Drug interactions
Methadone + Midazolam
Severity: Major
Methadone and Midazolam: major interaction.
Last updated Sources: US FDA label
For healthcare professionals — reference only. This page is a brief summary, not medical advice and not a substitute for official labeling or clinical judgement. Always verify before prescribing or dispensing.
Summary
Midazolam with methadone causes additive CNS and respiratory depression, which can lead to profound sedation, respiratory failure or death. Methadone may also modestly reduce midazolam clearance through CYP3A4 competition.
What this interaction means in plain words
Methadone and Midazolam can interact in a way that may be serious. Using them together is sometimes necessary, but it needs a deliberate decision by the prescriber, a plan for monitoring, and clear advice on the warning signs to watch for.
Methadone belongs to Musculoskeletal; Midazolam belongs to Central Nervous System.
Why it happens
Additive CNS and respiratory depression via opioid and GABA-A receptor effects.
What to do
Use the lowest midazolam dose and titrate slowly, with continuous monitoring of oxygen saturation and respiration. Have airway support and reversal agents available.
What to ask your pharmacist
- Does the benefit of taking both outweigh the risk in my case?
- Do I need any blood test, ECG or other check while on both?
- What early warning signs should I watch for, and what should I do if they appear?
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References
Other interactions of Methadone
- Alvimopan + Methadone Contraindicated
- Calcium / magnesium / potassium / sodium oxybates + Methadone Contraindicated
- Droperidol + Methadone Contraindicated
- Ibutilide + Methadone Contraindicated
- Isocarboxazid + Methadone Contraindicated
- Lefamulin + Methadone Contraindicated
Other interactions of Midazolam
- Atazanavir + Midazolam Contraindicated
- Cobicistat + Midazolam Contraindicated
- Darunavir + Midazolam Contraindicated
- Elvitegravir / cobicistat / emtricitabine / tenofovir df + Midazolam Contraindicated
- Fosamprenavir + Midazolam Contraindicated
- Indinavir + Midazolam Contraindicated
Frequently asked questions
Can I take Methadone with Midazolam?
MediHelp rates the interaction as major. Methadone and Midazolam can interact in a way that may be serious. Using them together is sometimes necessary, but it needs a deliberate decision by the prescriber, a plan for monitoring, and clear advice on the warning signs to watch for. Midazolam with methadone causes additive CNS and respiratory depression, which can lead to profound sedation, respiratory failure or death. Methadone may also modestly reduce midazolam clearance through CYP3A4 competition.
How serious is the interaction between Methadone and Midazolam?
MediHelp rates it major, on a four-level scale (minor, moderate, major, contraindicated) based on published labels and references. What to do, in brief: Use the lowest midazolam dose and titrate slowly, with continuous monitoring of oxygen saturation and respiration. Have airway support and reversal agents available.
What other medicines interact with Methadone?
MediHelp also lists interactions of Methadone with, for example, Alvimopan, Calcium / magnesium / potassium / sodium oxybates, Droperidol. The full list is on the Methadone page.
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