Methadone (Methadose)

• 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

• Methadone comes in oral tablet and liquid formulations.

• Do not co-prescribe with naltrexone, as this will trigger opioid withdrawal.
• Be very careful about co-prescribing with benzodiazepines.

• 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

• QTc prolongation
• Serotonin syndrome (if combined with other serotonergic drugs)

• 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.

• Kumai, M., Maeda, Y., Miura, M., Tsuruga, K., Yamada, T., Takekuma, Y., & Sugawara, M. (2020). Serotonin syndrome developing immediately after the initiation of low-dose methadone therapy: a case report. Case reports in oncology, 13(1), 281-284.