Clinical Assessment of Abuse-Deterrent Formulations

In 1985 and 1996, the World Health Organization issued guidelines on cancer pain relief.¹ The ethical mandate for pain treatment has been extended to chronic nonmalignant pain, and some have argued that this type of pain produces suffering similar to that of cancer pain but with a higher prevalence and longer duration.^2,3 The Institute of Medicine was enlisted by the US Department of Health & Human Services to examine pain as a public health problem and published its report in 2011, Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research.⁴ Chronic pain is estimated to affect approximately 100 million adults in the United States, more than the total number of people affected by heart disease, cancer, and diabetes combined. The financial burden is estimated to approach $635 billion each year in medical treatment and lost productivity.⁴ Meanwhile, there were approximately 15,000 prescription opioid overdose deaths in the United States in 2008, which was 3 times the rate in 1999, secondary to abuse, misuse, and inadvertent ingestion. Demographic groups at the highest risk are men; middle-aged, rural, and poor whites; and Native Americans.⁵

Although randomized controlled trials have demonstrated clear analgesic efficacy of short-term opioid treatment, strong outcome data are lacking for long-term use in the setting of chronic pain.⁶ There have been no high-quality outcomes data reported in the literature on long-term opioid therapy (>1 year) compared with no opioid therapy as it relates to pain, function, quality of life, opioid abuse, or addiction. Good- and fair-quality observational studies suggest that opioid therapy for chronic pain is associated with increased risk for overdose, opioid abuse, fractures, and markers of sexual dysfunction.⁷ Evidence for the effectiveness and/or harm of different opioid dosing and risk mitigation strategies is limited. Nevertheless, opioids remain a valuable tool commonly used in the treatment of intractable and refractory pain conditions.⁴

Concerning data from the National Survey on Drug Use and Health show that nearly one-third of people aged ≥12 years who abused drugs for the first time in 2009 began by using a prescription drug for nonmedical uses.⁸ The majority (70%) of abusers received medication that had been diverted from a relative or friend, whereas approximately 5% of individuals obtained medication from a drug dealer or an Internet source.⁸ A recent large-scale survey demonstrated that prescription drugs are now the second most abused category of drugs after marijuana.⁹ Available evidence indicates that 72% to 97% of opioid abusers prefer the oral route of administration,¹⁰ followed by intranasal and intravenous (IV) administration.¹¹ Extended-release (ER) formulations, while originally designed to offer slower onset and lower peak concentrations compared with immediate-release (IR) counterparts, often contain high opioid content and are manipulated to overcome the ER mechanism and rapidly achieve euphoria via insufflation, injection, or inhalation.^11,12 However, in the RADARS System Poison Center database, the overwhelming majority of deaths attributed to the abuse of oral formulations were caused by ingestion of the opioid.^11,13 This may be expected, as ingestion is the most common method of abuse. However, the database also reports that injection is the most dangerous route of abuse (associated with the highest percentage of deaths), followed by inhalation. Injection of tampered opioids is also associated with higher risk for HIV and Hepatitis C virus infections and endocarditis.¹³

Various strategies have been implemented in an attempt to remediate the problem. In 2007, the Food and Drug Administration Amendments Act gave this agency the regulatory authority to require postmarketing studies and to mandate the implementation of a risk evaluation and mitigation strategy (REMS).¹⁴ More recently, REMS educational resources have been made available to providers on a voluntary basis. Of concern, a recent study revealed that of the 259 primary care physicians who responded to a survey, 13.4% reported they would refrain from prescribing opioids if they were required to obtain training under the current format, which consists of 4 to 8 hours of training plus 2 hours of continuing medical education every 2 years. However, these physicians would be tolerant of a lesser training requirement.¹⁵ Nevertheless, the REMS approach may be an important component for addressing the iatrogenic aspect of the opioid epidemic in the United States. The US Food and Drug Administration (FDA) also offers additional guidance on methods to reduce opioid abuse through education, tracking and monitoring, proper medication disposal, and enforcement.¹⁶

In 2011, The US Office of National Drug Control Policy responded to the growing problems of abuse with a proposed national strategy that stressed the development of abuse-deterrent formulations (ADFs).¹⁶ These ADFs are classified into several categories, including physical or mechanical barriers, inclusion of sequestered antagonists, and incorporation of aversive agents.¹⁷ ADFs discourage abuse; however, the frequency, nature, and route of administration for each formulation varies by opioid product¹¹ and demographics, and, therefore, abuse cannot be eliminated altogether. As noted in the main article in this publication, IR oral formulations do not require tampering to induce euphoria. Conversely, ER oral formulations appear to be commonly associated with tampering and are administered through chewing, insufflation, inhalation, or IV injection. These methods of tampering increase peak plasma concentration/time to peak plasma concentration and absolute bioavailability,^11,18 thereby enhancing psychotropic effects. However, it is difficult to extrapolate outcomes for the effectiveness of investigational ADFs from existing studies, which are performed on known opioid abusers and addicts, and apply them to the treatment of chronic pain in the general population.

Meanwhile, first-generation reformulations containing mixed opioid agonist–antagonist pairs have shown promise.¹⁹ One agonist–antagonist opioid, long-abused historically with antihistamines, has been reformulated to include an opioid antagonist that has poor oral bioavailability. In theory, the opioid antagonist may reduce euphoria when injected, but has no effect when ingested appropriately with an intact oral formulation. These efforts have indeed resulted in reduced emergency department and medical examiner mentions of the drug per million prescriptions in the 2 years following the introduction of the product.²⁰ As to be expected, the reformulation did not eliminate abuse via the nonparenteral route,²¹ and, unfortunately, there was some evidence that analgesic efficacy is affected by the addition of an opioid antagonist, despite poor oral bioavailability.²²

A second mixed agonist–antagonist opioid, marketed in oral, injectable, and transdermal formulations, is associated with data from regional poison control centers in the United States demonstrating that both the drug alone and its combination formulation with the opioid antagonist have relatively low rates of abuse compared with full agonists. The low-abuse potential associated with these formulations is likely attributable to an intrinsic characteristic of partial agonists, namely, the ceiling effect. Therefore, abusers favor full opioid agonists that provide enhanced effects and desired euphoria. The opioid agonist–antagonist is FDA approved for the treatment of patients with opioid dependence and chronic pain and is available in injectable and transdermal formulations. An oral formulation and a combination formulation are available for the treatment of patients with opioid dependence only. Providers should take note that some studies have demonstrated that the μ-opioid receptor binding affinity of the opioid agonist–antagonist is greater than that of the antagonist; therefore, the opioid antagonist is imperfect and often ineffective in preventing abuse and reversing overdose.²²

The FDA recently finalized its guidelines in a release titled Guidance for Industry: Abuse-Deterrent Opioids—Evaluation and Labeling.¹² The FDA stresses that there is no one-size-fits-all approach to abuse deterrence. It may be achieved in 1 of 5 forms or preferably in combination: (1) physical or chemical barriers to prevent tablet crushing or extraction using solvents, (2) pharmacologic combinations that reduce the euphoria associated with appropriate use or abuse, (3) aversion techniques that confer dose-dependent unpleasant effects, (4) delivery systems, such as sustained release patches, that prevent tampering and excessive dosing at 1 time, and (5) prodrug formulations that require enzymatic activation. Notably, the FDA expects the pharmaceutical industry to engineer iterative improvements and gradually raise the bar; however, it has stopped short of requiring that an opioid drug be abuse deterrent as a condition for marketing approval. The FDA has focused on drug “likeability” and the “likelihood to redose drug,” as these measures appear to correlate most directly with potential for abuse. Visual analog scales, such as the proposed Opioid Attractiveness Scale, are tools to help predict the abuse potential of new opioid formulations.²³ The FDA has provided clear guidance for the type of studies the pharmaceutical industry is expected to conduct to demonstrate abuse deterrence. Rigorous studies are now mandatory, including laboratory-­based in vitro manipulation and extraction (category 1); pharmacokinetic studies (category 2); clinical abuse potential studies, specifically in opioid-experienced, recreational drug users (category 3); and postmarket data analysis of actual abuse (category 4). The FDA has also stressed that drug labeling must now include detailed information regarding a product’s abuse-deterrent properties to best inform the community, including healthcare professionals, patients, and the public, about a drug’s abuse potential. For example, a drug that has been established as resistant to abuse by injection routes may not be immune to other forms of tampering, and labeling must now reflect such caveats. Finally, unless postmarket data are available, labeling should reflect the predictive quality of premarket studies.

Recent advances in pharmaceutical engineering offer a broad array of impediments to abuse, such as physical barriers, components that cause aversion, and formulating opioid prodrugs.¹⁹ In addition, formulations have been developed that combine agonists with antagonists. New formulations of short-acting opioids are in late-stage clinical testing, and several have recently entered the US market.^24,25 Postmarketing data in the way of large epidemiologic studies will determine the true value and impact of ADFs in settings of abuse and inadvertent ingestion/overdose.

References

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