__________________________________ Prescription Opioids: Risk Management and Strategies for Safe Use responding greater risk of serious adverse outcomes, including fatality, when taken by someone for whom they were not prescribed, by patients who succeed in defeating the delayed-release mechanism, or by any user co-ingesting alcohol, benzodiazepines, or other respiratory suppressant substances. Primary elements of the ER/LA REMS include changes in product labeling and the requirement that all ER/ LA opioid formulation manufacturers provide spe- cific information to prescribers and patients [135]. For example, there is a new indication for all ER/ LA opioids that the pain must be severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options are inadequate. The original indication for the treatment of “moderate” pain was eliminated. In addition, the distinctions between cancer pain and chronic noncancer pain were removed. Prescriber education regarding ER/LA opioids is provided through accredited continuing education activities supported by independent educational grants from ER/LA opioid analgesic companies. This includes guidance regarding patient education on the risks and benefits of ER/LA opioid analgesics [135]. In 2012, the FDA issued a class-specific REMS for all transmucosal immediate-release fentanyl (TIRF) opioid products. Training was required for all pre- scribers, pharmacies, distributors, and outpatients who prescribed, dispensed, or received TIRF prod- ucts [136]. In December 2020, the FDA approved modifications to this REMS. The modified TIRF REMS consists of a restricted distribution program to ensure the safe use of TIRF medicines, includ- ing use only in opioid-tolerant patients [136]. The modified REMS requires that prescribers docu- ment a patient’s opioid tolerance; that outpatient pharmacies dispensing TIRF medicines document and verify a patient’s opioid tolerance prior to dis- pensing; that inpatient pharmacies develop internal policies to verify opioid tolerance in patients who require TIRF medicines while hospitalized; and that a new patient registry be established to monitor accidental exposure, misuse, abuse, addiction, and overdose [136]. ABUSE-DETERRENT OPIOID FORMULATIONS Drug developers, manufacturers, and regulatory bodies face daunting challenges in formulating and implementing strategies to reduce the abuse, addiction, diversion, and overdose of prescription opioids. One challenge has been to identify and manufacture analgesics effective in the treatment of severe pain that also possess minimal abuse liability. These products must provide full analgesia with low “opioid attractiveness” to persons intent on abus- ing or diverting the drug; this strategy is consistent with the opioid REMS principle of drug benefit outweighing risk [137]. The development of abuse- deterrent formulations (ADFs) was also an approach to help avoid the unintended harms to patients with legitimate pain observed in Washington and Florida, where imposition of opioid prescribing restrictions were found to discourage legitimate treatment of chronic pain while making little or no impact on opi- oid analgesic abuse and diversion [138]. Although ADF opioids retain some abuse liability if used inap- propriately or combined with other substances, most ADFs are now being developed to prevent defeat of the delayed-release mechanism or use through illicit routes of administration [139; 140]. Helping to prompt the development of ADF opioids were reports that as many as 80% of prescription opioid abusers in drug rehabilitation tampered with ER opioid formulations [141]. Strategies used by opioid abusers to disable the delayed-release mecha- nism to accelerate drug release include crushing and swallowing; crushing and snorting; crushing and smoking; or crushing, dissolving, and injecting. The FDA states that ADFs should target known or expected routes of abuse for the opioid constituent in the given formulation [142]. ADVANTAGES AND DISADVANTAGES OF DIFFERENT ADF STRATEGIES Several ADF opioids have received approval for marketing in the United States; others are in the process of evaluation, and one ADF was released for marketing and subsequently recalled by the
37
MDMS1526
Powered by FlippingBook