Cimetidine and Methadone
68. One week later, B.D.'s wife calls and says that he is very drowsy and that his speech has started to slur. On further questioning, his wife notes that B.D. restarted oral cimetidine 400 mg TID for symptoms of gastritis. She confirms that B.D. has been taking oral methadone 20 mg every 6 hours. What may explain B.D.'s symptoms of apparent opioid toxicity?
Cimetidine (Tagamet) inhibits CYP3A4 isoenzymes, thereby decreasing the metabolism of methadone and potentially subjecting patients to toxic levels. B.D. also could be reaching serum methadone steady-state levels at this time. He should be instructed to withhold the methadone until his mental status returns to baseline; then, the dose of methadone needs to be decreased to 10 mg every 6 hours. When adding cimetidine to existing methadone therapy, methadone doses need to be decreased; the doses should be increased again if cimetidine is subsequently withdrawn.228
Similar precautions need to be instituted for other CYP3A4 inhibitors, such as antiretroviral agents, ketoconazole or fluconazole, erythromycin, and other agents.
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