Methadone – a complex tool for pain management

Methadone is a valuable tool for patients with chronic benign pain, but it is a medication with a complex pharmacology and potential dangers in prescribing. It is often used for patients who require a long acting pain medication when they have failed or have side effects with long acting morphine or as an alternative to long acting oxycodone.

Methadone Pharmacology

Methadone is rapidly absorbed by oral or rectal administration and is 80% bioavailable. The peak effect is in 3-4 hours, but methadone is very lipophilic and is quickly and widely distributed, then slowly released from tissue stores. Methadone has variable protein binding with a fourfold variation among patients. Methadone is metabolized by the liver, again with significant variation among patients. The result is the elimination half-life varies from 5-130 hours with a mean of about 20-35 hours. Methadone takes 4-10 days to achieve steady state. Because of the variable half-life and metabolism, methadone should be prescribed at low initial doses and the dose should not be increased any sooner than every 5-7 days.

Methadone is affected by a cytochrome P450 metabolism. Cytochrome P450 inducers will increase methadone metabolism and decrease blood levels. Common examples include rifampin, several anticonvulsant medications, spironolactone, St. John’s Wort, and several anti-retroviral medications. Cytochrome P450 inhibitors decrease methadone metabolism and increase blood levels. Common medications in this list include azole antifungals, many antidepressants, and several antibiotics. Many of these medications may commonly be co-administered with methadone and we need to be cautious of unintentional increases in blood levels.


Cytochrome P450 enzyme inducers:

Increase metabolism and may decrease blood levels


Phenobarbital, phenytoin, carbamazepine


St John’s Wort

Nevirapine, efavirenz, amprenavir, nelfinivir, ritonavir

Cytochrome P450 enzyme inhibitors:

Decrease metabolism and may increase blood levels

Fluconazole, ketoconazole, itraconazole

Fluoxetine, paroxetine, sertraline, citalopram, fluvoxamine

Amitriptyline, desipramine


Erythromycin, clarithromycin

When to Use Methadone

Methadone may be used when a patient has a true morphine allergy (not just itching). It is generally safe with renal impairment. It is valuable for neuropathic pain or pain refractory to other opioids. It is inexpensive for patients with higher drug copays.

Methadone is contraindicated in patients with a long QT interval and it should be avoided in patients taking any medication that may increase the QT interval. It should be avoided in patients with a history of syncope or arrhythmias. It should not be used in patients with poor cognition, those who are unreliable, or who have problems with compliance or adherence to pain plans. A baseline and annual EKG should be done on patients on methadone.

Conversion to Methadone

Methadone should be dosed every 8 to 12 hours with a roughly equal milligram amount per dose. Conversion to methadone from other long acting narcotics is non-linear and can be very tricky. It is best to be conservative and to titrate the dose very slowly – do not increase faster than every 5-7 days. The biggest mistake in beginning methadone is to prescribe too high a starting dose and to increase the dose too fast. The initial dose of methadone is at most 25% of the equivalent morphine dose and should be decreased in a non-linear fashion as the MED increases (see table below). Methadone tablets are small and it is important to educate your patients that the medication is potent and builds up in their body. It has to be taken exactly as recommended and not taken PRN or ahead of your dosing schedule. The following is a quick estimate followed by a chart of methadone conversion examples.

Quick estimate:

Less than 100 mg morphine equivalent dose (MED):                give 25%

100 to 300 MED:                                                                         give 15%

300 to 600 MED:                                                                         give 10%

Over 600 MED:                                                                           give   5%


Current MED Healthy Adult < 70 years of age Frail or > 70 years of age
Opioid naïve 2.5 mg every 8 hours 2.5 mg once daily
30-90 mg daily 25% (60 mg morphine = 15 mg methadone

5 mg TID

2.5 mg TID
90-300 mg daily 15% (200 mg morphine = 30 mg methadone)

10 mg TID

5 mg TID
300-1000 mg daily 10% (450 mg morphine = 45 mg methadone)

15 mg TID

7.5 mg TID
Over 1000 mg daily 5% (1200 mg morphine = 60 mg methadone)

20 mg TID

10 mg TID

Jim Cotter, MD

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