Methadone

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Methadone is an opioid and NMDA-receptor blocker that is often useful in patients with terminal illnesses, especially those who have pain with a neuropathic component that has been refractory to other opioids and adjuvants. Small doses (e.g. 10mg of daily methadone) can sometimes bring about improvement in pain, even when large doses of other opioids are being used concurently.

Methadone has unusual pharmacokinetics with a very long half-life of days and toxicity can occur unexpectedly after a week or more of an apparently well tolerated dose regimen.

Methadone is safe to use in renal failure.

Indications

Pain refractory to other treatment, especially pain associated with a neuropathic component, opioid-tolerance or central sensitisation.

Pharmacokinetics

The oral to subcutaneous equivalence of methadone varies markedly amongst patients. A 2:1 ratio is relatively commonly used (e.g. 10mg oral ≈ 5mg SC).

Metabolism of methadone is via the cytochrome P450 pathways, including CYP3A4 and CYP2B6, in the liver to inactive metabolites.

Methadone is safe in renal failure and does not need specific dose reductions, although some texts suggest a 50% dose reduction.

The peak concentration of methadone in the plasma is 4 hours post administration and the half-life of methadone is highly variable, ranging from a few hours to many days, but in most patients is around 16-24 hours.

Pharmacodynamics

Mechanism of Action

Methadone acts on multiple receptors to bring about analgesia, including

  • Mu opioid receptor agonist
  • NMDA-receptor blocker
  • Serotonin re-uptake blockade

Duration of action of methadone is often up to or more than 12 hours post intake.

Adverse Drug Reactions

  • Sedation
  • Respiratory depression
  • Arrhythmias associated with QT prolongation
  • Constipation
  • Nausea

Methadone has been associated with arrhythmias and therefore caution should be used in patients with:

  • Previous arrhythmias
  • Prolonged QTc > 0.5

Dosing and Route of Administration

There are two common ways methadone is used in palliative care. Firstly in small doses as a second adjuvant agent in addition to a primary opioid. And secondly as the sole opioid in place of another opioid.

There is no clear equivalence between morphine and methadone. A single one-off dose of methadone is about half as potent as a single-one off dose of morphine, but because methadone accumulates over days (due to, for example, it's long half-life) and because it has multiple mechanisms of action, there is no clearly defined dosing equivalence for other opioids. In patients who are rotated from one opioid (e.g. morphine) to methadone, the methadone dose is often markedly lower than the previous dose of opioid (e.g. a patient on 100mg of morphine daily may end up on only 10mg of methadone despite).

Methadone tends to be less well tolerated than morphine on average with more patients ceasing methadone than morphine due to adverse effects in studies.

A reasonably safe approach to methadone is:

Methadone 5mg at night initially

Titrate up to 5mg twice daily after 5-7 days if needed and no significant adverse effects 

Titrate up gradually every 5-7 days if needed

A typical upper end dose is 20mg twice daily, although there is no theoretical reason why higher doses cannot be used

In patients who are on another opioid and where methadone is added as an adjuvant and brings about good analgesia, consideration should be given to gradually tapering the dose of the initial opioid.

Prior to commencing methadone, an ECG should generally be performed to exclude a prolonged QT interval which would indicate that the patient is at an increased risk of a serious ventricular arrhythmia. A repeat ECG should occur 1-2 weeks after commencing methadone and 1-2 weeks after any dose increment. If a prolonged QT interval develops, then cessation of methadone should be considered.

Routes of administration for methadone include:

  • Oral (once or twice daily)
  • Subcutaneous (once or twice daily)
  • Continuous subcutaneous infusion

In addition to regular doses of methadone, PRN doses can also be given but caution is required given methadone's ability to accumulate. 4-hourly PRN is an appropriate as the time to peak plasma concentration is 4 hours.

Compatibilities in a CSCI

The following combinations have been described as safe in a continuous subcutaneous infusion:

Dual opioid combinations
Methadone + Diluent
Morphine + Haloperidol + Midazolam Water
Hyoscine butylbromide Water
Hyoscine butylbromide + Midazolam Water
Levomepromazine + Hyoscine butylbromide Water
Metoclopramide Water
Midazolam & Water
Metoclopramide + Ranitidine @ Water
Oxycodone + Haloperidol + Midaolam Water
Levomepromazine + Midazolam Water
Midazolam Water
Ketorolac Saline
Alfentanil + Metoclopramide + Ranitidine @ Water
Haloperidol + Midazolam Water
Ketamine & Water
Levomepromazine + Hyoscine hydrobutylbromide Water
Midazolam + Ketamine Water
& Use caution as this combination is basde on reported experience with a 5th drug
@ Add ranitidine last once all the other drugs and diluent have been combined
Table: Dual Opioid Compatibilities

For methadone combined with other opioids see: Dual Opioid Compatibilities Table

Methadone 2 drug compatibilities
Diluent
Methadone + Cyclizine Water
Haloperidol Water
Ketamine Water or Saline
Levomepromazine Water
Midazolam Water
Table: Methadone Compatibilities
Methadone 3 drug combinations
Diluent
Methadone + Haloperidol + Ketamine Water or Saline
Midazolam Water
Hyoscine butylbromide + Ranitidine @ Saline
Ketamine + Midazolam Water
Levomepromazine + Hyoscine butylbromide Water
Midazolam ~ Water
Metoclopramide + Midazolam Water
Ranitidine @ Water
@ Add ranitidine last once all the other drugs and diluent have been combined
~ Precipitation reported with doses of methadone greather than 40mg
Table:Methadone compatibilities
Methadone 4 drug compatibilities
Diluent
Methadone + Haloperidol + Ranitidine + Hyoscine butylbromide Saline
Levomepromazine + Midazolam + Hyoscine butylbromide Saline
Table: Methadone compatibilities

Drug Interactions

Due to methadone's metabolism by the cytochrome P450 pathway, there are many possible interactions with other drugs.

Methadone levels are increased by:

  • Various SSRIs
  • Various anti-fungals

Metahdone levels are decreased by:

  • Various anti-convulsants
  • Various anti-retroviral agents

Author

Graham Llewellyn Grove