US Pharm. 2013;38(10):21-26.
analgesics are the mainstay treatment of moderate-to-severe pain.
However, opioids carry a risk of misuse, abuse, and death, and recently
have become a public health challenge. In response to the steady
increase in opioid abuse, pressure has been growing on pharmaceutical
companies to develop prescription opioid formulations that help deter
abuse while remaining readily accessible for pain management. This
article discusses some of the novel abuse-deterrent formulation methods,
including aversion, physical barrier, and agonist-antagonist. It also
addresses some of the legislative initiatives and the role of
pharmacists in providing education to health care professionals and
patients as well as increasing their awareness of prescription opioid
misuse and abuse.
Pain is a significant public health problem in the United
States. It is estimated that over 100 million people in the U.S. live
with chronic pain, a prevalence that is greater than heart disease,
diabetes, and cancer combined.1 The consequences of
unrelieved pain are associated with reduced quality of life and are
estimated to cost society over $635 billion annually.1 Pain
is recognized as a disorder, and is associated with many psychosocial
conditions, including depression, decreased appetite, and insomnia.2
Prevalence of Opioid Abuse
Prescription opioid analgesics are the mainstay of
pharmacologic management of pain. They are administered through various
routes and are available in many dosage forms, some of which are novel.
Over the last few years, there has been a debate regarding the long-term
use of opioids in the treatment of chronic nonmalignant pain. This
discussion stems from ongoing concerns about adverse effects, lack of
long-term data, and the potential for opioid misuse and abuse.
In the past two decades, the use of opioid therapy for the
treatment of pain has dramatically increased. Simultaneously, opioid
prescription abuse and overdose has markedly increased.3,4
From 1997 to 2007, the milligram-per-person use of prescription opioids
in the U.S. increased from 74 to 369 mg, an increase of 402%.3
In addition, in 2000, retail pharmacies dispensed 174 million
prescriptions for opioids; by 2009, 257 million prescriptions were
dispensed, an increase of 48%.5 National surveys show that
opioid misuse has increased dramatically over the past decade and that
opioid medications have surpassed cocaine and heroin as the leading
drugs of abuse.6,7
Risk Evaluation and Mitigation Strategy
Due to the emerging issues of opioid misuse and abuse, the
FDA issued a new Risk Evaluation and Mitigation Strategy (REMS) for
extended-release (ER) and long-acting (LA) opioids in July 2012.8 The REMS program stems from the national prescription drug abuse plan that was announced by the Obama administration in 2011.8
REMS is a risk management plan that exceeds standard drug prescribing
information; the FDA selected the ER and LA formulations of opioids
because of the inherent risks of using these drugs. These formulations
contain greater amounts of drug compared to the short-acting
formulations, thus making those medications more dangerous in situations
of abuse and misuse. The program focuses on educating providers and
patients on the safe use of ER and LA opioids while ensuring that
patients who require treatment with opioids have access to them.
Manufacturers are responsible for creating educational programs and
materials for all Drug Enforcement Administration (DEA)–registered
Prescribers’ education is an essential element of the REMS
program; it encompasses knowledge about the drug, patient assessment,
initiation, modification or discontinuation of therapy, management and
monitoring of patients, and providing counseling. Furthermore,
prescribers are encouraged to use assessment tools to stratify risk of
addiction in patients receiving opioid prescription drugs.9
Pharmacists will distribute an updated Medication Guide with ER/LA
opioid prescriptions instructing patients to consult their health care
providers prior to modifying doses, describing signs of overdose, and
giving emergency contact information and recommendations for safe
storage to prevent accidental ingestion. The FDA hopes to train 25% of
the 320,000 prescribers in the United States within 1 year, 50% after 2
years, and 60% within 4 years. Follow-up surveys will be conducted to
assess prescriber understanding and to determine if the program is
negatively affecting patient access.7,9
Most recently, in an effort to further safety precautions
with the use of ER/LA opioid analgesics, the FDA has imposed safety
labeling changes and postmarket study requirements. The labeling changes
will include an updated indication emphasizing the use of ER/LA opioids
in patients with pain severe enough to require daily, around-the-clock,
long-term opioid treatment and for which alternative treatment is
inadequate. In addition, the FDA is requiring a new boxed warning on
ER/LA opioids analgesics to caution that chronic maternal use of these
products during pregnancy can result in neonatal opioid withdrawal
Prescription Drug Monitoring Programs
Prescription Drug Monitoring Programs (PDMPs or PMPs) are
statewide electronic databases that collect prescribing and dispensing
data on controlled substances dispensed in the state. These programs aim
to reduce prescription drug abuse and diversion. The benefits of PDMPs
are multifactorial in that they help to provide patient care, act as a
warning system, and monitor prescribing to prevent diversion. Licensing
boards can utilize this system to track prescribing habits and deter
diversion. Each state has its own rules and regulations that govern
Abuse-Deterrent Formulations (ADFs)
The pharmaceutical industry recognizes the growing problem
that accompanies the increased use of opioids and has set out to create
unique compounds that prevent abuse and diversion. This step has
spurred the development of abuse-deterrent and abuse-resistant
formulations of opioids.13 Current innovations focus on the
development of drug delivery systems that are resistant to abuse and
diversion. Pharmaceutical developers are experimenting with adding
active ingredients or excipients, making the active ingredient(s)
unavailable for unintended routes of administration, and preventing the
modification of the drug for a faster onset of action. These new special
formulations have the potential to reduce the public health burden of
prescription opioid abuse. Several different types of ADFs have emerged,
including aversion, physical barrier to tampering, and
agonist-antagonist combination (TABLE 1).
Aversion: One approach to deter abuse
potential is the addition of substances with opioid products that
produce some type of unpleasant effect in patients who ingest tampered
products. Acura Pharmaceuticals has been developing abuse-deterrent
products for nearly 10 years using the patented abuse-deterrent AVERSION
technology.14 This technology impedes opioid extraction via
dissolution of tablets using water or alcohol, which causes the tablet
to form into a viscous gel. The active ingredient is then trapped in the
gel and becomes difficult to draw up into a syringe for injection.
Furthermore, the delivery system also discourages nasal snorting of
crushed tablets by including excipients that can cause nasal irritation.14
Oxecta (oxycodone hydrochloride [HCl]), a new formulation
of oxycodone that implements AVERSION technology, was approved in 2011.15
Available as 5- and 7.5-mg tablets, Oxecta is indicated for the
management of moderate-to-severe pain. When crushed, the tablet breaks
down into chunks instead of powder. Furthermore, it is not viable as an
injection because when mixed with liquids, it becomes “sudsy.”16 Oxecta contains sodium lauryl sulfate, which will cause discomfort to the nasal passage if snorted.15
The manufacturer has recommended that Oxecta not be given via
nasogastric, gastric, or other feeding tubes as it may cause
obstruction. Thus, Oxecta may only be appropriate in patients who can
tolerate oral therapy.
Physical Barrier: Other common
methods of tampering with prescription opioids include physical
manipulations (e.g., crushing) and chemical manipulation (e.g.,
dissolving in alcohol). In 2008, the U.S. Substance Abuse and Mental
Health Services Administration’s National Survey on Drug Use and Health
reported the number of nonmedical users of OxyContin (controlled-release
oxycodone) aged ≥12 years was approximately half a million.17
In response to the increased abuse of OxyContin, the FDA approved a new controlled-release oxycodone formulation in spring 2010.18
The new version was reformulated with physical and chemical properties
that make abuse via the intranasal route and injection difficult. The
reformu-lated tablets contain polyethylene oxide (PEO). PEO serves as an
abuse deterrent because it is a nonionic hydrophilic polymer that is
insoluble in alcohol. Upon contact with water, it forms a viscous gel.
Attempts to dissolve the tablets in liquid result in a gummy substance
that cannot be injected or snorted. The new formulation is
also harder to break, cut, chew, or crush. The tablets either do not
break or break into pieces that retain some controlled-release
functionality. According to the new package insert labeling approved by
the FDA in April 2013, in vitro physical and chemical tablet
manipulation studies of the new formulation show that it resists
crushing, breaking, and dissolution using various tools and solvents.18
Another example of physical barrier is Opana ER
(oxymorphone HCl), which is indicated for the relief of
moderate-to-severe pain in patients requiring around-the-clock opioid
treatment for an extended period of time.19 It is available
in 5-, 7.5-, 10-, 15-, 20-, 30-, and 40-mg tablets. This formulation
uses INTAC technology created by Grüenthal. INTAC is a tamper-resistant
technology designed to prevent modification of the drug into a fine
powder. The technology for the ER formulation incorporates PEO, which
has a high molecular weight, and uses a “hot-melt extrusion process.”
This process combines heat and pressure so that tablets have mechanical
strength that resists crushing.20 Furthermore, if the
delivery system is compromised, INTAC also provides resistance to
dissolution via liquids, as the remnants of a broken tablet will form a
viscous gel to trap the active ingredients.21
Exalgo (hydromorphone HCl) is indicated as once-daily
administration for the management of moderate-to-severe pain in
opioid-tolerant patients. It is available as 8-, 12-, 16-, and 32-mg
tablets. Exalgo uses the Osmotic Extended-Release Oral Delivery System
(OROS).22 This technology has an osmotically active bilayer
core enclosed in a semipermeable tablet shell membrane that allows both a
consistent 24-hour delivery rate and provides a barrier to abuse.23
Agonist-Antagonist Combination: Several
formulation products containing an opioid agonist in combination with
an antagonist are already on the market. Suboxone (buprenorphine
HCl/naloxone HCl) is indicated for treatment of opioid dependence and is
available as a sublingual film in strengths of 2 mg/0.5 mg, 4 mg/1 mg, 8
mg/2 mg, and 12 mg/3 mg.24 This drug uses a different method
to deter abuse. Suboxone combines buprenorphine, a partial opioid
agonist-antagonist, and naloxone, an opioid antagonist. Buprenorphine
provides analgesia while its combination with naloxone prevents IV
abuse. The naloxone component is not sublingually absorbed and has
minimal oral absorption; therefore, it does not exert its antagonist
effect when taken orally or sublingually. However, if Suboxone is
crushed and then injected IV or IM, the naloxone component will be
directly introduced to the systemic circulation, where it will
antagonize the effects of buprenorphine. This antagonistic action,
produced by the naloxone contained in Suboxone, causes opioid-dependent
patients to experience withdrawal, thereby deterring abuse.24,25
Pipeline Abuse-Deterrent Formulations
Acura Pharmaceuticals has multiple pipeline products in development with its patented abuse-deterrent AVERSION technology.
Acuracet, a combination of oxycodone HCl and acetaminophen, is
currently in the formulation and stability stages of development.
Vycavert, a combination of hydrocodone bitartrate and acetaminophen, is
in the clinical and laboratory testing phases of development. Both are
immediate-release opioids with a proposed indication for relief of
moderate-to-severe pain, designed to limit abuse via nasal snorting and
Naloxone Access Law
With the steady increase in fatal drug overdoses related
to opioid use, many states have amended laws to allow for access to
emergency care and treatment of opioid overdose. As an opioid
antagonist, naloxone is essential for the reversal of an overdose.
Overdoses often occur when a victim is with friends or family;
therefore, if these people can act quickly and administer naloxone, they
may be able to save a victim’s life. Naloxone access and “Good
Samaritan” laws remove the possibility of negative legal action against
prescribers who act in good faith to prescribe naloxone to those who may
benefit from it. They also encourage bystanders to become Good
Samaritans by summoning emergency responders without fear of arrest or
unfavorable legal consequences.28
Role of the Pharmacist
Pharmacists are in a unique position to provide education
regarding opioid use in both inpatient and outpatient settings.
Pharmacists are valuable members of the interdisciplinary team because
of their knowledge of opioid medications, their ability to perform a
comprehensive review of past and current pharmacologic interventions for
pain, and their ability to provide valuable insight regarding the most
appropriate opioids for pain management. The implementation of PDMPs and
the REMS program opens up the opportunity for pharmacists to be further
involved, such as in tracking prescriptions and alerting providers of
potential abuse or illegal prescription filling. Pharmacists can educate
providers and patients on the use of opioids, help prevent their abuse
and overuse, and reduce the potential for addiction and dependence.
Pharmacists can also emphasize to patients the techniques for proper
opioid use, storage, and disposal. With the newer formulations on the
market, pharmacists can educate both health care providers and patients
about types of abuse-deterrent formulations and their advantages.
Overall, education by pharmacists can help to decrease the potential for
As the use of opioids reaches an all-time high, concern
for their misuse and abuse rises simultaneously. In response to the
clinical concerns about drug abuse, many manufacturers are developing
opioid products that have abuse-deterrent qualities. The pharmaceutical
industry has begun to offer solutions and will likely continue to
innovate and design new methods to address this concern. The new
technologies described here and future improvements will give health
care providers the means to address pain management while mitigating the
concern for and rise of opioid abuse and misuse. It is imperative that
clinicians understand the characteristics of these agents if they are to
improve the care of their patients with pain.
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June 12, 2013.
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