Published: 8 June 2018

Medicines Interacting with Methadone

Prescriber Update 39(2): 20
June 2018

Key Messages

  • Pharmacokinetic and pharmacodynamic interactions can both occur between methadone and a number of other medicines.
  • Check for medicine interactions when prescribing new medicines for patients currently taking methadone, or when starting a patient on methadone.

Methadone is an opioid analgesic used as an adjunct in the treatment of opioid dependence and for the relief of moderate to severe pain1,2 .

Methadone is extensively metabolised by cytochrome P450 enzymes in the liver, with CYP3A4 and CYP2B6 being major contributors and CYP2C19, CYP2D6 and CYP2C9 being minor contributors3 . Methadone is also a substrate for P-glycoprotein.

Inducers and inhibitors of these proteins can alter methadone concentrations, potentially leading to a withdrawal syndrome or an increased risk of respiratory depression, sedation and QT prolongation4–6 . Concurrent use of other opioids, alcohol or central nervous system (CNS) depressants (eg, benzodiazepines) can also increase the risk of respiratory depression and sedation6 .

Tables 1 and 2 give examples of medicines that interact with methadone. Please refer to the New Zealand data sheets for a full list of interactions with methadone (

Table 1: Examples of methadone pharmacokinetic interactions and their effects6–8

Medicine Classification Examples Mechanism Effect
Anticonvulsants carbamazepine, phenobarbitone, phenytoin Induction of methadone metabolism Reduced methadone levels
Antibiotics rifampicin
Non-Nucleoside Reverse -Transcriptase Inhibitors efavirenz, nevirapine
Azole antifungals fluconazole, ketoconazole Inhibition of methadone metabolism Increased methadone levels
Selective serotonin reuptake inhibitors fluoxetine
Protease inhibitors atazanavir, darunavir, indinavir, ritonavir Inhibition or induction of methadone metabolism Increased or decreased methadone levels

Table 2: Examples of methadone pharmacodynamic interactions and their effects6–8

Medicine Classification Examples Mechanism Effect
  alcohol Additive central nervous system depression Increased sedation, increased respiratory depression; combination may also increase hepatotoxicity potential
Benzodiazepines and hypnotics clonazepam, diazepam, lorazepam, nitrazepam, oxazepam, temazepam, triazolam, zopiclone Enhanced sedative effect; increased respiratory depression
Neuroleptics aripiprazole, clozapine, olanzapine, quetiapine, risperidone Enhanced sedative effects; which are dose dependent
Other opioids codeine, fentanyl, morphine, oxycodone Enhanced sedative effect; enhanced respiratory depression
Sedating antihistamines cyclizine, promethazine Enhanced sedative and psychoactive effect; anecdotal reports of injection of cyclizine with opioids causing hallucinations
Opioid antagonists naloxone, naltrexone Compete for opioid receptors Blocks effect of methadone
Partial opioid agonist buprenorphine Partial agonist of opioid receptors Antagonistic effect or enhanced sedative effect and respiratory depression

Up to 31 December 2017, the Centre for Adverse Reactions Monitoring (CARM) had received eight cases describing a medicine interaction with methadone. Three of these cases describe additive CNS depression, where methadone was co-prescribed with a benzodiazepine, another opioid or a neuroleptic. In one case, a patient experienced somnolence when co-prescribed fluconazole.

Consider potential medicine interactions when prescribing new medicines for patients currently taking methadone, or when starting a patient on methadone.

Please report any adverse reactions to methadone to CARM (

  1. New Zealand Formulary. 2018. New Zealand Formulary v67: Methadone hydrochloride 1 January 2018. URL: (accessed 31 January 2018).
  2. Best Practice Advocacy Centre. 2008. WHO Analgesic Ladder: Methadone — safe and effective use for chronic pain. Best Practice Journal 18: 21–9 URL: (accessed 31 January 2018).
  3. UpToDate. 2018. Methadone Drug Information URL: (accessed 15 May 2018).
  4. Medsafe. 2014. Methadone – don't break your heart (QT prolongation). Prescriber Update 35(3): 35. URL: (accessed 31 January 2018).
  5. Biomed Limited. 2014. Biodone Data Sheet 24 June 2014. (accessed 31 January 2018).
  6. Brown R, Kraus C, Fleming M, et al. 2004. Methadone: applied pharmacology and use as adjunctive treatment in chronic pain. Postgraduate Medical Journal 80: 654–9.
  7. PSM Healthcare Ltd t/a API Consumer Brands Ltd. 2017. Methatabs Data Sheet November 2017. URL: (accessed 31 January 2018).
  8. AFT Pharmaceuticals Ltd. 2017. Methadone Injection BP Data Sheet 4 July 2017. URL: (accessed 31 January 2018).