Methadone (Methadose)

Methadone (Trade name: Methadose) is a synthetic mu-opioid agonist, similar to morphine. Methadone is used in the treatment opioid use disorder, but prolonged use of methadone itself can also result in dependence.

Pharmacokinetics of Methadone

Absorption Well absorbed following oral administration. The bioavailability of methadone ranges between 36 to 100%.
Distribution 1 to 8 L (mostly in plasma and blood)
Metabolism Hepatic, via cytochrome P450 enzymes
Elimination Excreted mainly in the urine
Half-life 25 hours

Methadone: Cytochrome P450 Metabolism

Substrate of (Metabolized by) 3A4, 2B6, and 2C19
(lesser extent by CYP2C9 and CYP2D6)
Induces -
Inhibits -
  • Methadone is a mu-opioid agonist with multiple actions that are qualitatively very similar to morphine.
  • Methadone also acts like an SSRI in that it also is also a serotonin transporter (SERT) inhibitor.
  • Opioid use disorder
    • This is the most common indication for methadone, and has been a mainstay of treatment of this disorder.
  • Chronic pain
    • In patients using methadone for treatment of chronic pain, the methadone dose can be split into a BID dose for better pain control
  • Chronic cough
    • Methadone has depressant action on the cough center and can be given to control intractable cough associated with terminal lung cancer.

Suboxone (buprenorphine/naloxone) has the following advantages over methadone:

  • Safer in overdose (due to its partial-agonist activity)
  • Faster in stabilization (less than a week), compared to methadone which is titrated more slowly due to its long half-life
  • Causes a milder withdrawal syndrome (due to its partial-agonist activity)
  • Is comparable to methadone at daily doses >16mg
  • Lower side effect profile
  • Lower likelihood of QTc-prolongation
  • Less sexual side effects and less drug-drug interactions
  • Better performance on cognitive, psychomotor and driving tests
  • More flexible dosing (can give take home doses earlier)
  • Less stigma

Dosing for Methadone

  • Methadone comes in oral tablet and liquid formulations.

Avoid Prescribing Benzodiazepines!

The concomitant use of opioids with benzodiazepines or other central nervous system depressants such as alcohol can cause profound sedation, respiratory depression, coma, and even death.
  • Do not co-prescribe with naltrexone, as this will trigger opioid withdrawal.
  • Be very careful about co-prescribing with benzodiazepines.

Methadone is also a Serotonin Reuptake Inhibitor!

Although it is classified as an opioid, many people forget that methadone is also a serotonin re-uptake inhibitor that specifically inhibits serotonin transporter (SERT). This means it can cause serotonin syndrome if co-prescribed with other serotonergic medications!
  • Methadone is a CYP 3A4 substrate, this means inhibitors of CYP3A4, such as azole antifungal agents (e.g. - ketoconazole), macrolide antibiotics (e.g. - erythromycin), selective serotonin reuptake inhibitors (specifically fluvoxamine, which is a potent 3A4 inhibitor) can increase methadone plasma levels and result in increased opioid effects or toxicity.
  • Sedation, drowsiness, constipation
  • Avoid highly serotonergic SSRIs such as citalopram and escitalopram (instead use sertraline, fluoxetine, or venlafaxine)
  • The dosing for older adults should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, concomitant disease or other drug therapy.
  • In the second and third trimester of pregnancy, women will have increased weight and blood volume and may need an increase in methadone dose.
  • If tapering methadone during pregnancy, the risk for relapse in opioid use disorder is high.

Opioid Use Disorder Guidelines

Guideline Location Year PDF Website
Canadian Medical Association Journal (CMAJ) Canada 2018 - Link
BC Centre on Substance Use (BCCSU) Canada 2023 Link Link
META:PHI Canada 2019 Link Link
Canadian Guidelines on Opioid Use Disorder Among Older Adults Canada 2020 PDF Link
National Institute for Health and Care Excellence (NICE) UK 2007 - Link
American Psychiatric Association USA 2006, 2007 - Guideline (2006)
Guideline Watch (2007)
Quick Reference