Abuse-Deterrent Opioid Formulations: Barriers to Broader Use
Although abuse-deterrent opioid formulations were introduced to the US market in 2010, they are not yet widely used.
Abuse-deterrent opioid formulations (ADFs) are among the various strategies aimed at reducing opioid misuse and abuse. Although ADFs were introduced to the US market in 2010, they are not yet widely used. In a study published in Expert Opinion on Drug Delivery, investigators explored potential barriers to the widespread use of ADFs.1
Many of the parameters thought to impede acceptance of ADFs are related to the higher cost of these drugs compared with conventional opioid formulations. For example, one study found that annual median prescription expenditures by the Oklahoma state Medicaid program were $8313 higher for patients using ADFs compared with those using conventional long-acting opioid drugs (P <.01).2 In addition, payer reimbursement for ADFs is limited, and the Centers for Medicare & Medicaid Services have prioritized other strategies to target opioid abuse and overdose, including reduction of physician overprescribing and expansion of naloxone use, respectively.3
Limited reimbursement is a deterrent to the prescription of ADFs by physicians and hospitals. In addition, pain management courses are required by only 4% of medical schools in the United States; therefore, many physicians have not received adequate training in pain medicine and lack sufficient understanding of opioid analgesics, including ADFs and their potential benefits.4 In a 2016 survey of 420 primary care physicians, 46% wrongly believed that ADFs are less addictive than conventional formulations.5
The US Food and Drug Administration's approach to ADF approval further impedes their wider acceptance. The product testing required for ADF labeling is resource intensive, and there are no incentives for manufacturers to develop or submit these formulations. The FDA endorses the use of ADFs but continues to accept submissions for the approval of non-ADF opioid analgesics. “At best, ADF opioids are one piece in a very large mosaic of tactics that are needed in order to help stem opioid misuse and abuse,” noted the authors of the current study. “As such, ADF products serve an important but circumscribed purpose” and should be supported by payers. They anticipate that future research will strengthen the case for increased use of ADFs.
For additional perspectives on the topic, Clinical Pain Advisor interviewed the following experts: Raeford E. Brown, Jr., MD, FAAP, professor of anesthesiology and pediatrics at the University of Kentucky Medical Center and Kentucky Children's Hospital, and chair of the FDA Anesthetic and Analgesic Drug Product Advisory Committee; and Joshua P. Cohen, PhD, an independent healthcare analyst who was formerly a research associate professor at Tufts University Center for the Study of Drug Development.
Clinical Pain Advisor: What are your thoughts on the benefits and potential downsides of ADFs?
Dr Brown: If all opioids were produced as an ADF, and there was not a substantial illicit market, then it would be much more difficult for those with substance use disorder to obtain and misuse large quantities of opioids and hurt themselves. That was the original intent of ADFs — to decrease the mortality rate by reducing the opportunity to obtain large quantities of the drug. Unfortunately, the market in opioids is divided 3 ways: Illicit opioids such as heroin and fentanyl, non-ADF opioid preparations, and ADFs. The illicit drugs are available and cheap. The non-ADFs are still being prescribed, and the ADF formulation that was the first on the market has the weakest abuse-deterrent technology.
The real downside of ADFs is that, despite the desire to improve public health, the introduction of ADFs may have driven users to illicit drugs because of cost and availability issues.
Dr Cohen: ADFs are not a panacea. They represent modest advances in abuse deterrence, specifically deterrence against inhalation and injection abuse. ADFs are opioids and therefore still have the potential to be addictive, but they are a tool to be used in the battle against opioid misuse. Physicians should consider their use, particularly for the subgroup of patients presenting with chronic pain who may have a greater propensity for addiction.
Clinical Pain Advisor: What are some of the barriers to their widespread use?
Dr Brown: The biggest current barrier is not having a clear understanding of the efficacy of this drug class. There are cheaper drugs on the market that have the same analgesic effect, and most people don't abuse opioids. We are also rethinking the widespread use of opioids for noncancer chronic pain, which is a setup for chronic use disorders.
Dr Cohen: ADFs in current use cost about twice as much as non-ADF opioids, and cost-effectiveness numbers for ADFs are not spectacular. This has resulted in high levels of payer resistance. Some physicians are also not aware of ADFs.
Clinical Pain Advisor: What are the current treatment implications for clinicians?
Dr Brown: The largest group of prescribers of opioids for long-term use in the United States are primary care physicians and nurse practitioners. This group of clinicians is in the unfortunate circumstance of being on the front line every day, facing patients who believe that there is a pill for every ill and that there are no risks to taking opioids for a long time. Recently, as we have begun to recognize the issues associated with chronic opioid use in some patients, clinicians and regulators have attempted to place a ceiling on use. This has made life difficult for clinicians with large numbers of patients on chronic opioids.
In the future, clinicians must develop a clearer understanding of the limits of chronic opioid therapy, the risks of increases in dosage, and the warning signs for the development of opioid use disorder. For most chronic noncancer pain situations, opioids are not the first line of therapy, but they are often used as the only therapy now. The public health would be best served by an approach that uses a broad range of management strategies before implementing chronic opioids.
Dr Cohen: ADFs are an important tool in the fight against opioid abuse. However, opioid dependence and abuse is a public health crisis that will only partly be remedied by ADFs. Much more will be needed, including improved stratification of patients with chronic pain into those who need opioid treatments — standard or ADF — vs those who would benefit more from nonopioid therapies.
Clinical Pain Advisor: What should be next steps in terms of research in this area?
Dr Brown: The next big thing will be a compound that blocks pain receptors appropriately but is not associated with risks for addiction, respiratory compromise, or other effects on the central nervous system. These agents will be unique and likely will have their own set of problems, but to date, as effective as opioids have been over 4000 years, they are associated with risks as great as or greater than the benefits. We should be able to do better.
Dr Cohen: Nine of the 10 ADFs approved by the FDA since 2013 are extended-release reformulations of existing opioids, and only 1 is an immediate-release reformulation. It's important therefore that immediate-release reformulations are developed. Twenty-five to 30 ADFs are currently making their way through the industry drug development pipeline. Many of these are using new pathways to deterrence, such as aversive agents, novel delivery systems, and prodrugs. The latter 2 pathways target the most prevalent form of abuse — oral abuse — and so if we have an effective novel delivery system or prodrug that mitigates the effects of oral abuse, then we will have made real progress.
1. Pergolizzi JV Jr, Taylor R Jr, LeQuang JA, Raffa RB. What's holding back abuse-deterrent opioid formulations? Considering 12 U.S. stakeholders. Expert Opin Drug Deliv. 2018;15(6):567-576.
2. Keast SL, Owora A, Nesser N, Farmer K. Evaluation of abuse-deterrent or tamper-resistant opioid formulations on overall health care expenditures in a state Medicaid program. J Manag Care Spec Pharm. 2016;22(4):347-356.
3. Centers for Medicare & Medicaid Services. Centers for Medicare & Medicaid Services (CMS) opioid misuse strategy 2016. https://www.cms.gov/Outreach-and-Education/Outreach/Partnerships/Downloads/CMS-Opioid-Misuse-Strategy-2016.pdf. January 5, 2017. Accessed June 25, 2018.
4. Mezei L, Murinson BB; Johns Hopkins Pain Curriculum Development Team. Pain education in North American medical schools. J Pain. 2011;12(12):1199-1208.
5. Hwang CS, Turner LW, Kruszewski SP, Kolodny A, Alexander GC. Primary care physicians' knowledge and attitudes regarding prescription opioid abuse and diversion. Clin J Pain. 2016;32(4):279-284.