Excerpted from Pharmaceutical Technology's editorial titled, "Reducing Risk with Abuse‑Deterrent Formulations."
Increasing prevalence of drug misuse and abuse is driving a heightened and more stringent approach to abuse-deterrent formulations.
Possibly the most publicized and well-documented form of drug misuse and abuse has been that of opioids—prescription pain-relief medicines. The opioid crisis, which has impacted the global health community for several years, has paved the way for increased demand in abuse-deterrent formulations.
Abuse-deterrent formulations essentially have the potential to provide an effective way of reducing the capabilities of an end-user to abuse or misuse a medical therapy, while maintaining the drug’s clinical benefit. To explore the topic of abuse-deterrent formulations in more detail, Pharmaceutical Technology spoke with Angela Moore, scientist, Analytical Development, Alcami.
In Need of Risk Mitigation Approaches
PharmTech: Could you discuss some of the reasoning behind abuse-deterrent formulations and why there may be an increase in interest in this area?
Moore (Alcami): Doctors continue to prescribe opioid medications for pain management, generating an inevitable association with abuse and addiction. Government officials and pharmaceutical professionals alike are in need of risk mitigation approaches.
In the United States alone, there have been estimates, released by the US Department of Health and Human Services (HHS), revealing that in 2018 over 47,000 citizens died from an opioid overdose and that two million people in the country were suffering from an opioid use disorder (1). The economic costs associated with the opioid epidemic have been estimated at $504 billion, according to analysis by Johns Hopkins University Bloomberg School of Public Health (2). And, the issue of opioid addiction is not isolated to the US, with countries worldwide experiencing significant healthcare costs associated with prescription opioid abuse, such as those experienced in the five largest European countries as reported by Shei et al. (3).
Pharmaceutical companies have responded to this need through more stringent abuse-deterrent formulations and studies. Although abuse-deterrent does not equate to ‘abuse-proof,’ medications that contain abuse-deterrent properties make it more difficult for abusers to obtain the euphoria associated with common manipulation techniques.
PharmTech: Currently, what abuse-deterrent formulation approaches are available and what are the benefits and/or limitations to these approaches?
Moore (Alcami): The current products on the market that contain abuse-deterrent labeling approved by the Food and Drug Administration fall into two categories of abuse-deterrence: physiochemical and opioid/antagonist. Physiochemical abuse-deterrent properties include products that are formulated to resist crushing, chewing, and physical manipulation. They contain excipients that will ‘gel’ upon contact with solvents to make them difficult to inject intravenously. Opioid/antagonist products contain the active opioid intended for therapeutic use and also a sequestered antagonist so that if the product is manipulated intentionally it will release a chemical that will prevent the user from feeling the euphoric effects of the opioid.
There are benefits and challenges to both physiochemical and opioid/antagonist abuse-deterrent formulations. Benefits of physiochemical formulations include having physical barriers that make it more difficult to resist tampering and manipulation. Abusers avoid these formulations as they cannot easily crush and/or inject the drug. One of the biggest challenges of these types of formulations, however, is that there are still drug abusers who find ways to abuse these products. The excipients that are present in the formulations to prevent abuse can cause many health issues if injected. For example, OpanaER (Endo Pharmaceuticals) was an extended-release oxymorphone hydrochloride oral drug product. The drug was approved by FDA in 2006 but was being abused mainly by insufflation. The drug was reformulated in 2010 with physiochemical properties intended to be resistant to intranasal and intravenous routes. However, in June 2017, FDA requested OpanaER to be removed from the market as abusers had moved from insufflation abuse to injection abuse (4). The reformulated drug product was being shared between multiple users for injection. OpanaER was directly linked to outbreaks of Hepatitis C (New York, 2011), thrombotic thrombocytopenic Pupura-like (TTP) illness (Tennessee, 2012), and HIV (Indiana, 2015) (5,6).
A benefit to opioid/antagonist abuse-deterrent formulations is that the drug product contains a sequestered antagonist within the formulation. If the drug product is administered to patients as intended, it will work therapeutically. However, if a drug abuser tried to crush or manipulate the drug, the sequestered antagonist would be released and block the euphoric effects of the opioid. However, these abuse-deterrent products are not ‘abuse proof.’ Drug abusers have found ways to chemically extract the opioid from the antagonist with common household solvents to still abuse these formulations.
Another challenge that is related to all of the eight approved, abuse-deterrent opioid products that are on the market is cost. The products are all name-brand and expensive to patients. There are currently no FDA-approved generic equivalents to abuse-deterrent formulations, and insurance companies are reluctant to pay the extra expense for an abuse-deterrent opioid when the cost is vastly different from generic non-abuse-deterrent equivalents.
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