Reduced Codeine Analgesic Efficacy Associated with Nicardipine in a Patient with Medication-Overuse Headache: A Case Report

Codeine is a prodrug opioid whose analgesic efficacy depends on its bioactivation into morphine via cytochrome P450 2D6. Its use in migraine is discouraged because of limited efficacy, tolerance, and the risk of medication-overuse headache. Drug-drug interactions affecting its metabolism may further compromise pain control. We report the case of a 72-year-old man with chronic migraine and daily codeine use. A pharmacist-led medication review identified a potential pharmacokinetic interaction between codeine and extended-release nicardipine. Plasma concentrations of codeine and its metabolites were measured before and after codeine intake under nicardipine treatment and three months after substitution with candesartan. The fold increase in morphine-glucuronide concentration between baseline and peak rose from 1.6 with nicardipine to 3.5 after discontinuation, consistent with restored codeine bioactivation. This case highlights a clinically relevant interaction between nicardipine and codeine leading to reduced opioid efficacy. Beyond tolerance and medication-overuse headache, pharmacokinetic interactions should be systematically considered in patients with refractory pain.