A patient on chronic methadone therapy for opioid use disorder is given a new prescription for clarithromycin for pneumonia. The critical drug interaction is:

• A Clarithromycin is an opioid receptor antagonist at kappa receptors, precipitating withdrawal
• B Clarithromycin induces CYP2D6, the primary metabolic enzyme for methadone, causing acute withdrawal
• C Combined macrolide-opioid inhibition of GI motility causes paralytic ileus
• D Clarithromycin inhibits CYP3A4, reducing methadone metabolism and raising plasma levels, potentially prolonging QTc and causing torsades de pointes ✓

Explanation

Methadone is primarily metabolized by CYP3A4 (and secondarily by CYP2D6, CYP2B6). Clarithromycin is a potent CYP3A4 inhibitor (macrolide antibiotic). Inhibition of CYP3A4 raises methadone plasma concentrations significantly, increasing the risk of QTc prolongation (methadone blocks hERG cardiac K+ channels) and potentially fatal torsades de pointes. This interaction is a real-world cause of opioid-related cardiac deaths. Safer alternatives include azithromycin (not a CYP3A4 inhibitor) or doxycycline. If clarithromycin is necessary, ECG monitoring and dose reduction of methadone are required.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.