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Methadone is only used as a third-line opioid for patients with complex pain that is poorly responsive to other opioids, or where these opioids have resulted in intolerable side effects.

• Patient has responded poorly or had intolerable side effects from first and second-line opioids (for example morphine, diamorphine, oxycodone, fentanyl).
• In complex neuropathic pain: if the patient has not responded to first and second-line opioid and adjuvant analgesic combinations.
• In end-stage chronic kidney disease (eGFR less than 30ml/min).

Adjuvant methadone may also be used for the above indications under specialist supervision.

Methadone should always be used with caution but particularly in the following situations.

• Methadone has a long and unpredictable half-life which can lead to side effects/severe opioid toxicity without a change in the regular dose, particularly when methadone is started for the first time – careful monitoring is needed.
• Patients with incident pain or unstable pain where repeated doses of methadone may accumulate and cause opioid toxicity.
• Pain suspected to have a strong psychological component as repeated demands for as needed doses of methadone may lead to opioid toxicity.

Drug interactions:

• Hepatic methadone metabolism varies considerably between individuals and this variability is responsible for the large differences in methadone clearance and the doses needed to manage pain. 
• QTMethadone levels may increase if given with fluoxetine, sertraline, clarithromycin, ciprofloxacin, fluconazole. Methadone should not be given with monoamine oxidase inhibitors (for example phenelzine and linezolid) or within 2 weeks of stopping them.
• Methadone levels may decrease if given with phenytoin, phenobarbital, carbamazepine, St John’s Wort.
• Concurrent administration with medications that affect methadone metabolism via the hepatic cytochrome P450 system (CYP3A4) – refer to British National Formulary (BNF). Methadone can cause QT prolongation – caution with other drugs that may have this effect, for example QTclarithromycin, amitriptyline, QTcitalopram, QTdomperidone, prochlorperazine, QThaloperidol, QTamiodarone. Refer to BNF.

Liver impairment: Reduced clearance. Dose reduction may be necessary.

Renal impairment: No dose reduction necessary. Not significantly removed by dialysis.

Side effects

• Patient may become unexpectedly drowsy or develop respiratory depression particularly when first starting methadone – refer to cautions above.
• Side effects that are common to all opioids, including dry mouth, constipation may be less common.

• Patients starting methadone will usually require inpatient admission for 5 to 7 days. A stable methadone dose for 48 to 72 hours before discharge is needed.  
• Methadone may occasionally be started safely as an adjuvant analgesic for selected patients in the community. The palliative care specialist will recommend an individual dosing regimen and discuss and review the management plan with the patient’s GP.
• Methadone is usually given twice daily (occasionally three times daily). 
• A shorter acting opioid than methadone is often used for breakthrough pain in patients on a stable methadone dose. 
• The methadone dose and the timing of doses should not be changed without instructions from a palliative medicine specialist.

Discontinuing methadone: Seek specialist advice.

This may be needed if treatment is ineffective, the patient is experiencing side effects, is unable to take oral medication or is in the last days of life.

• Undertake an individual risk assessment prior to initiating methadone. Consider if drug diversion/misuse is likely and if weekly/twice weekly dispensing from a community pharmacy is required.
• Discuss the methadone prescription with the GP and provide written information.
• Ensure the GP is aware which methadone preparation should be prescribed if the patient is receiving methadone liquid.
• Ensure the patient is reviewed by a member of the specialist palliative care team as soon as possible after discharge (within 2 to 3 days).
• Discuss the prescription with community pharmacy and explain methadone has been prescribed for pain management not drug dependency.