Abuse-Deterrent Formulations: An Early Epidemiologic Appraisal

A prescription opioid addiction and abuse epidemic has been escalating in the United States over the past 2 decades, having progressively developed into a pressing national public health concern.¹ The Institute of Medicine, which was enlisted by the US Department of Health & Human Services to examine pain as a public health problem, published its report in 2011, titled Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research.² In 2013, a record 16,235 prescription opioid overdose deaths were reported in the United States—more than 3 times the rate in 1999—secondary to abuse, misuse, and inadvertent ingestion.³ Risk factors vary as to the propensity of an individual to abuse opioids; nonetheless, inadvertent ingestion and accidental overdose in children have also arisen as serious public health problems. The main article in this publication provides an overview of this crisis, including the US Food and Drug Administration (FDA)’s position and guidance on appropriate prescribing practices, monitoring, and disposal of opioids. The FDA has also more recently (in 2015) issued its finalized guidelines on abuse-deterrent formulations (ADFs) in a release titled Guide for Industry: Abuse-Deterrent Opioids—Evaluation and Labeling.⁴ Therein, the FDA has set forth a multipronged strategy for the assessment of ADFs and has provided clear guidance as to the type of clinical studies that the industry is expected to conduct to demonstrate abuse deterrence. Rigorous studies are now mandatory, which comprise laboratory-based in vitro manipulation and extraction studies (Category 1), pharmacokinetic studies (Category 2), and clinical abuse potential studies, specifically in opioid-experienced, recreational drug users (Category 3), as well as postmarket data analysis of actual abuse (Category 4), including the requirement for postmarketing, population-based health studies to demonstrate outcome benefits of ADFs and the ability to extrapolate results to the general population.⁴

Although the use of first-generation reformulations of a pair of opioid agonist–antagonists with the inclusion of an opioid antagonist have shown promising results, including a reduction in the number of emergency department visits and related deaths, these agents remain imperfect as ADFs.^5,6 In 2010, the industry brought to market an extended-release (ER) opioid reformulation that uses physicochemical barrier technology to make it more difficult to crush, break, or dissolve, and, subsequently, inappropriately inject or “snort” the manipulated drug.⁷ Following the aforementioned reformulation process, the transition was conducted in August 2010, with providers and pharmacists notified, but not the general public.⁷ This has provided a unique epidemiologic opportunity for examining outcomes over the past several years. More recently, it should be noted, the industry has brought to market a second ER opioid reformulation that uses multiple deterrent technologies—namely, both a physical barrier and a sequestered opioid antagonist.⁸

In recent years, several studies have demonstrated overwhelming success in a real-world setting regarding abuse deterrence of the initial ER opioid reformulation.^9-11 Cicero and colleagues showed a significant reduction in the proportion of patients using this agent as the primary drug of abuse and significant reductions in its use for “getting high.” A concomitant increase was reported in the abuse of other prescription opioids as well as illicit drugs such as heroin.⁹ These results strongly suggest that although the reformulated product was indeed effective in its abuse deterrence, it has not prevented abusers from using alternatives. This phenomenon was mirrored in a study by Severtson and colleagues, with data derived from the Rocky Mountain Poison and Drug Center in Denver, CO. The authors compared data from the 2-year period prior to introduction of the ADF with data from the 1.5 years following introduction of the reformulated product, clearly demonstrating a reduction in abuse and diversion reports, as well as decreased attractiveness in terms of abuse potential. The effect was again unique to the specific drug being evaluated, however, and not to other prescription opioids.¹²

As opioid abusers have flocked to uncensored, peer-to-peer communications on the Internet, systematic online surveillance studies have emerged as a feasible, important means of monitoring and evaluating the overall impact of ADFs.^13,14 The results of such a study, published by McNaughton and colleagues in 2014, demonstrate that ADFs have been difficult to manipulate, and only a relatively small proportion of abusers reported manipulation with a reformulated version.¹³

Taken together, it is apparent that although the industry has successfully engineered reformulated opioids that have discouraged tampering and abuse, epidemiologic evidence exists as to the transitioning of abuse to other non-ADFs and illicit opioids, such as heroin. Limiting misuse and abuse of opioids necessitates a broad comprehensive strategy that includes the use of more ADFs, but also emphasizes enhanced educational resources to providers (ie, Risk Evaluation and Mitigation Strategies) and the public, as well as improved prescribing practices and monitoring.

References

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2. Institute of Medicine of the National Academies; Committee on Advancing Pain Research, Care, and Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: National Academies Press; 2011.
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