Disposition while
Promoting Human Health. II. Drag Disposal, Waste Reduction, and Future Direction," Environmental Health
Perspectives, 2003, lll(5):775-785; doi: 10.1289/ehp.5948; available:
http://www.epa.gov/nerlesdl/bios/daughton/green2.pdf.
Book Chapters:
Daughton CG and Ruhoy IS. "Pharmaceuticals in the Environment - Why Should We Care?" In: Pharmaceuticals in
the Environment: Current Knowledge and Need Assessment to Reduce Presence and Impact. B. Roig (Ed.), IWA
Publishing, London, UK, Foreword, pages xiii-xvii, 2010 ISBN: 9781843393146
http ://www. epa. gov/esd/bios/daughton/IW A -2010 .pdf:
http://www.iwapublishing.com/template.cfm?name=isbn9781843393146
Daughton CG and Ruhoy IS. "Reducing the Ecological Footprint of Pharmaceutical Usage: Linkages between
Healthcare Practices and the Environment," In: Green and Sustainable Pharmacy. Klaus Kummerer and Maximilian
Hempel (Eds.), Springer, Chapter 6, 2010, pages 77-102; ISBN: 978-3-642-05198-2;
http://www.springer.com/environment/environmental+management1)ook/978-3-642-05198-2
Daughton CG and Ruhoy IS. "Pharmaceuticals and Sustainability: Concerns and Opportunities Regarding Human
Health and the Environment," In: A Healthy Future - Pharmaceuticals in a Sustainable Society, collaborative
publication of Apoteket AB, MistraPharma, and Stockholm County Council, Sweden; Chapter 1, pp 14-39, 2009;
ISBN: 2184-01; available: http://www.epa.gov/nerlesdl/bios/daughton/Pharmaceuticals-Sustainabilitv-2009.pdf.
Daughton CG and Ruhoy IS "PharmEcovigilance: Aligning Pharmacovigilance with Environmental Protection," In:
An Introduction to Environmental Pharmacology. SZ Rahman, M Shahid, and V Gupta (Eds.), Ibn Sina Academy,
Aligarh, India; 2008, Chapter 1 (Introductory Overview), pp 21-34; ISBN # 978-81-906070-5-6; available:
http://www.epa.gov/nerlesdl/bios/daughton/IntroEnvironPharmacol-Chapterl-2008.pdf.
Daughton CG and Ruhoy IS "Accumulation and disposal of leftover medications: A key aspect of
pharmEcovigilance," In: An Introduction to Environmental Pharmacology. SZ Rahman, M Shahid, and V Gupta
(Eds.), Ibn Sina Academy, Aligarh, India; 2008, Chapter 5, pp 101-107; ISBN # 978-81-906070-5-6; available:
http://www.epa.gov/nerlesdl/bios/daughton/IntroEnvironPharmacol-Chapter5-2008.pdf.
Posters & Illustrations:
Daughton CG "Illicit Drags and the Environment," [illustration published in: Daughton CG "Illicit Drags:
Contaminants in the Environment and Utility in Forensic Epidemiology," Reviews of Environmental Contamination
and Toxicology, in press, March 2011)], US EPA, Las Vegas, Nevada, 7 December 2009 (rev 17 June 2010).
Daughton CG and Ruhoy IS. "PharmEcokinetics of APIs [illustration published in: Daughton, C.G. and Ruhoy IS
"Environmental Footprint of Pharmaceuticals - The Significance of Factors Beyond Direct Excretion to Sewers,"
Environmental Toxicology & Chemistry, 2009, 28(12):2495-2521; doi: 10.1897/08-382.1]," US EPA, Las Vegas,
NV, 7 June 2008.
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Daughton CG. "Role of PharmEcovigilance: Minimizing Human & Ecological Impacts [illustration published in:
Daughton CG and Ruhoy IS "The Afterlife of Drugs and the Role of PharmEcovigilance," Drug Safety, 2008,
31(12): 1069-1082]," US EPA, Las Vegas, NV, 16 April 2009.
Daughton CG and Ruhoy IS. "PharmEcovigilance & Stewardship: Reducing Human and Ecological Exposure from
Pharmaceutical Residues," illustrated poster prepared for the "Environmental Sciences Division Peer Review," 14
May 2009, National Exposure Research Laboratory, Office of Research and Development, US EPA, Las Vegas,
NV, Session 5: Water Quality - Stressor/Receptor Characterization, poster #SRC-3; available:
http://www.epa.gov/esd/chemistry/images/pharmEcoviginlance_stewardship.pdf.
Daughton CG. "Unintentional, Unanticipated Exposure to Drugs [illustration published in: Daughton CG and Ruhoy
IS "The Afterlife of Drugs and the Role of PharmEcovigilance," Drug Safety, 2008, 31(12):1069-1082],"
illustration, US EPA, Las Vegas, NV, 8 December 2007 (rev 4 June 2008) 2007.
Daughton CG. "Accumulation and Disposal of Pharmaceuticals [illustration published in: Ruhoy IS and Daughton,
C.G. "Beyond the Medicine Cabinet: An Analysis of Where and Why Medications Accumulate," Environ. Internal.,
2008, 34(8): 1157-1169]," US EPA, Las Vegas, NV, 10 May 2008.
Daughton CG. "Factors Influencing Drug Consumption [illustration published in: Ruhoy IS and Daughton, C.G.
"Beyond the Medicine Cabinet: An Analysis of Where and Why Medications Accumulate," Environ. Internal.,
2008, 34(8): 1157-1169]," illustration, US EPA, Las Vegas, NV, 8 December 2007 (rev 28 April 2008).
Daughton CG. "The Environmental Life Cycle of Pharmaceuticals [illustration published in: Daughton, C.G.
"Pharmaceuticals as Environmental Pollutants: the Ramifications for Human Exposure," In: International
Encyclopedia of Public Health. Kris Heggenhougen and Stella Quah (Eds.), Vol. 5, San Diego: Academic Press;
2008, pp. 66-102]," US EPA, Las Vegas, NV, December 2006; available:
http://www.epa.gov/nerlesdl/bios/daughton/drug-lifecvcle.pdf.
Daughton CG. "PharmEcovigilance and Environmental Risk [published in: Daughton CG and Ruhoy IS
"PharmEcovigilance: Aligning Pharmacovigilance with Environmental Protection," In: An Introduction to
Environmental Pharmacology. Ed. SZ Rahman, M Shahid, and V Gupta, Ibn Sina Academy, Aligarh, India; 2008,
Chapter 1, pp 21-34]," US EPA, Las Vegas, NV, 4 November 2007.
Ruhoy IS and Daughton CG "Pharmaceutical Disposal and the Environment," U.S. EPA, Las Vegas, NV; illustrated
poster, December 2007, NERL-LV-ESD-07-132; available: http://www.epa.gov/nerlesdl/chemistrv/images/drug-
disposal-2.pdf.
Ruhoy IS and Daughton CG "Disposal as a Source of Pharmaceuticals in the Environment," U.S. EPA, Las Vegas,
NV; illustrated poster, December 2007; NERL-LV-ESD-07-129; available:
http://www.epa.gov/nerlesdl/chemistry/images/drug-disposal-l.pdf.
Other:
Daughton CG "Drug Usage and Disposal: Overview of Environmental Stewardship and Pollution Prevention (with
an emphasis on activities in the Federal Government)," US EPA, Office of Research and Development,
Environmental Sciences Division, Las Vegas, Nevada, 23 pp, 15 October 2008; prepared for: Research Triangle
Environmental Health Collaborative - an Environmental Health Summit, "Pharmaceuticals in Water: What We
Know, Don't Know, and Should Do," 10-11 November 2008, North Carolina Biotechnology Center, Research
Triangle Park, North Carolina; available: http://environmentalhealthcollaborative.org/summit/presentations-and-
materials/; http://environmentalhealthcollaborative.org/images/ChristianDaughtonAbstract.pdf.
Ruhoy IS and Daughton CG. "Drug Disposal and Environmental Stewardship," invited presentation for
teleconference call on Drug Disposal for area agencies on aging in Maryland, organized by EPA's Aging Initiative
and the Office of Water, 22 June 2010; available: http://www.epa.gov/aging/resources/ddes/index.html.
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Ruhoy, Ilene Sue "Examining Unused Pharmaceuticals in the Environment," Ph.D. Dissertation, University of
Nevada, Las Vegas, Dept. Environmental Studies; August 2008, publication number 3352183; ISBN
9781109091083; 153 pp; accessible: http://gradworks.umi.com/33/52/3352183.html.
Daughton CG "Environmental Stewardship of Pharmaceuticals: The Green Pharmacy," In: Proceedings of the 3rd
International Conference on Pharmaceuticals and Endocrine Disrupting Chemicals in Water, National Ground Water
Association, 19-21 March 2003, Minneapolis, MN, p. 5-14; available:
http://www.epa.gov/nerlesdl/bios/daughton/ngwa2003.pdf.
Literature Database:
A major problem that pervades the field of pharmaceuticals and personal care products (PPCPs)
is that the published literature tends to languish unused (Daughton 2009). Little of it is ever read
- leading to much reinvention, duplication, and failure to capitalize on existing knowledge. Since
the field is now so large, it is no longer possible to summarize in a useful manner the published
literature surrounding its many facets, including that of drug disposal. This was one of the major
reasons behind assembling the first-ever literature database on PPCPs.
A product central to this project is the literature bibliographic database on leftover drugs, drug
disposal, and environmental stewardship (DOS). The DDS database was constructed from the
main PPCPs literature database, which is the most comprehensive compilation publicly available
of the resources published on the many aspects of the general topic of PPCPs as environmental
contaminants. As of mid-2010, the main PPCPs database comprised over 10,000 entries. Each of
the 10,000 records was assessed for its relevance to DDS. Of the total records in the main PPCPs
database, roughly 1,400 addressed topics relevant in some way to DDS, and about 600 of these
were journal articles (as of August 2010); roughly 600 of these 1,400 records are cited in this
report. Simple text listings of the citations from both the main database and from the stand-alone
DDS database (first made available for public access on 18 August 2010) are available for
download at:
U.S. EPA. 2010. "Pharmaceuticals and Personal Care Products (PPCPs): Relevant
Literature," U.S. Environmental Protection Agency, Las Vegas, Nevada (a comprehensive
database of literature references compiled and maintained by CG Daughton and MST Scuderi;
first implemented 19 February 2008); available: http://www.epa.gov/ppcp/lit.html; the direct
links to the DDS database are: http://www.epa.gov/ppcp/pdf/citations-disposal.pdf [and .txt]
The complete electronic databases are available for EPA use; versions without the associated
PDFs of the complete articles are available for public use. They run on EndNote (current version
as of mid-2010 is EndNote X4). Information regarding the content and usage of the database is
available here: http://www.epa.gov/ppcp/PPCPdatabaseSynopsis.pdf The main database
represents over 3 years of ongoing literature searching (both keyword-directed and freeform
browsing). The depth of its content and the ease and speed of access cannot be reproduced even
with sophisticated searching using a combination of subscription-based search engines. A
particularly useful feature of the complete EndNote version of the database is that it captures
web pages as they existed at the time of citing; this is useful since URLs are commonly changed,
leaving the original web pages inaccessible.
The DDS database serves not just as a resource for quickly locating current information
(including gaps) but also as a repository for materials that are now considered historic. The
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database serves as a simple way to quickly access the published literature on any of the many
aspects of the drug disposal issue, including topics as diverse as donations, recycling, poisonings,
compliance, and many others. It is expected that the database could be invaluable for anyone
wishing to study a specific aspect of the larger topic.
The published literature in the DDS database captures all of the archival literature, which began
to first appear in the 1960s, with papers such as: Matthew (1966), Gunn and Lishman (1967),
Nicholson (1967), and Robin and Freeman-Browne (1968).
The articles in the DDS database focus on several major aspects of the issue, primarily: (i) the
many factors responsible for the generation of leftover, unwanted medications; (ii) surveys of the
types and quantities of medications stored in the home or healthcare facilities; (iii) the
approaches actually used for disposing of leftover medications (such as flushing to sewers,
discarding in trash, take-back programs); (iv) obstacles to the design of optimal disposal
strategies (such as existing law or regulations - the CSA being one example); (v) new legislation
to allow or promote more "prudent" disposal; (vi) pollution prevention and stewardship - ways to
prevent generation of leftover medications; (vii) poisonings (human and animal); and (viii)
diversion and abuse.
A significant portion of the published literature is in foreign reports and journals (e.g., German,
French, Italian, Spanish, Swedish). A limited, core set of publications tend to be the only ones
cited in most paper (from among the hundreds that exist). Evidence exists that certain papers are
cited after never having been read by the author; the same mistake is then perpetrated by
subsequent authors. A case in point is the following paper, which has been cited by a number of
authors but which apparently does not exist (Collins and Johnston 1992). One of the reasons for
incorrect citations is that the publication source is obscure or difficult to locate.
Of most significance and critical for a complete understanding is that among the DDS articles,
very few (perhaps a couple of dozen or so) provide any hard scientific data needed to support the
major assertions regarding this topic. Most of these studies have been performed in a number of
different countries and tend to focus on: (1) written or oral surveys of consumers regarding drug
usage behavior (e.g., compliance, storage, and disposal habits), (2) inventory of medications
stored on-site of homes and healthcare facilities, (3) consumer disposal practices (e.g., the route
selected for discarding leftover drugs), and (4) the monetary value of unused, wasted drugs.
These data might facilitate better understanding to the drivers for leftover medications, but they
have not proved useful in effecting any sustainable and effective solutions.
The difficulty in locating papers relevant to the many dimensions of drug disposal can be readily
seen just by considering a small portion of some of the search terms that are needed in Boolean
searches to cover the entire breadth of the scientific and medical literature. Examples include:
disposal, dispose(d), discard(ed), returns, returned, expired, expiry, expiration, outdated,
wastage, drug waste, medication waste, pharmaceutical waste, medical waste, waste medicines,
medicine cabinet, DUMP, RUM, unused, unusable, unwanted, unneeded, leftover, etc. Further
complicating the need to narrow literature searching is that some of the literature relevant to
household disposal of leftover drugs intersects partly with the problem of waste disposal at
hospitals and other healthcare facilities - where "medical waste" primarily deals with sharps,
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infectious waste, hazardous waste, and general waste; the occurrence of drugs (or APIs) in
medical waste is usually viewed as incidental.
Each of the nearly 1,400 records in the DDS database was examined to determine what aspect(s)
of the DDS issue it concerned; each record was tagged accordingly. The tags served as
keywords, allowing fast retrieval of subsets of the database that are relevant to specific aspects of
the DDS topic. They also provided some insight as to the scope of the articles in the database.
Included are articles on the following aspects of DDS, all of which contribute to understanding
excess drug usage, the accumulation of leftover drugs, drug disposal, or stewardship (ways to
minimize wastage):
• compliance (patient non-compliance or non-adherence)
• conferences devoted to DDS
• counterfeiting (which exacerbates drug use and waste, as well as contributes to poisonings)
• destruction or encapsulation techniques (relevant to on-site pretreatment prior to disposal)
• diversion (which exacerbates drug use and waste, as well as contributes to poisonings)
• donation (redistribution for humanitarian purposes)
• expiry (API reactivity, shelf-life, stress testing, stability testing, degradation-related
impurities: DRIs)
• guidance on disposal (for drugs and packaging)
• incineration
• inventory (drug stocks maintained in homes)
• legislation (governing: take-backs, disposal, CSA, Congressional hearings)
• patient behavior (including attitudes, expectations, customs, and beliefs; doctor shopping)
• poisonings (occupational, especially with regard to chemotherapeutics)
• poisonings (unintended, accidental) in humans, companion animals, and wildlife
• prescribing/dispensing (practices that increase or reduce drug wastage; polypharmacy)
• recycling (reuse, redispensing)
• sampling (free samples provided by detailing and other practices such as direct-to-consumer
(DTC) advertising that increase drug prescribing)
• self-medication
• sharing (transfer of prescription drugs to those without a prescription)
• stewardship (holistic approaches for reducing drug waste)
• storage (accumulation, stockpiling, hoarding)
• take-backs
The query capabilities of EndNote allow the user to examine any aspect of the DDS topic
desired. The database comprises articles published in peer-reviewed journals (about 600 total,
with a representative selection in non-English languages), books and book chapters (about 50),
reports (government, academic, and private sector), legislation and legal articles, local and state
government documents, doctoral and masters dissertations (two dozen), conference
presentations, news stories, and other gray literature (documents not readily retrievable through
publishers and other conventional sources). Citations for some of the references, as cited in the
publications of others, were discovered to be incorrect. Many of the resources are from obscure
sources and rarely cited. Many are available by subscription only. Many are extremely difficult
to locate even with intensive literature searching using Google Scholar, Science Direct, and other
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resources. Nearly 500 of the 600 journal articles have PDFs of the complete article. This is
extremely valuable as it provides the user with immediate access to the complete paper. Using
third-party software (or the PDF search capabilities new to EndNote X4), all of the PDFs can be
searched as well; file-searching software supporting line-specific Boolean searching is
particularly useful.
While this is a large number of references, the vast majority cover similar ground and simply
adds further confirmation to preceding studies. Few papers have offered truly new insights. By
examining the resources of the DOS database, a number of insights, conclusions, and
recommendations were formulated. Some of these run counter to the consensus opinions that
have emerged over the years regarding leftover drugs and disposal. Some question the validity of
conventional guidance regarding drug disposal. These represent major findings from this work.
These were itemized in "Major Findings and Insights."
HISTORICAL PERSPECTIVE
The issues surrounding the generation of leftover medications and their eventual need for
disposal are only part of the larger puzzle that encompasses the myriad aspects of drugs as
environmental contaminants. This larger puzzle exists within an even larger one of so-called
"emerging contaminants" or "contaminants of emerging concern." Pharmaceuticals as a class of
contaminants in the environment is a topic captured under the term PPCPs ("pharmaceuticals and
personal care products"), coined by Daughton and Ternes (1999). The published literature on
PPCPs and emerging contaminants has grown exponentially since the 1980s, and now comprises
thousands of papers reporting on the shape, scale, intensity, and spatiotemporal aspects of the
origins, environmental footprint, exposure envelope, potential for biological effects, and
mitigation of PPCPs (Daughton 2009). So the topic of drug disposal must be understood within
this much larger context. This larger context is sometimes ignored.
Many of the ideas for reducing the incidence of leftover medications were first proposed in the
1960s and 1970s and have been repeatedly resurrected or rediscovered in numerous studies
since. Most of the very same concerns and issues regarding the storage of unneeded drugs in the
home, the causes for hoarding medications (such as non-compliance), the risks associated with
hoarding (such as abuse and diversion), and programs designed to collect them had already been
expressed in the 1970s (and perhaps earlier) in Australia (e.g., Medi-dump and Medidrop
programs) and elsewhere. Unfortunately, most of the data derived from these programs were
compiled in unpublished reports (Wilks and Withers 1989).
Probably the first reported comprehensive inventory of household medication resulted from a
collection event for drug waste in 1967 (Nicholson 1967): "A total of 43,554 tablets and capsules
were handed in, of which 36,242 were identified."
The first major review of patient non-compliance was published over 30 years ago (Blackwell
1976). Thousands of papers on this topic have since accumulated in the peer-reviewed medical
literature.
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Comprehensive discussions and examinations of the role played by prescribing in the generation
of leftover medications have also been underway for over 30 years (Hemminki 1975; Taylor
1978).
The increasing cost of medications and their overuse has been a topic of concern for over 30
years, prompting investigations of the types and quantities of medications that go unused in
households (Leach and White 1978).
The early literature (pre-1980s) is an eye opener with regard to the issues surrounding drug
disposal in the sense that few of these issues (or their solutions) are new. They are all rooted in a
long history that began in the 1950s with a continual escalation in the numbers of written and
dispensed prescriptions (using a widening spectrum of different types of ever-more potent drugs)
for a seemingly endless array of maladies. What this shows is that many of the issues faced by
drug disposal persist because the underlying causes have proved recalcitrant to any solution.
In the intervening 30-40 years, there has been little new associated with the collection campaigns
currently being pursued in the US. Perhaps the only significant new aspect is the concept of
using mail-backs (pioneered by the State of Maine) (Kaye et al. 2010); even the comprehensive
inventory of the types and quantities of returned drugs in order to assess a number of questions
surrounding prescribing, dispensing, and compliance was an objective of collection campaigns in
the 1970s. Otherwise, everything is basically the same. A sense of how little things have changed
with respect to collection campaigns can be gained from reading any of the older literature, such
as Wilks and Withers (1989).
In the US, historical accounts usually point to the work of Kuspis and Krenzelok (1996), whose
paper was the first to provide a sizeable survey in the US of drug disposal pathways. The main
driver for their work was accidental poisonings (they worked at the Pittsburgh Poison Center),
postulating that at least a portion of these poisonings might result from the unnecessary
stockpiling of drugs or their imprudent disposal in trash. They were also among the first to point
out the lack of guidelines for disposal in the US (including the State level or even from poison
control centers): "It is interesting that state Boards of Pharmacy, the FDA and the EPA do not
have policies on the disposal of medications when many other public hazards are under
regulatory scrutiny... It seems prudent to have uniform guidelines and policies on medication
disposal. Safe disposal of medications in the home should be addressed and guidelines
formulated."
Even though the topic had received attention since the 1970s, and although disposal to sewers
was recognized in the UK as a potential risk for the environment in the 1980s (e.g., Davidson
1989), in North America the topic began to receive very limited but broader attention only in the
early 2000s, marked by two presentations at different conferences (Daughton 2003c; Smith
2002). It was not until 2004, however, that the general topic of drug disposal garnered sufficient
attention to warrant focus as a topic for a conference, sponsored by the Northeast Waste
Management Officials' Association (NEWMOA 2004). The Maine Benzodiazepine Study Group
Conference and Unused Medicine Return Conference (http://www.benzos.une.edu/) has been
held since 2002, but its early focus was on benzodiazepines, not drugs in general.
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The EPA first sponsored a conference (jointly organized by the National Center for
Environmental Research and the Office of Research and Development-National Exposure
Research Laboratory) involving a focus on consumer drug disposal in 2005 (USEPA 2005).
Follow-up EPA meetings focused on consumer disposal have included one held at Region III
(excelleRx and USEPA Region III 2008). The DEA held its first conference in 2006 (DEA
2006).
Probably the earliest consensus statement regarding the need for controls on the consumer
disposal of drugs was the so-called Athens Declaration (Maine Benzodiazepine Study Group
2007) [crafted by delegates at the International Conference on Environment in Athens, Greece,
Aug 2007]. The Declaration codified six basic reasons to address unused drug disposal:
1. To curtail childhood overdoses
2. To restrict household drug theft
3. To limit accumulation of drugs by the elderly
4. To protect our physical environment
5. To restrain improper international drug donations
6. To eliminate waste in the international health care systems of all countries.
In 2009, the so-called Maine Declaration was proposed to augment the Athens Declaration
(University of Maine Center on Aging 2009). The Maine Declaration, proposed at the 20
October 2009 International Symposium on Pharmaceuticals in the Home and Environment
(Northport, Maine), articulated five, more-specific measures to achieve the basic objectives of
the Athens Declaration, as excerpted here:
To encourage a decrease in the amount of drugs wasted and a reduction in the costs of dispensing and related
healthcare costs, adverse drug events, inappropriate international drug donations, and the disposal of unused
prescription drugs, and in support of the Athens Declaration of August 3rd, 2007, we, a diverse group of
stakeholders, support the following five measures:
1. Limited first-time prescriptions on selected drugs based on returns data as initiated by the State of Maine.
2. Opposition to financial penalties for consumers on these initial prescriptions.
3. Involvement of third party payers in the drug waste reduction process.
4. Evaluation of all aspects of refill systems used by mail-order pharmacies to reduce waste.
5. Participation of manufacturers, distributors, prescribers, hospitals, clinics, and pharmacies to assist with
foremost improving adherence and concordance and improving patient outcomes and the reduction of
medication waste.
We call upon governments, NGO's, private insurers, and citizens to improve and refine dispensing policies and
procedures to reduce medication waste.
We call upon patients to recognize the need for medicine to be taken as intended if it is to be effective.
We call upon others to endorse these principles with us for the betterment of the health of the environment and
citizens in the United States and internationally.
In 2007, the World Health Organization (WHO) set forth its core principles for managing
healthcare waste (WHO 2007):
"The management of health-care waste is an integral part of a national health-care system. A holistic approach
to health-care waste management should include a clear delineation of responsibilities, occupational health and
safety programs, waste minimization and segregation, the development and adoption of safe and
environmentally-sound technologies, and capacity building. Recognizing the urgency of this problem, a
growing number of countries have taken initial steps to respond to this need. These include the establishment of
regulatory frameworks, development of national plans, and the demonstration of innovative approaches.
However, funding for health-care waste management remains very inadequate."
The WHO's principal recommendation is:
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"The WHO core principles require that all associated with financing and supporting health-
care activities should provide for the costs of managing health-care waste. This is the duty of
care. Manufacturers also share a responsibility to take waste management into account in the
development and sale of their products and services." In particular, "The private sector should:
take responsibility for the sound management of health-care waste associated with the
products and services they provide, including the design of products and packaging."
[emphasis added]
The management and minimization of healthcare waste, while traditionally focused on infectious
waste, has long had an additional focus on chemical management. This focus, however, has
always been rather narrow, being limited to cytotoxics and genotoxics (and radionuclides).
Rarely has any focus been applied to pharmaceutical waste in general. The management of
Pharmaceuticals has rarely been considered in development of sustainable healthcare (e.g., Tudor
et al. 2005). But drug disposal has begun to be covered in pharmacy continuing education
(Albrant 2010; Prescott and Estler 2010).
In 2009, drug disposal became a feature of the FDA's new Safe Use initiative (USFDA 2009b).
Excerpted from page 14:
"Efforts to Mitigate the Risks of Unintended Exposure. Recently, FDA announced a new effort,
Disposal by Flushing of Certain Unused Medicines: What You Should Know, directed at
preventing serious harm and death caused by exposure of children to certain drugs, including
opioid drugs, used in the home. Unused portions of these medications must be disposed of
properly to avoid harm."
Drug disposal is also the subject of ONDCP's 2010 National Drug Control Strategy (ONDCP
2010). To achieve their objective ("Curb Pharmaceutical Abuse: Preserve Medical Benefits of
Pharmaceuticals"), the ONDCP notes six actions. One of these is "Increase Prescription
Return/Take-Back and Disposal Programs." This action is shown as collaboration among
DOJ/DEA, EPA, and HHS/FDA (page 32).
In 2010, several events will mark the first nationwide days for collection of unused prescription
medications. One of these is the National "takeback day," being coordinated by the DEA for
September 25 (Cotter 2010; DEA 2010a; b).
Over the course of the roughly 5 years since the beginning of these seminal events, very
substantial investments in time, money, and effort have been devoted to the topic by a wide array
of public and private organizations and agencies. An extremely confusing spectrum of agencies
and organizations, across all States, involved with regulations that touch upon the disposal of
drugs is a major impediment to designing a streamlined nation-wide approach. Regulations
directly or indirectly involving drug disposal exist at the local, city, state, and federal levels, and
come under the purview of Boards of Pharmacy, departments of health, departments of the
environment, DEA, FDA, DOT, etc. Myriad others are involved with issuing guidance, some of
which conflicts with others. Further exacerbating the problem is that guidance and regulations
for handling pharmaceutical waste in the institutional setting is mixed in with (and often
confused with) the guidance and regulations for controlled substances, hazardous waste, and
infectious waste.
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Much of the confusion and conflicts could perhaps be avoided if one federal agency had the lead
in development of disposal guidance and regulations. The major reason that drug disposal has
become an orphan problem is that its origin and solution cuts across such a wide number of
professions and disciplines, few of which communicate with the other.
Interest in drug disposal is witnessed by the large and increasing numbers of government
agencies in numerous states and cities that now have web pages devoted to drug disposal.
Because of the sheer number of participants and stakeholders, there has been substantial
repetition and duplication of effort, much of it simply amounting to rediscovery or reinvention -
or dead ends; some is even contradictory. This points to the need for a lead agency (or at least a
national clearinghouse) responsible for setting the agenda and coordinating efforts along the
many fronts of inquiry surrounding the expansive drug disposal issue.
The topic has received so much exposure via the news media and public relations campaigns
from states, cities, public utilities, Congressional Hearings, and health organizations that it is
now encountered in key documents not directly related to the issue. For example, drug disposal
is specifically discussed in the annual report of the President's Cancer Panel; see page 75 of
LeffallandKripke(2010).
BACKGROUND AND RATIONALE
The collective actions and behaviors of those involved in the healthcare system - - from drug
manufacturers, physicians, insurers, and pharmacists, to patients themselves - - often result in
contamination of the environment with many of the thousands of active pharmaceutical
ingredients (APIs) used in medications. APIs from human and veterinary medications are now
known to be widespread and common trace contaminants in the environment - - primarily in
surface waters (including drinking water supplies) but also in terrestrial settings where treated
sewage is used for irrigation and soil amendment; although occurrence in finished drinking
waters is much more limited, the scope of APIs known to be present in drinking waters is
growing (Daughton 2010a). The potential ecological and human toxicological ramifications of
chronic exposure to extremely low individual levels of multitudes (tens to hundreds) of
chemically distinct APIs have not been fully revealed (Daughton 2010a). Much research has
been published on the topics of environmental monitoring methodologies, environmental
occurrence and fate, aquatic toxicity, and waste and water treatment. In contrast, the numerous
controllable factors that contribute to, and exacerbate, the potential for exposure have been
largely ignored; these largely comprise source-control and stewardship measures.
APIs can enter the environment from a broad spectrum of sources but primarily via three major
routes. The three pathways of API entry to the environment are: (1) excretion of unmetabolized
APIs or bioactive metabolites, (2) direct release from the body during bathing, and (3) disposal
of unwanted, unused, leftover medications (and used delivery devices, such as dermal patches,
still containing significant API residues). All three of these routes involve discharge via
sewerage. The last can also involve domestic and municipal trash; trash can also be a minor
conduit of excreted APIs from the discard of soiled clothing. Other, minor routes include direct
transfer from the skin of dermally applied medications and APIs excreted via sweat to surfaces
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that surround our daily lives (essentially anything that our skin comes in contact with, including
other people, phones, doors, etc); this route is capable of resulting in acute exposures because of
the high levels involved. These routes have been comprehensively examined in (Daughton and
Ruhoy 2009a).
The sources and magnitudes of each route are critical to understand for gauging their relative
importance as source terms leading to potential exposure. Excretion has been long considered as
the only meaningful route of API entry to the environment, rather than disposal to sewers or
release from manufacturing, but little empirical data or even modeled data exist for justifying
this assumption and making it anything more than a guess. While this might be true for the
roughly 1,500 APIs when considered in toto, it might well not apply when considering each API
individually. After all, pharmacokinetics (namely, to what degree is an API excreted unchanged),
overall usage rates, and patient compliance or adherence to medication regimes will largely
dictate the importance of disposal (as well as bathing). While the disposal of leftover drugs adds
to the environmental burden of drug residues, it is currently not known how significant it might
be to APIs collectively or individually.
Of the many aspects of APIs as environmental contaminants, drug disposal continues to capture
the attention of the public, the media, the water industry, regulators, and Congress, where several
hearings have been held over the last couple of years. This attention has resulted in the
proliferation of an uneven patchwork of drug take-back or collection projects across the nation.
These one-time events or ongoing services allow consumers to bring their unwanted medications
(subject to restrictions imposed by those medications that are controlled substances) to locations
where they can be collected and "properly" disposed - generally as hazardous waste, which
invariably involves landfill burial or incineration. One measure of how far the drug disposal
issue has advanced is the number of laws, regulations, and resolutions passed by city, state, and
federal legislators; a sampling of state statutes and bills pertaining drug returns is maintained by
The National Alliance for Model State Drug Laws (NAMSDL 2009).
Perhaps an ultimate form of recognition is reflected by the Congressional resolution for
"Prescription Drug Disposal Awareness Day" (Casey et al. 2010). The topic has even garnered
the attention of the White House, as shown by the President's SAVE Award (Securing
Americans' Value and Efficiency). The very first recipient of the SAVE award, in 2009 (The
White House 2009), had proposed that the U.S. Department of Veterans Affairs (VA) reissue
medications owned by admitting patients upon their discharge, thereby avoiding the traditional
practice of disposing of all patient medication upon discharge. As of 2010, the VA had
completed phase I of its pilot to re-label and re-dispense all patient medications.
Even approved approaches for disposal have carbon footprints. Take-back events are probably
not a sustainable solution because of the costs associated with staffing and the disposal process
itself. The inordinate costs associated with take-backs have been noted by many, one example
being the Bay Area Pollution Prevention Group (2006), which reported $175 per person served
or $450 per pound disposed. But even for larger, ongoing programs that avoid some of the costs
of smaller collection events, the complete lifecycle costs associated with entire collection process
have never been evaluated in a comprehensive manner. As one example, there are significant
hidden costs. Unexpired but no longer wanted medications represent not only unrecoverable
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purchase costs for the consumer, but more importantly, they often represent lost opportunities to
have achieved their intended therapeutic outcomes. Another example is the collection of unused,
unwanted antibiotics; consumption of partial treatment regimens can encourage the emergence of
antibiotic-resistant pathogens. Worse yet, would formal programs for collecting unwanted drugs
actually perpetuate the generation of leftover drugs by sending consumers the implicit message
that leftover drugs are expected and acceptable. By facilitating easy, "cost-free" disposal of
drugs with formal take-back programs, we may be inadvertently encouraging consumers to not
hesitate in buying large quantities (to achieve false economies of lower unit-dose pricing), only
to again find themselves unable to fully consume them before expiration. Disposal would then be
followed by repurchasing new supplies - perpetuating the cycle of purchase-disposal.
Although the work subject of this report represents the first in-depth examination of the many
aspects of the drug disposal pathway, it too fails to cover some of the factors governing
sustainability. In a series of publications in peer-reviewed journals and books, drug disposal is
examined with regard to the: (i) numerous factors that promote, control, and drive the usage or
accumulation of leftover drugs, (ii) many and diverse locations in society where drug
accumulation occurs and which then necessitate the need for disposal, (iii) scope and magnitude
of the types of APIs that tend to be disposed (including development of the first approach for
accurately identifying those APIs and their actual quantities being disposed), (iv) pollution
prevention and source reduction actions and activities that can reduce or minimize the need for
disposal of medications, (v) possible role it plays in the efficiency and sustainability of our
healthcare system, and (vi) role it plays in drug diversion and human poisonings.
The ultimate outcome envisioned for this project could have broad consequence of national
significance with regard to both the cost and efficacy of healthcare as well as the overall levels of
APIs in the environment. By identifying which drugs accumulate unused, and where, how, and
why they accumulate, more sustainable measures aimed at the practice and delivery of healthcare
could be designed and implemented. These could not only reduce the consequent need for
disposal, but also improve healthcare outcomes, reduce healthcare expenses, and reduce the
incidence of diversion and poisonings. This could be done preferably not by focusing solely on
ecologically prudent methods for disposing of leftover medications (the equivalent of end-of-
pipe control), but rather by focusing up-stream - - changing the human and healthcare processes
that lead to accumulation in the first place. The ultimate objective should be to eliminate the
need for disposal altogether.
A major underlying theme that pervades the drug disposal issue is drug diversion and
unintentional poisonings. It must be noted that the use of the word "accidental" in describing
poisonings is ambiguous, as it often does not distinguish unintentional poisonings caused by
abuse (which requires intentional exposure) from those truly caused by unintended exposure (for
example, a child not realizing what they are ingesting or applying to their skin). This has
significance with respect to databases on poisonings. It is not always possible to cull data from
poisonings databases that are tagged as "unintentional or undetermined intent" and discern which
are from ingestion with the intent for beneficial outcome (e.g., abuse, recreational usage) and
which were from ingestion with no expected outcome (e.g., so-called accidental ingestions).
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Medications that accumulate unused have long been suspected to promote misuse by those for
whom the medications were never intended - - for recreational purposes (e.g., teen "pharming")
or for abuse. Accumulated supplies of medications also increase the chances of both intentional
and unintended poisonings - - not just for infants and toddlers, but also for those who have
trouble remembering or following dosage instructions and where unnecessary accumulated
medications serve to amplify the confusion. Stored, unused medications encourage self-
medication, which can lead to fatal medication errors (FMEs) as a result of the confusion caused
by the presence of multiple (or a multitude) of medications. The dual problems of diversion and
poisonings were the major drivers behind the White House Office of National Drug Control
Policy (ONDCP) effort to formulate the nation's first guidance for drug disposal (2009 [updated
October]). It should be noted, however, that the published evidence supporting the claim that
leftover, unwanted medications stored in homes (as opposed to medications in active use) are a
major contributor to diversion and poisonings is sparse. This is because the portion of diversion
and poisonings resulting from unwanted drugs (e.g., data inventoried by the national poison
control centers) cannot be teased apart from that resulting from medications that are in current
use as intended.
Ironically, the very problem the ONDCP wishes to control (primarily the diversion and abuse of
controlled substances) involves regulations that also prevent an easy solution via encouraging
disposal. Regulations restricting the disposal of controlled substances pose a major obstacle to
formulation of a disposal system that can be easily implemented nationwide. Use of the
Controlled Substances Act or CSA (DEA 2008) in the U.S. to ameliorate diversion and abuse has
created a number of problems and impediments for designing disposal solutions. The primary
impediment is that the CSA narrowly restricts the options for those to whom controlled
substances are prescribed for transferring their leftovers; this is a result of the CSA originally
having not foreseen the fact that patients would have unused drugs. These problems have only
recently begun to be addressed by proposed federal regulation to amend the CSA, such as H.R.
5809 "Safe Drug Disposal Act of 2010" (Inslee et al. 2010).
One of the dichotomous problems imposed by the CSA is the opposing needs of preventing
diversion of certain controlled substances (by use of the fastest, easiest, and least costly means of
drug disposal - - namely flushing down the sewer) and protecting the aquatic environment. While
flushing medications as soon as they are no longer needed eliminates diversion/abuse (therefore
minimizing accidental and intended acute human exposures), at the same time it maximizes
aquatic exposures and can lead to unwanted and perhaps unrecognized trace-level, chronic
human exposure (via contaminated drinking water).
But further complicating this is that if all, most, or some APIs pose little hazard to aquatic life,
flushing the most hazardous may indeed be the best approach for minimizing human exposure
risk. Even those APIs that pose measurable hazard, without knowing the quantitative
contributions of their disposal to total environmental loadings (portions contributed by disposal
versus excretion and bathing combined), their continued flushing may not add measurably to the
overall loadings. For example, if an API is extensively excreted unchanged (i.e., it undergoes
little metabolic alteration or tends to be excreted as reversible conjugates) or if the API happens
to be used in a medication with extremely high patient compliance (which generates
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proportionately few leftovers), then disposal to sewers will contribute immeasurably small
increments to total environmental loadings (Daughton and Ruhoy 2009a).
Traditionally, consumers in the U.S. have used trash receptacles and toilets for medication
disposal. But, as mentioned above, two directly competing concerns complicate what initially
appears to be a simple action. Historically, poison control centers have recommended that drugs
be flushed down the toilet (whether leading to a septic system or to a municipal waste treatment
facility) as the best means of preventing their accidental or purposeful ingestion by those for
whom the medication was not intended, especially children. Although disposal to the toilet
prevents immediate accidental exposure or ingestion, it unfortunately can add to the overall level
of pharmaceutical pollutants in the environment (by way of treated wastewater or sludge) and
consequently also holds the potential to eventually lead to extremely low-level, chronic human
exposure via contact or ingestion of minute residues in drinking water (as a result of the natural
"water cycle") or by ingesting food crops grown on land treated with sludge or irrigated with
treated wastewater.
Without knowing the role played by disposal in contributing to the environmental loading of
each individual API, risk to neither the environment nor humans can be truly assessed. Should
the fail-safe approach be used - - where disposal to sewers is avoided for ALL medications - - the
efficient use of resources and safest option for disposal are unnecessarily discounted.
In light of these unknowns, a new paradigm is proposed for medication usage. This paradigm
seeks to solve the disposal issue while at the same time minimize the use of resources. Leftover,
unused medications should be viewed not as chemical waste but rather as measures of wasted
healthcare resources and as opportunities lost for achieving intended therapeutic treatments.
Leftover drugs are essentially serving as messengers of critical importance to the state of our
healthcare system - and the many ways in which this system could be improved. By redesigning
and optimizing the use of medication, the need for disposal can be minimized. Further, by
implementing systems that can readily inventory and catalog the types and quantities of leftover
medications in a central database, alterations can be made to prescribing and dispensing practices
that can reduce the incidence of leftovers while also improving healthcare outcomes. These data
could be extremely valuable to many sectors of health care. The study of James et al. (2009) is an
example of the types of data that can be collected and the types of conclusions that can be drawn
regarding the causes of medication accumulation.
Finally, a potentially significant collateral benefit from minimizing the need for disposing of
drugs has yet to be recognized. Although minimizing leftovers by increasing patient compliance
can increase the quantities of those APIs excreted unchanged or discharged to sewers by way of
bathing, minimizing leftovers resulting from unnecessary or imprudent prescribing (e.g., wrong
medication) will reduce API excretion. Of the numerous facets of medical care that can be
modified to reduce the incidence of drug accumulation and subsequent need for disposal, many
would entail modification of dosage regimes, generally resulting in lower amounts over the
course of treatment. Lower overall dosing (e.g., via evidence-based prescribing and personalized
prescribing) will necessarily result in lower excretion. By taking actions to reduce the need for
drug disposal, overall drug usage can decrease. Residues entering sewage from both disposal and
excretion could thereby be reduced simultaneously.
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If new approaches to medical care were developed that eliminated leftover drugs, the consequent
environmental residues could be eliminated, therapeutic outcomes could improve, healthcare
expenses could be reduced, and human morbidity and mortality (due to addictive usage and
poisonings from diverted, leftover drugs) could decline. Reducing the need for disposal would
also reduce the ecological footprint of medications and save on the costs associated with
landfilling of hazardous wastes or incineration. Reducing, minimizing, or eliminating leftover
drugs represents a very significant opportunity to improve both ecological and human health, all
at reduced costs for consumers.
This project has involved the first conceptualization of a stewardship framework for optimizing
the use of pharmaceuticals throughout the healthcare system. Implementing some well-targeted
actions in the delivery of health care could have profound, far-reaching benefits for human and
ecological health, both of which are intimately linked. By integrating ecological concerns with
conventional pharmacovigilance programs (a worldwide program that tracks the detection,
assessment, and prevention of adverse effects from the use of medications), a more holistic
system for care of both human health and the environment could be created - - one newly termed
"pharmEcovigilance" (Daughton and Ruhoy 2008a). Its implementation could reduce the cost of
health care, improve therapeutic outcomes, and lessen unintentional acute and chronic exposures
of humans and wildlife.
Overviews of the Drug Disposal Issue
There are many articles published in the peer-reviewed and gray literature that cover the
immediate aspects of the drug disposal issue. All of these can be found in the DDS database.
Two of the first comprehensive and holistic assessments of the issues surrounding the occurrence
of leftover drugs and drug collection programs are provided by Mackridge (2005) and Morissette
(2006). The dissertation of Mackridge (2005) (and the ensuing journal articles) remains one of
the most comprehensive examinations yet published on this multi-faceted issue.
Other comprehensive overviews, from a spectrum of perspectives, have all been published in the
last 3 years (Albrant 2010; Bain 2010; Grasso 2009; Hubbard 2007a; b; Johnson 2007; Kallaos et
al. 2007; Ortner and McCullagh 2010; Prescott and Estler 2010; Siler et al. 2008; Spartz and
Shaw 2009; White 2010).
A series of papers co-authored by Braund (e.g., Braund et al. 2009a) provides a body of
comprehensive information. An overview from the European perspective is provided by Vollmer
(2010).
The National Resources Defense Council (NRDC) provides its perspective on various aspects of
disposal; recommendations for future actions are on page 47 of Wu et al. (2009).
CalRecycle (201 Ob) has prepared a document that summarizes the many factors involved with
determining the best way to handle drug waste (in California). California's SB 966 directed the
then California Integrated Waste Management Board (now the California Department of
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Resources Recycling and Recovery: CalRecycle) to report back to the State legislature by
December 2010 with: (i) an evaluation of model collection programs for efficacy, safety,
statewide accessibility, and cost effectiveness that factors in diversion of drugs for unlawful sale
and use, and (ii) recommendations for potential implementation of a statewide program and any
needed statutory changes.
Many overviews focus on particular aspects, such as the one from Struglinski (2009), which
examines the many and conflicting obstacles and challenges facing the accumulation of leftover
drugs and need for disposal (especially in LTCFs: long-term care facilities). The Product
Stewardship Institute (PSI) has played a significant role in the US in advancing the dialog on
drug disposal (PSI 2008a). Some of the most definitive guidance available on drug take backs is
provided by the National Association of Drug Diversion Investigators (NADDI 2010).
SPECIFIC AREAS OF RESEARCH RELEVANT TO UNDERSTANDING
THE ORIGINS OF LEFTOVER DRUGS, THE SIGNIFICANCE OF
DRUG DISPOSAL, AND THE IMPORTANCE OF STEWARDSHIP
The following section summarizes some of what is known regarding most of the major factors
surrounding the drivers for leftover drugs (origins and causes for the accumulation of unused
drugs), the actual disposal of leftover drugs, and the management of drugs via principles of
evidence-based medicine and environmental stewardship. Additional, comprehensive
information can be obtained by searching the DOS database.
Non-compliance/Non-adherence
Introduction. The issues of drug leftovers, hoarding, and disposal have been discussed for
over 40 years in the medical literature. Significantly, few new insights have emerged over these
years. Little progress has been made in solving the problem. Of the many forces at work, two of
the major entangled causes are believed to be patient non-compliance and the prudence of
physician prescribing; these in turn are at play with an enormously wide array of other factors.
The complex interconnectedness of countless driving forces makes development of prudent
approaches to minimizing drug waste a risky venture, but one also having the potential for
considerable positive impacts.
A topic that figures prominently in discussions regarding drug disposal is patient non-compliance
(or non-adherence). Non-compliance refers to the patient's failure to take prescribed medications
as directed. Non-compliance results from a patient's conscious decision; non-adherence refers to
failure to follow directions because of an inability on the part of the patient (such as not being
able to remember or from confusion); the differences are subtle and they are used largely
interchangeably in this document. There are many forms of non-compliance and numerous
causes. The medical literature is replete with articles discussing the scope of the issue, what
types of interventions might improve the incidence of compliance, and therapeutic outcomes
studies (which attempt to demonstrate improved outcomes from enhanced compliance - and
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degraded outcomes from non-compliance). Indeed, a search using Google Scholar for
"medication AND (compliance OR adherence)" yields over a half-million records.
A major long-standing problem faced by compliance researchers is how to both define and
measure compliance, which is an extraordinarily complex, multi-faceted problem with numerous
variables. This is thoroughly discussed in Unni (2008) and Unni and Farris (2008).
Note that compliance is sometimes equated with adherence. These are sometimes referred to as
"concordance" in the more recent literature. In reality, there are distinctions among these terms.
They are often loosely used interchangeably.
The behaviors underlying non-compliance can be classified as conscious and unconscious. The
former refers to purposeful deviation from prescribed directions, for any of countless different
reasons. The latter refers to well-intentioned efforts on the part of patients who do not succeed or
are not able for whatever reason. Unconscious noncompliance is unintentional. It can result from
oversights (e.g., forgetfulness or disruption of routines, such as traveling) and from insufficient
attention (e.g., taking the wrong dose by mistake).
Worth noting is that non-compliance includes both under-adherence and over-adherence (better
described as oversupply). But the rate of under-adherence is usually considerably larger than that
of oversupply, as shown in a study of VA patients taking psychiatric medications (Yang et al.
2007).
Non-compliance has proved extraordinarily refractory to simple solutions after many decades of
efforts by the medical communities. One reason is that the causes of non-compliance may vary
greatly from drug to drug. Given the vast spectrum of causes of non-compliance, and since these
can vary widely among drugs, only general conclusions are possible. To have more utility in
actual practice, it is probably more productive to study non-compliance and its effect on drug
wastage as a function of particular categories of medications. Specific recommendations
regarding expensive antiretrovirals are one example (Ostrop and Gill 2000).
While drug abuse is clearly a major threat to the public and healthcare alike, non-compliance and
poor adherence to medication regimens have been called "America's other drug problem"
(NCPIE 2007). The problem is worldwide, and persists regardless of socioeconomics. Even in
developing countries where drugs are scarce and expensive (e.g., Papua New Guinea), non-
compliance is rampant (Kiyingi and Lauwo 1993).
Compliance is an enormously important problem in medical care - one with extraordinarily large
direct and indirect costs associated with excess morbidity and mortality. The critical importance
of better understanding and addressing the numerous aspects of non-compliance are emphasized
by Rosenow (2005), who has referred to it as the "sixth vital sign."
Sorensen et al. (2005) present a rather detailed analysis of the compliance factors associated with
poor health outcomes. They found that the number of medications present in a home serves to
reflect poor healthcare outcomes more reliably that the number of medications a patient is aware
of taking. The greater the differential, the worse the outcomes. Large differentials reflect a higher
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incidence of polypharmacy and non-compliance; large differentials indicate hoarding, poor
storage practices, and forgetting that the drugs were even present. Others have also noted that
poor storage strategies and accumulated medications are strongly correlated with adverse
healthcare outcomes for those for whom the medications had been originally prescribed.
Non-compliance is frequently singled out as a major cause of wasted drugs. Non-compliance is
also widely recognized as a major problem in healthcare, with its purported adverse impacts on
achieving desired therapeutic outcomes. The cited frequencies of occurrence for non-compliance
vary widely, but 50% is often asserted. But no one really knows the extent of unused drug
accumulation, because of the paucity of data and the unknowns regarding generalizing across
geographic locales.
The estimated portions of dispensed drugs that go unused vary immensely. In reality, there are
few good data to support any reliable number. One study representative of the type of data
collected is Bronder and Klimpel (2001). Equally unknown are the relative contributions from
OTC versus prescription drugs (Garey et al. 2004; Isacson and Olofsson 1999). The consensus
seems to be emerging, however, that the proportion of unused prescribed medications is
increasing - at least in Britain (Langley et al. 2005).
Non-compliance and the problems it causes in health care and in the generation of leftover drugs
is also frequently misrepresented. Data are often ambiguous or contradictory with respect to
achieving therapeutic outcomes, and non-compliance does not always lead to leftover drugs -
sometimes it actually prevents them.
A major assumption in the drug disposal debate has been that patient compliance (or adherence)
is a primary driver for whether dispensed drugs are fully consumed as directed. A logical
conclusion from this is that by improving compliance, fewer drugs will remain unused. A focus
therefore tends to end up on ways in which compliance can be improved - and the ways are
myriad indeed, as patient compliance is a topic that has received immense attention in the
medical literature for decades (e.g., see: Gellad et al. 2009). But it is not that simple.
In reality, non-compliance cuts both ways with respect to the generation of leftover drugs. The
common manifestations of non-compliance can have opposing effects on the types and quantities
of drugs that remain unused, eventually needing disposal. Only a portion of non-compliant
behavior involves failure to take medication. A sizeable portion deals with failure to procure
medication that has been prescribed. Another portion deals with taking more medication than
intended by the prescriber. Both of these behaviors result in fewer leftover medications. Some
aspects reduce the problem and some exacerbate the problem. This is readily evident from some
of the major findings of a survey by the National Council on Patient Information and Education
{, 2007 #22097}. While almost half of those polled said they had forgotten to take a prescribed
medicine (and nearly a third prematurely ceased treatment and a quarter used less than the
recommended dosage), nearly a third failed to fill prescriptions they had been provided. In
another study, over 20% of prescriptions languished unfilled by the patients (lesson et al. 2005).
There are four common manifestations of non-compliance, leading to two different outcomes
regarding the generation of leftovers:
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(1) forget to take a prescribed and dispensed medication as directed (promotes leftovers).
(2) fail to fill a prescription (immediately results in fewer leftovers, but in the longer
term, can result in the need to take more medications than originally required).
(3) take less than the recommended dosage (splitting pills or conserving doses results in
leftovers and promotes hoarding).
(4) substituting OTC medication in place of filling a prescription (may result in purchase
of greater quantities of medications than needed, although the APIs will probably
differ).
Premature discontinuation of medications by patients is common and can occur with very high
frequencies depending on the class of drug. High rates of premature cessation are frequently seen
with antipsychotics, antidepressants, anti-asthmatics, and other drugs prescribed for long-term,
continual usage (such as statins). Rates of discontinuation can exceed 70%. Note, however, that
studies involving patient persistence and discontinuation often cite data that reflects failure to fill
or re-fill a prescription, rather than failure to complete a prescription already dispensed. So
overall compliance rates do not necessarily translate as a direct measure of leftover medications.
When examining compliance rates in the literature with regard to their possible impact on the
accumulation of leftover drugs, it is therefore necessary to know the type of non-compliance
under discussion.
Behaviors preventing the filling of prescriptions at least initially serve to prevent the
accumulation of unused medications - until, that is, this type of failure to comply might lead to
degraded health and the need for yet more medical intervention. But beyond this, a certain (but
unknown) portion of dispensed medication should ultimately not be consumed by the patient, as
compliance in these cases could lead to adverse outcomes. This includes medication that was
dispensed in error (pharmacy error), medication that was prescribed in error or imprudently (e.g.,
physician judgment), and medication for which the patient is intolerant (e.g., adverse reactions).
A certain portion of leftover drugs needing disposal therefore reflects the patient's conscious or
subconscious attempt to avoid adverse health outcomes; this is referred to later as proactive non-
compliance.
Further complicating the compliance-leftover drug connection are clinical and epidemiological
studies that show the extreme difficulty in drawing strong connections between improved
compliance and enhancement in the intended therapeutic outcomes. After all, the ultimate
objective in therapy is not perfect patient compliance, but rather the therapeutic outcome sought
by the physician and patient - is the intended objective of the medication ever achieved? So a
focus solely on blindly improving compliance to lessen the incidence of unused drugs is not
necessarily always in the best interest of the patient.
The "healthy-adherer" or "healthy-user" effect. Two types of scenarios loom large in
the arguments surrounding measures designed to improve compliance for reducing leftover
drugs. First, a host of studies over the years demonstrates an absence of improved, intended
outcomes with fully compliant patients - where the medication simply did not achieve its
intended effect. Second, a very significant confounding effect can complicate the interpretation
of compliance-outcomes studies - known as the "healthy-adherer" or "heal thy-user" effect (a
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form of self-selecting bias). The healthy adherer effect is when adherence is simply a
manifestation or reflection of overall healthy behavior - adherent behavior and health-seeking
behaviors are directly linked. Healthy adherers might not actually be benefitting from certain
medications even when it appears they are. Those with healthy lifestyles have inherent behaviors
that necessarily lead to better compliance with prescribed treatment regimens, including
medication adherence; a simple example is seemingly improved outcomes from adherence to
preventive medications, but which instead may simply reflect existing healthy behaviors such as
regular exercise. There have been numerous studies regarding the healthy adherer effect (e.g.,
Dormuth et al. 2009; Simpson et al. 2006), which was first noted from the data of the Coronary
Drug Project (conducted between 1966 and 1975). Studies on the healthy adherer effect have
shown that even adherence in placebo control groups can be associated with better outcomes
compared with others who are non-adherent to active treatment. In some studies, adherence to
either medication or placebo can be associated with improved outcomes.
The second deals with a portion of what first might seem like "non-compliance" but which
actually results from the patient realizing that the medication is not achieving its intended
outcome. This type of behavior does not have a formal name, but for the discussion here, it will
be referred to as "proactive" non-compliance - that is, purposeful non-compliance aimed at
avoiding a negative outcome. This contrasts with non-compliance in the conventional sense - that
is, non-compliance associated with negative outcomes. A patient might display proactive non-
compliance, for example, to avoid the continuation of adverse effects or because the expected
therapeutic outcomes fail to emerge.
These two groups of non-compliance clearly have ramifications relevant to the entry of APIs to
the environment. The first (healthy-adherers) deals with unnecessary full compliance (consuming
drugs that serve no purpose), and the second deals with necessary non-compliance (avoiding
drugs that do not serve positive outcomes). Healthy-adherer compliance unnecessarily adds to
the loadings of APIs via excretion. Proactive non-compliance unnecessarily adds to the
accumulation of leftover drugs. For both of these groups, any actions designed to reveal which
medications could be avoided by either group will reduce excretion of APIs or the generation of
leftovers. These actions must ultimately come from the prescriber.
These two groups of patients also show that measures to blindly improve patient compliance in
order to reduce the incidence of leftover drugs may be seriously misguided as they might
jeopardize the patient's health or at the least allow the continued consumption of unnecessary
medications. Indeed, studies focused on interventions to improve adherence infrequently
improve outcomes (e.g., see: Kripalani et al. 2007).
It is completely unknown what portion of leftover drugs result from proactive non-compliance.
But proactive non-compliance is known to result from a number of factors, many of which
originate with the prescriber. Effort could be devoted to minimizing the prescribing of
medications in those situations for which they are ineffective or imprudent. Evidence-based (or
"rational") prescribing is an ultimate goal, especially when coupled with the practice of
personalized medicine, which can maximize the probability of achieving intended therapeutic
outcomes (Daughton and Ruhoy 2008a). These aspects of the non-compliance issue place
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responsibility not on the patient, but instead on the pharmaceutical industry, physicians,
pharmacists, and insurers of health care.
Documenting an emerging understanding in the healthcare community regarding the complexity
of drug wastage and the drug life cycle, the Centers for Medicare & Medicaid Services (CMS) is
beginning to recognize the interconnections between imprudent or over prescribing, non-
compliance, drug leftovers, diversion, poisonings, and environmental impact (Moseley 2010);
see page 83, section "Encouragement of Sponsor Practices to Curb Waste of Unused Drugs
Dispensed in the Retail Setting":
"Current physician prescribing patterns and pharmacy benefit management payment practices result in most
prescriptions being dispensed in 30 or 90 day quantities. Whenever the full amount dispensed is not utilized
by the patient due to death, adverse reactions, medication substitution, or other reason for discontinuation,
the remaining unused medication becomes waste. It also becomes an environmental hazard when disposed
of, and is sometimes a safety hazard in the home or diverted to illegal use."
Some of the many causes of (and means of controlling) non-compliance. Like most
aspects of the leftover drug issue, patient non-compliance can play complex and unpredictable
roles. For example, if proactive non-compliance could be identified more quickly and actions
taken to reduce it, the course of action might just involve changes in the types of medications
prescribed rather than eliminating them.
In light of these insights regarding the possible relevance of non-compliant (or even fully
compliant) behavior to the accumulation of leftover drugs, the remainder of this section on non-
compliance will touch upon some of the many broad issues that may play important roles. But
the published literature on this topic is immense, and the interested reader is encouraged to
further examine it on their own; the DDS database is an easy place to start.
The published literature on the causes of (and possible solutions to) non-compliance is immense
and cannot be covered in its whole even in lengthy review articles or books. There are two
primary focuses of the published literature - the effects of non-compliance on healthcare
outcomes (e.g., therapeutic endpoints) and the monetary value of wasted drugs. There are also
associated concerns regarding the loss of resources that could have otherwise been put to better
use (e.g., wasted time in prescribing and dispensing). Although these have proved to be the
greatest motivators for better understanding the causes and solutions for non-compliant behavior,
the focus here is on how non-compliance leads to the generation of leftover drugs. Only a portion
of this topic can be summarized here.
Some of the notable contributions discuss how to identify and measure compliance, the causes of
non-compliance, and potential approaches for its improvement (Coambs et al. 1995; Fincham
1995; Fincham 2007; Gellad et al. 2009; Kleinsinger 2010; Kripalani et al. 2007; Kusserow
1990a; Nathan et al. 1999; NCPIE 2002; 2007; Osterberg and Blaschke 2005; Perri -Year
Unknown; Pound et al. 2005; Rosenow 2005; Taylor 1978; Vermeire et al. 2001; WHO 2003).
Also discussed will be some of the many ways to possibly reduce the incidence of leftovers by
lessening the pressure on patients to enlist protective, proactive non-compliant behaviors.
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Of the numerous causes of non-compliance, a core group tends to have been the primary focus
for decades. Other causes, however, are infrequently mentioned but probably play important
roles. One of many examples derives from impatience and the desire for instant gratification. For
drugs that require weeks-long regimens before outcomes become evident, this group of patients
often stops taking their medications after a short initial period of frustration. As one example, a
drug class that experiences this behavior is acne medications for teens (Van Dusen 2008).
One of the only works to ever attempt synthesizing the voluminous information published on
compliance is Pound et al. (2005). The authors note that over 200 factors have been assessed
since the 1980s as causes of non-compliance. Their own study, however, concludes that the
major reason for non-compliance is the patient's concerns regarding the medication itself- not
because of any specific failing on the part of the patient or physician.
The comprehensive work of Mackridge (2005) covers a variety of causes for non-compliance.
Several illustrate the difficulty in countering: (i) a basic dislike by the patient for using drugs, (ii)
fear of becoming addicted to non-addictive drugs or of the possibility of long-term adverse
effects, (iii) patient's distrust of doctors, believing that the prescribed drug is unnecessary, and
(iv) patient's belief that the mere act of taking a drug verifies that the patient is indeed ill.
Cost is another little-discussed factor driving non-compliance. It has three manifestations: (i)
failure to fill scripts because of high cost, (ii) desire to conserve medications for future use by
hoarding, skipping doses, or splitting doses, and (iii) the sheer cost of the dispensed medication
prevents the consumer from parting with leftover drugs - even when they no longer have any
utility (Kennedy and Erb 2002).
Mackridge (2005) presents scenarios of drug non-use that are counter-intuitive. One involves
whether the patient shares in the cost of prescribed medications versus whether the medications
are provided at no cost (fully covered by healthcare providers). The former might be expected to
purchase fewer medications or to purchase only what they intend to consume. But the data
indicate that the former group might better appreciate the value of drugs and therefore refrain
from fully consuming them - hoarding them for possible future use. This is essentially non-
compliant behavior motivated by economic concerns. Patients who both overvalue or undervalue
medications are prone to having leftovers.
With regard to its impact on accumulation of leftover drugs, a particularly insidious form of non-
compliance involves patients with repeat prescriptions who persist in reordering solely to hide
their non-compliance from their physicians. This problem is further exacerbated with the use of
auto-refills by mail-order pharmacies. Some even fill prescriptions knowing that they have no
intention of ever using them (often because the prescription is free or of nominal cost) (Braund et
al. 2009b).
That patients have prescriptions filled but never use them was noted in a letter from a UK
pharmacist nearly 20 years ago (Wilson 1991): "Today, I was asked to dispose of a large plastic
bag of assorted tablets following the death of an elderly lady. I quickly realised that, far from
being the remnants of her most recently prescribed medicines, the contents were, in fact, the last
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four or five prescriptions that we had dispensed for her, in their entirety, with virtually no tablets
consumed."
In a study designed to improve compliance with automated dose-dispensing, some users
persisted in creating stockpiles and had no interest whatsoever in giving them up (Larsen and
Haugb011e 2007). Indeed, most drug collection events note the surprising incidence of unused
drugs in their original factory-sealed packaging - sometimes approaching 50% of the total
number of packages returned (Conventry Teaching PCT 2007).
Some take-back programs report that the majority of returned medications are for long-term
maintenance. Polypharmacy, largely driven by the need for concurrent long-term maintenance
medications, is believed to often be a major contributor to non-compliance.
As the number of medications increases for a patient, the compliance goes down - for a wide
array of reasons. A survey conducted for Medco revealed that one in four seniors take between
10 and 19 pills daily (Medco 2009a). That polypharmacy can exacerbate the generation of
leftovers via noncompliance is clearly shown by the increasing rates of non-compliance once a
medication regime consists merely of three medications (Van Dusen 2008).
The very young and the elderly are at the center of the problems surrounding leftover drugs. The
elderly are involved with disproportionate inappropriate drug use (often resulting from confusion
or self-medication) and non-compliance. Both of these problems largely emanate from
polypharmacy and the confusion sown by the need for the patient to track multiple drugs, all
having differing dosage directions and dosing schedules. The incidence of adverse reactions (and
drug-drug interactions) also increases as polypharmacy grows larger for a patient. These factors
all breed more leftover medications. These problems for the elderly all coalesce, leading to large
loses in healthcare resources (wasted drugs) and enormous increases in hospitalization costs (a
result of inappropriate treatments and adverse reactions). Adding to the challenges posed by
polypharmacy are dosing methodologies or delivery devices that are too difficult, too
uncomfortable, or too confusing to administer. Even child-resistant closures can discourage some
(such as those with arthritis) from taking their medications. These are all limitations that are
under control of manufacturers, prescribers, or dispensers.
Some causes of non-compliance can be directly corrected by manufacturers and dispensers. It
involves consumer literacy and label design. While drug names and instructions have long been
recognized as contributors to poisonings (e.g., like-sounding names), the ease with which labels
can be read and understood directly impacts compliance. For example, a common problem in the
misreading of labels is confusion of the dispense date with expiry date, leading to premature
disposal. High rates of error have been noted when prescription container labels are translated to
other languages (Sharif and Tse 2010). Functional and marginal illiteracy reduce the impact of
labels. This is a factor that needs to be considered when developing proposals to guide consumer
disposal via new labeling requirements (Mrvos et al. 1993).
With all of the complexities aside regarding the origins of non-compliance, one aspect is clear.
Noncompliance often persists for any given patient over long periods of time before it is ever
discovered by a healthcare professional. Sometimes it is never discovered. This points directly to
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the key role that physicians could play - not with respect to preventing non-compliance, but
rather with reducing its duration.
Shared decision-making and "brown-bag medication review." Increasing the
visibility and awareness of the consumer/patient as an integral part of the drug life-cycle is a key
objective for more effective drug usage. The linkages between humans and drug waste are
downplayed to such an extent that most consumers are not aware of how the many actions,
activities, and behaviors they engage in during their daily lives directly influence the burden of
drugs in the environment as well as their healthcare expenses and overall health status. For
example, consumers do not fully understand or appreciate the consequences of two major aspects
of their relationships with medications: (i) acquisition of excessive quantities of medications and
(ii) failure to consume these medications in the manner required for achieving the intended
therapeutic outcomes (non-compliance/adherence). Not only do these two work against each
other to maximize the magnitude of leftover drugs later requiring disposal, they often result in
sub-optimal or poor therapeutic outcomes (or even jeopardize health), increase the cost of
healthcare (for multiple reasons), and increase the potential for drug diversion and poisonings.
Healthcare costs are increased not just because of medication waste but also because sub-optimal
therapy often requires additional future medical intervention.
One of the most effective interventions for a physician to improve patient compliance is the so-
called "brown-bag review" (or "medication review") which could at least be conducted
periodically for patients undergoing polypharmacy. The physician asks the patient to bring all of
their medications to a consultation - not just prescription drugs, but also OTC medications. This
serves to also reveal those medications being prescribed by other physicians or those being
unwisely purchased OTC. Preferably, the physician and patient can then work together to discuss
whether any medications are no longer necessary, and adjust dosing and schedules to improve
compliance. The value of this collaborative practice has been recognized for over four decades
(Gunn and Lishman 1967).
The process of "shared decision-making" (SDM) is a facilitated collaboration among patient,
prescriber, and dispenser. Medication reviews are just one possible aspect of SDM. This
arrangement empowers and closely involves the patient in the decisions involved with their own
healthcare. One of the expectations is that a fully involved patient will make decisions regarding
medications that result in more efficient utilization and less wastage. An overview of SDM is
available from Edwards and Elwyn (2009). In their overview, they point out numerous terms
employed over the years in attempts to capture the intentions of SDM; these include: evidence-
based patient choice, informed (shared) decision-making, patient-centered care, concordance,
participation and partnership, informed consent, autonomy, consumer involvement and
consumerism, and expert patient.
SDM especially involves more active communication between the patient and healthcare
providers; one of many examples would be a patient notifying a prescriber regarding any
problems they encounter while taking a medication - instead of continuing with an ineffective
course of treatment or discontinuing one that they should persevere with.
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One form of SDM that has gained particular attention is making a patient's medical records
readily available to the patient. Providing patients easy and ready access to the medical records
maintained by their primary physicians may be one way to foster better adherence to medication
regimes by making patients more aware of what medications they are taking and why they are
taking them. This approach has been piloted as the OpenNotes Project (BIDMC 2009; Delbanco
etal. 2010).
Dispensed quantities - the roles ofstat and PRN. Many of the issues surrounding drug
accumulation and disposal are intimately linked to various aspects of the actual practice of
medical care. A major factor often cited is the quantity prescribed and dispensed. It is therefore
critical to evaluate any guidance or controls developed with the intent of reducing drug wastage
so as not to degrade the quality or cost of medical care. As an example, for certain medications it
might make sense to limit the quantity dispensed for a first prescription. But for long-term
maintenance medications that a patient has been successfully taking, short-term prescriptions
may greatly increase dispensing costs, and worse, perhaps even discourage compliance.
One of the most frequently cited ways of reducing leftovers is by dispensing smaller quantities
and reducing the use of automatic refills. While these might seem at first to be logical targets for
reform, the issue is far more complex and changes to dispensing practices can have unforeseen
consequences. Like many aspects of the leftover drug issue, the impacts of quantity prescribed
and quantity dispensed are extremely complex and a function of a bewildering array of variables,
spanning patient and physician behaviors and cost.
An often cited (suspected) cause of drug wastage is longer-term prescriptions - designed for
patient convenience (reduce trips to pharmacies) but moreover to reduce dispensing costs. Very
surprisingly, however, few studies have ever been done to quantify the effect on wastage of
reducing dispensed quantities (for example, from 90 days to 30 days). Two studies have noted
that indeed larger dispensed quantities cause wastage (Domino et al. 2004; Parikh et al. 2001).
The study of Domino et al. (2004) was a simulation for six different classes of drugs and showed
that reducing quantities from 100 to 34 days could result in wastage reductions ranging from 5 to
14%. However, considerably higher dispensing costs would result, as well as the possibility of
increased costs for the patient - exacerbated by increased transportation costs - and reduced
patient compliance introduced by making refills harder to acquire. This latter issue can have
adverse impacts on therapeutic outcomes.
All aspects of the drug cycle are extremely complex, often convoluted, and have intricate inter-
relationships modulated by marked feedback. This is readily seen just by examining the issues in
one paper associated with prescribing/dispensing (Braund et al. 2009b).
To illustrate the complexity of assessing the costs of larger - versus smaller- quantity dispensing,
consider models developed to estimate the total unnecessary costs (TUC) associated with
different fill quantities (usually 15-30-day vs. 90-day). These models usually account for the: (i)
quantity of drug wasted, (ii) cost of the wasted drug, and (iii) costs associated with dispensing
the prescription (Walton et al. 2001). Important to note, however, is that these models invariably
fail to account for indirect and hidden costs, such as those associated with: (i) disposal of wasted
drugs, (iii) human and animal poisonings, and (iii) environmental impact. The study of Walton et
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al. (2001) found that the TUC for 90-day courses of statins was nearly half that for 30-day. But
as for the absolute quantities wasted, the 90-day supplies wasted 5 times as many daily doses
(5.33 versus 1.06). These data would be expected to vary among other drug classes - as the rates
of physician switching treatment mid-course will differ.
Since drugs often go unused when a patient first begins treatment (as adverse effects cannot be
anticipated), one common approach is the use of evaluation trials using small quantities ("trial
scripts"); this is one of the roles that free samples are supposed to play. One body of evidence,
however, shows that small trial prescriptions would have only a small impact on the
accumulation of leftover drugs, as most leftovers do not result from new prescriptions (Ekedahl
2006).
Much has been written regarding the adverse impact of medications prescribed on a PRN basis
(pro re nata, "as needed", "when needed", or "as the situation arises"). PRN scripts are
particularly prone to result in leftover medications. Common examples are inhalable beta
agonists and corticosteroids; this is also especially true for drugs formulated in dermal lotions
and creams (Daughton and Ruhoy 2009a). These commonly expire before they are fully
consumed. Coupled with "stat" dispensing, the two can greatly increase the chances of leftover
medications.
Stat dispensing (statim, "immediately") usually involves all-at-once 90-day supplies of
medication (Braund et al. 2007). Stat dispensing can be particularly prone to leftovers with first-
time prescriptions since physician changes in treatment are more common during the initial stage
of medication evaluation. This points to the possible key importance of trial scripts. Moreover,
since stat dispensing results in larger quantities of drug present in homes for longer periods of
time (e.g., 3 months instead of 1 month), the opportunities for poisonings (accidental or
deliberate) and diversion or thefts increase.
In New Zealand, stat dispensing has increased the quantities of dispensed medications, especially
those needed for long-term treatment. It has also exacerbated the portion of unused medications
being disposed or hoarded (Braund et al. 2009b).
A report from White (2009a) discusses the many nuances and points of confusion regarding the
data on drug wastage. White maintains that certain new policies for dispensing in Britain are
mis-guided, especially requirements for smaller-quantities. These policies not only do not reduce
wastage, but they cost more and jeopardize patient health. White (2010) maintains that pharmacy
dispensing charges for repeat prescriptions of less-expensive generic maintenance drugs can
exceed the cost of the medications themselves. White (2010) also maintains that as lower-cost
generics become more frequently prescribed, the increased dispensing costs for shorter-term (1-
month) repeats has the potential to eventually outweigh the estimated cost of medicines wastage
in the UK. White (2009b) expresses further concern regarding one-size-fits-all policies on fill
quantities, maintaining that life-long therapies have low costs associated with physician
switching of prescriptions, especially for those therapies with no alternatives.
Concern over the vastly increased cost of dispensing shorter-duration scripts is certainly central
to the debate. This has been documented in a number of studies over the years - all showing how
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90-day supplies were much more cost effective - even after taking into consideration the cost of
the wasted medications (but clearly not factoring in the unknowns regarding added disposal costs
and impacts on the environment) (Brady 2005). This was one also of the many points raised in a
joint letter from the American Society of Consultant Pharmacists regarding America's Healthy
Future Act (ASCP 2009b).
Important to note, however, is that a focus solely on dispensing costs fails to consider the entire
life cycle of a drug. It discounts the unknown costs associated with potential environmental
impact. The lowering of per-prescription dispensing costs (such as by encouraging 3-month
supplies), may lead to increased total cost per quantity consumed (as a result of leftover
medications) and increased environmental loadings of APIs from discarded medications. Narrow
assessments targeted at reducing costs at isolated, discrete points in the healthcare system often
only result in shifting (or even increasing) the cost associated with other, perhaps distantly
connected, points in the system.
On the other side of the debate, numerous studies have determined that smaller dispensed
quantities can reduce leftovers. A study of leftover antimicrobials (many of which had been
purposefully stockpiled for possible future self-medication) in the UK found that if the standard
duration of treatment could be shortened and package size reduced to contain enough drug for 3
to 5 days, the temptation to stockpile might be diminished (McNulty et al. 2006). The study
found that prescriptions for quantities exceeding 6 days composed 61% of leftover drugs,
whereas prescriptions for quantities less than 3 days composed only 6%.
There are significant obstacles to wholesale switches from 90- to 30-day supplies. The major
problems are covered by Parikh et al. (2001). The major concerns are not just dispensing costs
but perhaps more importantly gaps in therapy should the 30-day course run out before the next
30-day course is dispensed. The authors showed that 30-day refills cost nearly 3 times as much
as 90-day, once all factors are considered - e.g., costs associated with dispensing and mailing,
even after the savings for wastage were considered.
Some maintain that both under-prescribing and over-prescribing can lead to increased needs for
future treatment - with an attendant need for yet more medication and additional costs (Stroupe
et al. 2004).
Mail-order stat dispensing is frequently cited as a primary origin for wastage. The relative costs
and resulting wastage from mail order is very difficult to assess. Conflicting data have been
reported, but the focus is generally on the impact of 90-day courses on generation of leftovers
(Coster 2010; Halberg et al. 2000). But there are also other, little understood factors (specific to
mail-order pharmacy), that may also lead to wastage. These include: lost, diverted, or damaged
mail shipments, accelerated expiration caused by adverse conditions encountered by mail (e.g.,
excessively high temperatures or humidity), and failure of the patient to pick up a shipment.
To encourage the use of trial scripts ("start-up packs"), Sweden requires the same price per dose
dispensed, regardless of the quantity (Landstinget Vastland 2004). Trial-dispensing programs
have been in effect in Canada for some time. The dollar value of leftovers dispensed in 90-day
courses was found to vary among the individual medications. Changes to dispensing should first
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be targeted at those medications used in the largest quantities, those that cost the most, and those
known to result in wastage (Paterson and Anderson 2002). The CMS has been discussing the use
of trial supplies in Medicare (The Pink Sheet 2010).
Although it might prove unwise in many cases to switch from 90- to 30-day courses, a better
approach might be to begin treatment with the shortest trial course, followed by 30-day courses
until efficacy is established, before finally settling on 90-day courses.
Another possible approach to minimize wastage is the use of "installment dispensing" (a
variation on refills), which allows repeated dispensing of small portions of the total quantity
prescribed over a set time period (Millar et al. 2003; Millar et al. 2009).
If any conclusion can be made regarding dispensed quantities, it can only be safely surmised that
a number of factors must be considered with regard to each patient, the type of treatment, and the
medication being employed. Across-the-board restrictions on quantities dispensed (in either
direction) can have adverse consequences for therapeutic outcomes, patient health, and
associated costs. Guidelines for shorter courses of medications would have to be tailored for
specific drugs or classes. As one example, the State of Maine implemented a 15-day limitation of
initial prescriptions for certain medications that they deemed subject to frequent switches
(opiates and second-generation antipsychotics and second-generation anti-depressants) (Cook
2009; Department of Health and Human Services 2009).
Asynchronous repeat prescribing (misalignment) and inequivalence. A specific,
little-recognized aspect of dispensing may have the most impact with regard to leftovers. The
term "asynchronous repeat prescribing" refers to a "misalignment" between repeat prescription
intervals for two or more medications; that is, two or more long-term medications are prescribed
for different repeating intervals, so they often get out of sync. While this can occur when a
patient is under the treatment of multiple physicians, it can also occur with a single physician. It
can be particularly problematic when all of the drugs are prescribed for the same condition. A
major outcome from this can be the accumulation of an excess remainder for one or more of the
medications when the shortest-interval medication needs to be reordered. Another outcome can
be increased non-compliance (resulting from patient confusion), amplifying the rate of leftover
accumulation. Asynchronous repeat prescribing has been infrequently discussed in the literature
(Clews et al. 2001; Conventry Teaching PCT 2007; Dowell and Ellis-Martin -Year Unknown).
Physicians sometimes purposefully employ asynchronous repeat prescribing when the patient
wants to avoid multiple trips to a pharmacy. When one order needs to be refilled, they then wish
to refill all. Note that this is no longer possible with pharmacies using databases that alert them to
attempted early refills; but the pharmacist can decide to defer to the patient's desire for
convenience and fill the premature prescription anyway. The Conventry report (Conventry
Teaching PCT 2007) found that asynchronous prescriptions were a major cause of drug wastage.
When patients had linked asynchronous repeat prescriptions, and when one ran out, they often
ordered refills of the others as well, even when substantial quantities still remained.
Another related aspect of linked prescriptions is "inequivalence," where the different medications
come pre-packaged in different quantities (Dowell and Ellis-Martin -Year Unknown).
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Asynchronous repeat prescribing (sometimes exacerbated by inequivalence) can result in non-
adherence caused by missed doses as a result of having medications running out at different
times. When this occurs with long-term medications, the patient often changes their refill
behavior - hoarding to prevent a possible recurrence.
In the final analysis, the major factor that encourages patient stockpiling is
prescribing/dispensing policies that make it more difficult or inconvenient (or too easy) to get a
prescription filled. Both can lead to stockpiling - but for different reasons.
Role of the prescriber and rational prescribing. The actions, activities, and behaviors
behind the generation of leftover medications do not all originate with patients. Often forgotten
is that prescribers also play significant roles (Doran and Henry 2003). Even a portion of patient
non-compliance originates from physician behavior and prescribing practices. The role of the
physician in drug accumulation derives from the prescribing of medications that are unnecessary
or imprudent. "Presumptive prescribing" plays an important role. The impacts from prescribing
when not clinically indicated span the spectrum from simple overuse of drugs to adverse
reactions or poor therapeutic outcomes.
Given the essential difference between prescription-only and OTC drugs (i.e., whether self-
administration is safe) (USFDA 2009a), an important irony results from the way in which
prescription-only medications are actually prescribed. Lack of attention by the prescriber
regarding the effectiveness or appropriateness of medications prescribed, or the prescribing of
excessive quantities, increase the likelihood for the accumulation of unused, leftover drugs.
Leftovers, in turn, are often used by others for self-medication. In the final analysis, by not
applying sufficient oversight over the practice of prescribing, prescription-only medications are
essentially transformed into OTC medications.
There are many reasons that physicians overlook or ignore the best practices as delineated by
clinically indicated prescribing. Some reasons provided by Bellingham (2001) for presumptive
prescribing include: (i) responding to the unfounded demands or expectations of patients, (ii)
giving the patient unfounded expectations regarding diagnosis, treatment, or prognosis, (iii) an
event indicating a clear conclusion to a consultation. Within each of these lie a number of other
more specific reasons. But a major additional reason is insufficient or incorrect knowledge on the
part of the physician.
A reason often mentioned for issuing a prescription is simply because the physician believes the
patient is expecting one (and this belief is often unfounded) (Cockburn and Pit 1997). Patient
expectations and whether a prescription is written has been a point of debate for quite some time
(Britten and Ukoumunne 1997). Studies such as this reveal that a large portion of prescribing can
later be deemed "not strictly indicated on purely medical grounds."
Patients' expectations can be inflated by promotional practices such as DTC advertising. If the
inflated expectations are unmet, early cessation of the medication occurs - another cause of non-
compliance.
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In the final analysis, non-clinically indicated, presumptive prescribing is a tremendously difficult
and complex problem to assess. "Rational prescribing" has been a major, long-discussed goal
sought by clinical medicine, with discussions in the published literature dating back to the 1970s
(Taylor 1978).
Organizations promoting evidence-based medicine such as the Cochrane Collaboration attempt
to document the efficacy of drugs for intended and off-label treatments, with the intent of
facilitating rational prescribing (Daughton and Ruhoy 2008a). An overview of evidence-based
prescribing is given by Tamblyn (2002).
The concept of adherence/compliance is sometimes replaced by the more current notion of
"concordance," which entails communication and collaboration between the patient and
prescriber.
The basic questions long faced in prescribing have been whether a medication is necessary,
effective, and safe. Only more recently has a new driver emerged - cost. To these can be added
questions regarding the potential for environmental impact. This has been the objective of an
effort pioneered in Sweden that provides the prescriber additional information regarding
environmental properties, such as potential for bioaccumulation, persistence, and environmental
toxicity (Wennmalm and Gunnarsson 2010).
Cockburn and Pit (1997), however, note the difficulties that would be encountered in
establishing objective measures defining the "medical necessity" for a medication. The authors'
study concluded that physicians prescribe more than patients expect (poor assessment by the
prescriber of the patient's expectations). When patients expected prescriptions, they were three
times more likely to gain prescriptions for new conditions. In contrast, when the physicians
assumed that the patient was expecting a prescription, the patient was 10 times more likely to be
issued a prescription: "Although patients brought expectations to the consultation regarding
medication, it was the doctors' opinions about patients' expectations that were the strongest
determinants of prescribing."
In 2007, the National Audit Office (NAO, London) produced a report aimed at reducing
prescribing costs (NAO 2007). Portions of the report, however, are directly relevant to reducing
the overall usage of medications. The report recommends a number of alterations to prescribing
practices and ways to minimize drug wastage. The NAO notes, for example, that UK general
practitioners generally do not receive formal training in clinical pharmacology and prescribing,
despite the fact that the majority of their consultations result in a prescription. Clearly, questions
are appropriate as to whether the most prudent decisions are being made with respect to
whether apharmacologic intervention is warranted and then, whether the correct API is
selected. Benchmarking of an individual prescriber's habits and behaviors against those of the
profession as a whole was one recommended practice. This can be done with the use of
Morbidity Matrices, which graph prescribing volume versus prevalence of disease. These graphs
readily reveal where over-prescribing is resulting in excessive morbidity. An earlier report by the
HHS OIG also placed emphasis on suboptimal decisions made by physicians when prescribing
(Kusserow 1989).
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Rational prescribing is probably not an end but rather a journey of continual improvement. One
of the ways to acquire better knowledge to improve prescribing practices would be to examine
the medications that go unused. Many have advocated the key data that could be mined from
detailed inventories of medications collected in take-backs. Oxley proposed that these data could
at least serve to deter over-prescribing (Oxley 1996).
Costs of non-compliance (and hospital wastage). Historically, the measurement of
leftover drugs has been accomplished by taking inventories within homes, hospitals, or collection
events. One of the motivations for this work has been to determine the economic losses
associated with wasted drugs. The objectives are often to provide the public with a more
meaningful assessment of wasted healthcare resources and to spur more efficient use (such as
changes in dispensing practices).
Many studies have examined the cost of wasted medications. In general, they arrive at the same
conclusion - that the economic losses are substantial. The DDS database has more than 50 papers
with a focus on economic losses. Only a few are mentioned here.
The monetary value of wasted drugs has been estimated for a variety of countries, including
Canada, Iceland, New Zealand, Saudi Arabia, Spain, Sweden, UK, and US, among many others
(Abou-Auda 2003; Asberg 2004; Boivin 1997; Brady 2005; Craig et al. 2001; Grainger-
Rousseau et al. 1999; Hawksworth et al. 1996; Orero et al. 1997; Sigurjonsson 2009).
Studies of drug wastage in both hospitals and homes extend back to the 1970s (Hart and
Marshall 1976; Leach and White 1978).
Perhaps the first major report that examined the costs surrounding waste created by non-
compliance was published by Coambs et al. (1995).
While the economic values can be staggering, even these estimates are usually based on the
value of medications returned during collection events or on-site inventories. These estimates are
therefore probably gross underestimates of the true wastage.
Many cost analysis studies have focused on wastage emanating from specific niche uses of
drugs, especially in hospitals. Some of these studies have targeted drug wastage in oncology and
surgery (Esaki and Macario 2009; Fasola et al. 2008). Avoidable drug wastage from anesthesia
represented 26% of one hospital's entire anesthesia budget (Gillerman and Browning 2000).
Incompletely used anesthesia drugs (e.g., in syringes) and unadministered anesthesia drugs can
constitute over a quarter of a hospital's anesthesia drug budget (Weinger 2001). Over 30 drugs
were found to be used during the study, which made a detailed inventory of 166 weekday
surgeries. Those most frequently unadministered were atropine, phenylephrine, ephedrine,
vecuronium, and succinylcholine. Others have also published examinations of drug wastage in
hospitals (Mankes year unknown [ca 2008-2010]; Nava-Ocampo et al. 2004; Nessa et al. 2001;
Tornquist 2005).
Of all the studies that attempt to calculate the costs associated with leftover drugs, none has yet
to attempt a comprehensive Life Cycle Sustainability Analysis (LCSA) (Guinee et al. 2010). A
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comprehensive understanding of the costs associated with leftover medications cannot be
obtained by limiting the assessment solely to the retail value of the leftovers. A meaningful
assessment can only be obtained by factoring other costs, including: (i) medical costs associated
with incomplete treatment (resulting from patient non-compliance), (ii) disposal costs (including
transport and landfill/incineration costs), (iii) costs associated with diversion (including theft)
and counterfeiting (e.g., illegal repackaging of diverted drugs), (iv) unintended and purposeful
poisonings (human and animal), and (v) environmental impact (e.g., landfill leachate,
incineration emissions).
Technology, personalized medicine, and other approaches for improving
compliance. Given the perceived importance of non-compliance to healthcare, much effort has
been devoted to determine best approaches for improving patient compliance. One of the best
ways has proven to be so-called "brown bag reviews" ("medication reviews" or "retrospective
drug utilization review"; called "medication use reviews" or MURs in the UK), where the
physician encourages the patient to bring all of their medications to an appointment, including
OTC drugs (Kusserow 1990b). Although discussed as early as the 1960s (Gunn and Lishman
1967), brown bag reviews first attracted interest in the early 1980s. They have been insufficiently
utilized, however, not just by physicians, but also by pharmacists and nurses. While the intent of
this process is to improve therapeutic outcomes (and prevent adverse effects, such as from drug-
drug interactions), it can be facilitated in such a way that medications are more efficiently used
(e.g., eliminating improper or inappropriate medications or those that interact, or uncovering
medications having poor compliance). Better outcomes often result in higher patient compliance
and therefore fewer leftover medications. In a study of 205 patients, review of their medication
stocks and consequent interventions resulted in identifying the potential for serious adverse
effects in 12%, and opportunities for improving therapeutic outcomes existed for 34% (Nathan et
al. 1999). Nathan et al. (1999) also present a significant number of ideas for improving
compliance.
Despite the proven usefulness of medication reviews, they are resource-intensive. This has
opened the door to technology-based solutions for improving compliance. Approaches span the
gamut of modifying behavior to facilitating the tracking of behavior by healthcare providers.
A wide assortment of low-tech and electronic approaches currently attempt to improve
compliance. Over 160 existing devices have been identified - and many more have been
patented or are under development. An overview is provided by Ukens (2005). Some of the more
advanced current approaches incorporate technology into the drug itself for both reminding
patients and for tracking usage, as discussed by Landau (2010).
Quite a number of companies are tackling non-compliance with redesign of various facets of the
drug life cycle ranging from improved packaging to better use of electronic health care records
(EHRs). Basta (2010) presents a current summary of some of the major efforts underway with
EHRs.
One example of the many innovative approaches is the recent advancement in "printable pills"
(Canavan 2010; University of Leeds 2010). This advancement is being driven largely by the
expanding array of highly potent APIs (HPAPIs), where the dose is in the microgram range.
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Such low quantities make formulation of a reliable dose impossible using conventional tablet-
formulation technology intended for minimum doses in the milligram range. By solubilizing or
suspending the HP API in solution and applying it to the outside of the pill form using inkjet
printing technology, the correct dosage can then be easily handled by the consumer. But
printable pills offer other advantages, and some are relevant to patient compliance. For example,
theoretically, printable doses could allow the creation of custom combination pills (multiple
APIs, each at specific doses). This would permit the patient to take just one pill as opposed to
multiple pills, a particularly valuable advance for improving compliance with polypharmacy.
Another way to improve compliance is development of long-acting formulations that require
much less frequent dosing. This would be particularly useful for antipsychotics, a drug class that
tends to appear frequently in unused drug collections (Velligan et al. 2003).
Regardless of the anticipated effectiveness of any technological approach for improving
compliance, it may be impaired simply because of the vagaries of human behavior. As an
example, consider a Danish survey regarding an automated dose-dispensing system, designed to
minimize confusion caused by the complex dosing regimens often encountered in polypharmacy.
On its own, the dispenser proved of no utility. It needed to be coupled with active involvement
by healthcare providers (concordance) to ensure the patient understood the objectives and
required commitments (Larsen and Haugb011e 2007).
Perhaps the most ambitious approach for improving compliance, but also one with the largest
potential for success, is the application of pharmacogenomics and implementation of
personalized medicine. An overview of this topic is provided in Daughton and Ruhoy (2010) and
references cited therein. Even direct-to-consumer (DTC) genetic testing has begun to emerge in
the last few years (Daughton and Ruhoy 2010; Evans et al. 2010). But DTC genetic testing has
generated substantial controversy, especially with regard to quality control and interpretation of
results (Erickson 2010a; Evans et al. 2010). The Human Genetics Commission (UK
Government's advisory body on new developments in human genetics) has taken a proactive role
and developed a framework to better ensure development of reliable and useful DTC genetics
tests (HGC 2010). With over 1,600 genetic tests available for clinical use, the National Institutes
of Health is planning to create a national registry (the Genetic Testing Registry: GTR) to catalog
test data and applicability from test developers (NIH 2010).
Primary objectives of personalized medicine are to actively avoid the use of medications for
individuals with a contraindicated predisposition (reduce adverse events and improve tolerance)
and to facilitate earlier diagnosis and treatment (permitting less sustained pharmacologic
interventions). One of the major attributes of personalized medicine with respect to vastly
improving compliance would be removal of much of the uncertainty that currently exists in
initiating (or maintaining) a medication regimen. With possession of knowledge in advance of
beginning drug therapy that the potential for adverse events would be minimized and that the
likelihood of therapeutic success would be maximized, patients would probably adhere to dosing
regimens much more fastidiously. Increased trust or certainty by the patient in the efficacy of
drugs would improve compliance. An empowered patient will be much more compliant since
they will have more control over the outcomes from their own therapy. The connections between
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personalized medicine and improved patient compliance have been pointed out by Castensson
(2008), Daughton and Ruhoy (2009b), and SACGHS (2008).
The introduction of new technology also has the potential to worsen non-compliance. One
example is the use of automated dispensing machines for public use (Lever 2010). Vending
machines for dispensing repeat prescriptions directly to consumers are being evaluated in
Britain. Dispensing without the interaction of a pharmacist, however, was found to increase the
chances that a patient will misunderstand dosing directions and the chances of dispensing errors
not being caught.
Redesigns targeted at any of the processes or features of the existing life cycle of medications, as
well as the implementation of new technology never before used, or creation of new drug
formulation or delivery devices can all make major contributions toward improved compliance
and reduced leftovers. These advancements, however, must be done by incorporating principles
of sustainability and green design. This wide spectrum of approaches have been discussed
(Daughton 2003 a; Daughton and Ruhoy 2009b; 2010).
Leftover drugs as contributors to human poisonings
The potential for poisonings from improperly discarded medications has long been known. One
case study was published over 50 years ago (Jacobziner and Raybin 1959): "This child was
playing out-of-doors with another child. They found many medicine bottles with different
colored pills in them in the public garbage bin on the grounds of the housing project in which
they lived. Thinking the pills were candies, the child swallowed several of the different pills
from the various bottles. ...This accident certainly could have been prevented if more caution
were exercised in discarding unused drugs."
Human poisonings resulting from stored medications is a concern in numerous countries, as
reflected by the international breadth of the literature. The DDS database contains over 130
studies regarding poisoning, from countries worldwide.
The potential for drug poisoning (excluding suicide) can involve a number of different scenarios,
many of which involve death or gross morbidity. Three primary scenarios are:
(1) accidental poisonings - such as infants and toddlers coming into contact with new and used
medications (primarily ingestion or dermal contact);
(2) unintended poisonings - purposeful ingestion without prior knowledge for potential effects
(e.g., diversion by teens); an important factor in unintended poisoning but rarely discussed is
medications that hold little hazard for the intended patient but which pose great hazard for
those not intended for the drug; certain at-risk sub-populations cannot be exposed to certain
drugs (examples are drugs under restricted distribution programs, such as isotretinoin and
thalidomide);
(3) therapeutic misuse (inadvertent poisoning) - such as the those who might be confused by
drug names or those involved with polypharmacy regimes; these commonly involve the
elderly.
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Two age groups account for nearly all unintended poisonings by medications - the young (under
5) and the older (over 65). While the risk factor for the former is inquisitiveness, the factor for
the latter is forgetfulness - leading to over-medication or dosing with the wrong medication
(medication errors). The older age group is also a factor in exacerbating poisoning for the
younger because of the higher frequency with which medications get misplaced (forgotten),
dropped, or disposed improperly.
Showing the highly refractory nature of the problem, poisonings of children by medications has
long been recognized as a major cause of morbidity (and sometimes mortality). Many of the
same concerns, recognized causes, and proposed solutions have remained unchanged for
decades, as shown in a 1966 report (Matthew 1966).
Estimates for the US (from 2004 to 2005) show that annual unintentional medication poisonings
in children younger than 18 exceeded 70,000, nearly double that for unintentional poisoning by
all non-pharmaceutical products; while this includes medication errors (overdoses), it is
undoubtedly an underestimate as it included only those cases presenting to an emergency room
(Schillie et al. 2009). The rate of subsequent hospitalizations was 4 times higher for
pharmaceutical ingestions. Over 80% of poisonings were from unsupervised medication
ingestions. Over 80% of these cases were among children younger than 5, with the highest rate
among 2-year olds. The most common APIs involved with unsupervised ingestions were oral
medications (usually available OTC), including acetaminophen, non-opioid and
noncarbinoxamine cough and cold medications, NSAIDs, and antidepressants. OTC medications
were involved in over a third of the poisonings.
Schillie et al. (2009) note that drug poisoning data also likely underestimate the incidence that is
not captured by emergency rooms, such as when patients do not receive medical attention
(especially those who die prior to receiving medical attention). They emphasize that
"Medication overdoses among children, notably unsupervised ingestions, represent a substantial
public health burden in terms of emergency department visits and hospitalizations."
It is generally agreed that the incidence of poisonings published by a wide spectrum of
organizations worldwide is lower than the actual incidence - primarily because of under-
reporting (for example by clinics, doctors, and parents) and the difficulty in ascribing morbidity
and especially mortality to ingestion of a particular drug.
Accidental poisonings are classed as a subset of adverse drug events (ADEs). In a 2-year sample,
nearly 160,000 annual emergency room visits for ADEs were made for patients under 18 years
old. Nearly half were 1-4 years old, and roughly 45% were for unintentional ADEs. Nearly half
of the ADEs were caused by antimicrobials (25%), analgesics (14%), and respiratory
medications (11%) (Cohen et al. 2008). Acetaminophen is particularly problematic, as
emphasized by Daughton (2003 c). A good overview of the drugs most commonly involved with
poisonings (in the UK) is presented by Greene et al. (2005). Many citations of published
accounts of accidental poisonings in children are available from Geib et al. (2006).
While it has been long established that drugs are a major cause of poisonings, especially among
young children, it is rather surprisingly that it is not known what portion of these poisonings
occur from contact with, or from ingestion of, drugs that are no longer being actively used for
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their original intended purposes. These include drugs that: (i) have expired and should have been
disposed, (ii) are being stockpiled (perhaps indefinitely) for future disposal, (iii) are awaiting
imminent disposal (regardless of the route by which they will be disposed), or (iv) have been
imprudently disposed (especially in the trash). Such leftovers must be distinguished from drug
stocks that are still in active, current use for their intended purposes and which would not be
subject to disposal. In the absence of being able to distinguish those drugs no longer needed
from those that are, it is not possible to determine whether programs designed to facilitate
households in getting rid of their drugs no longer legitimately needed can be effective in
reducing unintended poisonings.
Even more difficult is to assess is what portion of unwanted drugs improperly disposed or
improperly stored are diverted and then contribute to abuse. The absence of any study attempting
to link poisonings with the improper disposal of medications (or the stockpiling of useless
medications that should have been disposed) is striking, as this would be a major evidence-based
driver to justify the implementation of steps designed to reduce the incidence of drug
accumulation in households.
Significantly, no study was located that had tried to distinguish in-home drug poisonings caused
by medications still being used therapeutically versus those that are no longer being used and
which should be disposed or that are awaiting disposal. The sole exception is poisonings caused
by transdermal patches (see section later below) that have been used but not properly disposed.
Such data are available in one of the only surveys (unpublished) to date, which revealed that of
the 10% of Washington/Oregon residents who knew someone who had been accidently poisoned
by a household medication, 13% said that the poisoning resulted from a medication that was
expired or unwanted (Whittaker 2010; see slide 19).
Of the published reports on poisonings by transdermal patches, several have involved used
patches. Of those involving used patches, one could assume that at least a portion of these have
resulted from patches that were either improperly disposed (e.g., in accessible trash) or that had
not yet been disposed (e.g., left on countertops); some poisonings by used patches result not from
discarded patches, but rather from patches still applied to the body but accidentally transferred to
someone else (such as when sharing a bed). As an example anecdote from one report: "...callers
commonly reported that the child was found with a disposed patch, which often contained a large
amount of medication, in his or her mouth" (Parekh et al. 2008). But similar anecdotes for
delivery devices other than patches were not located in the literature. An overview of drug
poisonings is presented in Daughton and Ruhoy (2009a).
It may well be that a possible linkage between poisonings resulting from unwanted versus in-use
medications can only be tested in prospective studies. Such a study would involve locales having
extensive bodies of historical data on drug poisonings. After implementing programs designed to
facilitate the rapid removal of all unwanted medications from homes as soon as possible, a drop
in poisonings should be readily apparent if unwanted medications play a significant role. But few
studies have ever attempted to establish whether childhood poisonings decrease even after a
large-scale take-back event. Two of the only such studies were conducted in the 1970s (Bradley
and Williams 1975; Harris et al. 1979) and involved some of the largest take-back events ever
conducted before today's renewed interest. For example, from the work of Harris et al. (1979):
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"In a returned-medicines campaign lasting 3 weeks 362 000 tablets and capsules were returned in
11 400 containers from a population of 1.5 million."
The following sections discuss the major aspects of human poisoning that are related to leftover
drugs and disposal.
Data from poison control centers and coroner reports
Data for studies that attempt to estimate the contributions to human poisonings from medications
come primarily from the Poison Control Centers (AAPCC 2010). Few studies examine all
sources of poisoning records to ascertain the incidence of unintentional fatal poisonings. In
Sweden (Jonsson et al. 2009), drug poisoning fatalities are relatively common, with the
incidence of unintentional poisonings roughly less than 5 per 100,000 person-years in the general
Swedish population; benzodiazepines, antihistamines, and analgesics are most commonly
involved. These rates apparently reflect those worldwide.
The paucity of data needed to directly link poisonings with imprudently disposed or stored
leftover drugs is primarily a consequence of the information collected during (or mined from)
investigation of accidental poisonings. Poison control centers generally exclude notation of the
storage location or whether the drug has expired. When considering data on fatal poisonings
compiled by poison control centers, it is important to keep in mind that these data are not
comprehensive, as they often do not contain data from coroner reports and many other sources;
one estimate is that they capture perhaps only a quarter of the actual incidence of cases (Roberge
et al. 2000).
Coroner reports can provide a rich array of data, including whether a drug has expired. The types
of data that can be mined from coroner reports are discussed in Ruhoy and Daughton (2007).
Mining data from death certificates has also been discussed by Wysowski (2007).
The creation and growth of the Poison Control Center movement in the US is captured in an
historical exhibit at the Duke Medical Center, which served as the nation's second Poison
Control Center. The Duke Center was established in 1954 and was involved with development of
the first safety cap (for Saint Joseph's aspirin); aspirin had been made more appealing to children
in the 1940s with the addition of flavorings, and was responsible for a quarter of all childhood
poisonings in the 1940s-50s (Duke Medical Center Library & Archives 2010).
Drugs are historically one of the leading causes of poisonings each year, worldwide. Until 2007,
poison control centers had long-advised against discarding leftover medications to domestic trash
and had instead favored discarding to sewers. Disposal to sewers had historically proven the best
way for protecting human safety - preventing accidental poisonings of children, adults, and pets,
as well as purposeful ingestion by those for whom a medicine was not intended. As a
consequence, even the newest disposal guidance issued by the FDA (USFDA 2009 [revised
March 2010]) continues to recommend the disposal of certain hazardous drugs or those likely to
be diverted and abused, by flushing down the sewer. Although the pressure grows from a wide
spectrum of stakeholders to discontinue the disposal of all drugs to sewers, the major question is
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really whether this list is sufficiently comprehensive as to include all the medications that pose
acute risks associated with diversion or poisonings if disposed to trash? The question might not
be whether to discontinue disposal to sewers, but rather, whether disposal guidance should
include recommendations to flush yet more drugs. In the final analysis, the decision to flush or to
dispose to trash could be based not just on whether a drug poses extreme risks to human safety
but also on whether flushing would make significant contributions of a particular API to the
environment. This is a function of the pharmacokinetics of each API (Daughton and Ruhoy
2009a). For those APIs that are excreted largely unchanged, disposal of these drugs to sewers
might contribute negligibly to environmental loadings. In contrast, for those APIs that are
extensively metabolized, disposal to sewers could prove to be significant of these APIs in the
environment (Daughton and Ruhoy 2009a).
Factors that can exacerbate poisonings - the roles of packaging (especially
child-resistant closures - CRCs). drug design, and consumer behavior
Other than the toxicological nature of the API (some being very potent or having very narrow
therapeutic windows), several factors serve to increase the risk of poisonings by drugs. Most of
these factors pertain to infants and children, as medications have long proved particularly
attractive to children.
Drug packaging and container design play direct roles in drug waste; this is discussed in a later
section. The design of packaging also plays dual roles in poisonings - by encouraging and
facilitating poisonings and also by preventing them.
The overall design of packaging can make drugs more attractive to children. The color, taste,
odor, shape, and graphics of the medication itself can also enhance the attractiveness of drugs for
children. This is true even for certain veterinary medications, which are often flavored to
encourage pets to consume their medications.
Adults can unwittingly contribute to childhood poisonings. Adults referring to medications as
"food" or "candy," or as "tasting good," in efforts to encourage children to take needed
medications can enhance the attractiveness of leftover drugs and promote drug-seeking behavior
(Chatsantiprapa et al. 2001). For the same reason, adults are encouraged to refrain from taking
their own medications in front of children, as children will also try to mimic the drug usage
behavior of adults (Massadeh 2007).
A major exposure factor governing children's exposure and how children intentionally access or
accidentally encounter drugs is the spatial location of medications - not just the household room
location but the spatial elevation. More data could assist in better focusing countermeasures. Not
surprisingly, storage of drugs in the kitchen (especially the refrigerator) promotes poisoning in
children. The considerable numbers of surveys of home inventories and their possible
relationship to unintentional poisonings have rarely ever collected data on spatial elevation or
accessibility of the medication within particular rooms (e.g., Kaufman et al. 2005; Smolinske and
Kaufman 2007).
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One of the most extensive studies of medicines stored in homes is also one of the only to
examine differences between countries in the types or drugs stored and their locations within the
home (Sanz et al. 1996). The numbers and types of medications, and the locations in which they
were stored, were found to vary widely between and within countries. Interviews with children
from all locations studied said they had access to home medications. Medications were
commonly found stored with foods.
Regardless of the controls placed on preventing access to children, two key risk factors are (i)
those medications that are in active use and therefore might not be securely stored, and (ii) those
medications that cannot be stored because they have been forgotten (polypharmacy and
stockpiling are contributors to this problem). Many retrospective poisoning studies reveal a
correlation between the incidence of poisoning and the expiration of the medication. The reason,
however, does not derive from toxicity of expired drugs, but rather that expiration of a
medication is an indicator of imprudent storage (since the medication has been kept too long)
(Margonato et al. 2008).
Surprisingly, few studies have focused on storage behavior as a function of consumer beliefs
regarding toxicity. Little is known regarding the factors that might influence consumer behavior
for the storage of specific medicines. Perception of toxicity (irrespective of reality) seems to
dictate the likelihood of where a medication will be stored. A select number of medications
perceived as being toxic were more likely to be returned to their normal (secure) storage
locations immediately after use, as well as being stored more safely. OTC medications, being
perceived as less toxic than prescription medications, were less likely to be safely stored (Patel et
al. 2008). The inherent toxicity of certain OTC APIs, such as acetaminophen, coupled with the
perception that they are not hazardous, perhaps partly explains why certain OTC drugs are
almost always involved with the highest numbers of unintended poisonings (USFDA 2010a;
Woodcock 2009).
Household poisonings of young children (2 years of age and younger) is unquestionably a major
cause of morbidity and mortality from accidental poisonings. These poisonings commonly
involve opioids, especially methadone, oxycodone, and hydrocodone (Bailey et al. 2009). The
elderly, however, suffer higher rates of hospitalization and death from poisonings compared with
children (Haselberger and Kroner 1995).
An irony noted by Bailey et al. (2009) is that although "medications are often labeled 'keep away
from children,' no products to our knowledge note extreme danger, such as warning that 1 pill
can kill a young child." The critical importance of understanding the extreme risks posed by
drugs that can be fatal in a single dose is covered in a section below. This is perhaps the major
factor that should be evaluated in future considerations for revising drug disposal guidance. The
lethal potential of many medications (those designed for administered via the skin were
summarized for the first time in Daughton and Ruhoy (2009a).
In a study by McFee and Caraccio (2006), 10 to 20% of unintentional pediatric poisonings in the
US were found to involve grandparents. The authors referred to this as the "granny syndrome,"
for the propensity of non-parent medications to be left unsecured.
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The elderly are particularly prone to accidental poisonings, in part because of confusion caused
by excessive numbers and quantities of stock-piled or hoarded medications. Polypharmacy is a
major factor that exacerbates unintentional poisonings in the elderly. Unintentional poisonings in
the elderly often involve drug dosing errors, incorrect medication, incorrect route of
administration, and toxicity from long-term use (including self-medication) (Cassidy et al. 2008;
Haselberger and Kroner 1995).
A 2009 national survey conducted for Medco of those over 65 and taking medications, found that
51% take at least five different prescription drugs; one quarter take between 10 and 19 pills daily
(Medco 2009b).
Adding to the overall burden and hazard of medications in the home is the availability of highly
toxic and expired medications available from Internet auction sites (Cantrell 2005).
Child-resistant closures (CRCs). The Poison Prevention Packaging Act of 1970 (PPPA), 15
U.S.C. §§ 1471-1476, is administered by the U.S. Consumer Product Safety Commission
(CPSC). The US CPSC issues the regulations governing those aspects of packaging that impact
the potential for poisonings. For most oral prescription drugs, the PPPA requires child-resistant
packaging (which must also be adult-friendly) (US CPSC 2005).
Although the numbers of deaths annually for children younger than 5 years who are
unintentionally poisoned is low compared with most other causes (about 30) as reported by the
US CPSC (2005), this number becomes a critical consideration when disposal guidance is
designed with the primary objective of reducing APIs in ambient waters to below their already
minute levels - and especially when redirection of API disposal away from sewers has an
unproven impact on these trace levels. Furthermore, disposal guidance that directs consumers to
transfer their medications from original special packaging (e.g., CRCs) to containers that are less
secure circumvents the intent of CRCs.
Despite the reductions in childhood poisonings attributed to the advent of child-resistant
packaging, this special packaging has proved surprisingly controversial over the years. Many
studies show a positive impact on reducing poisonings, while others have shown no effect.
One source of this controversy is that the efficacy of CRCs in reducing unintended poisonings in
children is complex to measure. Long-term post-hoc studies require rigorous controls for a wide
variety of other factors unrelated to CRCs. One study showed a 45% reduction in poisoning
mortality in children younger than 5 from the period 1964 through 1992 (Rodgers 1996); this
translated to a total national annual reduction of 24 deaths (changes in morbidity were not
assessed). This study also found that 50% of all poisonings from oral prescription drugs may
have involved "medicines either originally dispensed in conventional non-child-resistant
packages or in child-resistant packaging that has been disabled."
A study by Franklin and Rodgers (2008) determined that about 55% of poisonings may have
involved child-resistant packaging. Other studies have also shown CRCs do not have any effect
on the incidence of childhood poisonings (e.g., Hon et al. 2005; McFee and Caraccio 2006).
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One source of CRC failure seems to be inadequate understanding of how to (or inability to)
properly re-close a CRC. This possibly reflects poor design (for example, inadequate sensory
feedback for the user signifying when the CRC is fully closed) or inadequate consumer education
or capability. An in-depth examination of closures is provided by Sherrard et al. (2005).
One force that might be in play to either work against or promote development of better CRCs is
the predicted growing demand by seniors for packaging that meets a whole new spectrum of
needs. The baby boomers "do not want their pharmaceuticals to look like pharmaceuticals." The
desire is for packaging that no longer resembles conventional screw-cap drug containers, but
which is instead more stylish and easier to carry, and at the same time promotes better
compliance (Valigra 2008). More stylish containers, however, could prove even more attractive
to children, so child-resistance will need to be enhanced.
For those with impaired hand-strength or poor dexterity, the current generation of CRCs can
actively discourage compliance, leading to leftovers. CRCs and polypharmacy can conspire to
frustrate and confuse the elderly, sometimes resulting in consumption of unintended medications
that should have otherwise been discarded.
Single-dose lethality and fatal medication errors (FMEs) at home. Some drugs pose
extreme risks in acute poisonings. Some are mutagenic or teratogenic. Some can be fatal in a
single dose. This is perhaps the major factor that should be evaluated in future considerations in
revising drug disposal guidance.
Drugs possessing the potential for single-dose fatality require special consideration in disposal
options. Very real acute poisoning risks are posed by improper disposal of drugs that can be
lethal at single doses, not just in children, but also adults. These APIs include not just those used
in oral dosage forms, but also those used in certain transdermal and other drug delivery devices
(e.g., medicated patches - see section below). Transdermal devices pose extreme hazard even
after their use is complete; as one of many examples, after 3 days of use, fentanyl patches can
retain up to 84% of their original fentanyl content, a more than sufficient fatal oral dose for an
infant or fatal dermal dose for an opioid-naive adult. Drugs with single-dose (or low-dose)
lethality should never be left unsecured - wherever they are located including the trash. This
topic has been covered for the first time by Daughton and Ruhoy (2009a).
The fact that a number of different medications can be fatal in children following ingestion of a
single dose demonstrates the extremely hazardous nature of disposal guidance that encourages
consumers to handle their medications more than absolutely necessary. This includes any
practice - even if intended to facilitate "safe" disposal - that involves the removal of medications
from their containers. It is critical to recognize that any mistake that results in a single tablet
falling unnoticed to the floor or other surfaces accessible to children poses grave risks.
A perspective regarding drug lethality can be gained by comparison with pesticide toxicities.
Lethal doses in humans for pesticides are often rated on a scale where the two most lethal groups
have LDSO's of less than 1 mg/kg (extremely toxic) and 1-50 mg/kg (highly toxic). But keep in
mind that these are two classes are no longer sold for home use; because of their extreme
toxicity, they are available only for use by professionals. If we examine fentanyl (or a number of
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other drugs not uncommonly available in homes) (Daughton and Ruhoy 2009a), we see that they
can be lethal to children in doses of mg/body - one or more orders more toxic than the most toxic
pesticides. Given that the less-toxic pesticides used by consumers are rarely stored inside homes,
the gross disparity in the way which these hazardous medicinal substances are treated is evident.
Some of the many medications that can be fatal to a 10-kg toddler ingesting only 1 or 2 tablets or
teaspoons include common ones such as: chloroquine, hydroxychloroquine, imipramine,
desipramine, quinine, methyl salicylate, theophylline, thioridazine, and chlorpromazine (Bar-Oz
et al. 2004; Koren 1993; Lex -Year unknown; Matteucci 2005; Mclntosh and Katcher 2005;
Morris-Kukoski and Egland 2009; Osterhoudt 2000).
It can sometimes take a while for sufficient poisoning data to accumulate to fully appreciate the
acute toxicity potential for certain drugs. An example is calcium channel blockers (especially
nifedipine and verapamil), which have been involved in a growing number of unintentional
poisoning cases in children. Exposure-toxicity response data are confusing, but one report
concludes that these medications can sometimes be fatal in children at a dose of a single pill. No
antidote is available, and the onset of mortality can be rapid (Ranniger and Roche 2007).
The opioids are a class of drugs posing major concerns with respect to poisonings. Fatalities
from poisonings in children are most common with hydrocodone, morphine, oxycodone, and
propoxyphene. Methadone is one of the most toxic opioids. In children younger than 6, a single
dose can be fatal (Sachdeva and Stadnyk 2005).
Arguments have been made for the need for special warning labels for medications that can be
fatal in low doses. Much could also be done to reduce access to medicines by young children,
especially by: (i) designing child-resistant closures (CRCs) that are more difficult for children to
open while being easier for older adults to open and fully close, and (ii) making medications less
attractive to children by modifying the taste, odor, appearance, and packaging.
An overview of childhood poisoning by drugs and prevention measures is available from
Ozanne-Smith et al. (2002).
Finally, the potential for unintended poisonings to result in serious morbidity or mortality is the
central concern to the FDA in its current drug disposal guidance. But concerns regarding a
limited number of medications require that they still be immediately flushed into sewers
following use (Daughton and Ruhoy 2009a). This requirement has bred considerable confusion
for the consumer, as prudent disposal guidance is not necessarily straightforward (e.g., Hornback
2007).
Transdermal and topical drug delivery systems (TDDS). Insights regarding which
APIs should be targeted with respect to the hazards they pose as leftovers and during disposal
can be gained from examining case histories published on childhood poisonings. This was done
in the discussion above for those drugs that can kill in a single dose. Many of these cases involve
APIs used in transdermal and topical drug delivery systems (TDDS). TDDS have certain
therapeutic properties superior to those of oral medications. For example, the delivered dose
avoids the possibility of poor GI absorption, the API bypasses first-pass metabolism, the API can
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achieve a constant systemic level, for long-acting APIs the dose can be removed from the body,
and patient compliance can often be improved. These properties have served to continually
increase the popularity of TDDS.
Among the types of TDDS, however, transdermal patches have posed some special concerns.
The literature is replete with case histories involving acute poisonings (especially infants and
toddlers) by medical patches, pointing to the critical need for much better guidance for disposal
of this special class of medications. These particular medications point to how generalized
guidelines for disposal may lead to the less-than-optimal and non-timely disposal of extremely
hazardous substances.
This topic, with a focus on transdermal patches, was covered for the first time with respect to its
relevance as a source for environmental contamination by Daughton and Ruhoy (2009a). An
overview of how transdermal devices or systems are designed and work is provided by Ball and
Smith (2008).
While TDDS in many circumstances eliminate the need to dispose of syringes, they pose a new
challenge for disposal of the device. Also, while transdermal delivery makes lower systemic
doses possible (by avoiding first-pass metabolism and poor GI absorption), and therefore can
sometimes lessen the excretion of unchanged API, it actually increases the total quantity of API
required in the device because of the incomplete absorption across the skin. This means that
significant quantities of API residuals can remain in used devices; from 10-95% of the initial
API content can remain in a transdermal patch that has been completely used as intended
(USFDA (Leslie Kux) 2010). These residuals are eventually disposed along with the device. The
API residuals in used TDDS pose more of a risk with regard to accidental poisoning than do
syringes because they can be accidentally ingested or contacted with the skin.
Some of the existing instructions for disposal of used patches (or new ones that are no longer
wanted) may be misguided. For example, cutting patches into pieces prior to disposal to trash
could increase the hazard should accidental ingestion or exposure to the skin occur (the routes of
exposure reported for young children and infants). This is because puncturing the device destroys
the drug reservoir integrity in the patch, making the highly concentrated API much more readily
available for absorption should inadvertent exposure occur.
An overview of the complexities and hazards associated with TDDS is presented by Roberge et
al. (2000). Historically, unintentional poisoning from transdermal patches has been dominated by
clonidine, fentanyl, and nicotine. Some cases of poisoning specifically from clonidine patches
are summarized by Klein (1991).
The study by Roberge et al. (2000) is unusual in that it provides data on poisonings actually
caused by retrieval of used TDDS from waste containers. The authors emphasize that the
growing popularity of TDDS, coupled with the formulation of yet more distinct APIs into TDDS,
will probably mean the incidence of poisonings will increase without better preventative
measures. The problem is exacerbated even further when TDDS are switched from prescription-
only to OTC. The greater availability then increases the probability of accidental exposures. This
is evident with nicotine patches, which were switched to OTC status in the US in 1996 (Woolf et
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al. 1997). An 11-year was poisoned by nicotine after applying a patch to his arm (Wain and
Martin 2004).
Other more-potent delivery formulations of fentanyl periodically enter the market place. These
dosage forms pose extreme hazards for those who are opiate naive and who may experience
incidental exposure. One example is the fentanyl buccal soluble film, BEMA fentanyl (marketed
as Onsolis in the US), which is used to treat break-through pain. These highly hazardous drugs
are required by the FDA to have a REMS (Risk Evaluation and Mitigation Strategy) - - a strategy
and plan for ensuring that risks are outweighed by the benefits (Olin and Ziglar 2010; USFDA
2010a); also see the following links:
http://www.fda.gov/Drags/DragSafety/PostmarketDragSafetyInformationforPatientsandProviders/ucmlll350.htm;
http://www.fda.gov/Drags/DragSafety/InformationbyDragClass/ucml63655.htm;
http://www.fda.gov/downloads/Drags/DragSafety/InformationbyDragClass/UCM163668.pdf;
http://www.drags.com/nda/onsolis_080828.html#ixzzOt6NkyHOO;
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drags/AnestheticAndLifeSuppo
rtDragsAdvisoryCommittee/UCM220952.pdf.
Development of REMS, however, is not straightforward because of the potential for impacts
across a wide range of stakeholders. This is reflected by the long discussion regarding the FDA's
proposed REMS for Extended-release and Long-acting Opioid Analgesics, which was held in
July 2010
(http://www.fda.gov/downloads/NewsEvents/Newsroom/MediaTranscripts/UCM220470.pdf).
The dose equivalents remaining in used transdermal devices is summarized by Daughton and
Ruhoy (2009a). As one of many examples, an excess of a fatal dose of fentanyl remains in
patches that have been used for 3 days (Marquardt et al. 1995).
Prudent disposal guidance that provides specific instructions for TDDS could therefore play a
major role in reducing the incidence of poisonings. Given the extremely hazardous nature of
transdermal devices, it is very noteworthy that they are rarely mentioned as special cases in the
guidance for conducting drug take backs. One example is the guidance provided by the National
Association of Drug Diversion Investigators (NADDI -Year Unknown).
The critical importance of ensuring immediate and secure disposal of used patches is shown by
the death of a 1-year old after ingesting a fentanyl patch found lying on the floor. This fatal
poisoning occurred after the grandmother thought she had disposed of a fentanyl patch (after 3
days of proper use) into the trash but had not noticed that she had instead dropped it on the floor
(Teske et al. 2007). Cases such as this clearly show that when handling a drug (for whatever
reason), a single mistake can ultimately lead to death. This is why disposal guidance that fosters
unnecessary handling or drugs (including transfer among containers or alteration of physical
form) is misguided.
Even manufacturers' guidance for transdermal patches does not ensure safe disposal if other
factors are not considered. As an example, a 9-month old was poisoned after he placed a
discarded dermal patch containing clonidine in his mouth. The patch had been used constantly
for 5 days prior to properly folding in half and then discarding in the trash, as instructed by the
disposal instructions (Caravati and Bennett 1988).
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Because of the route of administration and the nature of the device, transdermal patches may be
perceived by patients as inherently safer than oral medications. This perception, for example,
may have contributed to the death of a child after a "caregiver applied 3 of her fentanyl patches
to a 4-year-old child because she knew it helped with her own pain" (from: Parekh et al. 2008).
Used fentanyl patches are known to be reused, such as by abusers. One of many reported cases
involved the reapplication of used patches by a funeral home worker who had removed them
from a decedent (Yerasi et al. 1997). The extreme hazard of fentanyl in transdermal devices is
shown by its toxicity even among drug abusers when used orally (Woodall et al. 2008).
Dermal patches, unlike most oral dosage forms, can also pose acute risks merely from being
handled. A child need only hold a used patch to achieve a significant level of exposure. Even the
routine and proper handling of patches by caregivers has the potential for exposure via dermal
contact (Gardner-Nix 2001).
Worse yet is application by children of a used patch to the skin or placing the patch in the mouth
followed by chewing, sucking, or swallowing. The ease and variety of ways that patches can
cause inadvertent poisonings is shown by the report of a 2-year old poisoned with fentanyl after a
5-mg patch being worn by his grandmother accidentally transferred to the child's back while the
two shared the same bed (Hardwick et al. 1997). The patch was no longer at full dose as it had
already been worn by the grandmother for 36 hours. A 6-year old was poisoned after applying a
transdermal clonidine patch to their skin thinking that it was a bandage (Killian et al. 1997).
The design of safer transdermal devices has received attention in the patent literature (e.g.,
Cubbage et al. 1998). As an example, one approach proposes the use of a deactivating or
encapsulating agent as an integral part of the device or within the device's original container into
which it can be subsequently disposed (Warner et al. 2005).
Finally, a recent significant event is the guidance to industry issued by the US FDA for design of
new TDDS that minimize the residual API content (USFDA (Leslie Kux) 2010). More attention
by manufacturers during TDDS design to reduce API residuals holds great potential for
reducing unintended poisonings in humans, pets, and wildlife, as well as for reducing the entry
of APIs to the environment.
Leftover drugs as contributors to animal poisonings
Imprudent drug disposal also poses risks for companion animals and wildlife (particularly any
animal that scavenges through trash or landfills). As with human poisonings, however, the
published evidence for disposal of drugs from households as contributing to animal poisonings is
thin. With this said, household pets are known to be poisoned by drugs. Pet ferrets, for example,
show the ease with which pets can suffer acute poisoning by medications, especially by
commonplace analgesics (Vanderlip 2009). Veterinary medications (as well as many human
drugs, especially those formulated for children), are often flavored to encourage ingestion by
pets. This is a common cause of poisoning in cats.
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Some of the few resources that discuss companion animal poisonings by drugs include: (Berny et
al. 2010; Dunayer 2004; Fitzgerald et al. 2006; Murphy 1994; Vanderlip 2009).
Compared with human pharmaceuticals, the resources for veterinarians to assist in dealing with
leftover drugs is extremely limited (e.g., see: AVMA 2009; Haskell et al. 2003). While the
disposal of veterinary drugs is infrequently discussed in the English literature, a formal collection
system exists in Portugal (Valormed 2010).
The issues surrounding the complexities introduced to disposal from new and used delivery
devices apply also to veterinary medications. The use of these devices (including transdermal
systems) spans the full spectrum of animals: companion, domestic (food producing), sports,
laboratory, and wild. As with human delivery devices, the concerns apply to the API residue
contained in the device - as well as to the solid waste problems posed by the device itself. The
array of delivery systems in use and under development are covered by Brayden et al. (2010).
Unintentional or "indirect" disposal of drugs resulting from use in
veterinary practices
There are at least two ways in which drugs are used in veterinary practice that are known to
sometimes serve as alternative pathways of unrecognized disposal. Certain veterinary practices
involving drug use serve as indirect, unintended, hidden forms of "indirect" disposal. These
practices are known to result in the most overt and significant instances of acute wildlife
poisonings.
The first form of indirect disposal occurs when high-levels of drug residues remain in animal
carcasses and which are then not properly disposed to prevent subsequent access by animal
scavengers (e.g., shallow burial where the carcass can be easily retrieved by scavengers).
Improperly disposed, drug-laced animal carcasses have been known to cause mass poisonings of
wildlife, such as eagles and vultures. This phenomenon was first documented in the US when
carcasses from animals euthanized with pentobarbital were improperly disposed, leading to the
mass poisonings of eagles and other raptors and scavengers (USFWS 2003). In a unique study of
the longevity of pentobarbital residues in buried animal carcasses, parts-per-million levels were
detected in compost piles containing euthanized horse carcasses for up to a half-year (Cottle et
al. 2009).
The most dramatic and well-publicized incidence of mass poisonings by drug-tainted carcasses
occurred over a number of years in parts of Asia. First reported by Oaks et al. (2004), this
involved cattle that had been treated with certain NSAIDs (initially diclofenac) and that soon
died - leading to the mass extirpation of various vulture species that fed upon the carcasses. This
led to a large-scale ecological disaster. Wildlife poisonings by drugs have been covered by:
(Blanco et al. 2009; Enserink 2009; Green et al. 2004; Koenig 2006; Krueger and Krueger 2007;
Lu et al. 2009; O'Rourke 2002; 2004; Rattner 2009; Shultz et al. 2004).
The second form of indirect disposal involves the use or diversion of drug-laced animal carcasses
as feed for companion animals or for wildlife held in captivity. This has occurred by the use of
euthanized carcasses or use of tranquilizer-darted wildlife carcasses as feed. In one report, a fatal
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poisoning occurred in a captive mountain lion that was fed only a portion of a mule deer that had
been darted with 10 mg of thiafentanil oxalate (a synthetic opioid anesthetic used in tranquilizer
darts). Instances such as this show the susceptibility of non-target species to small amounts of
certain drugs (Wolfe and Miller 2005).
There have also been sporadic and controversial reports over the years of at least the potential for
euthanized carcasses to enter and contaminate the pet food chain (Martin 2002). While
pentobarbital used for cattle and horse euthanasia might be the only source of pentobarbital in
pet food (as verified in testing done by the FDA's Center for Veterinary Medicine, CVM), the
DNA testing used by the CVM to rule out the presence of meat from euthanized dogs or cats was
not able to detect contamination lower than 10% by weight (10% of the pet food mass
contributed by pets) (USFDA 2001; 2002a; b). The possibility of low-level contamination by
euthanized pets therefore could not be ruled out with certainty.
As a result of the FDA investigation, the FDA published a labeling change for pentobarbital used
for animal euthanasia. The revised label stated in part: "Limitations. Do not use in animals
intended for food."
Resources for veterinarians to assist in performing ecologically safe euthanasia and in dealing
with expired drugs in general are available from the USNER (2010).
Drug disposal guidance increasing the hazard of leftover drugs
By not sufficiently considering all the hazards posed in the life cycles of drugs, guidance for drug
disposal holds the potential for substantially increasing the incidence and severity of
unintentional poisonings.
A substantial body of evidence shows that used patches are directly responsible for poisonings.
Drug disposal programs (such as take-back or collection events) can exacerbate this problem
simply by encouraging consumers to set aside their leftover drugs while waiting for sufficient
quantities to accumulate - to justify making a trip to turn them in at a collection event. This
behavior could result in the temporary stockpiling of extremely hazardous, leftover drugs. This
could increase the potential for poisonings - simply because more types and higher quantities of
drugs remain on-site than might ordinarily if disposal were performed immediately. This
problem will grow worse as the development of transdermal and other deliver devices
proliferates and especially as the use of highly potent APIs expands.
Efforts to ensure proper disposal might be more effectively focused on two aspects of leftover
medications: (1) Acutely toxic medications (such as those in certain used delivery devices); these
are medications that are known to be fatal from exposure to a single dose (e.g., in children) and
are dominated by opioids. For this reason, any scenario that might increase the risk for contact
should be discouraged; stockpiling waste and disposal to trash are two examples. (2) Design
approaches for disposal that minimize the time during which an unwanted medication remains
on-site. The latter means that a safe disposal program needs to ensure fast removal of leftover
drugs from the home or provide secure storage while leftovers accumulate prior to disposal.
Drugs that are lethal in a single dose are discussed by Daughton and Ruhoy (2009a).
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The consumer cannot be relied upon to ensure secure storage. Unsecure storage occurs even with
medications that are highly hazardous for children, such as methadone (Williams et al. 2009).
A specific aspect of current disposal guidance that could place consumers at increased risk is
recommendations regarding pill destruction or alteration of pills to make them "unpalatable."
These practices introduce new hazards that would ordinarily not be present. This is a complex
and potentially very important topic, having broad ramifications for the design of drug disposal
guidance. It is discussed in more detail in the sections immediately below. These potential
hazards imposed as a consequence of drug disposal guidance were first comprehensively
discussed in Daughton and Ruhoy (2009a, especially p 2511-2513).
Guidelines for altering, manipulating, or treating drugs prior to their disposal
by consumers are ill-advised. Disposal guidelines for consumers often include steps to take
prior to final disposal that entail some sort of adulteration, physical alteration, or chemical
modification to the dosage form. This guidance might be directed to both solid and liquid dosage
forms. The intent of these "pre-disposal" steps is motivated by any of three objectives: (i)
rendering drugs unusable to others who might reclaim them (diversion), (ii) rendering drugs
undesirable or unpalatable to humans or wildlife that might accidentally attempt to ingest them,
or (iii) altering or degrading them for the purpose of preventing the possibility of future pollution
by their leaching from the landfills.
There are a number of approaches suggested for accomplishing these objectives - and even more
that consumers invent on an ad-lib basis. Regardless of the intent or motivation, it is highly
recommended that all guidance that encourages these practices be carefully examined, as they
can pose serious risks for humans, domestic pets, and wildlife.
Some of these risks are discussed here. Most have been previously discussed in prior ORD
publications, but the most comprehensive overview published to date is in several of the sections
of Daughton and Ruhoy (2009a).
The risks created by pre-disposal alteration of medications derive from two major sets of
liabilities of the recommended practices. The first set of liabilities results from encouraging the
consumer to handle medications more than necessary or to attempt physical alteration of a
dosage form. The mere act of transferring medications from their original containers poses the
risk of misplacing one or more doses by spillage. Drugs spilled unnoticed onto countertops or
floors can be readily picked up by toddlers and pets. This hazard is extremely high when the
medication belongs to a class of drugs that can kill with a single dose (see prior section).
The transfer of medications to other containers can lead to accidental poisonings. This is a well
known cause of pesticide poisonings, especially when the transfer is made to a recognizable food
container. Whether the transfer is done with the intention of using the medication in the future, or
whether the transfer is to another container intended for disposal, confusion results. Furthermore,
once the medication is transferred, it loses its ready identity and can increase the time it takes to
identify the causative agent should a poisoning occur.
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Others have noted that guidance to remove medications from their original containers may be
flawed (Dillon and Rubinstein 2005a, see page 26; Dillon and Rubinstein 2005b). Also, the
National Association of Clean Water Agencies (NACWA) has expressed concern regarding
guidance to remove pills from containers prior to disposal (Hornback 2007):
"NACWA's final concern with the current guidelines is the recommendation to take unused
prescription drugs out of their original containers. NACWA understands the reasoning for this,
but for many takeback programs, the original containers and labeling are very helpful for
classifying drugs and ensuring that control substances are handled properly. NACWA suggests a
revision to the guidelines to ensure these drugs can be properly classified by take-back program
managers."
Encouraging the consumer to physically alter a solid dosage form, such as by crushing tablets or
emptying capsules, not only poses the risk of losing one or more whole doses during transfer
from containers, it also poses the risk of releasing and distributing debris or dust from the
crushed dosage form. Moreover, some dosage forms are specifically designed to resist crushing
(unscored tablets are often not intended to be split because they are formulated for extended
release), and others can become highly toxic once their normally protected contents are exposed;
quite a number of oral dosage forms should not be crushed (Mitchell 2008). The consumer is
unable to identify these particularly problematic dosage forms.
The potential for generation of hazardous dusts from crushing pills or from unnecessary handling
is shown by studies of pharmacist exposure to particles and aerosols generated during the process
of dispensing medications (Scott 2008). And dispensing is a process much better controlled than
the myriad ad-hoc ways that a consumer might attempt for physically altering or destroying
medications. Consumer exposure via the skin, ingestion, or inhalation of dusts generated during
ad-hoc destruction has never been investigated. Inhalable dusts are of particular concern for APIs
known to sometimes elicit strong immune responses, such as penicillin.
The dangers posed by crushing are shown in the publications primarily from the nursing
literature (e.g., Paradiso et al. 2002; Stubbs et al. 2008). Tablet crushing and capsule opening are
standard (but under-reported) practices in geriatric nursing. It is a practice known as "dose
modification" and is used in healthcare (often unwisely) in attempts to make it easier for patients
having trouble swallowing their medication. Even when performed by experienced personnel
using proper equipment for crushing, the practice is viewed as one with noted risks - especially
with enhanced toxicity of the dose form (a particular concern with APIs having narrow
therapeutic indices).
Even if a drug is scored, indicating that it is also possibly crushable, this does not mean that it
would be safe to crush. Extended release dosage forms, for example, should not be crushed, as
their higher API content can be acutely toxic, especially to children and pets. While dose
modification may not result in severe adverse effects for those who have already been adapted to
a medication, for those who are naive to the subject API, the consequences from ingestion of
modified doses can be lethal; this is particularly true for opiate ingestion by those who are opiate
naive.
For the consumer, an additional likelihood is crushing multiple different types of medications
together, as drug-drug interactions could result from exposure to dispersed residues. Certain
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enteric-coated medications, when crushed, can act as severe esophageal irritants. Crushing of
extended release formulations is particularly hazardous for ingestion, as it promotes the rapid
release and absorption of API to levels that far exceed therapeutic levels. The dose that was
designed to be released over an extended period of time is released all at once. Some mortalities
have been reported from overdoses resulting from what would normally have been safe doses if
the dosage form had not been altered. Many drugs come in extended dose forms, examples being
aminophylline, diltiazem, and morphine. The potential for spillage and loss of crushed drugs
during crushing or capsule opening are real. Even among experienced nurses, unnoticed spillage
and loss have been observed (Stubbs et al. 2008).
Some drugs contain APIs that are extremely hazardous even under normal usage. They are
coated to prevent dermal exposure by the handler or during administration. Some should not be
handled by certain sub-populations (e.g., pregnant women handling teratogens, such as:
tamoxifen, methotrexate, and finasteride). Crushing can not only enhance dermal exposure, it can
also create an exposure pathway that would ordinarily never otherwise exist - for example,
pulmonary exposure via inhalation of dusts or particulates from oral dosage forms.
These two hazards (enhanced absorption of toxic doses and new exposure pathways) as a result
of pill crushing prior to disposal were first pointed out by Daughton and Ruhoy (2009a).
Sometimes adulterants are recommended in disposal protocols, such as the addition of diesel
fuel, which only serve to add to the overall environmental hazard once they enter landfills.
Another suggestion to consumers is to add water to medications prior to disposal. Many
medications will not readily dissolve in water, making them easy to reclaim. For those drugs that
will dissolve, a new hazard is created from the potential for leakage from the containers. This can
result in spillage of concentrated API anywhere along the route traveled by trash. It also
increases the potential for APIs to enter landfill leachate.
With these issues aside, since the major intent from all of these operations is simply to make the
drugs undesirable or unpalatable, this is not sufficient to discourage those who are determined to
reclaim a particular drug - - as a truly motivated abuser or addict can always re-purify a drug
from just about any type of mixture. This is best shown by the great efforts expended by
desperate meth addicts. Law enforcement periodically comes upon a type of clandestine lab
operation called a "urine extraction lab" or "pee lab," where methamphetamine that has been
excreted unchanged in urine or feces is reclaimed with the use of chemical extraction; those
engaged in this activity are called "tinkle tweakers." Others, termed "dirt barons," are known to
revisit the sites of abandoned clan labs and attempt to extract residues from dirt and discarded
waste (FACT 2006; Majors 2009).
Some of the limitations and potential hazards posed by disposal guidance can be observed in any
of the numerous videos posted on the web that discuss drug disposal or take backs. A video
showing the disposal protocol recommended by SMARxT (2008) serves as a representative
example. From this video, several observations can be readily made. First, there are multiple
steps involved in the recommended protocol. Not only is this a time-consuming task - one that
many consumers would likely not follow - but moreover, most of the steps impose new hazards.
For example, the plastic bag could be easily pierced or ruptured, spilling dry or wet contents on
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countertops or floors. Second, it inadvertently encourages improvisation by the consumer when
all of the needed materials (freezer bags, cat litter, coffee grounds, etc) are not readily available.
Also shown is the removal of container labels. While this may or may not be prudent (e.g., it
makes future identification of the disposed medication much more difficult, should an accidental
poisoning occur), it is not always feasible, as some labels are nearly impossible to remove from
containers because of the adhesive used. Note that the use of cat litter for drug disposal dates
back to at least 1996, but for a different purpose. Its use was originally evaluated to facilitate the
disposal of small amounts of leftover liquids - particularly anesthetics - not for the still unproven
purpose of discouraging the recovery of disposed drugs (Tarling et al. 1996). EPA's study of best
control practices in the healthcare industry for unused medications also cites disposal of
controlled substances by crushing and mixing with kitty litter (Lucy and Wu 2009).
The second set of liabilities results from suggestions to chemically modify medications in order
to render them unusable or more innocuous for the environment. There are uncharacterized
hazards with rendering drugs unusable by chemical alteration. If reactive chemicals (e.g.,
oxidants such as chlorine) are used to denature the drugs, the release of hazardous, volatile by-
products might result. Some consumers might be tempted to employ hazardous reactants such as
concentrated acids or bases - or even to apply heat such as with an oven or heat gun.
Here is an example of State disposal guidance where new, untested practices were introduced
(New Mexico Board of Pharmacy 2010): "Add water with bleach to container until contents are
completely covered." Bleach could react with amino functionalities common to many APIs,
creating toxic and volatile chloramines. Hypochlorite could also possibly react with APIs to
create a plethora of halogenated by-products.
With regard to chemical alteration, it is often suggested that rigorous chemical treatment might
serve as a replacement for incineration (such as for disposal of controlled substances). The
research that has been performed on chemical destruction of drugs has focused on genotoxic and
mutagenic drugs such as antineoplastics (as a means of occupational control). No single form of
treatment, however, has proved effective for all APIs, and many of the reactants used in these
studies are hazardous to handle themselves. The discussion that follows summarizes a few of the
many studies that have relevance to this aspect of drug disposal. In the final analysis, no simple,
safe, rapid, and green method exists for rendering unwanted medications unusable and
unrecoverable.
Pre-treatment of drugs prior to disposal by healthcare facilities and
pharmacies. The types of medications requiring disposal by healthcare facilities and
pharmacies can differ dramatically from those commonly stocked by households. Many are
highly hazardous, such as antineoplastics. For this reason, considerable research has been
targeted at occupational exposure, especially regarding ways to decontaminate or to destroy
leftovers. Some of the published results are also relevant to consumer disposal - pointing to the
many problems that could be encountered by the consumer who attempts to destroy medications.
The application of heat is often considered by consumers. Autoclaving and microwaving are
technologies used by healthcare facilities for destroying pathogens - for disinfection or
sterilization. By heating with pressurized steam for a half hour (at temperatures over 140°C),
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infectious agents are efficiently destroyed by autoclaving. They are not intended for destroying
chemicals. These technologies impart very low energies compared with incineration.
Certain drugs, most notably antineoplastics (e.g., oncolytics), can and will accidentally or
intentionally become mixed in with healthcare wastes (Armstrong and Reinhardt 2010);
examples are residues on soiled textiles and in syringes. They also become dispersed around
preparation areas and areas where treated patients stay, creating the need to minimize
occupational exposure after preparation of infusions and handling of patient wastes. There is
therefore great interest in having adequate decontamination protocols. These have been the
primary drivers for research on drug destruction.
Antineoplastics (and residual mutagenicity) have been shown to persist in urine stored for
several weeks (Monteith et al. 1987). Oxidation with sodium hypochlorite or potassium
permanganate is often the most successful treatment (as opposed to hydrogen peroxide), but no
approach has been shown 100% effective at stoichiometric destruction of both the parent API
and reaction by-products - as well as at avoiding the generation of mutagenic by-products. Much
of this work was initiated by the International Agency for Research on Cancer (IARC)
(Castegnaro et al. 1985).
A number of studies have examined the chemical degradation of a variety of antineoplastics:
(Barek et al. 1998; Benvenuto et al. 1993; Hansel et al. 1997; Lunn et al. 1989; Monteith et al.
1987; Roberts et al. 2006). A summary of drugs for which larger-scale chemical destruction
methods have been developed is provided by Priiss et al. (1999, see page 117). An important
feature that can be distilled from these studies is that not all antineoplastics can be effectively
destroyed by a single reactant or under the same physical conditions. Multiple reactants and
compositions would be required for rigorous destruction to innocuous mineral products.
NIOSH has compiled an extensive list of references that focus on antineoplastics in the
occupational setting (NIOSH 2010). The sections that have relevance to drug disposal are: (i)
Effects of Occupational Exposure, (ii) Environmental Sampling, and (iii) Decontamination and
Deactivation of Antineoplastic Agents.
Some studies have been done to determine the fate of antineoplastics in autoclaves. One study
(Bassi and Moretton 2003) investigated the mutagenicity of solutions of various antineoplastics
before and after autoclaving: cisplatin, carboplatin, doxorubicin, 5-fluorouracil, methotrexate,
and cyclophosphamide. Mutagenicity was not altered for doxorubicin, 5-fluorouracil, cisplatin,
and carboplatin. But it actually increased 5-fold for cyclophosphamide, presumably because of
the formation of mutagenic hydrolysis products.
Photolysis using a medium-pressure mercury lamp was also investigated as an effective means
for completely destroying a variety of APIs at high aqueous concentrations (grams per liter),
Some APIs required the presence of hydrogen peroxide; no mutagenic by-products were detected
(Lunnetal. 1994).
One approach to physical destruction has the potential to release significant dust or fine particles
- the use of shredders or disintegrators. These can pose very real hazards especially to those who
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operate the machinery. Perhaps the most telling evidence that should highlight the potential
hazard is the work published on the preparation of cytotoxics and other chemotherapeutants.
Even the use of stringent containment protocols during the preparation of chemotherapeutics
does not prevent their escape into unconfmed areas or the inhalation of vapors (Daughton and
Ruhoy 2009a). Further, crushed medications might also pose a greater hazard in landfills with
regard to leaching and exposure of wildlife.
Occupational hazards of drug waste and relevance to consumers. The one class of
drugs that probably demands the most attention regarding their use and disposal is the
antineoplastics. This class is diverse and comprises highly toxic mutagens and carcinogens.
Cytotoxics are documented contaminants of surfaces in healthcare settings. This problem has
been summarized by Daughton and Ruhoy (2009a). Contributions come from both the healthcare
provider and from treated patients. Even the standard use of the needle/syringe technique when
withdrawing highly toxic antineoplastics from their containers has been shown to contaminate
the immediate surroundings (Spivey and Connor 2003). Antineoplastics can also vaporize from
spilled solutions or contaminated liquids (Connor et al. 2000).
The potential for occupational exposure during preparation, administration, and waste
management are well known. Many are volatile and can readily contaminate surfaces in the
vicinity of their usage. An emerging concern is whether development of various cancers is a
widespread occurrence for those involved with continual occupational exposure to
antineoplastics (Smith 2010).
While these phenomena pose obvious occupational risks, by extension they also have
ramifications in the homecare setting. Originally confined to use only in hospitals and infusion
clinics, the use of hazardous drugs has been expanding, driven somewhat by off-label use (such
as treatment of various rheumatic diseases and multiple sclerosis) and also by use in physician
offices (ASSTSAS 2008). They are also experiencing growing veterinary use.
Most reported cases of occupational poisonings have involved steroid hormones and cytotoxic
anti-cancer drugs. Pulmonary exposure to dusts and particulates are a major problem, although
contact reactions, such as sensitization, from dermal exposure also are known to occur. These
instances all point to the potential risks that may be associated with recommending that
consumers "crush" their medication prior to disposal. Many new APIs are being designed with
much greater potency, with some having occupational pulmonary exposure limits below a
microgram per cubic meter (Cherrie et al. 2009; Heron and Pickering 2003).
Despite the extreme hazards associated with these chemicals, regulations for their safe use in
occupational settings are not set forth by OSHA, which only provides guidance and information
for occupational use of antineoplastics (OSHA 1996; Polovich 2004). Voluntary guidelines for
those who work with antineoplastics are issued by NIOSH (2004).
While occupational exposure and disposal is not the focus of this report, the expanding use of
antineoplastics in the home setting and in veterinary clinics does pose concern. The potential for
exposure is not limited to just the administration stage, but also the handling of patient (and
animal) waste (excrement and clothing) as well as leftover drug waste. Even interdermal transfer
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from those under treatment to others is possible (Daughton and Ruhoy 2009a). Unintended
exposure to ambient levels of antineoplastics for those not undergoing treatment has been termed
"secondhand chemo" in the popular media (Smith 2010).
The growing use of highly potent APIs (HPAPIs) will require the development of new dosage
forms, simply because of the difficulty in ensuring that each solid dose (which have convenient
weights of about 200 mg) contains such a small mass of API (e.g., a microgram). This problem is
being addressed with new approaches, such as the use of inkjet printing for making "printable
pills," where the dose of a highly potent API is printed on the surface of a conventionally sized
tablet that can be easily handled by the consumer (Canavan 2010).
Pre-treatment of leftover drugs prior to disposal by collection events. Some local
collection events have sought to independently solve the limitation of not being able to accept
the return of controlled substances by attempting to render the dosage forms unusable on-site (a
practice that the DEA does not permit). This practice has usually involved schemes to dissolve
the drugs in bulk containers containing acidified water. The problem is that the constituent APIs
are merely dissolved in an aqueous solution. They are not structurally destroyed as required by
the CSA.
On-site destruction has been tried, for example, in collection events in Florida (Musson et al.
2007). Some excerpts from this report reveal the inadequacies of the approach:
"It was desired that the unwanted medications became no longer recognizable and unusable
when deposited into the container. It was determined through experimentation that a mild
hydrochloric acid solution (1 mL of 20 Baume HC1 to 12 L of water) with a pH of 2.0 was
capable of dissolving the pharmaceuticals and rendering them unusable. This acidic solution
was used in collection containers at all of the locations except one location." ... "Although the
vast majority of the pharmaceuticals were disintegrated by the collection solution, some
partially decomposed medications were observed. In addition, during emptying of the
collection containers, it was observed that several medications remained in their tamper-proof
packaging, having not been removed by the participants during their disposal."
Another consideration regarding collection approaches that combine all medications into single
containers for chemical treatment pose chemical incompatibility concerns.
Pre-treatment of drugs by encapsulation prior to disposal As an alternative to
attempts at chemical alteration of drugs prior to their disposal, an approach used by pharmacists
in the UK for many years has involved kits that serve to encapsulate drugs in small batches,
purportedly permitting safer disposal in landfills and preventing diversion. These are often
referred to as DOOP (Disposal of Old Pharmaceuticals) Kits. Encapsulation using these kits has
never been evaluated for long-term effectiveness in providing a sustainable solution. In the US,
similar kits have become available for consumer use (F.P.R. Inc. 2010; Parrott 2010; Rx
Disposal Solutions 2010).
But all of these kits are surrounded by the same unknowns regarding the potential for
teachability, as well as the many concerns highlighted above with regard to encouraging
consumers to physically handle drugs more than necessary.
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Take-Backs: DUMP. POOP, and RUM campaigns: home and hospital
inventories
The en masse collection of unused, leftover medications is a hazard-reduction practice that has
been underway for roughly 50 years - since the 1960s and perhaps earlier. The DDS database
contains over 100 articles on various types of drug collection activities and on obtaining data on
drugs inventoried during collection events and in the home. One of the first published collection
events for drug waste was Nicholson (1967), who was also among the first to publish an
inventory of returned drugs - not just the quantities, but also the identities. Over 43,000 tablets
were collected, and over 36,000 were identified. But the first major study to inventory
medications that were naturally returned to a pharmacy was Hawksworth et al. (1996), who
provided data more representative of the public as it was done without any of the formal
advertising used in attracting attention to collection campaigns. Their study was also among the
first to study the reasons for returns.
Since the seminal reports up through the 1970s, a wide array of approaches have been attempted
for collecting unwanted drugs - ranging from simple one-time local events to ongoing formal
programs that span larger geographic regions. Depending on the country, approaches have
ranged from consumers transporting their returns to pharmacies or collection sites, or, most
recently, the use of the mail (in the US). Although most collection activities have been targeted
at consumer drugs, some have targeted healthcare facilities such as hospitals. Many of these
efforts were formal studies with intents on collecting data, but perhaps even more were done
simply as a public service to rid homes of leftover medications. Motivations for the former have
included the use of leftover drug data to study patient non-compliance or the monetary value of
the wasted pharmaceuticals (to see where savings could be made in the prescribing and
dispensing processes). Motivations for the latter have primarily been to reduce the potential for
drug diversion, drug abuse, accidental misuse, and unintentional poisonings.
The collection of leftover drugs has taken place under a variety of names, depending on the
country. The first formal collection events targeted at consumers began in Britain in the 1970s
and were called DUMP campaigns - Disposal of Unused Medicines and Pills - a term possibly
coined in a 1975 Manchester study (Bradley and Williams 1975). But since the acronym DUMP
had negative connotations (sometimes being misunderstood for random dumping), alternative
names were soon employed, such as Medidrop. An overview of the UK's DUMP campaigns is
presented by Forbes et al. (1989).
Mackridge (2005), however, points out that the origin of the DUMP acronym is ambiguous, as it
has been translated with a variety of meanings: Disposal of Unwanted Medicines and
Pharmaceuticals; Dispose Unwanted Medicines Properly; Disposal of Unwanted Medicines and
Pills; and Disposal of Unwanted Medicines and Poisons.
One of the largest and oldest take-back programs is RUM (Returning Unwanted Medicine),
whose collections have been averaging around 400 tonnes (400,000 kg) per year (Brushin 2005;
RUM 2008). Brushin (2005) provides a detailed examination of the RUM program. An
overview of the returns programs in Canada is provided by Gagnon (2008; 2009).
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In British Columbia, Canada, the Medications Return Program (MRP, launched in 2001) was
formerly the Post-Consumer Pharmaceutical Stewardship Association (PCPSA). All
manufacturers of prescription and OTC medications are required to take responsibility for the
safe disposition of leftover medications (Driedger 2002). Reports from the BC MRP provide
examples of the types and magnitude of data collected from returned drugs. During a 1-year
period (2005), over 18,000 kg (18 tonnes) of medications were collected (PCPSA 2006). For the
year 2007, the total collected had increased to 23,875 kg (Vanasse 2008). And for the year 2008,
the total collected had again increased, to 35,704 kg (Vanasse 2009). The usefulness of the
collection data from the MRP is also similar to that of other programs. It is important to
recognize that the data do not specify what exactly had been measured - the drugs by themselves
or also packaging; the data most certainly do not pertain to the mass of collected API.
France conducts pharmacy-based collections under the MNU program (Medicaments Non
Utilises: medicines not used). One such program is the Cyclamed program, implemented in 1993
and funded by the pharmaceutical industry; Cyclamed, however, does not accept return of OTC
or veterinary medications (Cyclamed 2008).
A number of other acronyms and terms are sometimes used for drug collections. Take-back
services provided by pharmacies in the UK and Wales use the term DOOP service: Disposal of
Old Pharmaceuticals. Collection programs are sometimes referred to as "drug amnesty"
programs, especially when illicit drugs can be included in the returns.
Summaries of some of the formal programs and organizations in other countries that collect
returned drugs are provided by the Northwest Product Stewardship Council (NWPSC 2008) and
by CalRecyle (CalRecycle 2010c).
Note that Federal laws and regulations have played a major role in the shaping and constraining
of approaches available for collecting unwanted medications in the US. This is the major reason
that the challenges in the US differ from those of other countries. The uneven patchwork of take-
back events and programs in the US is a result of an absence of national guidelines and
differences among local and state laws and regulations. As one of many examples, commonly
understood is that law enforcement needs to be present if controlled substances are going to be
accepted at a take-back event. Some states, however, require the presence of law enforcement
regardless, probably to prevent diversion of controlled substances that consumers inevitably
attempt to turn in; some have different requirements for additional agencies to be involved with
collection of controlled substances.
Various guidances from state and federal agencies for consumer drug disposal are compiled or
discussed by PSI (PSI2009). CalRecycle has summarized international and other state programs
(CalRecycle 201 Ob). Many listings of take-back efforts are provided by individual states; a few
web sites provide compiled listings for the US (Illinois-Indiana Sea Grant -Year Unknown;
NADDI 2010; PSI 2008b; Teleosis Institute 2010).
One of the most concerted efforts to date to develop statewide model programs for collection of
unwanted drugs from consumers for proper disposal is the effort by the California Integrated
Waste Management Board (CIWMB), which was mandated by state legislation (CalRecycle
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2010a; Simitian and Kuehl 2007). Texas has implemented a similar workgroup under the TCEQ
- the Pharmaceutical Disposal Advisory Group, which was convened to obtain information
required by Texas SB 1757 (TCEQ 2010).
The continually growing popularity of take-backs is shown by the entry of commercial interests
into the consumer take-back sector. The TakeAway(tm) program of Sharps Compliance, Inc., is
one example (Sharps Compliance 2010a).
Drug collection programs have been the central focus of nearly all efforts to reduce the entry of
APIs into the environment, despite there being little evidence that their impact would be
measurable. Although some obvious measures are possible (such as calls to poison control
centers, drug arrests for prescription drugs, confiscations in schools), few attempts have been
made to link possible trends to collections. The primary impetus is believed to be that drug
disposal is the most obvious aspect of the drug life cycle that can be easily and directly
controlled by the public. As seen in the many other sections of this report, however, there are
numerous other points of attacking the drug life cycle that would have much greater pay-offs in
reducing the presence of APIs in the environment.
With this aside, the real value in drug collection activities would potentially derive from key data
that could be mined - data that could be used for assessing, designing, and implementing other
approaches for up-stream pollution prevention. But these data must be collected by way of
detailed inventories of the collected drugs. Taking inventory of returned drugs is extremely time-
consuming, requires pharmacy experts, and incurs substantial costs. No evidence exists that these
costs could be justified on the basis of reducing down-stream impacts - that is, for removing an
unknown and possibly low percentage of drug residues from the environment. But the type of
data that can be mined from returned drugs could hold extraordinary central importance with
regard to solving the up-stream activities, actions, and behaviors that lead to API entry to the
environment in the first place. Examples include identifying which drugs are over-prescribed or
that elicit poor patient compliance so that adjustments in the prescribing system can be made,
resulting in fewer wasted medications or in fewer medications used (thereby also reducing
excretion).
One potential use of drug-returns data has never been capitalized on. Those drugs captured by
inventories most frequently or in the greatest quantities could be used to better inform or
prioritize the selection of APIs to target for environmental monitoring. One example of this is in
James et al. (2009).
The EPA has been working toward covering hazardous pharmaceutical waste under the
Universal Waste Rule (40 CFR, part 273). The intent has been to facilitate the collection and
disposal of drugs as hazardous waste. The UWR applied to drug waste would essentially allow a
facility to act as a "handler" of pharmaceutical universal waste instead of having to abide by the
more onerous requirements imposed generators of hazardous drug waste. This may simplify and
reduce the cost of handling waste collected from public take-backs (USEPA 2010a). Moreover,
this change would allow nonhazardous pharmaceutical waste to also be treated as Universal
Waste, helping to divert these products from municipal waste streams. This modification to the
rule, however, has not been without debate (e.g., NACWA 2009a).
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Mail-backs. The approach used in nearly all collections activities is physical transport by the
consumer to the drop-off site. This approach incurs added costs from transportation and
consumer time, and requires planning ahead. Some consumers are unable to conveniently travel
and many locales do not have access to collection sites. Most importantly, the use of episodic
take-back events encourages and perpetuates one of the major consumer behaviors long-sought
for elimination by drug-control programs - episodic take-backs force the consumer to amass and
store leftover medications - a practice that imposes the same risks for diversion and unintended
poisonings as does hoarding.
One of the only approaches explored beyond the drop-off paradigm is the use of the mail system.
The use of mailers ("mail-backs") addresses many of the shortcomings of drop-offs. Its major
advantages are that it is always conveniently available, and, moreover, it does not encourage
stockpiling while awaiting a take-back event. One of the little-mentioned aspects of physical, on-
site take-back campaigns is that the public is known to sometimes resort to prior practices (e.g.,
disposal to trash and sewers) as soon as the campaigns cease (Gill and Portlock 1990).
The State of Maine pioneered the mail-back approach with the "Safe Medicine Disposal for ME"
(SMDME) program. The SMDME is a statewide program established through state legislation. It
was first implemented in 2007 with a grant from the EPA's Aging Initiative. The program is
innovative in that it uses return mailers and can legally accommodate all medications - including
controlled substances and illegal drugs, should the consumer decide to include these types of
drugs. During its pilot stage, a major objective of the program was to catalog returned
medications. Maine is the first state to seek statewide solutions to drug disposal. It passed the
first proclamation in the nation on safe drug disposal to be endorsed by a governor (State of
Maine 2003). Kaye et al. (2010) provide a comprehensive report on the Maine SMDME
program. Some other discussions of Maine's mail-back program are provided by Crittenden and
Gressitt (2009) and Kaye (2008).
Some of the findings from the inventories performed by the SMDME program comport with
those noted by others. These include the receipt of drugs that span the spectrum of time held.
Some returned items were full containers of medications (many from mail-order pharmacies or
U.S. Department of Veterans Affairs [VA] pharmacy services, and some of which are quite
costly, such as antiretrovirals), while others were decades old. Some patients received the same
medication from different pharmacies (e.g., both mail-order and local). The monetary value of
narcotics received from some individuals had street values of thousands of dollars, representing
significant targets for diversion.
The major potential criticism of the mail-back approach is the risk of diversion. Although
instances of diversion of drugs en route from mail-order pharmacies has been documented, a
comparative risk analysis has not been done versus the alternative of continued storage in the
home or for physical take-backs. From its collaboration with the State of Maine, the USPS
announced on 8 April 2010 that it would be piloting an expansion of mail-back programs by
offering the service to the U.S. Department of Veterans Affairs (VA) in Washington, DC and
vicinity (USPS 2010).
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Role of the CSA. A unique aspect of the still-evolving approaches to drug disposal in the US is
the Controlled Substances Act (CSA) (US Department of Justice 1997). The CSA imposes
challenges and obstacles to the development of a straightforward, sustainable approach to drug
disposal, as it prevents the transfer of controlled substances from the patient who was issued the
prescription to any other entity except those few stipulated in the CSA. Among those excluded
from being able to accept the return of controlled substances are healthcare professionals and
pharmacists.
The CSA also impacts nursing homes and long-term care facilities (LTCFs), which inherit
unused controlled substances no longer needed by patients, such as in the event of death. The
CSA does not allow these facilities to transfer these controlled substances to others for disposal.
This is the origin of witnessed disposal to sewers at these facilities.
The CSA as it pertains to dispensing and disposal of undispensed controlled substances by
pharmacists is explained by the DEA (Ashcroft et al. 2004). A summary of the complexities and
nuances surrounding the CSA and the disposal of controlled substances is available from Vivian
(2009). An overview of the complexities, intricacies, and impacts of the CSA with respect to
dispensing is provided by (Van Dusen 2010).
The DEA has prepared two documents to assist those who handle drugs with understanding the
Controlled Substances Act and its implementation (Bonner and Haislip 1991; Rannazzisi and
Caverly 2006).
Much of the newly proposed federal legislation directed at improving the drug disposal process
in the US relies on changes to the CSA (e.g., H.R.1359, and its companion measures, S.1292 and
S.3397) (Klobuchar et al. 2010; Klobuchar et al. 2009; Stupak and Smith 2009). Discussion of
the CSA with respect to new federal legislation is available from Yeh (2010).
Other countries have laws governing other lists of controlled substances, but these laws have not
impacted the collection of leftover drugs as has the CSA. For example, the UK's specific
legislation for the handling and administration of drugs with abuse potential (referred to as
"controlled drugs") is regulated by the Misuse of Drugs Act 1971 and the Misuse of Drugs
Regulations 1985 (updated in 2001).
One of the ironies of the impact of the CSA on drug collections is the difficulty in obtaining data
on unwanted controlled substances via drug collections. Of considerable interest is better
understanding the overall contributions of controlled substances to drugs collected in take-backs.
The overall percentage of total drugs that comprise legal controlled substances in households is
unknown. The limited data gathered from drug collection events is not sufficiently
comprehensive to draw firm conclusions. Many reports simply repeat the figures that 5-15% of
all drugs collected at take-back events are controlled substances. But some real-world data report
up to one-half as being controlled substances (Bay Area Pollution Prevention Group 2006). The
report from the EPA-funded Maine pilot program contains data on controlled substances
(Schedules II-IV), where they represented roughly 17% of the total number of pills collected in a
mail-back program (Kaye et al. 2010). One of the only studies to focus on the return of
controlled substances and drugs of abuse (to pharmacies) is Mackridge et al. (2007). A study in
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Sweden showed a much lower return rate for controlled substances compared with other drugs.
The authors speculated that these drugs were preferentially hoarded or diverted for non-medical
use (Ehrling 2005).
Role of expiry and shelf-life
Drug expiry is a major factor at play in a number of aspects of the larger drug disposal issue,
including generation of leftovers, maintenance of drug stockpiles for national security and
national healthcare, imprudent humanitarian donations, drug reuse/recycling, purported toxicity
(e.g., from formation of impurities), counterfeiting, and stewardship.
Much confusion surrounds expiry. Comparatively little effort has been invested in trying to
determine the actual expiration of drugs and in developing ways to extend it. This is largely
because of the extreme difficulty and complexities in developing meaningful test criteria. This
has profound implications not just for the cost of healthcare (premature drug wastage), but also
for environmental impact (accelerated disposal). Much of what is known from actual data has
been made available from three major sources: (1) accelerated "stress testing" done by
manufacturers (e.g., Carstensen and Rhodes 2000; Ju and Chow 1996), (2) real-world shelf-life
testing done by the military to control costs (e.g., Rundstedt 1993), and (3) small studies by
independent investigators (data derived primarily from assay of drugs long past expiration).
A summary of the expiry issue is available from the American Medical Association (AMA 2001;
Okeke et al. 2000).
Complicating the debate even further (especially with the intent of legislation) is the use of
multiple terminologies. Sometimes used interchangeably, these terms refer to different aspects of
drug use and shelf-life. These include expiration date, discard date, and beyond-use date. The
expiration date is set by the manufacturer in accordance with guidelines set by the FDA and
USP.
Shelf-life is set by the manufacturer as the maximum time they guarantee acceptability
(generally over 90% potency). Discard or beyond-use dates are set by a dispensing pharmacist,
but cannot exceed the manufacturer's expiration date. Because dispensing medications often
involves breaching the integrity of the factory container, the dispensed drug can be exposed to
more onerous conditions (such as excessive humidity or microbial contamination), accelerating
the degradation of the API. The discard date therefore can commonly be sooner than the
expiration date. While consumers find this frustrating or uncalled for, and some states have at
times mistakenly regarded it as a fraudulent pharmacy practice, no suitable means has been
developed to quickly determine the potency of a medication; a test would have to be applicable
to all APIs and all formulations - an impossible requirement to meet with current technology.
Some effort has been devoted to developing more generic approaches to stress testing (Klick et
al. 2005). In silico approaches to predict degradation are under development (Lhasa Limited
Leeds UK 2009).
Expiration of valuable stores of critical medicines in developing countries is often perceived to
be caused in large part by the fact that many of the supplies have been donated, causing problems
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and confusion with regard to inventory of excessive numbers of medications. Some of the major
causes for expiration of medications in inventories maintained by healthcare providers and
pharmacies are provided by Nakyanzi et al. (2010). Many of these causes point to the need for
implementing just-in-time supply practices (Daughton and Ruhoy 2010).
The US FDA's required stability testing determines whether a drug can maintain its chemical
identity, strength (potency), purity, and overall quality over the duration of time that the
manufacturer stipulates for the stated shelf-life (via an expiration date); note that the guidelines
pertain to drugs with single APIs and therefore cannot account for the possibility of interactions
between multiple APIs (in combination dosage forms). Manufacturers establish expiration dates
by rigorous testing procedures called "stress testing" that attempt to emulate adverse storage and
usage conditions that might be commonly experienced under real-world conditions. In reality,
shelf-life is an extremely complex function of numerous interacting and wildly changing
variables. Some of the variables that should be considered are heat, cold, range and rate of
change in temperature, humidity, light, type of container, frequency of container openings,
interaction of APIs with other chemicals, dosage form (e.g., solid versus liquid), and how all of
these interact.
For these reasons, expiration dates (or discard dates) do not necessarily mean that a medication
cannot remain useable for longer periods. Indeed, stability has been noted for some medications
for periods of 10-15 years or more; this is especially true for solid dosage forms. But note that
two of the factors most affecting shelf-life are humidity and temperature, and these tend to be
maximized in the two locations of a home most used for medication storage (i.e., the kitchen and
bathroom).
There are so many factors involved with drug stability that it is simply not possible to
accommodate them all in stability testing. The results from stability tests therefore prompt many
questions with regard to their predictive value under real-world conditions. One of just many
examples showing the nuanced complexity is the difference between the removal of a container's
plastic cap during testing versus removal under actual usage by the consumer. The variables
become innumerable when considering the types of plastic caps and containers, types of closer
mechanisms, swings in temperature and humidity, and patient misuse or abuse of the container
(Shabir 2008). These problems are compounded with the introduction of ever-more diverse and
complex containers and delivery devices.
Concerns are not just loss of potency (from the physicochemical breakdown of the formulated
API), but also formation of hazardous reaction products, failure of the formulation (e.g., reduced
propensity of a tablet to dissolve; precipitation of API from solution), or growth of bacteria (e.g.,
from breakdown of the preservative). One criticism of accelerated stress testing is the use of
conditions that are unrealistically harsh, leading to the formation of "irrelevant" or unrealistic
degradation products or degradation-related impurities (DRIs) (Klick et al. 2005).
Long debated is whether a better understanding of shelf-life and ways to ensure optimal storage
conditions could extend expiry, possibly leading to fewer leftovers. The published literature is
replete with debates as to whether drugs really expire and arguments that better knowledge of
expiry could reduce the incidence of disposal.
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Loss of potency is perhaps the major concern with regard to use of expired medications. But also
frequently cited is the potential for increased toxicity. The published literature (e.g., Anon 2002),
however, does not support a focus on increased toxicity: "There are virtually no reports of
toxicity from degradation products of outdated drugs."
Human toxicity resulting from expired medications is a notion that originated with a single report
(in 1963) regarding degradation of tetracycline; but even this report has been called into question
(Pharmacist's Letter/Prescriber's Letter 2007). Even so, isolated reports sporadically surface of
new concerns, as illustrated by gabapentin degrading to 2-aza-spiro[4.5]decan-2-one (gabapentin
lactam), an DRI with demonstrated toxicity (Khan 2010).
A major program that has contributed much to the understanding of shelf-life is the DoD/FDA
SLEP program (Shelf-Life Extension Program), the largest and longest-running drug shelf-life
evaluation study. Many insights have emerged from this extremely useful program, which has
also served to save millions of dollars by allowing the military to delay its stockpiled drug
replacement schedules. The SLEP program has established that when properly stored, many
drugs can be used for periods extending substantially past their expirations - e.g., an average
extension of 66 months for 88% of the tested lots (Courtney et al. 2009; Lyon et al. 2006).
While real-world shelf-life might sometimes be much longer than stated (when stored under
optimal conditions), the range in shelf-life can vary markedly among production lots (Khan
2009).
Another program, the Strategic National Stockpile (SNS) monitors drug potency, but not past
expiry (OPHPR 2010).
The SLEP has demonstrated that expiration dates are extremely conservative for optimal storage
conditions, with many drugs maintaining over 90% of their API content for years longer. And
given the very large cost savings demonstrated by the SLEP (Woods 2005), many have found it
surprising that (with one recent exception) no analogous programs have been attempted for drugs
in the consumer domain. This is even more surprising given that the American Medical
Association made this recommendation nearly a decade ago (AMA 2001). An example of a
recent attempt at organizing some limited independent testing on a select number of drugs is the
program designed by the Prescription Research Institute (Prescription Research Institute 2010).
Many reports of shelf-lives that considerably exceed expiration lend controversy to the expiry
issue. An overview is presented by Lyon et al. (2006). Some specific examples include the
following. A number of drugs have been shown to have shelf-lives of 9 years and beyond those
stated (Stark et al. 1997). Amantadine and rimantadine hydrochloride (anti-influenza A) have
been found to be extraordinarily stable under ambient conditions for over 25 years - with no loss
in potency (Scholtissek and Webster 1998). Theophylline has been shown to retain 80% of its
potency more than 30 years after being stored under household conditions (Regenthal et al.
2002). Metoprolol and propranolol, when stored under routine conditions, had shelf-lives of at
least 5 years (Jasihska et al. 2009a; b). Even drugs that are the least stable, such as those
requiring refrigeration, are known to maintain potency past expiration. Of the roughly 200 or so
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drugs that require refrigeration, many are known to be stable at room temperature for days,
months, or years (Cohen et al. 2007). Some drugs have been shown to maintain stability even
under tropical conditions (Bate et al. 2009).
While much attention has been devoted to the fact that many medications can retain potency past
their stated expiration dates, much less attention has been devoted to the incidence of drugs
rapidly declining in potency prior to their expiration dates because of the adverse conditions of
their storage. This might be particularly true for medications requiring refrigeration or those
particularly susceptible to light, heat, freezing, or humidity. Known examples are rare, and
include: epinephrine (dark storage required; must also minimize oxidation by air),
carbamazepine (in tablet form reported failure to dissolve), and notably nitroglycerin, insulin and
some liquid antibiotics. It is important to recognize that drugs can be adversely affected not just
by excessive heat, but also by extreme cold. Freezing, for example, can alter the formulation of a
drug, changing the absorption characteristics of the API; this is a particular issue for liquid
formulations, where APIs can precipitate (Shea et al. 1981).
At this other end of the shelf-life spectrum are drugs stored under non-optimal conditions by
emergency medicine services, such as ambulances. These may degrade prior to expiration
(Fowler -Year Unknown; Gammon et al. 2008). Some stability studies targeted for the
potentially extreme environments of ambulances, however, sometimes show that certain
medications are extremely stable. One example is diazepam gel, which was shown to be suitable
for 48 months (Alldredge et al. 2002).
One aspect of shelf-life rarely mentioned is the possible role of microbial contamination in
serving to degrade the preparation (Baird et al. 1979).
Illustrating several of the countless factors that complicate prediction of shelf-lives are the
following. Pharmacy compounding makes determination of shelf-life much more complex,
especially for reactive APIs such as chemotherapeutics, which can have shelf-lives of hours
(Benizri et al. 2009). With medications having more than one API, if two or more APIs are
deliquescent, the relative humidity required for the solid-solution transition is lowered. This
leads to API dissolution at humidities lower than ordinarily expected. Once in solution, APIs that
are more reactive chemically can degrade faster (Mauer and Taylor 2010).
Finally worth noting is that expired drugs can serve as a source for counterfeit drugs, simply by
their relabeling with new expiration dates and reintroducing them to the distribution system
(Hileman 2003).
Roles of packaging and medication devices
Drug packaging can play significant but little-discussed roles in drug waste. The design of drug
packaging, including containers and delivery devices, can: (i) serve as a waste problem itself,
separate from that of the actual drug, (ii) amplify the generation of leftovers and the subsequent
need for their disposal, and (iii) be designed to minimize the generation of leftovers.
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Packaging constitutes waste in its own right, with a set of concerns distinct from APIs; it can also
complicate processing of disposed drugs or introduce new demands for disposal (such as when
sophisticated delivery devices are used). Packaging adds a number of variables and determinants
in the disposal of drugs themselves. Depending on its design, packaging can dictate what route of
disposal a consumer might select (e.g., bingo cards are not conducive to flushing), it can increase
the quantities of medications that are eventually disposed (e.g., large, bulk-size containers of
hundreds of doses that expire before use), or it can reduce the quantities of drugs being disposed
(e.g., drug dispensing containers that improve patient compliance). Many other possibilities are
also at play.
Drug products could be designed and packaged with the need for their eventual disposal as a
primary requirement. And proper design must take into account the fact that the needs imposed
for disposal might differ for used medications versus unused medications. Any special
considerations that might be necessitated by disposal need to be integral criteria at the start of the
drug design cycle.
Innovation in packaging design and function could play a key role in the drug disposal
conundrum. By improving compliance, fewer medications would require disposal. And by
adding improved safety features, fewer poisonings would result. By implementing a refundable
deposit fee on the container (which could be warranted with sophisticated recyclable containers),
consumers would also be encouraged to return to the pharmacy, increasing the odds of
communication with the pharmacist and further improving compliance.
A possible downside to adoption of new types of packaging is that the array of leftovers could
become much more confusing to the eye, possibly further complicating waste collections.
Packaging also adds to the burden of solid waste and can increase the difficulty in dealing with
drug residuals that remain in devices. Almost nothing is known regarding the fate of packaging
materials (or their API residuals) in landfills.
Advancements in package design have not been fostered by academic research - partly because
there has been little demand from the pharmaceutical industry. Impetus has come primarily from
consumers and the government (e.g., child-resistant closures) and from private sector research
and development. Several overviews of packaging design and technology used in the
pharmaceutical industry are available (Bauer 2009; Freedonia Group 2008).
Pharmaceutical packaging and delivery devices will pose increasing challenges for medication
disposal, especially as the medication and the packaging begin to merge as an integral whole
(such as the integration of electronics). One example of an electronic delivery system is the
lonsys system using fentanyl. The lonsys is an iontophoretic transdermal system that provides
on-demand dosing. As demand for innovation in pharmaceutical packaging grows, new
challenges will continually arise with respect to disposal.
Few take-back programs currently recycle conventional containers separately. One exception is
ElephantPharm (ElephantPharm 2010).
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The presence of residual APIs in used delivery devices and certain containers poses a major
route by which APIs can enter landfills. Comparatively little consideration has been devoted to
the design of packaging that allows complete dispensing of API contents or that facilitates
separation of the API from the packaging prior to disposal. A sustainable approach to disposal
must consider the disposition of the medication containers, packaging, and devices (Dillon and
Rubinstein 2005b).
One example of a delivery device that may contribute unnecessarily to solid waste is the device
used with pressurized metered-dose inhalers (MDIs). Each MDI comprises a canister, which
contains the formulated API, and a plastic inhaler actuator (or "boot"). Each MDI is dispensed
with a new "boot." As an alternative, MDIs dispensed in multiples could be dispensed with only
one boot, or consumers could opt to reuse old boots for new prescriptions. Alternatively, MDI
boots could be made from biodegradable polymers. Orally inhaled and nasal drug products
(OINDP) tend to be at the forefront of design of new delivery devices. They would therefore
make likely candidates for factoring in the potential solid waste footprint during design. Another
step in reducing the environmental footprint would be the development of self-contained
mechanisms for deactivation of the API residuals remaining in used devices - analogous to the
approaches that are being explored for transdermal devices (Cubbage et al. 1998; Warner et al.
2005).
An example of what can be accomplished with innovative packaging is the NextBottle (One
World DMG 2010) - a sophisticated design that attempts to address all of the major limitations of
conventional containers. The NextBottle attempts to provide a container that does not resemble
conventional pill bottles and at the same time provides unit dispensing, indication of day of
dispensing, better protection from humidity and oxygen, and child resistance while improving
ease of opening by adults. The intent is a container that reduces accidental poisonings while
improving patient compliance. The ability of the medication manufacturers to customize the
graphics on the container could also reduce medication errors, especially for patients with
multiple medications on complex dosing schedules (polypharmacy). Some of the recent package
redesigns have attempted to address a range of problems at once. One that tries to address child-
resistance and a number of aspects dealing with compliance is the Key-Pak (Keystone Folding
Box Co. 2010).
Packaging is a major determinant of API stability and therefore real-world expiration. Many
approaches are possible for extending the time to where medications require disposal because of
expiry. Examples include more effective oxygen and moisture scavengers and better ways for
protecting against heat, humidity, and light. One possibility would be the development of "smart"
or "intelligent" packaging systems - such as those used in the food industry - where the objective
would be lengthening shelf life and/or monitoring and providing real-time indication of the
quality of the medication and whether it is approaching expiry (whether the storage conditions
have been adequate, such as proper temperature, humidity, light, and duration). Knowing the
actual shelf life (which is a complex function of storage conditions and time) could prevent the
unnecessary, premature discarding of medications. The issues surrounding package redesign and
expiry are discussed by Daughton (2003b).
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Instead of adding to the solid waste burden, packaging and devices could be diverted to more
useful purposes. "Repurposing" or "up-cycling" reclaims constituent materials for uses that do
not match their original purpose. Repurposing has already been implemented in the medical
waste arena by Sharps Inc, in their "Waste Conversion Process" that repurposes used sharps,
syringes, and certain other medical devices into raw materials used in fabricating other non-
medical products; one outcome of this work has been development of a product called PELLA-
DRX™ , which can be used in the manufacture of many non-medical products, including cement
(Sharps Compliance 201 Ob).
Of peripheral relevance, the packaging used for physician samples can differ from that of
dispensed drugs. The average weight for the packaging used for samples is substantially greater
(Pai et al. 2000).
Role pharmaceutical promotions: sampling, detailing. PTC and drug data
mining
Manufacturer promotions are a contributory source to the need for drug disposal and for overall
pharmaceutical usage, which serves as the main source for API residues in the environment (via
excretion). This topic was covered in Ruhoy and Daughton (2008). Some additional perspective
will be provided here.
Promotions take place in the healthcare environment (referred to as "detailing" of sales
representatives), where free samples are often provided (referred to as "sampling") primarily to
physicians and sometimes to pharmacists. It also takes place directly to the consumer in the form
of direct-to-consumer (DTC) advertising. New and independent analysis of the investment in
promotions made by pharmaceutical manufacturers shows that they exceed investments in R&D
(Gagnon and Lexchin 2008). Many types of promotions are employed and are continually
evolving. Included are the less-recognized forms such as ghostwriting and illegal off-label
promotion; "seeding trials" and educational grants can also sometimes be included. Gagnon and
Lexchin (2008) conclude that in 2004, promotions per physician amounted to $61,000.
Promotions accounted for one quarter of sales dollars versus only 13% for R&D. So about twice
as much was spent on promotions as on R&D. The significance of this with regard to leftover
drugs is that a certain (but unknown) amount of promotions may contribute to distribution of free
samples and to imprudent or unnecessary prescribing (and eventually dispensing). When the
consumer experiences a lack of perceived benefit or side effects, the course of the medication is
ceased (non-compliance) (Gagnon and Lexchin 2008). Lo and Field (2009) present discussions
regarding conflicts of interest at the interface between the practice of medicine and the
pharmaceutical industry.
An overview of how pharmaceutical marketing can affect the practice of prescribing is presented
by Rodriguez Mari (2007). Pomerantz (2004) argues that DTC advertising and other drug
company marketing practices to physicians (e.g., provision of free samples that only comprise
expensive, brand-name medications) attempt to shift consumers to higher-cost but not
necessarily better drugs. This serves to inflate patients' expectations, eventually leading to unmet
expectations, followed by early cessation of the remaining course of medicine (non-adherence).
Pharmaceutical Research and Manufacturers of America (PhRMA) maintains that DTC can
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improve patient compliance (PhRMA 2008b); no peer-reviewed studies, however, were located
in the published literature to support this stance, nor were any studies cited in the PhRMA report.
It seems that the limited evidence points to promotions such as DTC as possibly being
interconnected with the issue of patient non-compliance and therefore a factor leading to leftover
drugs. Promotions such as sampling have more direct connections with drug wastage, as a result
of expiration. Locating, deciphering, reading, and tracking expiration dates on physician samples
can be surprisingly difficult and time consuming. This routinely results in accumulation of
expired samples in physician offices. Lohiya (2006) has proposed a labeling system to assist
physicians.
In attempts to avoid the problem with expiration, donation of unwanted samples by physicians is
often pointed to as a solution. But the practice of physicians donating unused drug samples to
"free" (charitable) clinics is controversial, as provisions of the US FDA Prescription Drug
Marketing Act (PDMA) prohibit distribution of drug samples "except by the manufacturer or an
authorized distributor of record"; see page 776 under the heading "Responsible Reuse,
Recycling, and Donation" in Daughton (2003a). A discussion of the law with respect to donation
of free samples can be found in McKee (2006, see page 53).
One argument in favor of sampling is that free samples serve as a "safety net" for those in need
and cannot afford medications. The counter argument is that they simply serve as a marketing
tool directed only at those who might later commit to purchasing. A finding from Cutrona et al.
(2008a) is that free samples are primarily given to those who can afford to buy longer-term
prescriptions. A letter in reply to Cutrona (2008b) maintains that providing free samples to the
poor represents a disservice because they would not have further access to expensive brand name
medications once the samples expire. This could also cause medical problems when a course of
treatment is terminated early. A number of reasons are provided for not providing free samples to
the indigent (Cutrona et al. 2008a; b; Vincent et al. 2008).
The study by Cutrona et al. (2008a), however, was deemed flawed in several press releases by
PhRMA (PhMRA 2008; PhRMA 2007; 2008c). Although PhRMA's main argument is that
sampling is needed as a source of free drugs for the indigent, the creation of the Partnership for
Prescription Assistance (PPA) would seem to have largely accomplished that purpose (PPA
2010).
In PhRMA's "Code on Interactions with Healthcare Professionals" (PhRMA 2008a), their stance
on sampling is clearly stated: "It is appropriate to provide product samples for patient use in
accordance with the Prescription Drug Marketing Act." PhRMA implemented a voluntary ban on
gifts in 2008.
Only in the last several years have some manufacturers begun to become sensitive to the issue of
promotions (Weintraub 2008). A comprehensive overview of the many issues surrounding
sampling is available from Chimonas and Kassirer (2009). The use of free samples possibly
subordinates a more prudent, cost-effective evidence-based approach to prescribing, as it
encourages the use of more expensive newer drugs. On the basis of existing evidence, Lo and
Field (2009) recommend that clinicians should not accept free samples.
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An organization that has actively argued against the practice of sampling and other drug
company giveaways in the physician office is "No Free Lunch" (Goodman 2010). Only recently
has the concept of educating physicians about the negative aspects of promotions emerged.
"Counter-detailing" is used by organizations that visit physicians to provide evidence-based
advice on prescribing and attempt to discourage the ad-hoc, blind acceptance of free samples.
One example is the SCORxE program (SCORxE 2008).
Sampling also has links to drug diversion, which is known to be practiced by both sales
representatives and doctors (Chimonas and Kassirer 2009).
Regardless of the usefulness of sampling, most of its negative attributes could be reduced if
physicians employed vouchers, where patients could then obtain the free samples from the
pharmacy. This would greatly reduce the problems with expiration, diversion, and leftovers (as a
portion of patients are known to accept free samples with no intention of ever using them, and
might then choose to not have the voucher filled).
Finally, there is one aspect of the many inter-connections between pharmaceutical manufacturers
and prescribers that is indirectly tied to promotions. It purportedly can have major ramifications
for whether a particular drug will be successful and experience an increasing sales trajectory.
Physician prescribing data has long been available to pharmaceutical manufacturers. These data
are called prescriber-identifiable [PI] data. PI data are mined by health information organizations
(HIOs) such as IMS Health. These data are specific to individual physicians. PI data are used for
a wide array of purposes, including monetary compensation for sales forces (Steinbrook 2006).
One of the outcomes of this practice is that PI data ultimately can be used to influence physician
prescribing practices and behavior. One example is the concern that use of PI data could shift a
physician's prescribing behavior away from a generic drug and toward a branded drug. PI data
can also be used to increase drug usage. Bans on PI data mining have already been enacted in
three states: New Hampshire, Vermont, and Maine. Over a half dozen other states have
introduced legislation to restrict mining of PI data (Chernove et al. 2009).
Roles of counterfeiting, importation, and Internet pharmacies
Counterfeiting is partly inter-related to diversion, as not all counterfeiting results in fake drugs
(those containing no API) or in drugs containing APIs different from those that should be present
(undeclared APIs). A portion of counterfeiting relies on the use of legal drugs (obtained by theft)
already in legitimate distribution channels. This could simply involve the repackaging of
legitimate drugs; for example, expired or nearly expired drugs can be relabeled with new
expiration dates and reintroduced to the legal distribution system (Hileman 2003).
Counterfeiting can contribute in two primary ways to amplifying the quantities of APIs entering
the environment: first by introducing more APIs (both legal and illegal) that would not otherwise
be dispensed as a result of legitimate prescribing, and second by diverting legitimate drugs from
the normal distribution channel and thereby requiring the manufacturing of additional inventory
to make up the difference (to meet legitimate prescribing/dispensing needs); clandestine
manufacturing also introduces APIs and other wastes associated with synthesis and formulation
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to sewers and waterways. When a drug shipment is stolen (and even if subsequently recovered),
often the manufacturer is required to recall and destroy all existing supplies - further
compounding the problem (Duggan 2010).
Counterfeiting can involve whole, formulated drugs diverted from the legitimate system of
distribution and then introduced back into the system; this is often accomplished via the gray
market (an ill-defined market that serves as the interface between the legitimate and illegal
markets) - or sold directly within the gray market itself. Or it can involve the clandestine
synthesis of APIs (some of which might be bona fide), which are then used to illegally
manufacture drugs anew. These clandestine drugs may or may not contain the API(s) declared on
their labels, and they may also contain a bewildering array of adulterants (including undeclared
APIs) or other contaminants as a result of not following good manufacturing practices (Daughton
2011). These counterfeited drugs are then introduced into the legitimate distribution system or
sold on the gray market. The interface between the legitimate and illegal drug markets can be
very nebulous and hard to define (Daughton 2011).
Overviews on counterfeiting are presented by Hileman (2003) and Jackson (2009). Counterfeit
drugs are also used as a way to finance terrorism (Jackson 2009).
The importation of drugs outside the regulatory system of the US is a source of additional drugs
with unknown, but likely very large, magnitude. Estimates from the FDA have ranged from
millions to tens of millions of packages of illegally dispensed prescription and counterfeit drugs
per year. All of these serve as additional contributory sources for leftover drugs by consumers as
well as a large source of drugs requiring disposal after confiscation by law enforcement and
customs. Importation is a complex issue. A comprehensive overview is provided by the USGAO
(USGAO 2005) and Hubbard (2001).
As with drug screening, technology to deter or simply detect counterfeiting is in a perpetual state
of evolution. Numerous of technologies, including RFID and holograms, have been tested over
the years to combat counterfeiting. Historically, however, each new deterrence technology is
quickly subverted or counterfeited itself. An example of current deterrence technology is
NanoGuardian, which uses a proprietary nanotechnology-based approach to deterring
counterfeiting and diversion (Marks 2010; Nanolnk 2010). NanoGuardian imprints each pill with
a microscopic logo and a 350-digit random code that is changed daily; this technology has been
approved by the FDA and is in the process of being implemented. A much simpler approach that
has been tested in Africa, where counterfeiting is rampant (especially for essential drugs such as
antimalarials), is the use of scratch-off ID codes on packaging that can be relayed by text-
messaging to authenticate the contents (Bennett 13 May 2010); several companies have been
involved with this approach, including mPedigree (http://mpedigree.net/), Sproxil
(http://sproxil.com/), and PharmaSecure (http://www.pharmasecure.com/products-and-
services/product-security/).
A variety of largely illegal means of dispensing drugs serves to exacerbate the entry of APIs to
the environment, as a portion of the dispensed medications are received by those who should not
be using these medications. Included are Internet ("rogue" or "online") pharmacies, "pain
clinics", "pill mills", and others who dispense "under-the-counter." A major focus for these
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dispensers is certain controlled substances, especially opiates used for pain treatment. The first
Internet pharmacies came online in 1999. Surveys show that while low percentages of drug
abusers obtain controlled substances via the Internet, it is suspected that drug dealers may be
obtaining their supplies from these rogue pharmacies. Internet pharmacies also play a role in the
distribution of illegal drugs (drugs not registered with the FDA, such as designer drugs)
(Daughton 2011), as well as diverted and counterfeit drugs (see FDA's page on purchasing drugs
over the Internet: USFDA 201 Ob).
Overviews of the issues surrounding Internet pharmacies can be obtained from: (Barthwell et al.
2009b; CASA 2006; 2007; 2008; deKieffer 2006?; Fox 2004; Lessenger and Feinberg 2008;
USGAO 2005). The sale of prescription drugs via Internet pharmacies or Internet auction sites is
regulated in the US under 15 U.S.C. § 45(a) by the Federal Trade Commission (FTC).
In response to the advent of Internet pharmacies, the National Association of Boards of
Pharmacy (NABP) developed the Verified Internet Pharmacy Practice Sites (VIPPS) program in
the spring of 1999 (NABP 2010a); the NABP also operates an analogous verification program
for online pharmacies that dispense for companion and non-food producing animals (NABP
2010b). Additional verification programs have followed VIPPS, such as: LegitScript (LegitScript
2010) and PharmacyChecker.com Verification Program (PharmacyChecker.com 2010).
The Ryan Haight Online Pharmacy Consumer Protection Act of 2008 amended the CSA and the
Controlled Substances Import and Export Act to prevent illegal dispensing of controlled
substances over the Internet. This was accomplished in part by requiring face-to-face patient-
physician meetings prior to prescribing (DBA 2009b). Prior to the Ryan Haight Act, National
Center on Addiction and Substance Abuse (CASA) had identified 159 web sites offering
controlled substances - 85% not requiring a prescription. Only two sites were VIPPS certified.
Role of donations - and recycling, reusing, reissuing
Discussions involving the donation of drugs invariably become intertwined with the topic of
drug "recycling"; see page 776 under the heading "Responsible Reuse, Recycling, and Donation"
in Daughton (2003a). In turn, the issues surrounding donations and recycling intersect with those
of drug diversion and sharing. So discussions on these topics can become convoluted and
confused.
Consumers are often attracted to the prospects of donating drugs they no longer want, with the
hope that others may benefit. But with few exceptions, consumer donation of drugs is either
illegal or misguided.
Drug recycling and reusing are loosely used terms. Neither really conveys the proper intent.
While reuse is probably a better term with respect to collecting unused, pristine medications for
their subsequent use by new patients, a better term would be "reissuing." Medications are not
actually reused, nor are they recycled, as this implies reuse of previously used medications. Drug
reissuing must take place within the closed loop of distribution/prescribing. These are conditions
that rarely exist - primarily currently limited within long-term care facilities - where the
medications never leave control of those providing the care.
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Medication recycling is fraught with dangers (such as tampering and self-medication errors). For
this reason, it is usually only practiced where tight controls exist on the history of the medication.
More information is in Daughton (2003a). The major question is whether safe programs could be
developed for drug reuse or reintroduction into the distribution/retail chain.
The history behind state legislation enabling donations and reuse within the US is summarized
by the National Conference of State Legislatures (NCSL 201 Ob). The National Association of
Boards of Pharmacy (NABP) is playing a major role in development of policies regarding reuse
of medication (NABP 2009a). Their initial efforts have been focused on those medications that
never leave the closed distribution loop, such as those dispensed in nursing facilities. The
National Association of Pharmacy Regulatory Authorities (NAPRA) in Canada has developed
guidance for pharmacists in Ontario for the reuse of medications (NAPRA 2009).
An overview of drug recycling is available from Pomerantz (2004), Struglinski (2009), and
(Baaklini 2009, in French). Examples of successful reuse programs for unused drugs exist in the
US and Switzerland (Besson et al. 2008; Dispensary of Hope 2009). Despite the laws limiting
the practice of recycling in the US, recycling may be even further restricted in other countries,
such as Canada (Doyle 2010).
The practice of donation is generally reserved for humanitarian disasters, but is sometimes called
the "second disaster" because it generally causes far more problems than it solves, especially
when it involves "dumping" (the shipment of expired or near-expiration medications to remedy a
pending or anticipated disposal problem or to gain tax advantages). Historically, donation of
drugs has essentially been used as a form of geographic "redistribution" - where drugs that are no
longer wanted are shipped to other countries. Donations often simply serve to transfer a pending
disposal liability from one geographic locale to another - frequently an impoverished country
lacking the means or money to properly dispose of medication wastes. Donation of drugs within
the US (for example to free clinics), is generally a practice that is prohibited. A summary of the
problems surrounding donations is provided by Pinheiro (2008). A focus on the role of expiry is
provided by Reich et al. (1999).
The donation of drugs to humanitarian relief operations and charities is an extremely
controversial issue - primarily because of numerous concerns regarding human safety (e.g.,
tampering, terrorist sabotage), disposal, and drug diversion (illegal reselling). While
pharmaceutical manufacturers and distributors can participate in donations, no formal guidance
exists for the public. The donation of pharmaceuticals unsuited for particular relief efforts has
resulted in the need for expensive warehousing of extremely large quantities of drugs that must
then be disposed; the added burden imposed by the need for more oversight also diverts
personnel from more urgent tasks. The two major reasons that donated drugs can be unusable are
that they have expired or do not match the most pressing therapeutic or healthcare needs; other,
unanticipated reasons can include illegible labels, labels that cannot be translated, and unfamiliar
dosage forms or strengths. This was a large-scale problem for the relief efforts during the
Bosnian conflict and later (well after the WHO guidelines were established), such as following
the Indonesian Tsunami. Most relief organizations prefer to receive money rather than
pharmaceuticals. Drug expiry and appropriateness are two major issues that make donation
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programs problematic. With this said, the donation of pharmaceuticals to those charitable
organizations that accept certain select drugs (in their original, sealed manufacturer containers)
for distribution overseas is a limited option.
Donations for humanitarian emergencies are renowned for creating massive problems with
respect to disposal of gross quantities of unneeded or expired medications. This has been
repeatedly documented by the WHO and others. Indeed, it was this very problem (the problems
imposed by the need to dispose of huge quantities of unwanted medications following the
Bosnian war) that prompted the WHO to establish its international guidelines for donations.
Despite the fact that these guidelines were published in 1999, they continue to be frequently
ignored in relief efforts (Grayling 1999; WHO 1999 [revised]).
Donated drugs are also known to cause human poisonings as a result of poorly labeled or
undocumented medications. One such instance occurred in Lithuania, where a veterinary drug
(the anthelminthic closantel) with no human use was administered to 11 women for
gynecological problems, resulting in temporary blindness and other problems ('t Hoen et al.
1993).
Some of the statistics on the quantities of drugs donated during humanitarian crises are presented
by Autier et al. (2002), who also proposed recommendations for improving the handling of
donations in future crises. As a result of the conflict in Croatia, thousands of tons of
pharmaceutical wastes resulted from foreign donations and required storage in 250 warehouses
(Autier et al. 2002). More than a decade after the war (in 2007), hospitals in Croatia still had
large repositories of donated drugs stored as hazardous waste (Marinkovic et al. 2008).
As a result of the 26 December 2004 tsunami that struck Aceh, Indonesia, 4,000 tonnes of
unrequested medications were received. Despite the issuance of the international guidelines on
drug donations 10 years prior by the WHO, the situation had actually grown worse. As a
consequence, the Pharmaciens sans Frontieres (PSF) [Pharmacists Without Borders]
recommended that the WHO guidelines be integrated into national drug policies worldwide and
that drug donations be regulated as a public health issue; it deserves noting that donations can
also be an environmental issue (PSF 2005).
The quantities of unwanted donated drugs are often so large that they far exceed any capability
or capacity to properly dispose of them - whether by incineration or burial as hazardous waste.
As a result, much is haphazardly discarded or stored indefinitely (where it poses diversion risks).
Many of the problems faced by donation "repositories" are summarized by Wapner (2009).
Examples of economic consequences of drug donations are recounted by Ette (2004) and
Guilloux(2001).
Drug diversion and sharing (possibly made worse by current disposal
guidance)
Informal surveys of those who have dropped off drugs at US take-back events reveal that the vast
majority would otherwise have elected to keep storing their unwanted medications at their homes
rather than discarding them to trash or sewers. While this may not reflect the behavior of the
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general population, the current absence of any prudent way to dispose of drugs other than
through a patchwork of take-back events and programs clearly exacerbates the potential for
diversion and unintended poisonings in the home setting. One indicator of the diversion of
medications from homes and elsewhere is the anecdotal reporting of large quantities of expired
medications sold at flea markets.
In reality, medications are located at seemingly countless locations throughout society (Ruhoy
and Daughton 2008). Diversion probably occurs from all of these locations. Perhaps the most
infamous instance of diversion was discovered in the Shipman Inquiry, begun in 2001. Harold
Shipman, a UK physician used controlled drugs diverted from deceased patients to murder
hundreds of patients under his care (Royal Pharmaceutical Society 2006).
Drug diversion was a recognized problem as early as the 1950s. A number of overviews of the
drug diversion problem are available (CASA 2005; Inciardi et al. 2009; Inciardi et al. 2007).
Efforts began in 1959 to amend the Federal Food, Drug, and Cosmetic Act to control diversion
from distribution channels. By the early 1970s, the linkage of diversion with abuse and crime
had become firmly established (Wochok 1973). Stockdale (2008) compiled over a hundred
abstracts of papers dealing with drug diversion, but the full literature is much more expansive.
Diversion includes the nonmedical use (NMU) of drugs, which could be as high as 20%
(Stockdale 2008). Efforts to control diversion have long been complicated by two opposing
needs that require careful balancing: the need to minimize diversion to the black market while
simultaneously not restricting access for medical treatment, especially pain treatment. Simply
put, the major dilemma for the drug distribution system (especially for the physicians) in the
treatment of pain is in balancing the restriction of medications prone to diversion and abuse
against the risk of under-treating pain (which requires ready access to medications with high
abuse potential). Doctors are caught in between the obligation to treat legitimate pain and the
need to be alert to abusive use. The dilemma in finding the right balance in the clinical use of
analgesics has been a top concern of the FDA's (Barthwell et al. 2009a; b; Woodcock 2009).
Diversion can occur in numerous ways and places within the drug lifecycle. It ranges from
outright theft to seemingly innocuous "drug sharing." Showing why the DEA prefers the closed
distribution loop with a system of internal and external controls, diversion occurs even within
reverse distributors and sometimes even by their owners (Walsh 2009). Thefts are not
uncommon (Solomon 2010) and have even been reported from USPS. Theft of drugs sent
through the mail (either new prescriptions or unused drugs being returned for disposal) could
eventually become a growing mechanism for diversion. It is most likely also a problem that is
under-reported by USPS to the news (Warren 2010). Diversion via theft and burglaries is
believed to be underestimated (Inciardi et al. 2007).
At least one report of a new drug diversion scheme has emerged that capitalized on the mere
existence of drug collection programs - diversion of drugs from sham medicine collections, made
to appear real (Ranger 2010). In a similar manner, diversion could easily occur from sham
charity programs set up to purportedly collect medications donated for emergencies. Diversion is
clearly a possibility for legitimate take-back programs, and is the major reason the DEA requires
the presence of law enforcement when controlled substances are involved.
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Leftover drugs represent opportunities not just for diversion and abuse but also for
"inappropriate" use, such as self-administration for incorrectly assessed but still legitimate
medical needs. A special aspect of diversion is drug "sharing" (sometimes called recycling or
reuse). Drug sharing is a more recent twist on NMU, a practice that involves drug loaning or
borrowing. An overview is provided by Goldsworthy (2008). Sharing promotes self-medication
involving inappropriate or imprudent use, and as such has great risks. Exposure to teratogenic
Pharmaceuticals (such as isotretinoin), for example, would be a unique concern for drug sharing -
particularly for young women. Self-medication can be particularly problematic with antibiotics
because of the unnecessary selection for pathogen resistance. Antibiotics are commonly found
stockpiled in homes throughout the world for future use (Stratchounski et al. 2003). Any drug
with a REMS (Risk Evaluation and Mitigation Strategy) in place could pose critical risks in
sharing.
Any measures designed to reduce the incidence of drug leftovers could greatly help in also
reducing drug sharing. But it is critical that these measures be designed to not restrict the practice
of medical care.
Roughly a quarter of those surveyed reported sharing of medications; rates varied depending on
the therapeutic class of drug (Goldsworthy et al. 2008). Estimates in Gulf countries are that 20 to
30% of household members use shared medications (Abou-Auda 2003).
Generally, the reuse or recycling of medications is illegal, especially for controlled substances.
The informal sharing of drugs among individuals on small-scale local levels is an increasingly
prevalent practice.
Ironically, a major driver of the consumer's desire to "recycle" their leftover medications by
inappropriately donating to charities or sharing with friends is the desire to avoid further
wastage. The perception is that leftovers (even when expired or hazardous) not only have
economic value but also continued therapeutic value. Consumers are frequently highly frustrated
that leftovers cannot be put to good use by friends or others in need. The realization that
unopened medications cannot be reused and must be disposed can discourage the return of
leftovers to collection programs once it is clear that returned drugs are simply disposed. At the
same time, one of the reasons cited by pharmacies in avoiding participation in drug returns
programs is the potential for the public to suspect that the returned medications would be used to
fill new prescriptions (Musson et al. 2007).
While drug sharing is indeed one practice with the potential to reduce the need for drug disposal,
it also heightens the potential for poisonings as a result of adverse drug events (ADEs). It can
also possibly increase the excretion of API residues above levels that might have normally
occurred if the recipients of the shared drugs would have otherwise never been prescribed the
medication.
In recent years, exceptions have been granted in certain situations for recycling where the
prescription-consumption cycle is closed and highly controllable. This ensures no opportunity for
tampering. For example, the recycling of drugs by nursing care homes, such as permitted by
Oklahoma's "Utilization of Unused Prescription Drugs Act" (Broyles et al. 2007) allows for the
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reuse (reissuing) of non-controlled substances prescribed in nursing care facilities for indigent
care. Wider-scale use of computerized unit-dose dispensing technology will continue to facilitate
this practice.
Despite the fact that the risk of tampering (adulteration, sabotage, etc) is a major driver behind
restrictions on recycling, no evidence was located in the published literature indicating that any
instances or poisoning have been reported. But this cannot account for the possibility that
instances may have occurred unnoticed.
Worth noting is a practice that intersects sharing and donations. It involves a few select
organizations that organize the collection of specific donations from the public and target special
uses. They ensure that the collected medications have valid uses by the recipient. One example is
the Starfish Project which collects unused antiretroviral medications to support HIV-positive
Nigerians (Normal 2008). Another that recycles AIDS medications is RAMP (RAMP 2008). One
organization is helping to coordinate excess supply (at the manufacturer level) with real-time
needs (at the free clinic level) (SIRUM 2010).
The most important aspect of diversion with respect to drug disposal is whether the two are
actually linked. Data are very rare regarding whether drugs are diverted from active household
stocks of medications (those still in use for their intended purpose) or from stocks simply being
stored by the consumer and awaiting disposal. This is an important point, as it determines how
important diversion might be as a driving force for reducing home stockpiles. One of the only
surveys to date determined that one in five residents of Washington/Oregon had experienced
instances of diversion from their drug supplies. But of this subpopulation, 80% said that the
diversion occurred from an active stock; only 10% said the diversion occurred from
expired/unwanted drugs (Whittaker 2010, see slide 17). This type of survey needs to be more
broadly implemented if a determination is to be made as to whether more timely disposal of
medications actually reduces diversion. The data presented by Whittaker indicate little impact.
The real question might be whether the dispensed medications or their quantities are necessary to
begin with.
There are also special circumstances that unintentionally lead to diversion. For example, many
patients admitted for in-patient psychiatric care leave their medications at home, where they can
be diverted by others (Robin and Freeman-Browne 1968). This could be easily prevented by
healthcare providers inquiring as to what medications the patient has remaining at home and to
ensure they are secured or properly disposed.
Diversion is a practice that continually evolves. There are too many varieties to discuss here.
Drugs not yet on the market are even known to be diverted from clinical trials (Daughton 2011).
There are two types of diversion not yet mentioned, however, that receive significant attention in
the press - doctor shopping and hospital shopping. These tend to be used by drug abusers and
addicts. These forms of diversion essentially capitalize on otherwise legal means for obtaining
drugs - with no outright theft involved. In doctor shopping, patients visit multiple doctors (often
for bona fide conditions, but sometimes with faked symptoms) to obtain multiple prescriptions
for the same medication (often opiates); the physicians are not aware of each other's prescribing
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for the same patient. Hospital shopping is a variant where free emergency services are duped into
prescribing unneeded drugs for faked conditions (Sullivan 2009).
To deter "shopping," prescription drug monitoring programs (PDMPs) have been established in
various states (41 states as of early 2010) (NCSL 2010a). PDMPs track pharmacy dispensing of
controlled substances. Physicians can request reports that list all medications that a patient has
received over a 6-month period. These programs, however, are not standardized and do not
communicate well with each other. There also is no requirement to make use of PDMPs, and the
system is easily circumvented by motivated drug abusers (Park 2010). The Department of Justice
is attempting to improve the PDMP system. It has selected the Heller School for Social Policy
and Management (Brandeis University) to work on a new initiative for reducing diversion: the
"PMP Center of Excellence" (Brandeis University 2010).
Drug disposal for reducing diversion and abuse
While the threat of diversion and abuse was the original driver behind development of the
ONDCP disposal guidance issued in February 2007, and which was revised in 2009 (ONDCP
2009 [updated October]), no study is evident that has tried to distinguish the origin in households
of medications being diverted or abused. As with poisonings, it is known that diversion and
abuse is a major problem. But it is not known to what extent expired drugs or drugs awaiting
disposal are contributors to the problem (as opposed to medications still being actively used for
their intended purposes). Clearly, a drug's owner will notice reductions in their supply of actively
used medication more readily than reductions in those medications no longer being used and
which should have been disposed; so it is possible that diversion from stocks of drugs no longer
being used could be important. But also, as with poisonings, used delivery devices such as
transdermal patches (especially those containing opioids) are a known source of abuse (e.g., via
reapplication to the skin).
Without research specifically targeted at determining the relative proportions of medications
diverted from household stocks that are still in active use versus those awaiting disposal (or those
just disposed to trash), it can only be assumed that ridding homes of unwanted drugs will help to
reduce drug diversion or abuse.
Drug disposal as a contributor to ambient environmental levels
Just as with the incidence of poisonings, the significance of drug disposal to sewers as a
contributing source of APIs to the environment is unknown and controversial. In brief, no
definitive statements are yet possible. Broad generalizations are not possible because the
contributions undoubtedly vary immensely among individual APIs. The contributions from
disposal probably vary depending on the individual API, as the rate of non-use can vary
dramatically across medications and the degree of excretion varies from nearly nil to nearly
100%. The rate of non-use can also vary among individuals, posing great challenges for
modeling. Clearly, disposal of a medication containing an API that can be extensively
metabolized (little would normally be excreted unchanged) holds a much greater potential for
contributing to its environmental loading than would a medication containing an API that is
largely excreted unchanged (Daughton and Ruhoy 2009a). Stated another way, generally an API
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that would normally be excreted unchanged (not altered by metabolism) has a greater chance of
contributing to its environmental levels when used as intended (e.g., ingested) compared with
when it is disposed to sewers.
Disposal's contributions may very well prove significant for a select few medications. But for
many or most others, it will undoubtedly prove minuscule. Many figures on the contributions
from disposal have been recited in the non-peer-reviewed literature and at conferences but they
lack any supporting data. Most are based on conjectures or guesstimates.
The use of collection programs for leftover drugs to reduce the occurrence of APIs in waterways
does not yet have a science-based justification. To date, no study has performed an assessment of
the effectiveness of take-back programs in reducing API levels in sewage or the environment.
The need for data showing the relative contributory role played by disposal in the occurrence of
APIs in the environment was identified as a research gap in EPA-ORD publications as early as
2004 (Daughton 2004; 2007). There are few other publications (e.g., Houskeeper 2009) that
highlight this unknown, and fewer yet that point out the lack of this evidence for justifying the
need for take backs. This means that much of the ongoing effort in developing drug collection
programs based on protection of the environment lacks a body of supporting data for
justification.
Representing the view that disposal to sewers is a comparatively unimportant source is the
perspective of PhRMA. Those involved with PhRMA's workgroup on pharmaceuticals in the
environment (PiE) (Anon 2010; Finan and Wood 2008; Finan et al. 2007) maintained that the
contributions of APIs to sewers via drug disposal are practically insignificant: "Even with current
disposal practices, drain disposal of unused medicines is very unlikely to contribute more than
10% of the APIs found in WWTP influents." "It is likely that there would be little effect (less
than a 1 part per trillion) on WWTP API influent concentrations as a result of implementing
unused medicine take back programs compared to household trash disposal." "Either household
trash disposal or take back programs can reduce the unused medicine contribution of APIs in
WWTP influent to < 1%".
From a different perspective, perhaps the first (and only) attempt at quantitative modeling based
on actual data for APIs disposed to sewers was published in 2007 (Ruhoy and Daughton 2007).
Calculations done for the disposal of carbamazepine by a county coroner's office estimated a
concentration in raw sewage influent of 1.4 ppt (1 ng/L). This is significant, as it represented the
disposal practices from but one small sector of society. The most in-depth examination of the
possible role of disposal in contributing to ambient environmental residues was presented by
Daughton and Ruhoy (2009a); among the many findings was that disposal could possibly serve
as a major source of certain select APIs in the environment - primarily those that are extensively
metabolized (poorly excreted).
In contrast to landfills that do not receive biosolids, APIs in the aquatic environment have origins
from excretion (including bathing, which releases residues not just from topical drugs but also
APIs excreted through the skin via sweat) as well as from direct disposal to sewers. As for
disposal, its overall contributory role played versus excretion is completely unknown. Stated
another way, if disposal of unwanted drugs to sewers were to immediately cease, it is unknown
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what effect this might have on residue levels in the aquatic environment. It is probable, however,
that if changes in aquatic levels could be detected from cessation of disposal, they would likely
be a function of the individual type of medication - perhaps significant for some medications but
not for most.
To show the difficulty is establishing the contributory role of disposal to APIs in the aquatic
environment, three approaches can be considered, but are primarily useful solely for hypothetical
purposes (Daughton and Ruhoy 2009a). One of these approaches relies on the acquisition of
comprehensive data on the types and quantities of medications that might be disposed to sewers
during a defined time interval. These data would be used to calculate estimated virtual
concentrations that would result in the sewage over this time. This requires that the population
surveyed for disposal is the same as the population served by the sewage treatment plants (STP).
These concentrations would in turn need to be compared with actual, measured API
concentrations in the raw sewage from the same STP used to service the population from which
the disposal data were acquired. Even then, conclusions would be difficult to draw because the
virtual and actual concentrations are acquired during different periods of time and because a
major assumption is that the virtual disposal to sewers is occurring evenly over time (no transient
change in levels). Moreover, API levels may vary widely not because of actual changes in levels,
but rather because of bias and error inherent in the way sampling is performed (Ort et al. 2010b).
Such a study would entail great effort.
The second approach would try to rule in or out whether disposal of a particular API simply has
the potential to add significantly to environmental burdens. This relies on a thorough
understanding of the human pharmacokinetics of each API. For those APIs that are normally
extensively metabolized (with little parent API being excreted unchanged or as a metabolic
conjugate), disposal could play a significant role (since excretion would be contributing very
small amounts) (Daughton and Ruhoy 2009a). For those APIs that are extensively excreted
unchanged, the probability is considerably lower that disposal would play a significant role.
Other factors, however, can greatly complicate these assessments - for example, the
compliance/adherence rate of a drug. For those drugs with very low compliance, a greater
portion will go unused, increasing the portion that might be disposed.
The third approach assesses the route of dosing. An example is those medications containing
APIs in transdermal devices and which are also not generally used in oral or topical dosage
forms. The disposal of these used (or new) devices to sewers could serve as the major or only
source of API residues in the environment; examples include transdermal rotigotine,
flurandrenolide, and lidocaine.
So we see that pharmacokinetics, exclusive dosage forms, and incidence of patient
compliance/adherence are three critical variables that must be known to assess the magnitude of
any contributory role for APIs in the aquatic environment played by drug disposal to sewers. To
model whether a particular API in the aquatic environment originated from disposal or from
other sources (such as excretion) is an extremely complex undertaking. Sufficient data are simply
not available for the many variables involved in the factors of such a model. For those APIs that
are extensively excreted unchanged (i.e., they undergo little metabolic alteration or tend to be
excreted as reversible conjugates) or for those formulated into medications that have unusually
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high rates of patient compliance (which results in proportionately few leftovers), disposal to
sewers would probably only add immeasurably to environmental residues.
With this said, some generalizations can be made:
(1) Disposal of APIs that would otherwise be extensively metabolized will tend to be responsible
for larger percentages of the respective APIs in the environment.
(2) Disposal of APIs that would otherwise be extensively excreted unchanged will tend to be
responsible for smaller percentages of the respective APIs in the environment.
(3) For APIs that tend to be used primarily in topical applications, the significance of disposal is
a direct function of the portion disposed versus the portion used as intended but not
absorbed (as well as the degree to which the medication is incompletely used).
The two extreme scenarios that maximize and minimize the significance of disposal are,
respectively: (1) disposal of a large fraction of an API that would otherwise be extensively
metabolized, and (2) disposal of a small fraction of a drug that would otherwise be excreted
largely unchanged (or of topical drugs). The former is amplified when the API is purchased in
large quantities, and the latter is made even less important when the API is purchased in small
quantities.
Drug disposal as a contributor to higher episodic spikes of APIs to the
environment
One aspect of drug disposal that distinguishes itself from the combined contributions resulting
from excretion is its ability to contribute episodic spikes in concentrations when a large quantity
of a medication is disposed to a sewer. Regardless of what percentage of APIs in the
environmental might be contributed by disposal, the very nature of disposal could lead to
transient, episodic spikes in the concentration of whatever API is being disposed via sewage.
These concentrations might be orders of magnitude greater than what are being continually
introduced via excretion. The significance of these hypothesized intermittent or episodic
transient surges in concentrations is not known. Normally, excretion and bathing (two routes that
probably lead to constant low-level input to sewerage) establish a continual presence in the
aquatic environment for many APIs (imparting "pseudo-persistence" for those whose short half-
lives would ordinarily lead to rapid losses) (Daughton 2002). Unknown is whether intermittent
discharge to sewers of large quantities of particular drugs could possibly generate spikes leading
to concentrations sufficiently high to have adverse effects on microbiota in sewage treatment
facilities (STPs). Although transient spikes in API concentrations at STPs have never been
demonstrated in real-world conditions to result from disposal, they could perhaps explain some
of the excursions in concentration values often seen during environmental monitoring; this is an
often observed problem for discrete sampling (e.g., grab samples) versus time-weighted
integrative sampling (Ort et al. 2010a). The ability to apportion environmental loadings of APIs
to specific sources would clearly be very useful in designing source control strategies. But very
few apportionment studies have even been performed. One recent study, as an example, limited
its investigation to hospitals (Ort et al. 2010a).
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Proper disposal is not the only approach for reducing ambient
environmental levels of APIs
Despite the lack of evidence for whether drug disposal to sewers is a meaningful contributor of
APIs in the aquatic environment, it has attracted the primary focus with regard to crafting
guidance, policy, and regulation - at local, state, and national levels worldwide. This has
certainly created a contradiction with respect to assessing risk and benefit, especially given the
significant costs associated with the collection of leftover drugs by take-backs. The rationale
usually provided for this inconsistency is that disposal is the one aspect of API pollution that is
under the control of the consumer and that other end-of-pipe solutions, such as wastewater
treatment, are costly and not completely effective. This rationale was used, for example, by the
National Association of Clean Water Agencies in a letter to the DBA (NACWA 2009b):
"Arguments have been made that the quantity of pharmaceuticals that would be kept out of the
sewer system and the Nation's waters through a nationally coordinated take-back program is
small, but currently this is the only controllable source of pharmaceuticals entering the
environment."
Such statements, however, misrepresent the range of options actually available. This stance
could also serve to distract from the real issue and therefore delay progress toward a more
sustainable solution. The belief that only the fate of leftover drugs (via disposal) is under the
consumer's control is simply not true. Numerous actions can be taken to reduce the incidence of
leftover drugs. Many of these actions would also have collateral benefits for human health and
safety as well as for healthcare. This is the focus of the concepts of the Green Pharmacy and
pharmEcovigilance, which strive to redesign all of the systems involved with medication with
sustainability as the major objective. This is where a concerted focus could have enormous
impact. Indeed, this is partly recognized by NACWA (2009b) and others, but usually only in
passing: "Minimizing the amount of unnecessary medications will greatly reduce the costs
associated with their disposal and destruction."
With these points aside, a major point is missed in all discussions surrounding drug disposal.
Green pharmacy and stewardship actions designed to improve the effectiveness and efficiency of
drug usage will have collateral benefits that extend beyond improved therapeutic outcomes and
reduced medication cost Any action that results in reduced usage or personalized
adjustment in lower dosages will necessarily also result in reduced excretion of API
residues. Excretion of unmetabolized APIs (and biologically active metabolites) is a
constant factor that has been touted as uncontrollable. The many actions discussed in the
body of ORD work cited in this report, however, point to the fact that excretion is indeed a
variable that is under the direct control of consumers and the healthcare community and it
can be reduced by any number of a wide array of approaches.
Disposal of drugs to landfills
Drug disposal via household trash may serve as the major source of APIs in landfills not
receiving biosolids. The highest levels of APIs in the environment (in the US) have been
documented in landfills and biosolids, where levels can reach into the parts per million - levels
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that are 3 or more orders of magnitude higher than in the aquatic environment. Occurrence of
APIs in landfills not receiving biosolids most likely originate almost exclusively from disposal of
whole and crushed, unwanted medications (both solid and liquid dose forms); secondary sources
can be hypothesized, such as API residues excreted into diapers or residues on discarded items
such as unlaundered fabrics that have absorbed sweat or contacted other body fluids, or items
used to wipe dermally applied drugs from the skin (Daughton and Ruhoy 2009a). Medications in
landfills then have the potential for wildlife exposures (such as for scavengers) or diversion by
those who glean from trash. APIs in landfills with liner defects also have the potential for entry
into groundwater via leachates.
In the absence of alternative means of collection, disposal to landfills may be one of the best
current approaches to containment of APIs; alternatives are incineration or combustion in waste-
to-energy facilities. A primary concern with landfill disposal, however, is the potential for
"gleaning" by humans and the possible ingestion of medications by scavengers (raccoons,
coyotes, raptors, pigs, and bears, being examples; rats and mice could be particularly problematic
should they get poisoned and their carcasses then serving as food for raptors and snakes). The
major problem is that there is scant published literature to support either side of the argument.
The occurrence of APIs in landfills would be expected to increase as a result of current disposal
guidance. Paradoxically, little is known regarding the extent, frequency, or magnitude of API
disposal to landfills or the fate of APIs in landfills. Perhaps the first comprehensive investigation
of drug wastes in landfills (and the first and only hand-sorting inventory of municipal solid waste
for drugs) was conducted by Musson (2006).
The rate at which drugs are discarded into the trash varies wildly. Musson and Townsend (2009)
cite data ranging from 3-65%. On the basis of an assumed 60% discard rate, the calculated
estimated API content of municipal solid waste in the US was 45 mg/kg. Actual sampling of
waste yielded a content of 8.1 mg/kg, comprising 22 distinct APIs. This represents the only
quantitative inventory to date of APIs in municipal solid waste.
If the ONDCP disposal guidance were fully complied with, the API content of municipal solid
waste could perhaps be expected to rise sharply (from redirection of drugs disposed to sewers) -
as the content measured by Musson and Townsend (2009) was obtained the year before (in 2006)
the ONDCP guidance was issued.
Only about three dozen studies involve certain aspects of APIs in landfills or landfill leachates,
with fewer than a dozen providing substantive data (Barnes et al. 2004; Behr et al. 2009; Buszka
et al. 2009; Geurts et al. 2007; Metzger 2004; Musson 2006; Musson and Townsend 2009;
Tischler et al. 2008). The first extensive characterization of landfill leachate for a wide range of
APIs was reported by Behr (2009). The data from this study also included ingredients from
controlled substances and illicit drugs; some of the reported concentrations were quite high. The
first reports of APIs in ground waters influenced by landfills appeared in the early 1990s (Eckel
etal. 1993; Holm etal. 1995).
With an increased emphasis in the US on disposal of leftover drugs to trash, the opportunities
and likelihood for diversion by, or unintended exposure to, waste handlers and landfill personnel
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could be heightened. Indeed, in a survey done in Turkey, over 90% of consumers dispose of
drugs in household trash. This posed concerns regarding not just the potential for environmental
impact, but particularly with regard to the potential for reuse or diversion by those who glean
trash at landfills (Uysal and Tinmaz 2004).
An often reported anecdote involves the disposal of drugs into sharps containers by healthcare
personnel. Operating under the assumption that these drugs could then be inadvertently
incinerated, some states instead divert sharps to landfills. This represents an unintended disposal
of drugs to landfills. Product recalls could result in unusually high transient loadings of disposed
APIs. The massive recall of children/infant OTC medications beginning in April 2010 may have
prompted the discarding of unusually large quantities of medications in trash (as advised by the
manufacturer) as well as the sewer (as many still practice); see links at:
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProduct
s/ucm210442. htm
http ://www.mcneilproductrecall. com/page.j html?id=/include/new_recall .inc
Given the concerns regarding containment, certain practices in limited use for drug disposal may
serve to significantly delay the possibility of leaching. The UK, for example, pioneered
development of various "kits" and patents that claim to encapsulate medications - immobilizing
them within some sort of polymer. One is the DOOP kit. In the US, several kits have been
recently developed (F.P.R. Inc. 2010; Parrott 2010; Rx Disposal Solutions 2010). None of these,
however, has ever been evaluated for long-term effectiveness in providing a sustainable solution.
Encapsulation could, however, mollify any potential problems with gleaning and animal
scavengers at landfills.
Also regarding encapsulation is the use of cementation (inertization), practiced to a very limited
degree in the US (e.g., Albuquerque, NM); this is apparently a result, however, of a New Mexico
state law that allows incineration only for drugs admitted into evidence for legal proceedings. No
research has been published on the fate of APIs from concrete weathering in landfills, but
cementation has been widely used in the management of hazardous and radioactive waste. Note,
however, that the weight of concrete (ca 1,000 Ibs per 55-gal drum) would be a significant factor
in energy/transport cost for lifecycle analysis.
Countries having formal drug-returns programs generally prohibit the discarding of prescribed
human drugs in trash or the sewer. Perhaps the first metropolitan area in North America to
specifically ban the disposal of drugs in household trash is Metro Vancouver (BC) (Metro
Vancouver 2010). The stance by Metro Vancouver and that of PhRMA, which maintains that
landfilling is the preferred alternative in the US (Finan and Wood 2008), clearly represent
contrasting views.
One of the first proposed bills in the US (S7998), which would require manufacturer collection
of unwanted medications (Maisel and Englebright 2010), would also prohibit "the disposal of
any drug by hospitals and residential health care facilities as mixed solid waste in a landfill."
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Incineration
Incineration has been long practiced for medical waste, but its primary objective has been to treat
infectious waste. Most of the published literature on medical waste management via incineration
focuses on biological waste, sharps, and plastic refuse. Drugs have been viewed essentially as
hazardous waste. Historically, as with municipal solid waste, the concern regarding incineration
of drugs (and plastic containers) has focused on the generation of priority pollutants (such as
dioxins, NOx, SOx, ammonia, and metals) rather than the fate of APIs themselves. This is
especially true since the relative masses or volumes of APIs would undoubtedly be many orders
of magnitude lower than the containers and other packaging waste. The main variable with
respect to incineration is the specific facility design and whether the incinerator is operated
within its design specifications; even transient excursions outside operational limits (such as
temperature) can cause release of unpredictable emissions. Little research has been done on the
fate of APIs during incineration. Drawing general conclusions would also be difficult since the
reactions during combustion/pyrolysis are highly complex functions of the incineration deign,
temperature regime, oxygen supply, and co-reactants. Maintaining a suite of proper conditions
within a narrow range is critical. Incinerators of insufficient temperature (or those having
excursions beyond design parameters) could theoretically emit API pyrolysis or combustion
products - or perhaps even unchanged parent API.
Only a couple dozen articles in the DDS database are relevant to incineration and drug waste.
Several of the more recent or significant articles include: Ciplet (2009), Priiss et al. (1999), and
Zhao et al. (2009). The related technology of waste-to-energy (WTE) reclaims the energy
content of the waste by generating electricity (McKenna 2009).
Two particular forms of incinerators may pose concerns extending past the conventional
concerns of regulated pollutants. One is the makeshift incinerators sometimes used in developing
nations and during humanitarian relief efforts. Another involves portable units often employed
by law enforcement for destroying comparatively small quantities of confiscated drugs. A
common design for small mobile incinerators is the cyclonic barrel burner. One example uses a
55-gal drum fueled by wood or charcoal with a blower to deliver air (Elastec/American Marine
2010). Little has been published regarding the performance characteristics of small or portable
medical incinerators (Rogers and Brent 2006; Vollmer 27 August 2010). Pulmonary exposure to
combustion/pyrolysis products or to the parent API could be a concern.
Since these rudimentary incinerators lack catalytic or scrubbing capabilities, they have the
potential to emit not only a wide range of hazardous combustion products and particulates, but
also unaltered parent APIs or partial pyrolysis products from APIs. Pulmonary exposure to APIs
or combustion/pyrolysis products of unknown composition poses exposure risks since it is such
an efficient absorption route. While these devices were originally intended for use by law
enforcement, they could find use by emerging community collection events not familiar with
environmental regulations.
One possible pathway of disposal rarely mentioned is open-air burning of residential trash, as
still practiced in certain rural parts of the U.S. and the world. In rural Lithuania, the most
common route of disposal may well be burning in trash, practiced more often than disposal to
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sewers (Kruopiene and Dvarioniene 2007). Other isolated reports include "burning in fire"
(Forbes etal. 1989).
Sustainabilitv/Stewardship/EPR
Discussion regarding the sustainable use of pharmaceuticals has yet to attract the attention it
requires. Sustainable use extends far beyond prudent disposal. Originally formulated as an
integral aspect of the Green Pharmacy concept (Daughton 2003b), it has since been a focus of
fewer than a couple dozen articles in journals and books - some the result of this project.
Up to now, reducing the entry of drugs into the environment has focused primarily on end-of-
pipe solutions - improving wastewater treatment and in reducing the disposal of drugs to drains
(e.g., with consumer drug-collection events such as take-backs). Efforts in preventative actions,
such as limiting initial prescribed quantities (e.g., Cook 2009), have been extremely limited. In
practice, however, there are countless other options for preventing or lessening API entry to the
environment; some of these were discussed for the first time in 2003 under the concept of the
"green pharmacy" (Daughton 2003a; b) and under the new concept of pharmEcovigilance
(Daughton and Ruhoy 2008b; 2010). These fall under the rubric of environmental stewardship.
These options could prove much more effective and more sustainable - reducing the
environmental footprint of health care and pharmaceuticals while at the same time improving the
quality and efficiency of healthcare. The major impediment for implementing these other
approaches is the need to engage and coordinate the active participation of a wide array of
stakeholders, beneficiaries, and agencies, especially the various healthcare communities,
pharmaceutical and pharmacy industries, and the health insurance industry.
All aspects of the drug life cycle are potential targets for a holistic stewardship program. Many
involve alterations to prescribing and dispensing practices. These include: drug substitution, drug
quantity (amounts suitable for one course of treatment), drug formulation (easier or more
effective delivery systems), lower doses (e.g., achieved with alternative delivery routes or
personalized doses), dose timing (e.g., chronobiology), pharmEcokinetic factors (e.g., drug half-
life in environment; excretion efficiency), palatability, medication reviews with patients (and
prevention of unnecessary polypharmacy), more informative and clearer labeling, elimination of
unnecessary repeat prescriptions, improved coordination among prescriber, dispenser, and
patient, and alternative treatments (exercise, physical therapy, diet, etc). The spectrum of options
for gaining better alignment with sustainability is clearly vast. Numerous others involve design
of APIs, drug formulation, and packaging. These factors and others have all been discussed in
the publications of Daughton and Ruhoy, spanning the years 2003-2011, which have served as
the basis for this report.
One of these approaches in particular has clear potential for immediate general implementation
but does not receive sufficient attention - lower doses. Lower doses can translate into smaller
dispensed quantities as well as reduced excretion of API residues. Lower doses can improve
therapeutic outcomes for some patients and greatly reduce adverse drug events. The
recommended doses for many medications may be too high for large segments of the population.
Effective doses are often one-half of the recommended dose (or even lower) (Cohen 2003); table
9 of Cohen (2003) lists the reasons that drugs are often marketed with recommended doses that
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can be unnecessarily too high. This is a very important but woefully under-researched aspect of
pharmacology and one that has the potential to also quickly cut drug loadings in the environment
significantly.
As pointed out in Ruhoy and Daughton (2008), high doses are often established for clinical trials
to maximize the opportunity for achieving therapeutic endpoints; once marketed, the doses are
not reevaluated or adjusted downward. Approaches for determining optimal, lower doses include
personalized medicine (Daughton 2003b), which factors obvious variables such as gender-
specific responses and less recognized practices such as chronobiology for ensuring maximally
effective dosing schedules (Daughton and Ruhoy 2009b). The major roadblock is the time
required on the part of physicians. Some insurers and healthcare providers have already begun to
allow "pill splitting." But only certain medications (and restricted to particular formulations, e.g.,
tablets but not capsules) are amenable (Jain and Jain 2006).
The need for efforts focused toward better understanding the actions of medications is reflected
in a statement attributed in 1999 (Cimons 1999) to Dr. Janet Woodcock, then director of the
FDA's Center for Drug Evaluation and Research (CDER): "The sad truth is that, even after all
the clinical development that occurs with every drug and even after drugs have been approved
for a long time, we only have a crude idea of what they do in people... We don't really know why
they work well in some people and not as well in others."
Note that at least one of the trends in the pharmaceutical development has served to also reduce
overall doses. As first pointed out by Daughton (2003b), replacement of racemic drugs (equal
mixtures of APIs that comprise optical isomers - or stereoisomers) with pure isomers
(enantiomers) can reduce dose size. Optical isomers have identical molecular compositions but
different 3-dimensional structures - which are mirror images of each other. The enantiomers can
exhibit dramatically different physiological properties; sometimes, one enantiomer is responsible
for the desired therapeutic effects, while its companion enantiomer may be ineffective or even
responsible for side effects. Enantiopure drugs serve to directly cut therapeutic doses by at least
one half (depending on how many optical isomers an API might comprise). This is a trend that
has continued in pharmaceutical development, driven partly by the fact that one or more API
enantiomers in racemic drugs might sometimes responsible for adverse drug reactions.
Regardless of any pharmacological advantage that one enantiomer might have over another,
enantiopure drugs hold the potential for resulting in the introduction of reduced quantities of
APIs to the environment than do their racemic counterparts. This could result, for example, from
the need for lower overall doses or because of more complete metabolism of one enantiomer to
inactive products.
No single document has yet cataloged the extraordinarily broad array of actions, activities, and
behaviors that determine and influence the entry of APIs into the environment. Some preliminary
attempts at conceptualizing a comprehensive, integrated approach for reducing the entry of drugs
to the environment have been made. One in particular is the actor modeling approach, which was
first applied under the START project (Keil 2008; 2010; Titz and Doll 2009); actor modeling
factors together all of the involved entities (e.g., manufacturers, stakeholders, healthcare
professionals, consumers, etc.) and the processes they influence.
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Green chemistry and other approaches to eco-efficient design can be applied to numerous aspects
of a product's life cycle; these approaches, however, are not applied comprehensively to the life
cycles of drugs. An ultimate challenge, for example, would be the design of drugs and the
methods used for their delivery to minimize the excretion of unchanged APIs and bioactive
metabolites. Much of the discussion in the US involving the application of green chemistry to
Pharmaceuticals has been led by the American Chemical Society's Green Chemistry Institute
Pharmaceutical Roundtable (ACS 2005). Redesign of drugs is a topic already underway with
respect to green chemistry. At the US FDA, it is being championed with respect to making drugs
safer (Woodcock 2009). An overview of this topic is provided by Dunn et al. (2010).
But even in light of the numerous ways that the impact of drugs on the environment can be
reduced, an emerging opinion is that these alone will not be sufficient in achieving truly
sustainable use. Also required will be reductions in overall consumption. Reducing the usage of
Pharmaceuticals has long been excluded as a possible option. Extensive evidence exists,
however, showing the numerous ways for how reduced usage could be achieved. The key to
reducing consumption will be maintaining - or preferably improving - overall satisfaction and
well-being for the healthcare consumer.
Unlike nearly all other consumer items, where approaches to sustainable consumption and usage
might be obvious, what might constitute sustainable use of medications is not so easily
articulated - especially for so-called "essential" drugs. Pharmaceuticals present one of the most
daunting challenges with respect to sustainable use while at the same time maintaining or
optimizing human health and ecological integrity. Innovative approaches are needed. Sustainable
use of commodities usually involves two major approaches: better design and more efficient use
(resulting in reduced consumption). Incentives for more efficient use are often oriented to
encouraging altruism or self-interest (such as improved sense of well-being). It is difficult to
currently see how this can be applied to medications - a commodity that is often begrudgingly
purchased and whose actual consumption after purchased is often avoided; a prime example is
the purchase of long-term maintenance medications for conditions having no overt signs (such as
cholesterol levels), so the patient receives little gratification or feedback indicative of progress.
A better understanding of the nuances involved with consumer motivation for sustainability (and
how it could be applied to the use of drugs) would be extremely useful. A recent article may
provide some insights (see: Marchand et al. 2010).
If sustainability were used as a measure of success, it becomes clear that an overwrought focus
on developing the best ways to dispose of unwanted drugs cannot succeed. By focusing on drug
disposal, the prospects for sustainability could actually be made worse simply by increasing
consumer purchasing of unneeded drugs since they are easy to dispose. The focus instead needs
to be on ways to prevent the generation of unwanted drugs so that the need for disposal is
minimized or eliminated. A focus directed toward an even more challenging goal would be how
to design drugs and the methods used for their delivery to minimize the excretion of unchanged
APIs and bioactive metabolites.
Formal recognition of the need for developing actions to reduce the incidence of leftover drugs
rather than focus on waste disposal has only recently begun to emerge, as reflected by a
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recommendation from the National Association of Boards of Pharmacy (NABP 2009b) that
prevention measures should be pursued: "Recommendation 3: Work with Appropriate Entities to
Research Methods that Reduce the Amount of Unused Medications."
One approach to reducing consumption would be to change the paradigm that has dictated the
conventional physician-patient-drug relationship - where the orientation has long been on the
drug itself, rather than on the therapeutic outcome actually desired. One far-ranging, but
currently hypothetical, approach involves what might be called "just-right prescribing," where
the patient would pay for services that succeed in achieving therapeutic outcomes, as opposed to
paying for medications (regardless of their effectiveness). Applying "just-right prescribing" to
healthcare, medication waste would be viewed as a prime metric of inefficient, non-optimal
administration of health care. Redesign of healthcare using this perspective and the knowledge
and expertise of medical practitioners, health-care administrators, pharmaceutical manufacturers,
and environmental scientists could lead to a holistic system of balanced and optimally targeted
delivery of medical care. Such a system could yield improved therapeutic outcomes, lowered
costs, and reduced environmental impact.
Such an approach would necessitate further advancements in evidence-based medicine and
personalized medicine. This concept is patterned after the practice called chemical management
service (CMS), which is part of the larger concept of "material flow management service." This
approach sells a service or the outcome desired from the use of a chemical - rather than the
chemical itself. As first proposed in Daughton (2009) and Daughton and Ruhoy (2010), in
applying the concept of CMS to healthcare, the ultimate objective would be the paradigm
whereby medications are no longer sold or prescribed by themselves, but rather the desired
therapeutic, lifestyle, or enhancement endpoint becomes the actual contract with the patient. This
would serve to drive down the unnecessary and imprudent use of medications.
With hypothetical approaches aside, the specific topic of drug disposal and the more general
topic of stewardship have fostered the involvement of several NGOs, such as the Product
Stewardship Institute (PSI 2008a) and the Teleosis Institute. The Teleosis Institute was one of
the early adopters of the Green Pharmacy concept, devoting an entire issue of its journal to the
topic in 2007 (Teleosis Institute 2007).
The growing interest in sustainability and broader solutions to the drug waste problem is evident
with the publication of the first books devoted to this topic:
"Green and Sustainable Pharmacy" (Kummerer and Hempel 2010)
"Towards Sustainable Pharmaceuticals in a Healthy Society: MistraPharma Research" (Ruden et
al. 2010)
"A Healthy Future - Pharmaceuticals in a Sustainable Society" (Bengtsson et al. 2009)
Other indicators of an emerging focus on sustainable use of pharmaceuticals include the
introductory remarks of Sen. Kohl at the 30 June 2010 hearing on "Drug Waste and Disposal:
When Prescriptions Become Poison" for the Senate's Special Committee on Aging (Special
Committee on Aging (chaired by Senator Herb Kohl) 2010):
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"One of the best strategies to tackle the problem of drug disposal is to make sure
drugs aren't wasted in the first place. We need to explore innovative ways to improve
patient care and reduce waste through programs like medication therapy
management, improved compliance, and patient education."
Finally, the emergence of legislation aimed at extended producer responsibility (EPR) to cover
Pharmaceuticals may help in developing more sustainable use (Blais and Maher 2010; Citizens
Campaign for the Environment -Year Unknown (Possibly 2010); Maisel and Englebright 2010;
Perry 2010; PPI 2010). EPR has been difficult to impose for pharmaceutical waste, as noted for
Maine's act for proper disposal, which died in the State legislature on 26 March 2010 (Perry
2010).
A largely unrecognized benefit could emerge from the closer involvement of pharmaceutical
manufacturers with drug waste. By using the data that could be mined from drug collections,
manufacturers could gain insights they currently lack regarding the extent, scope, and magnitude
of drug wastage. These data could be used to change manufacturing, packaging, and promotional
practices - or to alter prescribing/dispensing practices. Insurers could use the data to determine
optimal dispensing practices.
One embodiment of sustainable use of pharmaceuticals rarely discussed is the reclamation of
APIs from wastes, ultimately for re-use or re-purposing - a process dubbed "drug mining"
(Daughton 2003a). Such an approach might prove feasible for particularly costly drugs, such as
certain chemotherapeutics. As proposed by the patent holder, reclamation could possibly be
practiced in hospitals, where APIs could be mined from patients' excreta and other wastes
(Pharmaceuticals.org 2008). Reclaiming APIs from wastes has historical precedence, such as the
reuse of penicillin from soldiers' urine - a practice necessary during WWII when penicillin was
in very short supply (Clarke 1979).
Eco-labeling
When measures are lacking for reducing drug usage or the generation of leftovers, one
innovative approach pioneered in Sweden has involved the classification of APIs according to
their potential for environmental impact - incorporating values for PBT: environmental
persistence, bioaccumulation, and toxicity; with respect to bioaccumulation, note that the
potential for biotransformation may be emerging as a better factor for predicting
bioaccumulation than hydrophobicity (McLachlan et al. 2010). The objective of Sweden's
classification/labeling program has been to guide prescribing so that certain drugs within given
therapeutic classes can be preferentially prescribed - thereby limiting the entry to sewers of the
least desirable APIs via either excretion or disposal. Several articles describe the development
and status of this classification system (Gunnarsson and Wennmalm 2008; Stockholm City
Council 2010a; b; Wennmalm 2009; Wennmalm et al. 2010; Wennmalm and Gunnarsson 2005;
2009; Wennmalm and Gunnarsson 2010).
The drugs recommended for common diseases as classified according to the environmental
impact criteria of the Stockholm County Council are contained in a database - the "Wise List"
(Stockholm City Council 2008; 2009; 201 Ob). In keeping with Sweden's labeling effort, the
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implementation of so-called "eco-labeling" has also been discussed for personal care products
(Klaschka et al. 2007).
Sweden's classification and eco-labeling effort could be extended to guide the responsible
disposal of leftover, unwanted medications. By accommodating some other key parameters, such
as disposal information tailored for each medication and safety information regarding the
handling of waste, a labeling system could be devised that attempts to protect not just ecological
integrity, but also human safety. The advantages of clear disposal guidance tailored to each drug
is particularly attractive in several respects. First, certain drugs could probably be disposed to
sewers with minimal potential for environmental impact, thereby obviating the need for
alternative disposal mechanisms and also avoiding the increased potential for poisonings (from
storage of leftovers awaiting disposal or from drugs disposed to unsecured trash); this avoids the
current approach - which has caused considerable confusion and frustration - of "almost-one-
size-fits-all" (that is, all except for certain exceptions). For example, some APIs are extensively
excreted unchanged. For these, disposal to sewers adds only small incremental portions to
ambient levels; this was first discussed by Daughton and Ruhoy (2009a). Second, exposure to
certain APIs is extremely hazardous for certain sub-populations; these individuals must avoid
handling these drugs during disposal (an otherwise avoidable hazard but one that has been
introduced by current disposal guidance). Third, certain drugs are extremely toxic and can lead to
single-dose fatalities. Storage for these drugs must be secured at all times (including leftovers
discarded into trash); immediate disposal of these drugs might be preferably done by disposal to
sewers. Currently, such useful information is lacking for the consumer (and sometimes even for
the physician).
Biologies
Biologies comprise a broad and continually expanding class of pharmaceuticals whose chemical
structures are based on proteins, nucleic acids, or sugars. They are used in vaccines, gene
therapy, and other modalities not conducive to conventional "small molecule" APIs. These
substances are often unstable in heat, light, and air, and generally unstable in the gut or
inefficiently absorbed from the gut. In general, biologies do not pose the conventional concerns
associated with small-molecule pharmaceutical disposal. Biologies also attract comparatively
little attention from environmental scientists, as they pose considerably smaller environmental
footprints than the more structurally stable synthetic APIs. Those that do get excreted - and even
if surviving sewage treatment and environmental transformation or structural denaturing - would
probably have considerably lower potential for resulting in exposure of non-target organisms
because of their poor absorption across the skin or via the gut and their propensity for
environmental degradation or denaturing by microorganisms, sunlight, and other
physicochemical processes. An overview of biologies and the environment is provided by Kiihler
(2009).
No published evidence points to concerns that might be associated with disposal to sewers. On
the other hand, disposing of biologies via the trash may pose unknown risks should someone
unintentionally or unknowingly consume them orally or contact them with their skin, as the
possibility of allergic reactions exists. Most biologies will be administered by healthcare
professionals, since these drugs usually involve parenteral delivery routes. Exceptions include
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the self-administered biologies used in long-term maintenance therapy (one example is the class
of injectable TNF inhibitors, such as etanercept, which inhibit the production or recognition of
tissue necrosis factor). Two scenarios would call for disposal. First would be expired product,
usually in the form of some delivery device or container. The other is in the form of
unused/wasted product (e.g., residues remaining in delivery devices, such as syringes). In neither
case would flushing normally be considered a disposal option.
Legislative Activities
The last few years have witnessed an explosion of hearings and legislative involvement in
several aspects of the drug disposal problem. The growing number of laws, regulations, and
resolutions passed by city, state, and federal legislators has become very difficult to track.
Legislation is in a constant state of evolution and is far too complex to cover here. Over 100
records currently exist in the DDS database that focus on legislation; but these represent only a
fraction of the literature.
Given the wide range of legislative activities at the state and federal levels surrounding drug
disposal, the United States Pharmacopeial (USP) Convention decided in 2010 to refrain from
involvement in any standards-setting activities (USP 2010). A perspective from the law
profession on federal regulations governing drug disposal was published by Morgan (2009).
A number of Congressional hearings involving various aspects of PPCPs have taken place over
the last couple of years. The first Congressional hearing devoted to the topic of drug disposal
was held in 2009 (US House of Representatives 2009). Another hearing was held on 30 June
2010 (Special Committee on Aging (chaired by Senator Herb Kohl) 2010). The Kohl hearing
was covered in Erickson (201 Ob).
Congress has introduced a numbers of bills dealing with disposal, such as S. 3397 (Klobuchar et
al. 2010); S. 3397 passed the Senate in August 2010.
Only 10 years ago was one of the first papers published that recognized the inconsistencies in
how drug wastes are handled and regulated, as well as to bring some attention to the need for
principles of stewardship (Rau et al. 2000). An excerpt from the section "Improve awareness and
training":
"The research community, EPA, FDA, and pharmaceutical manufacturers should
work together to design educational programs to better inform investigators,
healthcare providers, and patients about the potential environmental impacts of
pharmaceutical use and appropriate disposal methods."
Some of the first legislation relevant to drug disposal focused on state statutes controlling the
reuse of medications, for example within LTCFs. Perhaps the oldest legislation recognized as
exacerbating the drug disposal problem is the Controlled Substances Act, which greatly
complicates how collection events or returns programs can be run (US Department of Justice
1997). For in-depth discussion of the role played by the CSA in drug disposal, see Yeh (2010).
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The first significant legislation intending to solve the consumer disposal problem was the State
of Maine's S.P. 671 - L.D. 1826: "An Act to Encourage the Proper Disposal of Unused
Pharmaceuticals" (State of Maine 2003). This act set the stage for the nation's first state-wide
mechanism for handling consumer leftover drugs - via an innovative mail-back program,
coordinated with the state DBA and the USPS. This was followed by the first state law directed
at mail backs (People of the State of Maine 2007).
A sampling of state statutes and bills pertaining to drug returns and reuse is available from
various sources (CESAR 2008; NAMSDL 2009; 2010a; b; NCSL 2010b; PSI 2010). Several
other references discuss the state of legislation and where the challenges reside (California
DTSC 2010; Hubbard 2007a; Siler et al. 2008).
Various States have passed legislation that mandates the study of approaches for prudent drug
disposal (e.g., Watson (sponsored by Donna Howard) 2009).
Although the initial forays into legislation have focused on consumer-level take backs and reuse,
the latest efforts are beginning to focus on extended producer (corporate) responsibility (EPR) -
where the manufacturers would take responsibility for collection of leftovers (Blais and Maher
2010; Citizens Campaign for the Environment -Year Unknown (Possibly 2010); Maisel and
Englebright 2010; PPI 2010).
In 2009, the National Association of Counties (NACo), the country's largest local government
organization, adopted a resolution supporting EPR for the collection of unwanted medicines:
"Resolution in Support of a Safe, Convenient Medicine Return Program" (NACo 2009a; b).
Some states have also considered (or have passed) EPR legislation (Morrell et al. 2009; State of
Maine 2010; State of Washington 2009).
In contrast to several other countries, legislation in the US that has focused on EPR has not been
received favorably by the pharmaceutical manufacturing sector. The argument most frequently
made against placing the responsibility for drug disposal on the drug industry is that healthcare
costs for consumers would increase because of the need to raise drug prices to fund the EPR
program. This argument, however, has not yet been successfully made in any peer reviewed
study, and extremely little has been published to assess consumer acceptance of increased costs
(e.g., Kotchen et al. 2009). In fact, the only existing data (namely, the existing EPR programs in
other countries) argue otherwise. By implementing ERP programs and by mining the wealth of
data that could be obtained from cataloging unused drugs, much could be learned about patient
compliance, which in turn could prove invaluable in improving future drug design, formulation,
and packaging. Such improvements could even serve to reduce the cost of medications in the
long term.
Enforcement activities
Other than DEA actions involving controlled substances, legal or enforcement actions involving
the disposal of medicinal pharmaceuticals have been exceedingly rare. Perhaps the first
noteworthy case was in New York, where five healthcare facilities were directed to immediately
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cease all discharges of pharmaceutical wastes into waterways within New York City's watershed.
Noteworthy was that this enforcement action was not based on any known harm to the public but
was instead justified on the basis of certain APIs, which, once treated as waste, were considered
hazardous wastes (a practice that has long proved confusing and problematic for healthcare
facilities nationwide) (Luxton and Walsh 2010; Office of the Attorney General 2010).
Worth noting here is that of the many APIs that are truly hazardous, only a few select APIs
(fewer than 3 dozen) are actually explicitly captured under Resource Conservation and Recovery
Act (RCRA) (i.e., as P- or U-listed chemicals); others, however, are implicitly covered if they
display at least one of the characteristics of hazardous waste (i.e., ignitability, corrosivity,
reactivity, or toxicity). Historically, this uneven classification has been an inevitable
consequence of the introduction over the years of APIs with ever-increasing potencies and new
targets for biological action. It is also a consequence of the problems associated with applying
RCRA criteria to the unique dosage forms of APIs. OSHA's hazard classification of APIs with
regard to occupational exposure is similarly uneven in its coverage. This is one of the reasons
that chemotherapeutics, for example, have received comparatively little scrutiny with respect to
workplace risks, despite posing considerable hazards. The intricacies and confusion surrounding
drugs and RCRA are covered by Smith (2008).
Antibiotics and selection for antibiotic resistance
Although the focus of this report is not on the ways in which drugs disposed into the
environment might have adverse impacts, antibiotics compose one particular class of drugs
(other than controlled substances) that often stands out. The linkage between antibiotics and
antibiotic resistance (AR) in bacteria is a multi-faceted issue - and one of keen interest with
respect to human pathogens. The topic is far too complex to discuss here in a comprehensive
manner; some of the many complexities underlying antibiotic resistance are summarized in
Livermore (2003).
In the PPCPs bibliographic database, there are roughly 300 articles dealing with AR and the
environment. With that said, it is important to recognize that a significant degree of naturally
occurring resistance exists in the ambient (natural) environment. This is caused primarily by two
factors: (1) continual "warfare" between microbes, many of which synthesize a broad spectrum
of antibiotics to out-compete each other; of the bacteria that suffer substantial exposure, the
survivors are conferred resistance, and (2) environmental stress is probably a common cause of
development of antibiotic resistance; the types of general stress that can lead to resistance
include changes or extremes in pH, osmolality, and temperature, among other stressors
(McMahon et al. 2007). This natural level of AR then undergoes horizontal gene transfer -
expanding the resistance across species. For these reasons, antibiotic resistance has always
existed - long before the use of antibiotics by humans.
On top of this natural background level of exposure is that resulting from the prophylactic,
therapeutic, and economic use of antibiotics for human, veterinary, agricultural, and aquaculture
purposes. Larger quantities of antibiotics (but of fewer types) are probably used in agriculture
(primarily CAFOs), but these have different routes to the environment. One additional source,
little investigated in the US, is manufacturing waste streams (Larsson 2010; Larsson et al. 2007).
12 September 2010 Drugs and the Environment: page <133> of 196
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It is simply not possible to ascribe the spread of AR to any one cause - especially to the
discarding of unused antibiotics. The presence of antibiotic-resistant bacteria in remote areas
lacking overt sources of anthropogenic antibiotic usage demonstrates how confusing this topic
can be (Sjolund et al. 2008).
While no one knows for sure the major contributors of AR as a result of human usage, it is
generally acknowledged to be therapeutic and prophylactic use. During treatment, bacteria with
AR are continually shed via excrement and washed from the surface of the body; AR bacteria
occur on the skin because of antibiotics applied topically and because systemically administered
antibiotics are excreted with sweat via the skin (Daughton and Ruhoy 2009a). These bacteria (or
their AR genetic elements) can then survive sewage treatment. At this point, gene transfer can
occur or humans/wildlife can be directly exposed to the AR bacteria. Resistance to one antibiotic
typically confers resistance to others (as the mechanism of resistance is often evolutionarily
conserved across genera). This is why multi-drug resistance is so common.
Antibiotics can be concentrated by several orders of magnitude in biosolids. Subsequent use on
land could serve to select for future AR. A very under-appreciated mechanism by which AR can
evolve is from exposure to substances that are not generally recognized as antibiotics. This is
done by a variety of mechanisms, including induction of over-expression of efflux-pumps,
metabolic routes, or other means. In fact, treatment with one antibiotic may result in
development of AR for other, unrelated antibiotics but perhaps not for the actual antibiotic
involved with the exposure. This is perhaps a major route by which resistance can develop from
exposure to low levels of antibiotics (e.g., see: Kohanski et al. 2010).
Finally, the disposal of antibiotics by flushing into sewers could theoretically introduce transient
spikes in antibiotic levels entering STPs, which might be sufficient to select for AR; but this has
not yet been reported. Flushing into septic systems could hypothetically result in the same
outcome, but the more likely outcome would be severe disruption of the septic system because of
mass die-offs of certain species or disruptions of the resident bacterial communities.
The occurrence of antibiotic resistant bacteria in any number of myriad environmental
compartments is often ascribed to disposal of leftover medications without any supporting
evidence. This leads to further confusion by those outside the field. A case in point is evident in
Roach (2010).
CONCLUDING ANALYSIS
No direct evidence links drugs disposed to sewers with increased levels of active pharmaceutical
ingredients (APIs) in the ambient environment. Assertions that disposal of leftover drugs to
sewers contributes measurably to environmental residues of APIs are based almost completely
on logical, but still unproven, assumptions.
In the absence of scientific data, the dominant drivers for developing state or national guidance
for consumer disposal of leftover medications should not be based solely on assumptions
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regarding adverse environmental impacts. This is not only misguided, but by placing the focus
on the symptoms of the problem (leftover, unwanted drugs), the consumer's attention is diverted
away from the actions required for curing and preventing the actual problem. The focus instead
needs to be placed on preventing waste rather than on disposing of the waste. Furthermore,
guidance designed to alter consumer behavior in the disposal of unwanted drugs could possibly
have unanticipated, adverse consequences when not developed from a holistic consideration of
the complex interplay of the myriad positive and negative feedback circuits involved with
prescribing, dispensing, and consumption of pharmaceuticals.
There appear to be innumerable points along the life cycle of a drug (spanning manufacture to
ultimate usage) where redesign or improvements could yield profound changes in the types and
quantities of APIs used. These changes could result in reduced usage or in usage having reduced
potential for environmental impact. Many of the myriad actions required to minimize the
incidence of leftover drugs happen to result in reduced consumption of medication. This in turn
results in reduced excretion of APIs. For consumer drugs, excretion is the primary origin of API
residues in the environment; manufacturing and agricultural uses (such as confined animal
feeding operations) may serve as other significant sources in certain locales, but these are issues
unrelated to consumer use. This means that the objective of reducing the entry of human-use
APIs to the environment is primarily accomplished indirectly by collaborating in the
development or redesign of policies and actions of the healthcare communities regarding the
usage of medications.
In-depth examination of the published literature reveals that the very same changes in the
actions, activities, behaviors, and customs practiced in the administrative of healthcare (and
veterinary care), and which are required for reducing the entry of APIs to the environment (by
reducing excretion and disposal), can have profound collateral outcomes, extending far beyond
any original intent of protecting the environment. These major outcomes could include
improvements in many aspects of healthcare, including: therapeutic outcomes, and reductions in:
(i) healthcare costs, (ii) morbidity and mortality from unintentional poisonings, (iii) diversion
(and its associated crime) and abuse, (iv) unnecessary and imprudent donation of drugs
(particularly during humanitarian relief efforts), and (v) unanticipated mass poisonings of
wildlife.
This examination points to the wide spectrum of benefits that could potentially ensue from
establishing transdisciplinary collaborations among the various healthcare and veterinary
communities, pharmaceutical and pharmacy industries, health insurance industry, water utilities,
regulators, environmental scientists, and numerous stakeholders and beneficiaries - with
participation of processionals from disparate fields, such as engineering, science, healthcare,
veterinary science, sociology, psychology, pharmacology, toxicology, pharmacy, health insuring,
and criminology.
With a concerted focus on solutions aimed at reducing waste instead of disposing of waste, a
healthcare system could evolve that is more effective, efficient, and environmentally sustainable.
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SUGGESTED FOR FUTURE CONSIDERATION
After an in-depth evaluation of the many facets of the drug disposal issue, it is clear that a very
wide range of actions could be considered for reducing the incidence of accumulation of leftover
drugs and the consequent need for disposal while also improving the quality of healthcare. Many
of these have been discussed in the articles that formed the basis for this report; others are
covered in the articles that compose the DDS database. Several ideas that are rarely ever
discussed, however, are captured below.
(1) Enlist the public to better track and understand the types and quantities of
medications that go unused. It is clear that a better understanding of the types and
quantities of medications that go unused would be extremely useful. It is also clear that
considerable expense, time, and obstacles are faced in obtaining inventories of leftover
drugs (either those stored in homes or collected during take-backs). Alternative means of
collecting these data would be extremely beneficial for improving prescribing and
dispensing practices as well as for reducing environmental impact.
An unexplored way to mine data from the public regarding leftover drugs would be to create
a publicly accessible Internet database where individuals can log the quantities and types of
their leftover drugs, together with whatever other types of additional data might be useful to
investigators, such as the reasons for the wastage, the method of disposal (or storage), and
the geographic locale. Although there would be obvious quality control issues (such as
ensuring truthful and accurate data), precedence exists for the potential utility of this
approach. One existing example is on-line database that catalogs self-treatment of autism -
operated as the Interactive Autism Network (IAN 2010). Applied to leftover drugs, this
approach has extraordinary potential for providing insights on a host of issues involving the
relationships and inefficiencies in the manufacturer-physician-patient chain. Such data could
lead to new ways to select optimal medications and to prescribe and dispense medications in
optimal quantities; it could also reveal significant geographic differences.
Furthermore, the mere act of a patient being able to enter the types and quantities of leftover
medications into a publicly accessible database (and to be able to see the data entered by
others) may alter their behavior and attitude toward future purchases of medications -
making them more cognizant of over-purchase, unnecessary purchase, and wastage.
(2) Centralized database for data mined from collected medications. As suggested above
for patients, drug collection programs having the resources to mine data from returned drugs
could log the collected data into a central database. These data could then be used by
manufacturers, prescribers, and dispensers to modify their practices so that leftovers are
continually reduced. Pollution prevention efforts involving prescribing and dispensing could
then focus on targeting those medications that: (i) are costly, (ii) have high abuse potential,
(iii) are acutely toxic (e.g., single doses that can be lethal), (iv) have poor compliance
resulting from patients' inability to perceive the need to continue with treatment regimens, or
(v) have been shown to otherwise be extensively metabolized (and therefore poorly
excreted) and therefore have higher potential for environmental harm if disposed.
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A pre-existing program based in Texas that collects consumer self-reported data regarding
leftover medications might serve as an example for how a nationwide database might be
designed: "Unused and Expired Medicines Registry (UEMR)" (Community Medical
Foundation for Patient Safety -Year Unknown; Mireles 2005; 2006).
(3) Other uses for data mined from collection of leftover drugs. One aspect of drug-returns
data has rarely ever been capitalized on. By determining which drugs are returned (e.g., in
take-backs) most frequently or in the greatest quantities, decisions can be better informed as
to which APIs to select for targeting in local environmental monitoring studies. One
example of the type of data that could prove useful is reported by James et al. (2009), in
Table 1 of which is presented the top 20 medications returned during a collection event in
New Zealand. Depending on their pharmacokinetics, these drugs would contain the APIs
having a high probability of being excreted into sewers. By focusing on those that are
normally extensively metabolized (resulting in little excretion), those APIs in the ambient
environment having significant contributions from disposal could possibly be identified.
Significant variations could occur across geographic locales, as first noted in Daughton
(2003b). Geographic variabilities are known to occur in prescribing, as exemplified in a
recent study of Medicare spending on drug purchases (Zhang et al. 2010). This study found
large variations in expenditures across hospital regions. Contributors to these discrepancies
were variations in the specific drugs that were prescribed as well as the number of
prescriptions filled.
(4) Explore the feasibility of deposit-refund systems. The handling and disposition of drug
waste has always differed markedly from the approaches used for other wastes. One aspect
never considered for drug waste is deposit-refund schemes, such as long-used for glass
bottles and aluminum cans. Deposit-refunds could be particularly attractive for drug
delivery devices or for the growing numbers of new sophisticated containers - one example
being the NextBottle (One World DMG 2010). As these devices become more sophisticated
and costly (such as with the integration of electronics or design of multi-function
containers), recycling, reusing, or re-purposing will become more viable. With a deposit-
refund system implemented through pharmacies, additional opportunities for pharmacist
counseling would arise, possibly serving to improve patient compliance. Deposit-refunds for
medications have rarely ever been discussed, however, one example being Polimeni (2008).
An example of one major class of commonly used devices is Orally Inhaled and Nasal Drug
Products (OINDP). OINDP devices (such as inhalers) could eventually pose special
challenges - especially once electronics become an integral part of the device. Perhaps the
best stewardship model for OINDPs could be the electronics industry, where the used
product would be returned to the manufacturer, who would then disassemble the device and
reclaim the constituents or detoxify them.
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ADE: adverse drug event
ADR: adverse drug reaction
APIs: active pharmaceutical ingredients
AR: antibiotic resistance
ASCP: American Society of Consultant Pharmacists
ATC: Anatomical Therapeutic Chemical Classification
System
CAFOs: confined animal feeding operations
CASA: National Center on Addiction and Substance Abuse
(Columbia University)
CDER: Center for Drug Evaluation and Research
CIWMB: California Integrated Waste Management Board
CMS: chemical management service
CPSC: U.S. Consumer Product Safety Commission
CRCs: child-resistant closures
CSA: Controlled Substances Act
CVM: Center for Veterinary Medicine (FDA)
DDS: literature bibliographic database on leftover drugs,
drug disposal, and environmental stewardship
DEA: Drug Enforcement Administration
DoD: Department of Defense
DOJ: Department of Justice
DOOP: disposal of old pharmaceuticals
DOT: Department of Transportation
DRIs: degradation-related impurities
DTC: direct-to-consumer (advertising)
DUMP: dispose unwanted medicines properly
EHRs: electronic health care records
EPA: Environmental Protection Agency
EPR: extended producer (corporate) responsibility
FDA: Food and Drug Administration
FMEs: fatal medication errors
FTC: Federal Trade Commission
HHS: Health and Human Services
HIOs: health information organizations
HTPAA: Health Insurance Portability and Accountability Act
HPAPIs: highly potent active pharmaceutical ingredients
IARC: International Agency for Research on Cancer
LCSA: life cycle sustainability analysis
LTCFs: long-term care facilities
MDIs: metered-dose inhalers
MNU: les Medicaments Non Utilises (unused medicines)
MRP: Medications Return Program (British Columbia,
Canada)
MURs: medication use reviews
NABP: National Association of Boards of Pharmacy
NABP: National Association of Boards of Pharmacy
NaCO: National Association of Counties
NACWA: National Association of Clean Water Agencies
NADDI: National Association of Drug Diversion
Investigators
GLOSSARY
NAMSDL: National Alliance for Model State Drug Laws
NAO: National Audit Office (London)
NAPRA: National Association of Pharmacy Regulatory
Authorities (Canada)
NCPIE: National Council on Patient Information and
Education
NCSL: National Conference of State Legislatures
NIOSH: National Institute for Occupational Safety and
Health
NRDC: National Resources Defense Council
NSAIDs: non-steroidal anti-inflammatories
OIG: Office of Inspector General
OINDP: orally inhaled and nasal drug products
ONDCP: Office of National Drug Control Policy (Executive
Office of the President)
ORD: Office of Research and Development (US EPA)
OSHA: Occupational Safety and Health Administration
OTC: over-the-counter
PBT: persistence, bioaccumulation, and toxicity
PCPSA: Post-Consumer Pharmaceutical Stewardship
Association (British Columbia, Canada)
PDMA: Prescription Drug Marketing Act
PDMPs: prescription drug monitoring programs
PhRMA: Pharmaceutical Research and Manufacturers of
America
PI: prescriber-identifiable data
PK: pharmacokinetics
PoM: prescription-only medicines
PPCPs: pharmaceuticals and personal care products
ppt: parts-per-trillion (ng/L)
PRN: "as the situation arises" or "as needed"
PSF: Pharmaciens sans Frontieres (PSF) [Pharmacists
Without Borders]
PSI: Product Stewardship Institute
RCRA: Resource Conservation and Recovery Act
REMS: Risk Evaluation and Mitigation Strategy
RUM: Return Unwanted Medicine
SLEP: Shelf-Life Extension Program
SMDME: Safe Medicine Disposal for ME program
SNS: Strategic National Stockpile
STP: sewage treatment plants
TDS: transdermal and topical drug delivery systems
TNF: tissue necrosis factor
UEMs: unused and expired medications
USNER: National Euthanasia Registry (Protecting
Veterinarians)
USP: United States Pharmacopeia
USPS: U.S. Postal Service
VA: U.S. Department of Veterans Affairs
VIPPS: Verified Internet Pharmacy Practice Sites
WHO: World Health Organization
12 September 2010
CG Daughton
Drugs and the Environment:
Stewardship & Sustainability
page <138> of 196
US EPA/ORD, Las Vegas, NV
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Acknowledgments
Review of this document by the following experts (in alphabetical order) was greatly appreciated:
• Dr. Stevan Gressitt (University of Maine Center on Aging, Bangor, ME)
• Charlotte Smith (Director, PharmEcology Services, WM Healthcare Solutions, Inc., Wauwatosa, WI)
• Virginia Thompson (Sustainable Healthcare Sector Manager, Office of Environmental Innovation, US
Environmental Protection Agency Region 3, Philadelphia, PA)
EPA Notice
The information in this document has been funded wholly by the United States Environmental
Protection Agency. It has been subjected to the Agency's peer and administrative review and has
been approved for publication as an EPA document. Mention of trade names or commercial
products does not constitute endorsement or recommendation for use.
12 September 2010 Drugs and the Environment: page <139> of 196
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ILLUSTRATIONS PERTINENT TO DRUG DISPOSAL AND
STEWARDSHIP (PREPARED DURING THIS PROJECT)
Following in this section are illustrations prepared during the course of this project that are
relevant to drug disposal and stewardship. Most of these have been published in the peer-
reviewed literature, as cited here (in the order following):
Daughton CG. "The Environmental Life Cycle of Pharmaceuticals [illustration published in:
Daughton CG "Pharmaceuticals as Environmental Pollutants: the Ramifications for Human
Exposure," In: International Encyclopedia of Public Health, Kris Heggenhougen and Stella
Quah (Eds.), Vol. 5, San Diego: Academic Press; 2008, pp. 66-102]," US EPA, Las Vegas,
NV, December 2006; available: http://www.epa.gov/nerlesdl/bios/daughton/drug-
lifecycle.pdf
Daughton CG "Illicit Drugs and the Environment [illustration published in: Daughton CG "Illicit
Drugs: Contaminants in the Environment and Utility in Forensic Epidemiology," Reviews of
Environmental Contamination and Toxicology., in press, March 2011)], US EPA, Las Vegas,
Nevada, 7 December 2009 (rev 17 June 2010).
Daughton CG. "Accumulation and Disposal of Pharmaceuticals [illustration published in: Ruhoy
IS and Daughton CG "Beyond the Medicine Cabinet: An Analysis of Where and Why
Medications Accumulate," Environment International, 2008, 34(8): 1157-1169]," US EPA,
Las Vegas, NV, 10 May 2008.
Daughton CG. "Factors Influencing Drug Consumption [illustration published in: Ruhoy IS and
Daughton CG "Beyond the Medicine Cabinet: An Analysis of Where and Why Medications
Accumulate," Environment International, 2008, 34(8):1157-1169]," illustration, US EPA,
Las Vegas, NV, 8 December 2007 (rev 28 April 2008).
Daughton CG. "Role of PharmEcovigilance: Minimizing Human & Ecological Impacts
[illustration published in: Daughton CG and Ruhoy IS "The Afterlife of Drugs and the Role
of PharmEcovigilance," Drug Safety, 2008, 31(12): 1069-1082]," US EPA, Las Vegas, NV,
16 April 2009.
Daughton CG. "PharmEcovigilance and Environmental Risk [illustration published in: Daughton
CG and Ruhoy IS "PharmEcovigilance: Aligning Pharmacovigilance with Environmental
Protection, In: An Introduction to Environmental Pharmacology, Ed. SZ Rahman, M
Shahid, and V Gupta, Ibn Sina Academy, Aligarh, India; 2008, Chapter 1, pp 21-34]," US
EPA, Las Vegas, NV, 4 November 2007.
Daughton CG. "Unintentional, Unanticipated Exposure to Drugs [illustration published in:
Daughton CG and Ruhoy IS "The Afterlife of Drugs and the Role of PharmEcovigilance,"
Drug Safety, 2008, 31(12): 1069-1082]," illustration, US EPA, Las Vegas, NV, 8 December
2007 (rev 4 June 2008) 2007.
12 September 2010 Drugs and the Environment: page <140> of 196
CG Daughton Stewardship & Sustainability US EPA/ORD, Las Vegas, NV
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Daughton CG and Ruhoy IS. "PharmEcokinetics of APIs [illustration published in: Daughton
CG and Ruhoy IS "Environmental Footprint of Pharmaceuticals - The Significance of
Factors Beyond Direct Excretion to Sewers," Environmental Toxicology & Chemistry, 2009,
28(12):2495-2521; doi:l0.1897/08-382.1]," US EPA, Las Vegas, NV, 7 June 2008.
Ruhoy IS and Daughton CG "Pharmaceutical Disposal and the Environment," U.S. EPA, Las
Vegas, NV; illustrated poster, December 2007, NERL-LV-ESD-07-132; available:
http://www.epa.gov/nerlesdl/chemistry/images/drug-disposal-2.pdf
Ruhoy IS and Daughton CG "Disposal as a Source of Pharmaceuticals in the Environment," U.S.
EPA, Las Vegas, NV; illustrated poster, December 2007; NERL-LV-ESD-07-129;
available: http://www.epa.gov/nerlesdl/chemistry/images/drug-disposal-l.pdf
Daughton CG and Ruhoy IS. "PharmEcovigilance & Stewardship: Reducing Human and
Ecological Exposure from Pharmaceutical Residues," illustrated poster prepared for the
"Environmental Sciences Division Peer Review," 14 May 2009, National Exposure
Research Laboratory, Office of Research and Development, US EPA, Las Vegas, NV,
Session 5: Water Quality - Stressor/Receptor Characterization, poster #SRC-3; available:
http://www.epa.gov/esd/chemistry/images/pharmEcoviginl ance_stewardship.pdf.
12 September 2010 Drugs and the Environment: page <141> of 196
CG Daughton Stewardship & Sustainability US EPA/ORD, Las Vegas, NV
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Role of PharmEcovigilance:
Minimizing Human & Ecological Impacts
created ty CG Daufikton
US EPA, Las Vegas
16 April 2008
Pharmacovigilance
stewardship
PharmEcovigilance
inform &
balance
Ecopharmacovigilance
surveil
detect
assess
prevent
v
resulting from
intended use,
disposal, &
diversion of APIs
Adverse Events &
Poisonings: humans and
domestic animals
surveil
detect
assess
prevent
V
Adverse Effects:
ecological (aquatic &
terrestrial)
exchange &
recycling of
environmental
residues
Environmental
pharmacology;
Ecopharmacology
-------
United States
Environmental Protection
Agency
Pharmaceutical Disposal and the Environment
llene S. Ruhoy, MD and Christian G. Daughton, PhD
U.S. EPA, Office of Research and Development, National Exposure Research Laboratory, Environmental Sciences Division, P.O. Box 93478, Las Vegas, Nevada 89193-3478
Pharmaceuticals can contaminate the
environment via a complex network of
sources and pathways.
[ Environmental \
Life-Cycle of
Pharmaceuticals
Pharmaceuticals have myriads of uses for both humans and animals
(see: yellow nodes), including therapy, disease prevention, diagnosis,
cosmetics, and lifestyle. Hundreds of widely used active pharmaceutical
ingredients (APIs) can gain entry to the environment from numerous
locations in society (green nodes), primarily as a result of their intended
use - as caused by excretion or bathing. Disposal of unwanted, leftover
medications to sewage and trash is another source of entry, but its relative
significance is unknown. As ultra-trace pollutants, wildlife and humans
can experience long-
term exposure to APIs
via contaminated
water and foods (red
*
Leftover, unwanted pharma-
ceuticals can accumulate at
many locations.
At numerous locations, unwanted Pharmaceuticals are
stored and eventually disposed by various means of
collection or by discarding directly into sewerage or trash
Collected, leftover medications are generally disposed at
landfills or by incineration.
Disposal of consumer medications
can occur after leftover drugs are set
aside or stored.
Disposal as a Contributor to
Drugs in the Environment
Leftover drugs tend to accumulate. These
unwanted medications are intentionally
(or unknowingly) stored prior to a decision
to dispose of them. During storage, a leftover
drug can be diverted to those for whom the
medication was never intended. This can lead
to poisoning of hurnans and pets, or to abuse
and addiction.
Many factors cause medications to
remain unused, creating leftover
drugs that accumulate.
A wide spectrum offerees underlies the generation
of leftover drugs, ranging from certain practices of
manufacturers, distributors, prescribers, dispensers, and
patients themselves. Much of the need for drug disposal
could be eliminated by focusing corrective actions on these
major causes.
Products
Ruhoy, I.S. and
Daughton. C.G. "Types
and Quantities of
Leftover Drugs Entering
the Environmenti/ia
Disposal to Sewage
- Revealed byCoroner Records/ Sci.
Total Environ., 2007,388(1-3)137-148,
Ruhoy, I.S. and Daughton, C.G.
"Beyond the Medicine Cabinet:
An Analysis of Where and Why
Medications Accumulate." Manuscript
in preparation, 2008.
Ruhoy, 1.3. "ExaminingUnused
Pharmaceuticals in the Environment,"
Doctoral Dissertation, University of
Nevada, Las Vegas, Departmentof
Environmental Studies. In preparation,
2008.
Daughton, C.G. "Pharmaceuticals
in the Environment: Sources and
TheirManagement/1 Chapter 1,1-
58, In Analysis, Fate and Removal of
Pharmaceuticals in the Water Cycle
(M. Petrovic and D. Barcelo, Eds.),
Wilson & Wilson's Com prehensive
Analytical Chemistry series (D.
Barcelo, Ed.), Volume 50, Efeev/ef
Science, 2007, 564pp.
itice: Although thu woiliwaj reviews a by EPA, ii
:es?aii}y reflect official Agency policy. Menlbno:
recommend*tiantiy EPA foruse..
available from: http://www.epa.gov/nerlesdl/chemistry/images/driig-disposal-2.pdf
-------
Environmental Protection
Agency
Disposal as a Source of Pharmaceuticals in the Environment
Pllene S. Ruhoy, MD and Christian G. Daughton, PhD
U.S. EPA, Office of Research and Development, National Exposure Research Laboratory, Environmental Sciences Division, P.O. Box 93478, Las Vegas, Nevada 89193-3478
INTRODUCTION
Active pharmaceutical ingredients (APIs)
from a large and diverse spectrum
of Pharmaceuticals can enter the
environment as trace contaminants,
especially in waters, at individual
concentrations generally less than apart
per billion (ug/L) but sometimes more.
These trace residues may pose risks for
OBJECTIVES
aquatic life and cause concern with regard to human exposure, such as
in drinking water supplies.
The predominate route by which APIs gain entry to the environment is
via the discharge of raw andtreatedsewage contaminatedwith APIs as a
result of their intended use in therapy or for lifestyle/cosmetic purposes.
Figure 1
Residues of APIs from parenteral and enteral
drugs are excreted in feces and urine, and
topically applied medications (plus APIs
excreted in perspiration) are washed from skin
during bathing.
For most APIs, the fraction of unchanged, parent
API transferred to the envi ronment is attenuated
as a result of metabolic alteration in the body
or transformation within a sewage treatment
facility. For some APIs, only a small percentage
of the total amount used is ever transported to
the environment.
A secondary route of transfer of APIs to the
environment is from the purposeful, direct
disposal of medications to sewers and trash.
The relative significance of this type of disposal
with respect to excretion and bathing is poorly
understood and subject to speculation. Two
major aspects of uncertainty exist. First, it is
unknown what p ercentage of any particular
API in the environment originates from
disposal; the individual percentages probably
vary dramatically among APIs, Second,
disposal undoubtedly occurs from a variety of
largely uncharacter!zed sources.
Sources of disposal, along with the types and
quantities of APIs resulting from each source,
are important to understand so that effective
pollution prevention approaches can be designed
and implemented.
The accumulation of leftover, unwanted drugs
can be used as an indicator of three major
conditions:
1) Leftover drugs, when disposed to sewage or
trash, represent a diverse source of potential
chemical stressors in the environment
2) Accumulated drugs represent increased
potential for drug diversion, with its
attendant accidental poisonings and
purposeful addictive usage.
3) Leftover drugs represent wasted healthcare
resources and lost opportunities for medical
treatment.
Summarized here is a project whose objectives were to:
• Catalog the diversity of locations where drugs are used and
accumulate, eventually requiring disposal.
• Define the processes that control and drive the consumption.
accumulation, and disposal of human Pharmaceuticals.
• Identify opportunities for pollution prevention and source
reduction.
• Develop an approach for accurately identifying the APIs (and
their actual quantities) being disposed.
ACCOMPLISHMENTS
Identification of Sources: Probably more than for any other
perishable., nonfood item consumed by humans, medications are
used and stored at a vast array of locations throughout society. These
products are frequently purchased in excess or not fully consumed as
directed (e.g., patient non-compliance), leading to the accumulation
of unwanted, leftover drugs. A broad spectrum of locations at which
drugs are used and can accumulate, eventually leading to disposal, are
shown in Figure 1. The relative significance of each of these sources
with respect to disposal is currently unknown.
Factors Governing Disposal: The processes leading to the disposal
of drugs by the individual consumer are illustrated in Figure 2. A
significant point is that accumulated, leftover medications pose several
major problems for human health and safety and for the integrity of the
environment. These problems result from the diversion of accumulated
drugs to those for whom they were not intended (leading to accidental
andpurposeful poisonings of infants, children, adults, andpets) and
from the disposal of accumulated drugs to trash and sewage. The latter
promotes the entry of APIs to the ambient environment.
Factors Governing Consumption and Accumulation: Numerous
factors affect the consumption of drugs by consumers (Figure 3). Most
serve to increase use, although several are at work to reduce use. Most
of these factors are amenable to measures that could be designed to
reduce their influence on the consumer. But these measures, in general,
are outside the purview of the EPA. The significance of these factors
is that each is amenable to targeting by various actions or activities to
actively and substantially reduce the potential for drugs to accumulate
prior to their disposal.
Possible Outcomes from Pollution Prevention: Progress with
pollution reduction/prevention activities could yield substantial
benefits, including: (i) reductions in the types and quantities of drugs
Figure 2
^^ *^ffi
CONCLUSIONS
that accumulate, and which then become targets for disposal,
(ii) reducing healthcare costs (by lessening wastage from unused
drugs), and (iii) improving healthcare outcomes (by ensuring
patients are prescribed prudent amounts of medications and that
they comply with prescribing directions),
An Objective Approach for Measuring the Magnitude and
Significance of Disposal: Finally, a new methodology has been
developed for identifying the types, and quantifying the amounts,
of individual APIs that are disposed to sewage at the level of the
local community. Such a tool had not been previously available.
This new approach makes use of the very comprehensive and
accurate inventory data collected by coroner offices (Ruhoy and
Daughton 2007). Coroners are actually a source of drug disposal
themselves as shown in Figures 1 & 2. This approach will lead to
an eventual assessment of the relative significance or impact of
drug disposal versus excretion/bathing on residues of APIs in the
environment.
While the disposal of leftover drugs adds to the environmental burden of drug residues, it is currently
not known how significant it might be. By identifying which drugs accumulate (Ruhoy and Daughton
2007), and where they accumulate (Ruhoy and Daughton 2008), measures could be implemented that
would not only reduce the consequent need for disposal, but also improve healthcare outcomes and
reduce healthcare expenses. This would be done preferably not by focusing on ecologically prudent
methods for disposing of leftover medications, but rather by changing the human and healthcare
processes that lead to accumulation in the first place — to eliminate accumulation altogether.
If new approaches to medical care were developed that eliminated leftover drugs, the consequent
environmental residues would be eliminated, therapeutic outcomes would improve, healthcare
expenses would go down, and hum an morbidity and mortality (due to addictive usage and poisonings
from diverted, leftover drugs) would decline. Reducing, minimizing, or eliminating leftover drugs
represents a very significant
opportunity to improve both
ecological and human health.
PRODUCTS
Ruhoy, I.S. and
Daughton, C.G.
"Types and Quantities
of LeftoverDrugs
Enteringthe
Environmentvia
Disposal to Sewage
-Revealed byCoroner
Records," 3d. Total Environ., 2007, 388(1-
3);137-148.
Ruhoy, I.S. and Daughton, C.G. "Beyond
the Medicine Cabinet: An Analysis of
Where and Why Medications Accumulate."
Manuscript in preparation, 200S.
Ruhoy, I.S, "Examining Unused
Pharmaceuticals inthe Environment,'
Doctoral Dissertation, University of
Nevada, Las Vegas, Department of
Environmental Studies. In preparation,
2008.
Daughton, C.G. "Pharmaceuticals
in the Environment: Sources and
Their Management" Chapter 1,1-
58, InAnalysis, Fate and Removal of
Pharmaceuticals inthe Water Cycle (M.
Petrovic and D. Barcelo, Eds.), Wilson
& Wilson's Comprehensive Analytical
Chemistry series (D. Qarcelo, Ed.), Volume
50, Etsevier Science, 2007, 564pp.
Hotice: AlthoughtMs work was reviewed by EPA, it may not necessarily reflect official Agency policy Mention
cf trade names or commercial products does not constitute endorsement or recommendation by EPA for use.
available from: http://www.epa.gov/nerlesdl/chernistry/images/drug-disposaM .pdf
27 November 2007
-------
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