Lauri R. Graham; Laurie Scudder, DNP, NP; Douglas Throckmorton, MD
Addressing the ongoing opioid epidemic in the United States is a complicated task, necessitating a variety of approaches, including education of clinicians and patients, guidance for clinicians on pain management, development of alternative strategies for treating pain, and new regulations (such as prescription drug monitoring programs) to monitor for and detect misuse and abuse of opioids. Critical to the success of these prevention efforts is the development of pain drugs with abuse-deterrent properties. Medscape spoke with Douglas Throckmorton, MD, deputy director for regulatory programs at the Center for Drug Evaluation and Research at the US Food and Drug Administration (FDA), about these up-and-coming formulations designed to reduce the risk for misuse and abuse of opioids.
Opioid Abuse-Deterrent Formulations
Medscape: Can you define abuse-deterrent properties? What makes these products less likely to be abused?
Douglas Throckmorton, MD, deputy director for regulatory programs, Center for Drug Evaluation and Research, US Food and Drug Administration
Dr Throckmorton: The term “abuse-deterrent” is often misunderstood to mean “abuse-proof.” Abuse-deterrent properties are defined as those properties expected to meaningfully deter abuse, even if they do not fully prevent it. Abuse-deterrent properties make certain types of abuse, such as crushing in order to snort or dissolving in order to inject, more difficult or less rewarding. This does not mean that the product is impossible to abuse or that these properties will necessarily prevent addiction, overdose, or death.
Of note, currently marketed abuse-deterrent formulation technologies do not effectively deter one of the most common forms of opioid abuse—which is simply swallowing a number of intact tablets or capsules. Abuse-deterrent opioids do not reduce the risk for opioid addiction, and they carry the same warnings about the risk for addiction as conventional opioids.
Medscape: Can you discuss the data examining the effect that abuse-deterrent opioids could have on misuse and abuse of these products in the community?
Dr Throckmorton: This is an area the agency has been working on for a number of years, and we are prioritizing the need for data and study methods that will help evaluate the impact of abuse-deterrent opioids on misuse and abuse in the community. To collect this important information, FDA is requiring all of the companies that have brand-name opioids with labeling describing abuse-deterrent properties to conduct postmarket studies to determine the impact of abuse-deterrent formulation technologies in the real world. Each company is given a timeline to which they must adhere. These types of studies take several years to conduct and analyze. Data collected will include the amount of prescribing for each product; adverse events related to the use, abuse, and misuse of the products; and epidemiologic data on the rates of abuse and misuse and their consequences (addiction, overdose, and death).
The studies should allow the FDA to assess the impact, if any, attributable to the abuse-deterrent properties in the community. Having that information is critical and will allow us to determine the next steps in this area. It’s important to understand that the science of abuse deterrence is relatively new, and both the formulation technologies and the analytical, clinical, and statistical methods for evaluating those technologies are rapidly evolving.
Medscape: How many products with these properties have been approved? How do they differ, and are there clinical scenarios that are particularly appropriate for each?
Dr Throckmorton: To date, the FDA has approved seven extended-release/long-acting (ER/LA) opioids with labeling describing abuse-deterrent properties (Table) that remain consistent with the FDA’s 2015 final guidance for industry, Abuse-Deterrent Opioids—Evaluation and Labeling.
Table. Abuse-Deterrent Products
Product Formulation Approval Date
OxyContin® Oxycodone—crush/extraction resistant April 2013
Targiniq™ ER Oxycodone hydrochloride and naloxone July 2014
Embeda® Morphine sulfate and naltrexone October 2014
Hysingla™ ER Hydrocodone—crush/extraction resistant November 2014
Morphabond™ Morphine sulfate—crush/extraction resistant October 2015
Xtampza™ ER Oxycodone—crush/extraction resistant April 2016
Troxyca® ER Oxycodone hydrochloride and naltrexone hydrochloride August 2016
ER = extended-release
Prescribers should carefully review the labeling of these products for more detailed information on the routes of abuse that each product is expected to deter and the studies that support those conclusions
Are Abuse-Deterrent Drugs Less Addictive?
Medscape: In a national survey of internists, family physicians, and general practitioners, nearly one half stated that they believed abuse-deterrent formulations were less addictive than their counterparts. What are the FDA’s efforts to provide correct information to clinicians?
Dr Throckmorton: We are working with health professional organizations and medical education providers to help educate prescribers about the value and limitations of current abuse-deterrent technologies. As I noted, abuse-deterrent properties do not signify that a product is abuse-proof; there is currently no technology that completely prevents abuse. Furthermore, addiction to opioid medications, with or without abuse-deterrent properties, can occur even when taken at recommended doses, so it’s important that both prescribers and their patients understand these risks before taking any type of opioid medication, abuse-deterrent or not.
Abuse-deterrent properties do not signify that a product is abuse-proof; there is currently no technology that completely prevents abuse.
Medscape: Earlier this year, the FDA released draft recommendations for the evaluation of generic versions of abuse-deterrent opioid drug products. Generic versions should have the same abuse-deterrent properties as their brand-name counterparts. Why is this an important element in the overall strategy to combat the problem of opioid abuse?
Dr Throckmorton: Generic drugs play an important role in the United States, especially for patients in pain. Each year, 100 million Americans experience significant pain, and 9-12 million have significant chronic pain. In general, generic drugs are important to help keep healthcare costs down. And for the millions of Americans with significant pain and the health systems that serve them, generics are crucial to delivering appropriate and affordable patient care. Many of these people have such serious and painful illnesses as cancer or sickle cell disease, and many have significant residual pain that is not effectively managed by other medications.
We hope that the availability of less costly generic products with abuse-deterrent properties has the potential to accelerate prescribers’ shift away from the older products that do not have abuse-deterrent properties. The FDA looks forward to the day, hopefully soon, when most opioids in the United States are marketed in abuse-deterrent forms. To facilitate an open dialogue on this important issue, and to obtain clinical and scientific input from outside experts, the FDA plans to hold a public meeting in November to discuss issues related to the development and evaluation of abuse-deterrent technologies, particularly for generic drugs.
Education Is the Cornerstone
Medscape: What are the key points that clinicians should be aware of in educating their patients about opioids?
Dr Throckmorton: The FDA’s work to improve the safe use of opioids is taking place within a larger policy framework aimed at addressing opioid abuse while ensuring appropriate access to pain treatment. The FDA has undertaken several efforts that can be helpful to clinicians. The Extended-Release and Long-Acting Opioid Analgesics Risk Evaluation and Mitigation Strategy (ER/LA REMS) is a program required by the FDA for all companies who make these products. The goal of the ER/LA REMS is to reduce serious adverse outcomes of inappropriate prescribing, misuse, and abuse of ER/LA opioid analgesics while maintaining patient access to pain medications. Adverse outcomes of concern include addiction, unintentional overdose, and death.
As part of the REMS, all ER/LA opioid analgesic companies must provide:
Education for prescribers of these medications through accredited continuing education activities supported by independent educational grants from ER/LA opioid analgesic companies; and
Information that prescribers can use when counseling patients about the risks and benefits associated with ER/LA opioid analgesic use.
It is critically important for clinicians to understand that all currently approved abuse-deterrent opioid products are still capable of being abused.
The FDA developed core messages to be communicated to prescribers in the Blueprint for Prescriber Education. The content is directed to prescribers of ER/LA opioid analgesics but also may be relevant for other healthcare professionals (eg, pharmacists). The ER/LA Opioid Analgesics REMS Program Companies provides a list of REMS-compliant continuing education activities.
Furthermore, it is critically important for clinicians to understand that all currently approved abuse-deterrent opioid products are still capable of being abused. Their abuse-deterrent properties are expected to deter, but do not wholly prevent, abuse. Because opioid medications must in the end be able to deliver the opioid to the patient, there will probably always be potential for abuse of these products.
Clinicians should counsel their patients on the following:
Keep medicines in a secure location, out of the reach and sight of children and pets. Put medicines away after every use. Accidental exposure to medicine in the home is a major source of unintentional poisonings in the United States.
If medicines are no longer needed, it’s important to dispose of them properly. Disposing of all unused opioid analgesics reduces access to these medications by family members and household guests seeking opioids for abuse.
We recommend returning most prescription medications through a local or US Drug Enforcement Administration (DEA)-sponsored take-back program or DEA-authorized collector. For a small number of drugs, we recommend immediate removal from the home by flushing them down the toilet or sink.
A Work in Progress
Medscape: Besides supporting the development of abuse-deterrent products, can you briefly describe the other strategies that the FDA is exploring to address the opioid epidemic that may be helpful to clinicians?
Dr Throckmorton: In February of this year, Commissioner Robert Califf (then the FDA’s Deputy Commissioner for Medical Products and Tobacco) announced the FDA Opioids Action Plan. The plan focuses on policies aimed at reversing the opioid epidemic, while still providing patients in pain access to effective pain relief.
The FDA actions include:
Convening an expert advisory committee before approving any new drug application for an opioid that does not have abuse-deterrent properties;
Consulting with the Pediatric Advisory Committee (meeting scheduled for this September) about a framework for pediatric opioid labeling before any new labeling is approved;
Updating the REMS requirements for ER/LA opioid analgesics after considering the advisory committee’s recommendations from a meeting held in May 2016 and reviewing existing requirements;
Improve access to naloxone (by facilitating the development of an over-the-counter version of naloxone, which is currently only available by prescription, making naloxone more accessible to treat opioid overdose), and medication-assisted treatment options for patients with opioid use disorders; and
Support better pain management options, including alternative, nonaddictive treatments for pain. For example, the FDA is conducting research on pain measurements for such conditions as chronic low back pain, osteoarthritis, diabetic neuropathy, postherpetic neuralgia, and fibromyalgia. The FDA is also working to support the development of nonopioid options for these patients.
Consistent with the plan, in March 2016, the FDA announced that it was requiring changes to the labeling on immediate-release opioids, including additional warnings and safety information that are expected to incorporate elements similar to the ER/LA opioid analgesics labeling that is currently approved.
Furthermore, among other steps, the FDA has contracted with the National Academy of Medicine to provide us with advice on how we should incorporate current evidence about the public health impact of opioid use (for patients who are prescribed opioids, as well as for nonpatients) into regulatory activities concerning opioids. We look forward to the recommendations from the academy, with a report expected in 2017, and other experts to further inform our policies in this area.
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