Development of abuse-deterrent opioid products, including reformulation of existing products, has become a priority for drug manufacturers and public health advocates. Three available opioid formulations, OxyContin (Purdue), Embeda (Pfizer), and Hysingla ER (Purdue), now include claims of abuse deterrence in their package inserts.
DETERRENCE MECHANISMS — No opioid formulation prevents consumption of a large number of intact dosage units, the most common method of abuse. Abuse-deterrent formulations have one or more properties that make their intentional nontherapeutic use more difficult, less attractive, or less rewarding; examples of such properties are listed in the table.1
LABELING REQUIREMENTS — For claims of abuse deterrence to be included in the labeling of an opioid formulation, the FDA requires that laboratory tests first be performed to assess how easily the abuse-deterrent properties of the formulation can be compromised. In vivo studies should then compare the pharmacokinetic profiles of the formulation before and after manipulation. Based on these results, a randomized, double-blind, placebo- and active-controlled study should evaluate subjective effects of the formulation, such as differences in "drug liking" in recreational drug users.
Postmarketing epidemiological studies are required for all opioid formulations that have claims of abuse deterrence in their labeling. These studies assess whether a formulation has been associated with meaningful reductions in adverse clinical outcomes related to abuse and misuse.
ABUSE-DETERRENT FORMULATIONS — OxyContin, an ER oxycodone tablet formulation, was reformulated in 2010 to deter abuse; the current product is more difficult to crush, break, or dissolve than the original, and when dissolved forms a viscous gel that is difficult to inject through a hypodermic needle. In an intranasal administration trial in nondependent opioid abusers, scores for "drug liking" and desire to "take drug again" were significantly lower with the newer formulation than with original OxyContin or with oxycodone HCl powder.2
Embeda is formulated as capsules of ER morphine pellets that contain a sequestered core of the opioid antagonist naltrexone. If the pellets are swallowed, the morphine is gradually released and absorbed, while the naltrexone core passes through the gut intact. If the pellets are crushed, chewed, or dissolved, naltrexone is released, blocking morphine-induced euphoria.3 In oral, intranasal, and IV administration trials in nondependent opioid abusers (one published; three summarized in the package insert), Embeda had significantly lower "drug liking" and "drug high" scores than morphine without naltrexone.4
Hysingla ER is an ER hydrocodone tablet formulation; when dissolved it forms a viscous gel that is difficult to inject through a hypodermic needle. In oral and intranasal administration trials in nondependent opioid abusers (summarized in the package insert), Hysingla ER had significantly lower scores for "drug liking" and desire to "take drug again" than immediate-release hydrocodone.5
Zohydro ER (Zogenix), an ER hydrocodone capsule formulation, was originally approved without abuse-deterrent properties,6 but now incorporates excipients that form a viscous gel when the capsules are crushed and dissolved. The manufacturer is expected to submit clinical data supporting claims of abuse deterrence in the labeling later this year.7
Targiniq ER (Purdue), an opioid agonist/antagonist combination containing ER oxycodone and naloxone, has been approved by the FDA with claims of abuse deterrence in the labeling, but is not yet commercially available. If the formulation is crushed and administered intravenously or intranasally, high naloxone concentrations block opiate-induced euphoria and can induce withdrawal symptoms.
The FDA has not provided guidance for developing generic equivalents of abuse-deterrent opioid products.
EFFECTIVENESS — FDA-mandated postmarketing epidemiological studies evaluating changes in drug abuse patterns after reformulation of OxyContin have been completed. One study found that reformulation was associated with a 32% reduction in the rate of ER oxycodone-related poison control abuse cases and a 15% reduction in the rate of poisonings related to therapeutic use of ER oxycodone. The rate of ER oxycodone diversion declined by 50%, and the street price of ER oxycodone declined by 22%.8 Another study in 140,496 people assessed for substance abuse problems found that the ER oxycodone abuse rate declined by 33% after reformulation of OxyContin; non-oral abuse of ER oxycodone declined by 66% and frequency of abuse by 30%.9
In other studies, reformulation of OxyContin was associated with similar declines in ER oxycodone abuse and its complications,10-14 but some reported increases in abuse rates of other opioids, including heroin.13-15 One study found that the estimated prescription opioid overdose rate was 20% lower 2 years after introduction of the new OxyContin formulation, but the estimated heroin overdose rate increased by 23%.16 Another found that the annual rate of change in ER oxycodone prescription sales declined from +4.9% to -23.8% in the year after reformulation, with no significant differences in the sales of other prescription opioids.17
Postmarketing studies of Hysingla ER and Embeda are scheduled for completion in 2018 and 2019, respectively. No studies comparing the relative safety of different formulations of abuse-deterrent opioids are available.
REMS — As part of a Risk Evaluation and Mitigation Strategy (REMS) program, the FDA has required the manufacturers of long-acting opioids to make training in their use available to prescribers.
CONCLUSION — Whether the availability of single-source, abuse-deterrent opioid products such as OxyContin, Embeda, and Hysingla ER will result in a reduction in overall opioid abuse remains to be determined. There are no generic equivalents to these products.
- FDA. Abuse-deterrent opioids – evaluation and labeling: guidance for industry. April 2015. Available at: www.fda.gov. Accessed August 20, 2015.
- SC Harris et al. Abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered crushed oxycodone HCl abuse-deterrent controlled-release tablets in recreational opioid users. J Clin Pharmacol 2014; 54:468.
- A morphine/naltrexone combination (Embeda) for pain. Med Lett Drugs Ther 2010; 52:22.
- J Stauffer et al. Subjective effects and safety of whole and tampered morphine sulfate and naltrexone hydrochloride (ALO-01) extended-release capsules versus morphine solution and placebo in experienced non-dependent opioid users: a randomized, double-blind, placebo-controlled, crossover study. Clin Drug Investig 2009; 29:777.
- Extended-release hydrocodone (Hysingla ER) for pain. Med Lett Drugs Ther 2015; 57:71.
- Extended-release hydrocodone (Zohydro ER) for pain. Med Lett Drugs Ther 2014; 56:45.
- Press release. Zogenix receives FDA approval of new formulation of Zohydro® ER. January 30, 2015. Available at: www.zogenix. com. Accessed August 20, 2015.
- SG Severtson et al. Reduced abuse, therapeutic errors, and diversion following reformulation of extended-release oxycodone in 2010. J Pain 2013; 14:1122.
- SF Butler et al. Abuse rates and routes of administration of reformulated extended-release oxycodone: initial findings from a sentinel surveillance sample of individuals assessed for substance abuse treatment. J Pain 2013; 14:351.
- NE Sessler et al. Reductions in reported deaths following the introduction of extended-release oxycodone (OxyContin) with an abuse-deterrent formulation. Pharmacoepidemiol Drug Saf 2014; 23:1238.
- JR Havens et al. The impact of a reformulation of extended-release oxycodone designed to deter abuse in a sample of prescription opioid abusers. Drug Alcohol Depend 2014; 139:9.
- L Degenhardt et al. The introduction of a potentially abuse deterrent oxycodone formulation: early findings from the Australian National Opioid Medications Abuse Deterrence (NOMAD) study. Drug Alcohol Depend 2015; 151:56.
- PM Coplan et al. Changes in oxycodone and heroin exposures in the National Poison Data System after introduction of extended-release oxycodone with abuse-deterrent characteristics. Pharmacoepidemiol Drug Saf 2013; 22:1274.
- TJ Cicero et al. Effect of abuse-deterrent formulation of OxyContin. N Engl J Med 2012; 367:187.
- TA Cassidy et al. Changes in prevalence of prescription opioid abuse after introduction of an abuse-deterrent opioid formulation. Pain Med 2014; 15:440.
- MR Larochelle et al. Rates of opioid dispensing and overdose after introduction of abuse-deterrent extended-release oxycodone and withdrawal of propoxyphene. JAMA Intern Med 2015; 175:978.
- CS Hwang et al. Impact of abuse-deterrent OxyContin on prescription opioid utilization. Pharmacoepidemiol Drug Saf 2015; 24:197.