Metabolism: Meperidine

Meperidine is a synthetic opioid widely used for treating pain. It is also used for controlling post anesthetic shivering. Its main pharmacological action is produced through μ receptors on the central nervous system (CNS). Meperidine is metabolized extensively in the human liver by 1) N-demethylation to normeperidine (6-N-desmethylmeperidine), which may be further hydrolyzed to normeperidinic acid and subsequently conjugated; and 2) by hydrolysis to meperidinic acid by human carboxylesterase-1 followed by conjugation. Meperidine metabolites account for over half the drug in the urine.

Normeperidine is devoid of analgesic activity, but it is a potent stimulant of the CNS. Its main adverse effect is neurotoxicity, producing symptoms that include nervousness, tremors, muscle twitches, and seizures.Multiple doses of meperidine result in accumulation of normeperidine due to its long elimination half-life (15-30 h) as compared with the meperidine (2.4-4 h). Meperidine is metabolized chiefly in the liver, with a half-life of ~3 hours. In patients with cirrhosis, the bioavailability of meperidine is increased to as much as 80%, and the t1/2 of both meperidine and normeperidine are prolonged.Normeperidine is eliminated via the liver and kidney; patients with significant impairment of hepatic or renal function have prolonged normeperidine half-lives and are especially predisposed to its toxic effects.Other individuals susceptible to the adverse effects of normeperidine include 1) individuals who receive prolonged administration of meperidine (such as cancer and chronic pain patients) or high meperidine doses (>400-600 mg/day), 2) patients receiving oral meperidine, 3) individuals treated with monoamine oxidase inhibitors, and 4) patients receiving medications that induce hepatic enzyme systems. As a result of these, meperidine is not recommended for the treatment of chronic pain because of concerns over metabolite toxicity. It should not be used for longer than 48 hours or in doses >600 mg/day (see www.ahrq.gov).

Interactions with Other Drugs

Severe reactions may follow the administration of meperidine in patients being treated with MAO inhibitors. Two basic types of interactions can be observed. The most prominent is an excitatory reaction (“serotonin syndrome”) with delirium, hyperthermia, headache, hyper- or hypotension, rigidity, convulsions, coma, and death. This reaction may be due to the ability of meperidine to block neuronal reuptake of 5-HT, resulting in serotonergic overactivity . Conversely, the MAO inhibitor interaction with merperidine may resemble acute narcotic overdose owing to the inhibition of hepatic CYPs.Therefore, meperidine and its congeners are contraindicated in patients taking MAO inhibitors or within 14 days after discontinuation of an MAO inhibitor.Similarly, dextromethorphan (an analog of levorphanol used as a non-narcotic cough suppressant) also inhibits neuronal 5-HT uptake and must be avoided in these patients.