Extended-Release and Long-Acting Opioid Analgesics Risk Evaluation and Mitigation Strategy (REMS):

Abstract

Toxicities and Drug Interactions Sedation and Respiratory Depression Most clinicians who prescribe opioid analgesics are aware that sedation occurs commonly with opioid use and that respiratory depression is the most serious adverse effect of opioid analgesics. Indeed, respiratory depression due to over-dose was the likely cause in most of the approximately 16,000 opioid-related mortalities that occurred in the United States in 2010, the most recent year for which data are available. The number of opioid-related overdose mortalities has nearly qua-drupled since 1999. 1 With continued use of opioid analgesics, individuals develop tolerance to the sedative and respiratory depressive effects. However, concomitant use of drugs that act on the central nervous system--including alcohol, sedative-hypnotics, tricy-clic antidepressants and, in particular, benzodiazepines 2 –can potentiate the sedative and respiratory depressive effects even in individuals who might otherwise be considered opioid toler-ant. A similar effect can be seen occasionally when opioid analgesics are used concomitantly with, or within 2 weeks of discontinuing, monoamine oxidase inhibitors. 3 Avoiding these substances while taking opioid analgesics will minimize the risk of opioid-induced sedation and respiratory depression. Constipation Most clinicians are also aware that constipation is an adverse effect experienced by individuals using short-or long-acting opioid analgesics. The reported incidence of problems related to constipation in users of chronic opioid analgesics is shown to be as high as 29% in large population-based stud-ies. 4 Among the extended-release and long-acting (ER/LA) opioid analgesics, one older study found that the rate of con-stipation is higher with sustained-release morphine than with transdermal fentanyl. 5 A more recent study that did not include morphine found the constipation rate (defined as no stools for more than 72 hours) was similar with transdermal fentanyl (22%) 5 and transdermal buprenorphine (21%), but substantially lower, at 2%, with extended-release hydromorphone (Exalgo). 6 Opioid-induced constipation is typically managed by increas-ing intake of fluids and dietary fiber, plus use of both stool softeners and stimulant laxatives; stool softeners alone are often insufficient. 7 Increasingly, however, the emphasis is on prevention of constipation rather than management, with insti-tution of stool softeners and stimulant laxatives when opioid therapy is started, rather than after constipation develops. 8 Decreased Effectiveness of Diuretics Opioid analgesics induce release of antidiuretic hormone (ADH), which counteracts the effect of diuretic drugs. Although not often considered by clinicians, this effect may be important for patients with medical conditions that require diuretic ther-apy, such as heart failure. 9 QT-Interval Prolongation Methadone and high doses of transdermal buprenorphine (greater than 20 mcg/hr) are known to prolong the electro-cardiographic QT interval, which in turn poses an increased risk of torsades de pointes, or torsades, ventricular tachycar-dia. Although either of these ER/LA drugs has the potential to induce torsades on its own, particularly at higher doses, the risk of torsades may be even greater when these opioid