Clinical guidelines and procedures for the use of methadone in the maintenance treatment of opioid dependence

Appendix 1: Possible drug interactions with methadone

Page last updated: August 2003

Alcohol

  • Status of interaction: Clinically important.
  • Effects:
    • Increased sedation.
    • Increased respiratory depression.
    • Combination may also have increased hepatotoxic potential.
  • Mechanism: Additive central nervous system depression.

Barbiturates

  • Status of interaction: Clinically important.
  • Effects:
    • Reduced Methadone levels.
    • Increased sedation.
    • Additive CNS depression.
  • Mechanism: Barbiturates stimulate hepatic enzymes involved in methadone maintenance.

Benzodiazepines

  • Status of interaction: Clinically important.
  • Effects: Enhanced sedative effect.
  • Mechanism: Additive CNS depression.

Buprenorphine

  • Status of interaction: Clinically important.
  • Effects: Antagonist effect or enhanced sedative and respiratory depression.
  • Mechanism: Buprenorphine is a partial agonist of opiate receptors.

Carbamazepine

  • Status of interaction: Clinically important.
  • Effects: Reduced methadone levels.
  • Mechanism: Carbamazepine stimulates hepatic enzymes involved in methadone metabolism.

Chloral hydrate

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  • Status of interaction: Clinically important.
  • Effects: Enhanced sedative effect.
  • Mechanism: Additive CNS depression.

Chlormethiazole

  • Status of interaction: Clinically important.
  • Effects: Enhanced sedative effect.
  • Mechanism: Additive CNS depression.

Cimetidine

  • Status of interaction: Two cases have been shown in patients taking methadone as analgesia.
  • Effects: Possible increase in methadone plasma levels.
  • Mechanism: Cimetidine inhibits hepatic enzymes involved in methadone metabolism.

Ciprofloxacin

  • Status of interaction: Case in a patient taking methadone.
  • Effects: Enhanced sedative effect and respiratory depression requiring naloxone.
  • Mechanism: Probably by inhibiting hepatic enzymes involved in methadone metabolism.

Cisapride, domperidone and metoclopramide

  • Status of interaction: Theoretical.
  • Effects: Theoretically might increase the speed of onset of methadone absorption but not the extent.
  • Mechanism: Possibly by reversing the delayed gastric emptying associated with opioids.

Cyclazine and other sedating anti histamines

(cyclazine is not available in Australia)
  • Status of interaction: Clinically important.
  • Effects:
    • Anecdotal reports of injection of cyclazine with opioids causing hallucinations.
    • Reports of injections of high doses of dephenhydramine to achieve 'buzz'.
  • Mechanisms:
    • Additive psychoactive effects.
    • Anti muscarinic effects at high doses.

Desipramine

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  • Status of interaction: Clinically important.
  • Effects: Raised desipramine levels by up to a factor of two.
  • Mechanism: Unknown mechanism not seen with other tricyclic antidepressants.

Other tricyclic antidepressants

  • Status of interaction: Theoretical.
  • Effects: Enhanced sedative effect which is dose dependent.
  • Mechanism: Additive CNS depression.

Disulfiram

  • Status of interaction: Avoid in combination with methadone formulations containing alcohol (check with manufacturer).
  • Effects: Very unpleasant reaction to alcohol which can be dangerous.
  • Mechanism: Disulfiram inhibits metabolism of alcohol allowing metabolites to build up.

Erythromycin

  • Status of interaction: In theory should interact but not been studied.
  • Effects: Increase in methadone levels.
  • Mechanism: Decreased methadone metabolism.

Fluconazole

In theory the same as ketoconazole.

Fluoxetine and sertraline

  • Status of interaction: Clinically important.
  • Effects: Raised methadone levels but not as significant as for fluvoxamine.
  • Mechanism: Decreased methadone metabolism.

Fluvoxamine

  • Status of interaction: Clinically important.
  • Effects: Raised plasma methadone levels.
  • Mechanism: Decreased methadone metabolism.

Other SSRIs

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  • Status of interaction: Theoretical.
  • Effects: Raised plasma methadone levels.
  • Mechanism: Decreased methadone metabolism.

Grapefruit juice

  • Status of interaction: Should interact in theory and there have been several anecdotal reports.
  • Effects: Raised methadone levels.
  • Mechanism: Decreased methadone metabolism.

Indinavir

  • Status of interaction: Clinically important.
  • Effects: Raised methadone levels.
  • Mechanism: Decreased methadone metabolism.

Ketoconazole

  • Status of interaction: Clinically important.
  • Effects: Raised methadone levels.
  • Mechanism: Decreased methadone levels.

MAOI (including selegiline and moclobemide)

  • Status of interaction: Severe with pethedine though unlikely with methadone and has never been described.
  • Effects:
    • CNS excitation.
    • Delirium.
    • Hyperpyrexia.
    • Convulsions.
    • Hypotension or respiratory depression.
  • Mechanism: Unclear, avoid the combination if possible.

Meprobamate

  • Status of interaction: Clinically important.
  • Effects: Enhanced sedative and respiratory depressant effect.
  • Mechanism: Additive CNS depression.

Naltrexone

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  • Status of interaction: Clinically important.
  • Effects: Blocks effect of methadone (long acting).
  • Mechanism: Opioid antagonist – competes for opiate receptors.

Naloxone

  • Status of interaction: Clinically important.
  • Effects: Blocks effects of methadone (short acting) but may be needed if overdose suspected.
  • Mechanism: Opioid antagonist – competes for opiate receptors.

Nevirapine

  • Status of interaction: Clinically important.
  • Effects: Decreased methadone levels.
  • Mechanism: Increased methadone metabolism.

Nifedipine

  • Status of interaction: Has been demonstrated in vitro only.
  • Effects:
    • Increased nifedipine levels.
    • No effect on methadone levels.
  • Mechanism: Methadone increases metabolism of nifedipine.

Omeprazole

  • Status of interaction: To date demonstrated only in animals.
  • Effects: Increased methadone levels.
  • Mechanism: Possibly an effect on methadone absorption from the gut.

Pentazocine

  • Effects: Antagonist effect or enhanced sedative and respiratory depression.
  • Mechanism: Pentazocine is a partial agonist of opiate receptors with weak antagonist effect.

Phenobarbitone

See barbiturates above.

Phenytoin

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  • Status of interaction: Clinically important.
  • Effects: Reduced methadone levels.
  • Mechanism: Phenytoin stimulates hepatic enzymes involved in methadone metabolism.

Propanolol

  • Status of interaction: To date demonstrated only in animals. Significance in humans is not known. Exercise caution when co-administering.
  • Effects: Enhanced lethality of toxic doses of opioids.

Rifampicin

  • Status of interaction: Very important. Most patients are likely to be affected.
  • Effects: Reduced methadone levels.
  • Mechanism: Rifampicin stimulates hepatic enzymes involved in methadone metabolism.

Rifabutin

  • Status of interaction: Occasionally clinically important.
  • Effects: Decreased methadone levels.
  • Mechanism: Increased methadone metabolism.

Ritonavir

  • Status of interaction: Clinically important.
  • Effects: Ritonavir may decrease plasma methadone levels.
  • Mechanism: Increased methadone metabolism.

Thioridazine

  • Status of interaction: Clinically important.
  • Effects: Enhanced sedative effect which is dose dependent.
  • Mechanism: Enhanced CNS depression.

Other protease inhibitors

  • Status of interaction: Theoretical.
  • Effects: May raise or lower methadone plasma levels.
  • Mechanism: Inhibits methadone metabolism.

Urine acidifiers

e.g. ascorbic acid – vitamin C.Top of page
  • Status of interaction: Clinically important.
  • Effects: Reduced plasma methadone levels.
  • Mechanism: Increased urinary excretion of methadone.

Urine alkalisers

e.g. sodium bicarbonate.
  • Status of interaction: Clinically important.
  • Effects: Increased plasma methadone levels.
  • Mechanism: Reduced urinary excretion of methadone.

Zidovudine

  • Status of interaction: Clinically important.
  • Effects:
    • Raised plasma levels of zidovudine.
    • No effects on methadone levels.
  • Mechanism: Unknown.

Zopiclone

  • Status of interaction: Clinically important.
  • Effects: Enhanced sedative and respiratory depressant effect.
  • Mechanism: Additive CNS depression.

Other opioid agonists

  • Status of interaction: Clinically important.
  • Effects:
    • Enhanced sedative effect.
    • Enhanced respiratory depression.
  • Mechanism: Additive CNS depression.

Other CNS depressant drugs

(eg neuroleptics hyoscine)Top of page
  • Status of interaction: Clinically important.
  • Effects: Enhanced sedative effect which is dose dependent.
  • Mechanism: Additive CNS depression.

This is based on a similar table published in: Department of Health, The Scottish Office Department of Health, Welsh Office, Department of Health and Social Services Northern Ireland (1999) Drug Misuse and Dependence – Guidelines on Clinical Management. Her Majesty's Stationary Office. Norwich.