Understanding the Utility of Abuse-Deterrent Opioids




  • Abuse-deterrent opioid formulations (ADOs) aim to make opioid abuse less rewarding and more difficult.

  • ADOs address the issue of dose dumping which leads to fatal overdose; however, there is insufficient post-marketing data to support substantial reductions in abuse.

  • The rise of ADOs has depicted a concomitant increase in other opioids, persistent efforts to undermine their abuse-deterrent properties, and continued abuse through the oral route.

  • Reformulated OxyContin ER, Hysingla ER, Xtampza ER, and RoxyBond IR are current FDA-approved ADOs that have depicted efficacy in pre-marketing studies.


Despite efforts to ameliorate the opioid crisis, unintentional overdoses are now the leading cause of death among individuals less than 50 years of age in the US (1). An important contributing factor to the crisis is the diversion of prescription opioids to patients’ friends and family (2). To address these concerns, abuse-deterrent opioid formulations (ADOs) have been developed with the aim of making abuse less rewarding and more difficult (3,4). Currently, however, only a third of clinicians consider whether an opioid is an ADO when making the decision to prescribe, and 80% of those who do not prescribe ADOs cited lack of familiarity as the primary reason (2). Understanding the utility and efficacy of established ADOs may be an important tool in combating the ongoing opioid crisis.


While there are several proposed mechanisms for abuse-deterrence, current FDA-approved ADOs employ one of two methods: physical barriers and chemical barriers (4). These methods are particularly important in deterring abuse through snorting and intravenous injection, the most common routes causing adverse effects (5). Physical barriers aim to prevent physical alteration, particularly crushing, of the medication with common household tools (e.g., hammer) or by chewing, while chemical barriers prevent dissolution and damage when in contact with an organic solvent such as alcohol or water. These physiochemical changes limit the release and/or change the form of the drug following mechanical manipulation, making abuse more difficult. Additional methods for abuse-deterrence include agonist/antagonist combinations, which provide analgesia only when administered via the intended route. For example, if the ADO is not swallowed and is instead snorted or injected, the antagonist will not be clinically activated. While ADOs employing agonist/antagonist combinations were once available, they have since been discontinued (i.e., Embeda) (6). Another proposed mechanism is aversion, which involves producing an unpleasant effect when the ADO is administered inappropriately, such as irritation of the nasal mucosa when snorting or inducing nausea, sweating, and headache symptoms when injecting (4).


Opioid overdose is often a direct consequence of inappropriately administering oral opioid formulations in an attempt to enhance the euphoric effects of the drug, a method known as dose dumping. This method increases the likelihood of tolerance, addiction, respiratory depression, and fatal overdose by bypassing controlled-release mechanisms and accessing the entire dose at once; ADOs have been specifically formulated to deter such abuse (4,5). Consider OxyContin: within a decade of its release, OxyContin became one of the most commonly abused drugs in the US. A new formulation with ADO technology was approved by the FDA which physically hinders snorting and intravenous injection using proprietary thermal processing and curing of high-molecular-weight polyethylene oxide, and non-ADO OxyContin has since been taken off the market (6). Following the implementation of reformulated OxyContin ER, non-oral abuse of OxyContin had decreased from 91.4% to 47.9% (7). Despite the availability of these ADOs, currently, there is limited post-marketing data concerning their efficacy and outcomes (4).


While ADOs provide a potentially safer profile against opioid diversion and abuse, according to a recent FDA analysis they only comprised about 6% of prescription opioids sold over the last decade. One reason for the relatively low utilization of ADOs is the high cost and associated limited payer coverage (6,8). Thus, prescribers must verify if the formulary placement of an ADO is covered by a patient’s insurance before selecting an ADO for treatment. Additionally, some post-marketing epidemiologic evidence suggests that while ADOs have the potential to deter abuse, they may also play a role in encouraging the use of non-ADO prescription opioids and illicit drugs (4). Figure 1 demonstrates that while ADO prescribing has increased and OxyContin has decreased, there has been a rise in oxycodone IR (4). However, data regarding an increase in illicit drug use are not consistent, as other studies have depicted a simultaneous decrease in heroin abuse with the rise of ADOs (9). Additionally, Internet forums in which users communicate efforts to undermine the abuse-deterrent properties of ADOs have surfaced. However, Internet surveillance data currently depict minimal abuse of the reformulated versions and a lack of novel methods to bypass the deterrent properties of these formulations (10). Despite this encouraging evidence, ADOs always have some potential for addiction and abuse, as most have inherent likability and no protection against excessive oral consumption (3-5).

Figure 1: Nationally estimated number of prescriptions dispensed for available ADOs from U.S. outpatient retail pharmacies, 2012–2016 (4).


At the time of writing, there are four FDA-approved ADOs: reformulated OxyContin ER, Hysingla ER, Xtampza ER, and RoxyBond IR. These ADOs meet the standards for abuse-deterrent properties outlined in the FDA’s “Guidance for Industry: Abuse-Deterrent Opioids – Evaluation and Labeling”; however, Figure 2 demonstrates several proposed ADOs along with their mechanisms of action (11,12). Pre-marketing studies include in vitro, pharmacokinetic, and clinical abuse potential studies, while post-marketing studies provide information regarding actual abuse trends. Pre-marketing data depict encouraging results; however, there is little post-marketing data concerning these ADOs to date to substantiate claims for reductions in abuse in a real-world setting. Furthermore, it should be noted that the FDA emphasizes that abuse is still possible despite current abuse-deterrent technology.

Figure 2: Strategies for developing abuse-deterrent formulations of opioids. Highlighted in green are FDA-approved ADOs to date (12).

Reformulated OxyContin ER replaces the original formulation of OxyContin through physiochemical modifications which have increased resistance to crushing, breaking, and dissolution. In vitro and clinical data depict increased difficulty of abuse via snorting and injection. The extended-release tablets are available in 10, 15, 20, 30, 40, 60, and 80 mg strengths (13).

Hysingla ER replaces the original formulation of hydrocodone bitartrate, and a series of in vitro, pharmacokinetic, and clinical abuse potential studies demonstrate reduced intravenous, intranasal, and oral abuse. The extended-release tablets are available in 20, 30, 40, 60, 80, 100, and 120 mg strengths (14).

Xtampza ER contains oxycodone HCl, and data from in vitro, pharmacokinetic, and clinical studies depict reduced intravenous, intranasal, and oral abuse. With regards to the oral pharmacokinetic studies, Xtampza ER depicted lack of dose dumping when crushed or chewed. The extended-release capsules are available in 9 mg (equivalent to 10 mg oxycodone HCl), 13.5 mg (equivalent to 15 mg oxycodone HCl), 18 mg (equivalent to 20 mg oxycodone HCl), 27 mg (equivalent to 30 mg oxycodone HCl), and 36 mg (equivalent to 40 mg oxycodone HCl) strengths (15).

RoxyBond IR contains oxycodone HCl, and data from in vitro and clinical studies depict increased difficulty of abuse via snorting and injection. The tablets are available in 5, 15, and 30 mg strengths, each containing an equivalent of 4.5, 13.5, and 27 mg of oxycodone free base, respectively (16).


ADOs have been formulated to deter opioid abuse by making their manipulation less rewarding and more difficult through a variety of physical, chemical, and biomolecular modifications. While ADOs may provide an important tool to combat the opioid crisis, prescribers should be aware of several areas of contention, including high cost and limited coverage, seeking of other opioids and illicit drugs, persistent efforts to undermine their abuse-deterrent properties, and the lack of truly abuse-proof formulations. Despite this, current ADOs, which include reformulated OxyContin ER, Hysingla ER, Xtampza ER, and RoxyBond IR, may provide one piece of the solution to the prevalent opioid abuse and fatal overdose in the US. Future studies regarding the efficacy of established ADOs are necessary for decreasing abuse while recognizing the importance of opioids for patients’ pain and improved quality of life (17).


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  14. PURDUE PHARMA LP. HYSINGLA ER [package insert]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/206627s012lbl.pdf. Revised March 2021. Accessed July 18, 2022.

  15. COLLEGIUM PHARM INC. XTAMPZA ER [package insert]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208090s015lbl.pdf. Revised March 2021. Accessed July 18, 2022.

  16. PROTEGA PHARMS. ROXYBOND [package insert]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/209777s007lbl.pdf. Revised March 2021. Accessed July 18, 2022.

  17. Adalbert J, Ilyas A. The state of opioid prescribing education in U.S. medical and dental schools. Rothman Orthopaedic Institute Foundation for Opioid Research and Education. https://www.rothmanopioid.org/post/the-state-of-opioid-prescribing-education-in-u-s-medical-and-dental-schools. Published February 11, 2021. Accessed June 13, 2022.

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