Methadone, a potent opioid agonist, has many characteristics that make it useful for the treatment of pain when continuous opioid analgesia is indicated. Although available for decades, its use has gained renewed interest due to its low cost and potential activity in neuropathic pain syndromes. Unlike morphine, methadone is a racemic mix; one stereoisomer acts as a NMDA receptor antagonist, the other is a mu-agonist opioid. The NMDA mechanism plays an important role in the prevention of opioid tolerance, potentiation of opioid effects, and efficacy for neuropathic pain syndromes, although this latter impression is largely anecdotal.
Any clinician with a Schedule II DEA license can prescribe methadone for pain; a special license is only required to prescribe methadone for the treatment of addiction. In some jurisdictions, it is necessary to apply the words "for pain" on the prescription.
Methadone is highly lipophilic with rapid GI absorption and onset of action. It has a large initial volume of distribution with slow tissue release. Oral bioavailability is high, ~ 80%. Unlike morphine there are no active metabolites; biotransformation to an active drug is not required. The major route of metabolism is hepatic with significant fecal excretion; renal excretion can be enhanced by urine acidification (pH <6.0).
Methadone is a highly lipophilic drug that is rapidly absorbed with extensive tissue distribution.2 Unlike morphine sulfate, methadone has no active metabolites and hepatic metabolism has no significant effect on methadone concentrations, clearance, or clinical disposition.3 It is predominantly excreted in the feces; however, acidification of the urine will increase renal excretion. It has a prolonged and variable elimination phase with a plasma half-life that ranges between 4.2 hours and 190.0 hours, depending on the literature that is reviewed.2,4-6
The mean plasma half-life of methadone is probably 15 to 60 hours,4 though even this range is extremely variable and dependent on single versus multiple dosing, individual adipose stores, and protein binding. This wide variation in half-life contributes to methadone's potential for toxic accumulation and has created difficulty with appropriately and easily dosing this medication.
Methadone has a rapid onset of action, with analgesic effects occurring within 30 to 60 minutes and an analgesic peak between 2.5 and 4.0 hours.
Its oral bioavailability, though variable, generally exceeds 80%. It binds with mu, delta and to a lesser extent kappa opioid receptor sites.
Unlike morphine, no dose adjustment is needed in patients with renal failure since there are no active metabolites. Methadone is available in tablet, liquid and injectable forms; oral preparations can be used rectally. Parenteral routes include IV bolus dosing or continuous infusion.
Unlike morphine, hydromorphone or oxycodone, methadone has an extended terminal half-life, up to 190 hours. This half-life does not match the observed duration of analgesia (6-12 hours) after steady state is reached.
This long half-life can lead to increased risk for sedation and respiratory depression, especially in the elderly or with rapid dose adjustments. Rapid titration guidelines for other opioids do not apply to methadone. An important property of methadone is that its apparent potency, compared to other opioids, varies with the patient's current exposure to other opioids.