Methadone is a strong opioid analgesic, with several non-opiate actions. It differs from morphine/diamorphine in a number of ways:

• δ-opioid receptor agonist
• NMDA receptor antagonist[1]
• serotonin re-uptake inhibitor[2]
• long and variable elimination half-life
• potential for numerous and complex drug interactions
• inactive metabolites (lower toxicity in renal failure)

The first three of these actions may help account for reports of its effectiveness in managing neuropathic pain.[3]

The pharmacology of methadone is complex and very variable, so it must be used with the utmost care and supervision. The commonest mistake in its use is to underestimate its duration of action, since up to 10 days may be required to reach steady state plasma levels. The greatest tendency to accumulate the drug is in the elderly or those with liver failure.

Drug interactions

Methadone metabolism is increased by a number of other drugs, which can cause opiate withdrawal symptoms when started in a patient on regular methadone. Other interactions which inhibit metabolism can lead to overdose and toxicity:

Subcutaneous Methadone

Subcutaneous methadone has been used but there is a problem with skin reactions, partly because methadone in solution is acid. If necessary to use, dilute as much as possible; hyaluronidase may also be added. In conversion of oral to subcutaneous or intravenous dosing, use a daily parenteral dose that is half the oral dose.[4]

Use of methadone

Indications

• Pain only partially responsive to morphine e.g. inflammatory, ischaemic or neuropathic pain.
• Alternative opioid when side effects develop with morphine (or other opioid).
• Renal failure
• Morphine tolerance - patients requiring ever increasing doses of opioids with no overall improvement in pain.
• Use with especial caution in the elderly, COPD or asthma.

Guidelines for use

Methadone's efficacy compared to morphine increases with chronic dosing and with higher dose. This is in part due to a long elimination half-life, and in part due to its non-opioid action. The dose ratio of methadone to morphine is inversely proportional to the daily morphine dose. Many studies have shown the difficulty in converting doses from another opioid to methadone or vice versa. At least two guidelines have been published.

Guidelines (A) are most commonly used in the UK, and are recommended for general use, and especially for patients switching opioid because of lack of effect. Guidelines (B) may be helpful for use in patients who have exhibited opioid toxicity.

Guidelines (A) for use of methadone[4]

• Stop all other strong opioids.
• Give fixed doses of methadone PO calculated as one-tenth of the 24h oral morphine dose (or equivalent), to a maximum of methadone 30mg.
• The fixed dose is taken as needed, but not more frequently than every 3h.
• On day 6, add the total dose of methadone given in last 48h, divide by 4, and give at 12-hourly intervals.
• Subsequent dose changes are by percentage increments as for morphine.
• Re-assess carefully as accumulation can occur up to 10 days after.

Guidelines (B) for use of methadone[5]

• Stop all other strong opioids.
• Give methadone at fixed intervals, every 8 hours:

• 10% dose of the daily methadone dose may be used for breakthrough pain.
• Re-assess carefully as accumulation can occur up to 10 days after.