INTRODUCTION — Prescription opioid abuse represents a large component of the opioid drug crisis in the United States. The rate of fatal overdoses due to oral formulations of semisynthetic opioids (eg, oxycodone, hydrocodone) has risen steadily since 2000, and in 2017 was greater than that of heroin [1].
Many individuals who abuse opioids progress from an initially legitimate, legal use of oral opioids, to misuse, tolerance, abuse, and possible addiction. Abusers may swallow many pills at once, but may also chew the tablets or crush them to facilitate smoking, inhalation, or intravenous (IV) injection, all of which increase the risks of overdose and addiction. Abuse deterrent formulations (ADFs) of opioids are designed to prevent these altered routes of administration, while retaining efficacy with oral administration for legitimate pain relief. Prescription of ADF opioids is controversial because of unanswered questions about their ability to reduce overall opioid abuse, and their higher cost. ADFs neither prevent individuals from taking the drugs in higher doses than prescribed (which is the most common form of opioid abuse), change the addictive properties of the drug, nor prevent the other adverse, multisystem effects of opioids.
This topic will discuss the technologies used, available formulations, and efficacy of ADF opioids for reducing opioid misuse and abuse. Opioid use disorder and abuse of prescription opioids is discussed separately. (See "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis" and "Prescription drug misuse: Epidemiology, prevention, identification, and management", section on 'Opioid analgesics'.)
GOALS FOR ABUSE DETERRENT FORMULATION — The primary goal for an abuse deterrent formulation (ADF) is to deter or dissuade an individual from chewing the drug, or using it for inhalation or intravenous (IV) abuse. These latter routes of administration are associated with an increased risk of respiratory depression and fatal overdose compared with oral administration [2], particularly because of the high dose of opioid that is concentrated in extended-release formulations. Chewing, inhalation, and IV routes of drug administration rapidly achieve a high blood level and greater degree of rewarding effects [3,4], and therefore may increase the risk of addiction and abuse. Non-oral routes of administration are also associated with a variety of other health consequences, including damage to nasal and oral structures [5,6] and blood-borne infections (eg, human immunodeficiency virus, hepatitis, and endocarditis) [7].
ABUSE DETERRENT TECHNOLOGIES — One or more abuse deterrent technologies are used for the abuse deterrent formulations (ADFs) currently available in the United States and approved for ADF labelling by the US Food and Drug Administration (FDA) (table 1). There are several abuse deterrent preparations available in Canada, none of which have been approved for tamper resistant labelling by Health Canada.
●Physical/chemical barriers – The most common ADF technology employs either physical or chemical barriers, or both. Physical barriers are used to prevent chewing, crushing, cutting, or grinding of the tablet. Chemical barriers (eg, gelling agents) resist penetration and dissolution by water or other solvents, and may change the form of the active drug to render it difficult to inhale or inject. As an example, with one chemical barrier technology, the active drug turns into a viscous gel when exposed to a liquid, making it difficult for the abuser to use a syringe to inject the drug [8].
●Agonist/antagonist combinations – An opioid antagonist can be added to the agonist drug. Opioid antagonists are not effectively absorbed when swallowed, and do not counteract the opioid agonist when taken as intended [9]. However, when the manipulated drug is injected or inhaled, the antagonist is effective at reducing or eliminating the euphoria associated with the agonist. The combination drug that includes buprenorphine and naloxone (Suboxone), used for pharmacotherapy of opioid use disorder, works by this mechanism. (See "Medication for opioid use disorder", section on 'Transmucosal formulations'.)
Additional formulations for abuse deterrence include aversion, whereby substances are added to produce unpleasant effects of the drug when misused; unconventional opioid delivery systems such as sustained-release depot injectable formulations or subcutaneous implants that are difficult to manipulate; prodrugs or new molecular entities that must undergo enzymatic activation or other chemical transformations in the gastrointestinal tract in order to release the active opioid [10,11]; combinations of two or more technologies; or novel approaches or new technologies.
ABUSE DETERRENT FORMULATION APPROVAL PROCESS — The FDA strongly recommends three types of premarket studies plus postmarket evaluation for abuse deterrent formulation (ADF) labelling [12]. The premarket studies use healthy, non-addicted, recreational drug users between 18 and 55 years of age, and are designed to evaluate the bio-equivalency of the active drug, integrity of the deterrent properties, the ease with which the altered drug can be drawn into and injected from a syringe for intravenous (IV) use, and the "likeability" of a manipulated ADF.
Postmarketing studies evaluate the real-world effect of the ADF on reduction of abuse, misuse, adverse clinical outcomes, overdose, and death. Postmarketing studies have been completed for the ADF of extended-release oxycodone (OxyContin), which was the first available ADF, but the results are inconclusive. (See 'Efficacy' below.)
The FDA approves abuse deterrent labeling for specific routes of drug use (ie, oral, nasal, or IV) based on clinical studies. The routes of drug use approved for abuse deterrent labeling for available ADF opioids are shown in a table (table 1).
ABUSE DETERRENT OPIOID FORMULATIONS — Three extended-release (ER) opioid preparations with abuse deterrent formulation (ADF) labelling are available in the United States, two with oxycodone and one with hydrocodone. Six other ADFs have been approved but are not available, including the only immediate-release (IR) oxycodone (Roxybond). One of the US Food and Drug Administration (FDA) approved ADFs with oxycodone (Targiniq ER) is available in Canada but not the United States.
An ADF of extended-release oxycodone (OxyContin) was the first opioid approved for ADF labelling, and is the most widely prescribed ADF opioid (figure 1 and figure 2). The available ADF opioids, the technology used for abuse deterrence, and available doses are shown in a table (table 1).
An oxymorphone preparation with abuse deterrent technology, reformulated Opana ER, was withdrawn from the market by the manufacturer in 2017 [13] because of reports of thrombotic thrombocytopenic purpura [14,15], and an outbreak of human immunodeficiency virus infection [16] associated with intravenous abuse of the manipulated preparation. Reformulated Opana ER never acquired FDA ADF labelling due to concerns about safety and efficacy [17].
EFFICACY — Abuse deterrent formulation (ADF) probably reduces the abuse of a specific opioid, but may also drive abusers to select a different non-ADF opioid, an intravenous opioid (eg, heroin), or another type of illegal psychostimulant (eg, cocaine).
Efficacy of technology — ADF labelling requires demonstration that the abuse deterrent technology makes it more difficult to extract the active drug, more difficult to draw the extracted drug into a syringe and inject it from a syringe, and that the manipulated drug is less "likeable" than the non-ADF equivalent [12]. (See 'Abuse deterrent formulation approval process' above.)
Real world efficacy — Real world efficacy of ADF technology may be reduced for the following reasons:
●ADF does not prevent patients from taking increased quantities of the ADF formulation and therefore higher doses than prescribed, which is the most common form of opioid misuse [18].
●ADF does not change the addictive property of the active drug.
●ADFs are not abuse-proof, and online forums for abusing opioids have posted instructions for subverting some ADF technologies [19-21].
Effect of abuse deterrent formulation on abuse of specific drug — The postmarketing studies that have been completed for reformulated extended-release (ER) oxycodone (OxyContin) have been inconclusive and have reported mixed results. It is unclear whether prescription of an ADF opioid rather than a non-ADF opioid reduces the risk of abuse, addiction, or overdose in opioid naïve patients or in those who do not abuse opioids at the time of prescription. There are no postmarket studies of abuse that have been conducted in cohorts of patients who are newly prescribed ADF and non-ADF opioids. There are also no studies of any type that have compared rates of addiction in ADF versus non-ADF users.
Most of the studies of the effects of reformulated OxyContin have reported a reduction in the rate of OxyContin abuse after reformulation, with reported reductions of 12 to 75 percent [22-26]. These studies are retrospective, and have been based on poison control center calls, reports from individuals in substance abuse programs, population-based drug use surveys, medical claims databases, and data from drug diversion programs; this data has been collected over time periods in which other interventions aimed at opioid abuse may have occurred.
It appears that very few individuals who abused OxyContin prior to reformulation ceased drug abuse because of the abuse deterrent formulation. In one survey of patients with opioid abuse disorder, 3 percent of patients reported that they stopped drug abuse because of OxyContin reformulation, whereas 66 percent of patients either continued to abuse OxyContin (either orally or by manipulation) or switched to other drugs [22]. (See 'Switch to other opioids or heroin' below.)
An industry-sponsored retrospective database study compared opioid related adverse outcomes in approximately 4850 patients who were prescribed extended abuse deterrent morphine (Embeda, extended-release morphine with sequestered naltrexone hydrochloride) with outcomes in 10,350 patients who received non-abuse-deterrent extended-release morphine [27]. Prescription of the abuse deterrent formulation was associated with lower incidences of abuse or dependence and non-fatal opioid related overdose.
Efficacy for overall opioid abuse — The impact of ADF technology on opioid misuse and abuse at the societal level is difficult to determine because these technologies are part of evolving multipronged strategies to combat the opioid epidemic.
ADFs represent only a small portion of the available and prescribed opioid products in the United States (US), and therefore may have a limited impact on overall rates of opioid abuse [28]. Ninety-six percent of all opioid products prescribed in the United States in 2015 (predominantly immediate-release [IR] formulations) lacked abuse deterrent properties. In 2016, prescriptions for ADF opioids represented about 20 percent of all dispensed extended-release opioids [12], though availability of ADFs in the US may increase as state legislatures or health insurance companies mandate or encourage ADF prescription. (See 'State legislation' below.)
However, even if all prescription opioids were changed to ADFs, illicit opioids including heroin, fentanyl, and other synthetic opioids would still be available and this change could drive users from prescription to illicit drug abuse.
NEGATIVE CONSEQUENCES OF ABUSE DETERRENT OPIOID FORMULATION
Switch to other opioids or heroin — As an alternative to abuse deterrent formulations (ADFs), many abusers have switched to other prescription opioids, or have chosen to inject or inhale heroin, which is increasingly available and less expensive than ADF pills [29], and is a more significant public health issue than abuse of prescription opioids. (See "Prevention of lethal opioid overdose in the community", section on 'Epidemiology'.)
●Increase in non-ADF opioids – A number of studies have reported an increase in the use of non-ADF opioids that are easier to abuse after introduction of reformulated OxyContin [22-26,30-32]. As an example, in one study, opioid use and abuse were assessed after introduction of the ADF oxycodone (reformulated OxyContin) in patients who were taking the ER preparation continuously prior to reformulation [31]. Thirty percent of patients avoided switching to ADF opioid, and instead changed to non-ADF extended-release (ER) opioids or immediate-release/short acting opioids, or stopped taking prescription opioids (presumably many of whom switched to illicit opioids). The diagnosed opioid abuse rates were higher in patients who avoided switching to ADFs than in patients who transitioned to ADFs (6.7 percent for those who switched to other ER opioids, 10.9 percent for those who discontinued ER prescription opioids, and 11.3 percent for those who switched to immediate-release opioids, compared with 3.5 percent in patients who transitioned to ADF oxycodone).
Evidence that ADFs have been related to an increase in heroin use includes the following:
●A survey of prescription opioid abusers who were entering treatment programs reported that after the reformulation of OxyContin to ADF, while OxyContin use fell by approximately 35 percent, use of other opioids (including high-potency fentanyl and hydromorphone) increased by approximately 50 percent, and heroin use nearly doubled [26].
●A survey from Purdue Pharma, maker of OxyContin, reported a 42 percent increase in heroin abuse after OxyContin was redesigned as an ADF [33].
●A 2017 study estimated that up to 80 percent of the threefold increase in heroin mortality since 2010 could be attributed to the formulation change of OxyContin [34].
Cost — Abuse deterrent formulations (ADFs) in the United States (US) are all branded drugs that are significantly more expensive than non-ADF counterparts. Estimates vary, but have suggested that ADFs cost the patient or insurance payor between 5 and 15 times as much as non-ADF opioids [35]. As an example, a cost analysis for 2016 from the Veterans Affairs health care system reported that 1.9 percent of opioids prescribed were ADFs, but that these drugs represented 37 percent of overall spending on opioids [36]. Conversion of all opioids to ADFs would result in approximately one billion dollars in cost per year, which could be as much as 20 percent of the entire VA pharmacy budget.
Many insurance plans require preapproval for ADF prescription. Cost to patients for ADFs vary depending on location, insurance coverage and copays, and availability of drug manufacturer discounts. Some states have mandated insurance coverage for ADF opioids. (See 'State legislation' below.)
Nonetheless, patients who use opioids in an entirely legal fashion to treat pain may be priced out of their ability to afford pain relief. An analysis in the state of Utah reported that in 2015 the average cost of one tablet of ADF opioid was approximately twelve dollars, compared with approximately three dollars for a non-ADF equivalent [37]. A claims study conducted by the Commonwealth of Massachusetts Health Policy Commission in 2017 reported that the mean daily cost for ADF opioids was $15.90, versus $3.44 for non-ADF opioids [38].
The high cost of ADFs has prompted analyses of the overall value of these drugs, considering indirect cost savings such as emergency room visits, hospitalizations, overdoses, and abuse treatment programs, in addition to ADF drug costs. Such analysis is necessarily based on assumptions about the efficacy of ADFs for deterring abuse and related clinical outcomes, without reliable supporting data.
One cost benefit analysis consisted of hypothetical cohorts of noncancer chronic pain patients prescribed ADF opioids compared with non-ADF opioids over five years, with 100,000 patients in each cohort [39]. In this study, ADF opioids prevented 2300 new cases of abuse per 100,000 patients treated, at a cost of an additional $533 million, over five years. Using ADF opioids cost the health care system $231,500 to prevent one case of abuse. A separate single state analysis in the same report estimated that conversion of all existing non-ADF prescriptions to ADF prescriptions over one year in Massachusetts would prevent 850 new cases of abuse at a cost of $599,000 for each case of prevented abuse, and increase statewide costs by $475 million.
This study did not include effects of individuals switching to other opioids, or to heroin. To the extent that patients prescribed ADF opioids switch opioids or use heroin instead, the economics of prescription of ADF opioids would have been even less favorable.
STATE LEGISLATION — State legislatures have enacted or are considering legislation requiring that clinicians prescribe or pharmacists dispense abuse deterrent formulation (ADF) opioids where they are available (figure 3) [40]. In 2014, Massachusetts became the first state to pass legislation that requires pharmacies to substitute ADFs by default for chemically equivalent non-ADF opioid prescriptions unless specifically directed otherwise by the prescriber, and to require insurance carriers to cover these ADFs with no additional cost burden to patients [41]. Clinicians should be aware of the regulations that apply in their states.
Data on the impact of these state policy interventions are limited and inconsistent [42].
INDICATIONS FOR ABUSE DETERRENT FORMULATION PRESCRIPTION — We do not routinely prescribe abuse deterrent formulation (ADF) opioids rather than non-ADF opioids. The decision to prescribe ADF opioids should be individualized, but data are not available that would stratify risk and determine which patients should receive these preparations [43]. Use of ADFs should never be a substitute for other relevant risk management approaches or risk mitigation tools. (See "Use of opioids in the management of chronic non-cancer pain", section on 'Monitoring and risk management strategies during trial'.)
The clinician who is truly concerned about abuse by the intended recipient should reconsider prescribing an opioid at all. An ADF may be indicated if there is high risk of diversion, such as a debilitated patient in a living situation that allows others access to the patient's medications.
Whereas ADFs make abuse more difficult for patients who are prescribed opioids for chronic pain, individuals already abusing opioids may switch to other illicit opioids (including heroin or fentanyl) if a specific opioid is replaced with an ADF. The added cost to the health care system (and possibly the patient) is substantial. The same heightened vigilance is required whether an ADF or regular opioid is prescribed. (See 'Real world efficacy' above.)
Further real world studies are required to elucidate the role of abuse deterrent opioids in attempts to curb the opioid epidemic.
SUMMARY AND RECOMMENDATIONS
●Abuse deterrent formulations (ADFs) of opioids are designed to prevent unintended routes of administration, while retaining efficacy with oral administration for legitimate pain relief. (See 'Introduction' above.)
●ADF technologies are intended to either make manipulation of oral medications (eg, chewing, inhalation, or injection) more difficult, or to make the drug less rewarding once manipulated. Available ADF opioids employ the following technologies (see 'Abuse deterrent technologies' above):
•Physical barriers that prevent chewing, crushing, cutting, or grinding of the tablet
•Chemical barriers that prevent dissolution with solvent and therefore make injection or inhalation more difficult
•Incorporation of an opioid antagonist that is inactive when taken orally but antagonizes the agonist opioid when the drug is manipulated
●Three opioid preparations with ADF labelling are available in the US, two with oxycodone, and one with hydrocodone (table 1). (See 'Abuse deterrent opioid formulations' above.)
●ADF probably reduces the abuse of a specific opioid, but may also drive abusers to select a different non-ADF opioid or heroin. Real world efficacy of ADFs may be reduced for the following reasons (see 'Real world efficacy' above):
•ADFs do not prevent individuals from taking multiple pills
•ADF does not change the addictive properties of the active drug
•ADF technology can be subverted
•As an alternative to ADFs, many abusers have switched to using other opioids or heroin
•ADFs represent a small portion of prescribed opioids
●ADFs in the US are branded drugs that are significantly more expensive than non-ADF counterparts, and may or may not be paid for by health insurance. (See 'Cost' above.)
●Some state legislatures have enacted or are considering regulations that govern the prescription of ADF opioids. (See 'State legislation' above.)
●We do not routinely prescribe ADF opioids rather than non-ADF opioids, unless required by law. Use of ADFs should never be a substitute for other relevant risk management approaches or risk mitigation tools. (See 'Indications for abuse deterrent formulation prescription' above.)
ACKNOWLEDGMENT — We are saddened by the death of Ronald S Litman, DO, ML, who passed away in April 2021. UpToDate wishes to acknowledge Dr. Litman's past work as an author for this topic.
