There are 3 main approaches to deter tampering with opioids, each based on a presumption that abusers will tamper with intact tablets. These include agents with physical barriers to crushing, chewing, and extraction; agents with sequestered aversive agents; and agents with sequestered opioid antagonists.
There are no tamper-resistant formulations directed at preventing abuse of intact tablets by taking them when they are not prescribed or in amounts that exceed the prescribed dose, although agents with sequestered aversive agents may have dosage ceilings imposed by the AEs precipitated by the noxious component (eg, niacin) when the product is taken as intended. For this reason, it may be advantageous to prescribe opioids that cause less euphoria compared with other formulations.
Although all 3 approaches have the potential to deter tampering, only opioids presenting physical barriers to crushing or chewing seem to provide additional benefit to nonabusers. Physical barriers prevent accidental crushing or chewing, providing a benefit to patients who may do this without intent of tampering. Moreover, physical barriers to chewing or crushing do not add to the risk of AEs for abusers or nonabusers.
In contrast, opioids with mechanisms of action based on precipitating AEs as a means of deterring inappropriate use have risks, regardless of the patient's level of compliance. Sequestered aversive agents will cause AEs in patients who chew or crush tablets accidentally without intent of abuse, and even intact tablets with sequestered aversive agents may produce AEs from the aversive component in some fully compliant patients. The extent of deterrence with these agents is unclear because individuals who intentionally abuse opioids may be willing to endure the discomfort of the aversive agent's AEs. Although sequestered opioid antagonists may represent a more effective approach to pharmacologically deterring abuse by rendering the opioid ineffective, there is evidence of sudden opioid withdrawal in patients who chewed their tablet, even accidentally.
None of the current approaches to deterrence has been validated by long-term postmarketing data as actually succeeding in deterring abuse. Such data are essential to a proper risk-benefit analysis. If one approach to formulation proves more successful than others in deterring abuse, a low incidence of AEs in compliant, nonabusing patients may be acceptable. In the meantime, it may be prudent initially to restrict the prescription of these putatively tamper-resistant opioids to patients with a high risk of abuse, misuse, or diversion and to cautiously weigh the risks they may present to low-risk patients. We would propose several recommendations for the use of tamper-resistant opioids in several key populations, including patients at risk for abusing opioids, patients who may be targeted for theft, and the elderly (). However, one could argue that the same level of scrutiny and precaution be placed on all patients, because some patients formally assessed to be low risk may use medications inappropriately.
Recommendations for Selecting a Tamper-Resistant Opioid Formulation
Risk management changes proposed by the FDA, including REMS proposed for a list of certain long-acting or modified-release opioid preparations, could have formidable effects on prescribing and possible long-term influences on misuse, abuse, and diversion. Many of the more recently approved and reformulated long-acting and ER opioid formulations have been approved with “interim REMS” and have delivery systems and pharmacokinetic properties that may make them more difficult to tamper with at some level, which may decrease the ease of misuse and abuse compared with that for older formulations. In the future, extending a class-wide REMS to include short-acting formulations (branded and generic) may even the playing field for all prescribed products and may further help to deter misuse, abuse, and diversions of prescription opioids.