This article has been sponsored by Purdue Pharma LP.
This article is intended to provide practical knowledge regarding the emerging technology being developed to add abuse deterrent (AD) properties to prescription opioids. A goal of this guide is to increase the pharmacist’s understanding of the different types of AD technologies and how these innovations can potentially contribute to the reduction of abuse and misuse of extended release (ER) opioids.
Opioid Abuse/Misuse and the Development of AD Technologies
The rising rate of chronic pain diagnoses has led to substantial increases in the use of prescription opioids.1 Unfortunately, this increase has been accompanied by a rapid escalation in the prevalence of intentional abuse of these drugs to stimulate an associated high, or euphoric or other psychotropic effect.2 Historically, the majority of chronic opioid abusers tamper with tablets in order to achieve these effects and ER formulations are favored by such abusers as they contain a high dose of active opioid, and ER properties are readily neutralized by crushing or dissolving. Non-oral abuse is a serious public health issue, as it greatly increases the risk of opioid addiction, overdose, and death.3 Tablet tampering can also increase the risk of these serious adverse outcomes for patients through unintended misuse (therapeutic error) such as crushing ER tablets into food to facilitate ingestion.4 Accidental exposures of nonpatients is also an important public health consideration, particularly among very young children who may chew ER opioid tablets prior to swallowing, thereby increasing exposure dose and adverse event risk, including fatal overdose.
The increase in the rate of non-prescribed exposures to ER opioids prompted the development of AD technologies, in an attempt to curb misuse and abuse, while allowing appropriate patient access. The US Food and Drug Administration (FDA) considers the development of these products a high public health priority and supports the development of opioids with AD properties as outlined in its Draft Guidance document “Guidance for Industry: Abuse-Deterrent Opioids—Evaluation and Labeling” released in January 2013.5 This document outlines the categories of testing that may lead to labeling claims. In this document the agency segregates AD labeling claims into 4 tiers. For Tier 1, the product is formulated with physicochemical barriers of abuse. To gain Tier 1 approval, data from laboratory manipulation and extraction studies are provided that show the ease with which the AD properties of a formulation can be defeated or compromised. For Tier 2, the product is expected to reduce or block the effect of the opioid when the product is manipulated. To gain Tier 2 approval, data from pharmacokinetic studies are provided that compare the profiles of the manipulated formulation with the intact formulation; and with manipulated and intact formulations of comparator drugs through 1 or more routes of administration. For Tier 3, the product is expected to result in a meaningful reduction in abuse. To gain Tier 3 approval, data from a clinical abuse potential study are provided that assess the impact of the potential AD formulation on measures that predict how probable it is that it will be attractive to abusers (“liked”). These studies generally are conducted in a drug-experienced abuser population and utilize standardized clinical trial methodology. For Tier 4, the product has demonstrated reduced abuse in the community. To gain Tier 4 approval, data from post-marketing studies are provided that determine whether the marketing of the potential AD formulation results in a significant decrease in population-based and use-based estimates of abuse, compared with estimates of abuse if only formulations without AD properties are marketed.5
The 3 types of AD technologies described in this article include: 1) physicochemical barriers conferring resistance to tablet tampering (crushing, chewing or dissolving), imparting viscosity to resist preparation for intravenous abuse and extraction of the opioid using common solvents like water, alcohol, or other organic solvents; 2) incorporation of an aversive ingredient intended to induce unpleasant symptoms following abuse; substances can be combined to produce an unpleasant effect if the dosage form is manipulated prior to ingestion or a higher dosage than directed is used; and 3) combining an opioid agonist with an antagonist such as naltrexone to interfere with, reduce, or defeat the euphoria associated with abuse.6 The antagonist can be sequestered and released only upon manipulation of the product. Alternatively, it may be freely available; an antagonist such as naloxone, which has low oral bioavailability and hence, little activity when ingested, is highly active when introduced through non-oral routes.7
Table 15 shows labeling claims outlined in the FDA’s Draft Guidance. Table 2 shows the current marketed opioid formulations that have to some extent been designed to deter abuse.
Parentheses refer to sections in the Full Prescribing Information.
Limitations of AD Technologies
AD technologies can deter some forms of abuse. However, the technologies introduced to date do not prevent oral abuse of intact, whole tablets and are not always effective against the methods of abuse they are meant to deter. In addition, AD technologies do not prevent or treat opioid addiction.1,3 Hence, these technologies, although promising, should be considered developmental until proven otherwise, likely to the satisfaction of the FDA. As such, the boxed warnings of these ER opioids continue to include language such as: “Exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions.”8
Role of the Pharmacist
The pharmacist can discuss with prescribers the prudence of integrating products that contain AD properties into their prescribing practices. It has been argued that the reduced attractiveness of these reformulations suggests that prescription diversion as a means to provide a surplus supply of drug will be reduced.9 It has been shown that prescriptions and theft from legitimate pain patients, prescribers, pharmacies, and manufacturers are important sources of diverted opioids; thus, this issue directly affects and is impacted by prescribers.10 Depending on the technology used to deter abuse, increased resistance in the ability to manipulate a tablet could also decrease tic errors by patients who can be exposed to an unintended high dose of an extended release medication as a result of chewing or breaking tablets to make them easier to swallow.10 It is also important for prescribers to understand that patients who are intent on abuse may change to a more readily abused formulation as data show that since the introduction of opioids with some AD properties, abuse of prescription opioids without AD properties has increased significantly.11 Hence, in order to substantially curtail diversion and abuse, and patient errors, opioid treatment utilizing medications with AD properties will need to become the common practice among prescribers. Pharmacists can facilitate this process by advocating with prescribers and other healthcare professionals for prescription opioids with AD properties.
Summary and Conclusions
The actions of FDA to date suggest that the threshold for testing and for receiving AD claims in labeling will be appropriately high. In order to have a meaningful public health impact, effective technologies that deter abuse will need to be incorporated into all opioids and become standard for the opioid analgesic class. Although this alone will not likely be sufficient to prevent prescription opioid abuse and misuse, it can be a critical component of a comprehensive public health strategy that includes educational (Risk Evaluation and Mitigation Strategy),12 governmental (drug take-back),13 and community (overdose prevention)14 programs to promote the safe and effective use of prescription opioids.
Please read the Full Prescribing Information, including Boxed Warning.