Cecilia Prudkin – Senior Analyst R&D
Health agencies, such as the Food & Drug Administration (FDA), endorse the implementation of measures to assess various aspects that prevent and discourage medication abuse. These measures span from packaging and labeling to storage, disposal, and formulation.
In this context, a method to discourage abuse, known as Abuse Deterrent Formulation (ADF), is defined as a strategy that can be implemented to make drug abuse more challenging or less appealing.
Pre-commercialization studies, conducted before a drug becomes available on the market, encompass research on potential clinical abuse, extraction methods, and various in vitro studies. These studies allow anticipation of potential abuse routes and the effects stemming from misuse of the medication.
On the other hand, post-commercialization studies provide specific information on abuse cases and evaluate the effects of anti-abuse strategies implemented in such cases. They also supply data on the impact of these strategies on abuse outcomes, such as addiction, overdose, and death.
Strategies to deter abuse can be incorporated both in drug administration and formulation, adapting to the most prevalent abuse route, whether inhalation, injection, or ingestion.
Examples of abuse-deterrent measures in administration include the use of pre-filled syringes with the exact medication dose or subcutaneous implants that can only be manipulated in medical environments. Physical barriers, such as tablets too resistant to be crushed, or chemical barriers, such as gelling agents preventing inhalation, can also be implemented.
Strategies can also focus on the drug’s formulation. The most common and easily applicable is to include an aversive agent; aversive agents are substances that cause a displeasing reaction in the user, such as pronounced itching or bitterness, or induction of vomiting. These sensations or reactions occur when the user employs the medication in a manner contrary to the doctor’s instructions. While this methodology does not prevent abuse, it makes the user’s experience less pleasant.
Another way to implement an ADF is to include an antagonistic agent in the formulation. Agonists are substances that can bind to different cellular receptors, producing physiological responses the body needs. Antagonists, on the other hand, inhibit receptor activation, blocking the agonist’s action.
Commonly abused or misused transdermal patches include those containing opioids such as fentanyl, morphine, and buprenorphine. However, anti-nausea patches, hormonal patches, antidepressants, and patches for symptoms of diseases like Parkinson’s or Alzheimer’s are also susceptible to abuse. Common abuse methods include applying multiple patches simultaneously, injection, inhalation, and transmucosal/oral routes.
Currently, there are no transdermal patch products on the market that incorporate strategies to deter abuse. However, the importance of exploring future developments that include these measures is recognized, considering the benefits these systems offer to the population, such as easy and convenient application.
These strategies focus on integrating an aversive agent into a location within the patch, preventing the transdermal delivery of the aversive agent but activating it if another route is used (intravenous, oral, etc.). This way, a quickly acting aversive effect can discourage continued abuse.
In addition to incorporating an aversive agent, there is the possibility of designing transdermal patches that integrate an agonist/antagonist pair. In this configuration, if the instructions are followed correctly, only the agonist will be activated transdermally. In situations of misuse, such as extraction in alcohol, the presence of the antagonist will nullify the agonist’s action, rendering the drug useless. It is crucial to highlight that in this design, it is ensured that the antagonist is not released antagonistically, ensuring the effectiveness of the anti-abuse approach.
Regarding product labeling, when there is data available that can significantly reduce the risk of abuse, such as potential side effects, it is advisable to include this information on the drug label. This would encompass in vitro, pharmacokinetic, or potential clinical abuse study results that contribute to highlighting the product’s effects when used through different administration routes or under diverse conditions.
In response to the growing issue of drug abuse, especially in transdermal patches, strategies known as ADF have been implemented to deter these practices. From the pre-commercialization phase to drug formulation, measures have been proposed ranging from labeling to the inclusion of aversive agents and the design of agonist/antagonist pairs in patches to prevent the risks associated with abuse. Although there are currently no patches on the market with these strategies, various companies are working on their development, seeking to offer safer and more practical options for medication and substance administration.
– Center for Drug Evaluation and Research, 05/06/2020. Transdermal and Topical Delivery Systems – Product Development and Quality Considerations | FDA
-J Multidiscip Healthc. 11/07/2018. An overview of abuse-deterrent opioids and recommendations for practical patient care – PMC (nih.gov)
– J Med Toxicol. 12/2012.
Tammi Schaeffer. Abuse-deterrent formulations, an evolving technology against the abuse and misuse of opioid analgesics – PubMed (nih.gov)
– Abuse-Deterrent Opioids-Evaluation and Labeling | FDA
– Abuse-deterrent formulations: transitioning the pharmaceutical market to improve public health and safety – PMC (nih.gov)
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