“Methadone”, the 3-syllable word that still brings most patients and some providers shudders of anxiety. However, when used appropriately, methadone can be a wonderful pain tool in your symptom management arsenal.
Here are some quick facts to ease your thoughts on methadone, as well as to assist with prescribing:
Synthetic opioid antagonist that inhibits the re-uptake of serotonin and norepinephrine (same mechanism of action for as antidepressants that are used to treat pain).
Antagonist at the N-methyl-D-asparate (NMDA) (prevents central sensitization and reduces opioid tolerance, as well as increases its effectiveness in treating neuropathic pain as compared to other opioids) (McPherson, 2010).
Routes of dosage include oral, rectal, intravenous (IV), intramuscular (IM – not recommended!), subcutaneous (SQ), epidural, and intrathecal (spinal administration is not FDA approved).
Primarily lipophilic (fat-soluble), detected in blood 15-45 minutes after oral administration with peak plasma concentrations achieved in 2.5-4 hours
Bioavailability 70-80% (McPherson, 2010).
Due to its highly fat-soluble nature, methadone is widely and quickly distributed to the brain, gut, kidneys, liver, muscles, and lungs. During redistribution and elimination, it is slowly released from these tissues back into the plasma; therefore, it has a very long and erratic half-life (time it takes the body to eliminate half the drug). In addition to being fat-soluble, it also variably binds to albumin and globulin which increases its variability on how each patient responds so differently to methadone. In other words, because each patient has a different build, muscle mass, and fat percentage it makes it unpredictable. (McPherson, 2010).
According to the Food and Drug Administration (2010), the elimination half-life (8-59 hours) is significantly longer than its duration of analgesic action (4-8 hours).
Metabolism takes place primarily in the liver, with additional metabolizing also being completed in the gut. The metabolite is then excreted in the urine and feces.
It is extensively metabolized into pharmacologically inactive metabolites. Again, the rate at which this is done is widely variable from patient to patient.
Cytochrome P450 (CYP450) are the enzymes responsible for metabolism and these enzymes are also influenced by other medications; therefore, the rate of metabolism is again widely variable from patient to patient depending on his or her medication regimen.
Elimination half-life ranges from 5-130 hours with a mean average of 20-35 hours. Due to this long half-life, methadone can result in toxicity due to accumulation in the body. Steady state (rate of drug in=rate of drug out) can take 4-10 days, therefore titration upward or addition of other routine medications should be done sparingly or conservatively prior to 4 days on current dose.
Caution advised in patients with QTc 450-500.
Methadone is contraindicated in patients with a QTc >500.
Be aware of interactions between methadone and other medications that also have QT interval prolonging properties.
Advantages of Methadone
Inexpensive option compared to other opioid pain therapies
Very effective in relieving chronic pain
Effectively treats neuropathic pain
Available in tablet or liquid form – both long-acting
**Methadone is the only long-acting elixir**
Been shown to have lower incidence of constipation
Disadvantages of Methadone
Associated stigma associated with “methadone clinics” and heroin addiction
Largely variable dosing among patients
Long half-life which makes titration difficult and a longer process, when compared to other opioids (takes 4-10 days to reach steady state)
Complicated equianalgesic conversion
Given all the information discussed, it’s easy to see how methadone could greatly help certain patients; while it’s equally apparent that methadone therapy is not appropriate for everyone! For example, patients with significant renal impairment, unrelieved neuropathic or other pain, limited income or inability to pay for medications, or those who need long-acting regimens but can’t swallow – methadone might be a worth a try. However, for those with very short prognosis, unknown or elevated QTc, history of syncope or arrythmias, or decreased cognition or ability to communicate – this would not be a good mediation option.
• Burns, E. (n.d.). Drugs causing QT prolongation. Retrieved from https://lifeinthefastlane.com/ecg-library/basics/qt-prolongation-drugs/
• Fleming, T. (2004). Drug topic red book (108th ed.). Montvale, NJ: Thomson Healthcare.
• McPherson, M. (2010). Demystifying opioid conversion calculations: A guide for effective dosing. American Society of Health-System Pharmacists: Bethesda, MD.
• Manfredonia, J. (2005, March). Prescribing methadone for pain management in end-of-life care The Journal of the American Osteopathic Association, 105, 18S-21S.
• U.S. Food and Drug Administration. (2013, August 23). Information for healthcare professionals methadone hydrochloride text version. Retrieved from https://www.fda.gov/Drugs/DrugSafety/ucm142841.html
• Vieweg, W., Lipps, W., and Fernandez, A. (2005). Opioids and methadone equivalents for clinicians. The Primary Care Companion to the Journal of Clinical Psychiatry, 7(3), 86-88.