Oxycodone and fentanyl are metabolised largely by CYP3A4, and methadone partly. Strong inhibitors — clarithromycin, itraconazole, ketoconazole, voriconazole and ritonavir-boosted regimens among them — can raise opioid levels substantially, and moderate inhibitors such as diltiazem, verapamil and fluconazole can also increase them.
The risk is greatest when an inhibitor is added to a stable opioid dose, or an inducer such as rifampicin or carbamazepine is stopped. Morphine and hydromorphone are not mainly CYP3A4-dependent and may be easier to manage when an inhibitor cannot be avoided.
- Check for CYP3A4 inhibitors before starting or continuing oxycodone, fentanyl or methadone
- Watch for sedation when clarithromycin, an azole or a boosted antiretroviral is added
- Remember that stopping an inducer such as rifampicin can raise opioid levels too
- Consider an opioid not mainly cleared by CYP3A4 when an inhibitor is unavoidable
Why it matters
A routine antibiotic or antifungal can turn a stable opioid dose into an overdose.
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