Clopidogrel and Methadone: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Clopidogrel
Methadone
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
What happens
Increased methadone exposure, an increased risk of opioid adverse effects and reduced efficacy of clopidogrel
Interaction Deep Dive
Concomitant use of methadone (a CYP2B6 substrate) and clopidogrel (a CYP2B6 inhibitor) may increase the plasma concentrations of methadone, prolong opioid adverse reactions, and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dosage of methadone is achieved. Consider dosage reduction of methadone when using concomitant CYP3A4 inhibitor in methadone-treated patients, and follow patients closely at frequent intervals for signs and symptoms of respiratory depression and sedation. When discontinuing a CYP3A4 inhibitor, follow patients for signs or symptoms of opioid withdrawal and consider increasing the methadone dosage as needed123. Coadministration of clopidogrel with opioid agonists delays and reduces the absorption of clopidogrel, presumably because of slowed gastric emptying, resulting in reduced exposure to clopidogrel metabolites. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring coadministration of morphine or other opioid agonists 4.
Why it happens (mechanism)
Inhibition of CYP2B6-mediated metabolism of methadone; delayed and reduced absorption of clopidogrel
Literature reports
1 report — tap to read
a) Coadministration of morphine 5 mg IV with a 600 mg loading dose of clopidogrel in healthy adults decreased the AUC and Cmax of the thiol metabolites of clopidogrel by 34%. Mean platelet aggregation was higher up to 2 to 4 hours with morphine coadministration 4.
Common questions
Can I take Clopidogrel and Methadone together?
Increased methadone exposure, an increased risk of opioid adverse effects and reduced efficacy of clopidogrel Always confirm with your pharmacist or prescriber before making any change.
How serious is the Clopidogrel and Methadone interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Clopidogrel or Methadone need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there a safer alternative to one of these medications for me?
References (4)
- Product Information: DISKETS dispersible tablets, methadone HCl dispersible tablets. Hikma Pharmaceuticals USA Inc (per FDA), Berkeley, NJ, 2023.
- Product Information: METHADOSE oral concentrate, methadone HCl oral concentrate. SpecGx LLC (per FDA), Webster Groves, MO, 2023. DailyMed
- Product Information: Methadone HCl injection, methadone HCl injection. Mylan Institutional LLC (per FDA), Morgantown, WV, 2023. DailyMed
- Product Information: PLAVIX(R) oral tablets, clopidogrel bisulfate oral tablets. Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership (per FDA), Bridgewater, NJ, 2018. DailyMed
Keep reading about Clopidogrel
Keep reading about Methadone
These medications also interact with supplements
Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
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