This year I began a two-year appointment as Chair of the FDA’s Analgesic and Anesthetic Drug Advisory Committee (AADPAC). Our committee is asked to convene several times a year to discuss and advise the FDA on new drug applications (NDAs) related to the practice of anesthesiology and pain management.
Most AADPAC meetings are held to discuss novel opioid formulations, such as abuse deterrent opioid formulations (ADFs). On some occasions, the meetings do not concern NDAs, but are held to provide our opinions to the FDA about opioid-related topics such as naloxone availability, or the effectiveness of the TIRF (transmucosal immediate release fentanyl) REMS (risk evaluation and mitigation strategy) program.
This June we will discuss the utility and safety high dose opioids in the outpatient setting. Advisory committees are convened at the discretion of the FDA, but in 2016, as part of the Opioids Action Plan, FDA expanded the use of the AADPAC to include all NDAs that are either non-ADF opioids, or ADF opioids that “raise novel issues”.
At the 2019 annual winter meeting of the Society for Pediatric Anesthesia, I delivered a presentation titled “Abuse Deterrent Opioid Formulations (ADFs): The Answer to an Epidemic or Wolves in Sheep’s Clothing?” An ADF is an opioid formulation manufactured with proprietary physical and/or chemical properties that are designed to deter the ability to crush the pills for chewing, snorting, or intravenous administration, all of which enhance the development of tolerance, addiction, and overdose. In theory, prescription of ADFs will prevent recreational opioid pill abusers from transitioning to these more potent forms of abuse.
To gain approval of an ADF, the sponsor of the NDA must perform three types of premarket studies:
- Category 1 in vitro studies evaluate the ability to compromise the integrity of the formulation by physical manipulation or chemical dissolution, using models of “syringeability”, the ease with which it can be drawn into and injected from a syringe. In these studies, the FDA asks the sponsor to manipulate the drug to the point of defeating its abuse-deterrent properties and compare it to the same non-ADF formulations.
- Category 2 studies evaluate the in vivo pharmacokinetic properties in healthy volunteers who are administered naltrexone to block the clinical opioid effects. These studies establish bioequivalency compared with the non-ADF version.
- Category 3 studies evaluate the potential for clinical abuse by asking experienced recreational opioid abusers to determine the likeability of a manipulated ADF compared with its non-ADF counterpart.
At present, the FDA has approved eight opioids with abuse-deterrent labeling, but only five are currently in distribution in the U.S. They include:
- OxyContin (Purdue) is an extended-release oxycodone formulation that contains a polyethylene oxide coating that resists crushing and becomes a viscous gel when exposed to a liquid solvent.
- Xtampza ER (Patheon) is oxycodone that has been chemically altered to resist crushing and dissolving, and will solidify when it comes in contact with solution, making it difficult to administer through a needle for IV abuse.
- Hysingla ER (Purdue) is hydrocodone that contains the same proprietary coating as OxyContin.
- Morphabond ER (Daiichi Sankyo) is extended-release morphine that contains a proprietary covering that resists crushing and chemical manipulation.
- Embeda (Pfizer) is extended-release morphine with a sequestered naltrexone core. Upon crushing for non-oral use the naltrexone is released, which counteracts the opioid effects. However, if the pills are swallowed, the naltrexone is not absorbed, and the pills work as intended.
FDA approval of an ADF is necessarily accompanied by the obligation for the sponsor to institute a Risk Evaluation and Mitigation Strategy (REMS) program, as well as the obligation to perform post-marketing studies that clarify the drug’s real-world risk-benefit relationship.
Will the prescription of ADFs ever decrease overall opioid addiction and overdose deaths? The only certain answer is that it’s too early to tell. At present, compared to the combination formulation of oxycodone-acetaminophen, single-ingredient ADFs still represent a small minority of all prescribed opioids in the U.S. In the short term, most research to date has demonstrated that when conventional pill forms of semisynthetic opioids (e.g. oxycodone, hydrocodone) are not available, individuals with established opioid abuse disorder transition to IV heroin, which is often easier to obtain and less expensive. This has resulted in an uptick in intravenous-abuse-related hepatitis and an increase in overdose deaths from heroin or bootleg (street-bought) oxycodone pills laced with fentanyl. It will take additional years of observational research to determine whether ADF opioids prevent new cases of opioid use disorder.
Ron Litman, D.O., M.L. is an anesthesiologist at the Children’s Hospital of Philadelphia and Professor of Anesthesiology and Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. He is the current Chair of the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) and the medical director of the Institute for Safe Medication Practices.
The views and opinions expressed in this blog belong solely to the author, and do not necessarily reflect the opinions of the author’s employers or their affiliates, or the Society of Pediatric Anesthesia.