An overview of prodrug technology and its application for developing abuse-deterrent opioids

The Centers for Disease Control and Prevention has classified prescription drug abuse and overdose deaths as an epidemic. Prescription drug overdose is now the leading cause of injury death, with rates that have more than doubled since 1999. This crisis has developed concurrently with the increased prescribing and availability analgesic drugs, especially opioids, resulting from an effort on the part of clinicians to address a critical need for improved pain assessment and treatment. Clinicians have recognized that oftentimes, opioid analgesics are one of the few remaining options for patients who suffer with severe pain. A 2015 fact sheet issued by the Office of National Drug Policy stated: "While we must ensure better access to prescription medications to alleviate suffering, it is also vital that we do all we can to reduce the diversion and abuse of pharmaceuticals." The US Food and Drug Administration has issued guidance that encourages the research and development of abuse-deterrent formulation of opioids which have the potential to curtail abuse. Included among the recommended formulations for development of abuse-deterrent opioids are prodrugs. Prodrugs are chemically modified versions of pharmacological agents that must undergo a biochemical conversion following administration, often by enzymatic cleavage, to free the active drug. Prodrugs may be inherently abuse-deterrent because they are inactive or significantly less active until conversion to the active drug. This requirement for conversion in the GI tract can modify the pharmacokinetic profile and eliminate or reduce the euphoria when abusers change the route of administration. Abusers often attempt to extract the active drug for injection or insufflation. Prodrugs can be designed to be resistant to crushing or dissolving. In this article, we review the concept of prodrugs and introduce and examine the potential of abuse-deterrent opioid prodrugs.