Methadone

Class: analgesic – opioid agonist; NMDA antagonist

Indications (NB some may be unlicensed): step 3 in the WHO analgesic ladder, opioid dependence; moderate to severe pain; intractable cough in palliative care

Contraindications/cautions: may accumulate as long half life; individually variable half life; history of cardiac conduction abnormalities

Adverse reactions: see morphine but less drowsiness, nausea, vomiting and constipation; dry mouth. Has a long and variable half life so watch for signs of accumulation e.g. decreased respiratory rate or mental status (particularly in the elderly). QT-interval prolongation

Metabolism/clearance: metabolised by metabolising enzyme CYP3A mainly in the liver. Demethylation is the major route of metabolism and metabolites are excreted by the kidney

Interactions:

• increased clinical effect/toxicity of methadone (due to increased blood concentrations) may occur with some CYP metabolising enzyme inhibitors (see above) e.g. aprepitant, clarithromycin, grapefruit juice, indinavir, itraconazole, ketoconazole, nelfinavir, ritonavir, telapravir, voriconazole
• decreased clinical effect/toxicity of methadone (due to decreased blood concentrations) may occur with some CYP metabolising enzyme inducers (see above) e.g. carbamazepine, phenobarbitone, phenytoin, rifampicin, St John’s wort
• additive CNS effects (including respiratory depression) with other CNS depressants e.g. benzodiazepines (e.g. lorazepam), phenothiazines (e.g. chlorpromazine), tricyclic antidepressants (e.g. amitriptyline), other opioids, alcohol
• additive increased risk of QT interval prolongation (cardiac adverse effect which may lead to arrhythmias) with other drugs that prolong it

Syringe driver: seesyringe driver compatibility chart

Mechanism of action: stimulates opioid receptors in the CNS and gastrointestinal tract and also thought to act at the NMDA receptor

Onset: 0.5 to 1 hour initially

Duration: 6 to 8 hours initially then 22 to 48 hours on repeat dosing

Notes:

• may be useful in opioid rotation
• dose conversion ratios from other opioids is variable as individuals have differing methadone half lives and the ratio varies with dose (see next page)
• as affects NMDA receptors may prevent ‘wind up’ (rapidly escalating doses) on long term use and is useful in neuropathic pain
• renal and hepatic impairment are rarely a problem
• subcutaneous injection/infusion may be irritant – may need larger volume syringe
• some centres use low dose methadone alongside other opioids as adjuvant pain relief
• in opioid naïve patients starting doses are usually 2.5 to 5 mg twice a day with 3 hourly prn breakthrough doses, usually of another opioid. Titrate dose weekly

Conversion to methadone[1] Table 2: Suggested safe and effective starting doses when changing patients from oral morphine to oral methadone