Meperidine × Selegiline

Selegiline irreversibly inhibits monoamine oxidase (MAO), the enzyme that breaks down catecholamines and serotonin. At recommended doses it acts mainly on MAO type B (MAO-B) and loses this selectivity above 10 mg a day (selegiline SmPC; US Food and Drug Administration (FDA) selegiline label). In patients taking MAO inhibitors, therapeutic doses of meperidine have occasionally caused unpredictable, severe and sometimes fatal reactions, and the mechanism is unclear (FDA meperidine label). The combination can cause acute excitation or depression of the central nervous system, with high or low blood pressure (meperidine SmPC). Because MAO inhibition is irreversible, the risk persists after stopping selegiline until the body makes new enzyme. Liver enzymes play no part here: selegiline does not inhibit CYP3A4 or CYP2B6, which break down meperidine (FDA selegiline and meperidine labels).

The reaction takes two forms. One resembles acute opioid overdose, with coma, severe respiratory depression, cyanosis and hypotension; the other shows hyperexcitability, seizures, tachycardia, hyperpyrexia and hypertension, sometimes as serotonin syndrome with agitation, hyperthermia, diarrhoea, sweating, tremor and impaired consciousness (US Food and Drug Administration (FDA) meperidine label). Patients given selegiline with meperidine have had stupor, muscle rigidity, severe agitation, hallucinations and raised temperature, and deaths have occurred; symptoms usually resolve over days once the combination is stopped (FDA selegiline label). Serotonin syndrome usually starts within several hours to a few days of combined use but can appear later (FDA meperidine label).

The combination is contraindicated (selegiline SmPC, sections 4.3 and 4.5; meperidine SmPC, sections 4.3 and 4.5; US Food and Drug Administration (FDA) selegiline and meperidine labels, section 4). Start meperidine no earlier than 14 days after the last dose of selegiline (meperidine SmPC, section 4.3; FDA selegiline and meperidine labels, section 4). Switching to another opioid does not lift the ban: selegiline is contraindicated with opioids as a class (selegiline SmPC, section 4.3), with tramadol and methadone among the examples (FDA selegiline label). General anaesthesia in a patient taking selegiline calls for caution. Monoamine oxidase inhibitors, selegiline included, can potentiate the central nervous system depressants used in anaesthesia, with reports of transient respiratory and cardiovascular depression, hypotension and coma (selegiline SmPC, section 4.4). If serotonin syndrome is suspected, stop meperidine (FDA meperidine label). Symptoms usually resolve over days once the combination is stopped (FDA selegiline label). Intravenous hydrocortisone or prednisolone have been used for severe reactions, with intravenous chlorpromazine added for hypertension and hyperpyrexia; the usefulness and safety of opioid overdose reversal agents in this reaction are unknown (FDA meperidine label).