Background Methadone is an effective opioid analgesic for severe pain.  Because of low cost (a month’s supply may be US $5-10) and apparent efficacy in complex pain syndromes such as cancer-related pain, it is increasingly used as a first-line opioid. Retrospective analyses of consecutive patients initiated on methadone in an outpatient palliative care clinic confirm its effectiveness and safety (1). It is, in effect, a combination drug – part opioid and part NMDA receptor antagonist – although there is yet to be convincing evidence from controlled trials that it is a clearly superior first-line analgesic to other opioids.  Methods of dose conversion to methadone from other opioid analgesics that account for its dual action are discussed in Fast Fact #75. This Fast Fact will describe strategies for beginning methadone when the patient has not been taking a strong opioid.  Note: due to its complex pharmacology, clinicians are advised to seek consultation prior to initiating therapy (see Fast Fact #171).

Pharmacology    Methadone is lipophilic, thus it takes time to develop tissue stores that maintain serum levels. There is enormous interindividual variation in how long this takes.  After a single dose there is a short distribution phase (associated with acute pain relief) with a half-life of 2-3 hours and a slow elimination phase (half-life 15-60 hours). Predominantly it is prescribed as a long-acting, scheduled opioid.  Dosing must account for the accumulation of drug over days.  It is this accumulation that accounts for most therapeutic misadventures, in fact dose titration is not recommended for at least 4-7 days.  Liver metabolites are inactive; therefore, no dose reduction is required with renal failure.  After steady-state is reached, about two-thirds of patients will get adequate pain relief with twice a day dosing. Some may require three times a day dosing. Increasingly, some clinicians are even prescribing methadone once a day for patients who are older or have cognitive frailty. The smallest tablet of methadone is 5 mg, but unlike most other long-acting opioids, it is copasetic to cut methadone in half and initiate at 2.5 mg if desired. It can be made available at doses smaller than 2.5 (e.g., even 1 mg) via a solution. Note: several drugs will alter methadone metabolism, so there needs to be close follow-up to drug interactions.  Close collaboration with a clinical pharmacist is recommended. 

There are several approaches to starting methadone for the treatment of pain. All consider the long half-life of the drug that leads to drug accumulation over days.

I. Conservative approach:  This is the much more commonly used approach.

1. Begin fixed dose methadone 2.5 or 5mg orally twice or three times a day for 4-7 days. Of note – for older or cognitively frail patients, consider once a day dosing to begin.
2. If incomplete pain relief, increase the dose by 50% and continue for 4-7 days. 
3. Continue increasing dose every 4-7 days until stable pain relief achieved.
4. Breakthrough pain: use an alternative short acting oral opioid with short half-life (e.g. morphine 10 mg) every 1 h PRN for breakthrough pain and to provide pain relief during titration phase.  This dose too may need to be titrated based on efficacy.

II.  Loading dose approach: This is a riskier method in that drug accumulation can occur and lead to opioid toxicity.  In general, this approach is reserved for comfort care/hospice patients with a short prognosis.

1. Load: Start oral methadone as an as needed short acting opioid in response to pain flares. For example, 5 mg) every 4 hours PRN only.
2. Calculate maintenance: On day 8, calculate the total methadone dosage over the last 24-hour period and give that in scheduled, divided doses bid or tid.  Give 10% of total daily methadone as PRN drug q 3 hours for breakthrough pain.  Instruct the patient, family, or hospice team to call you if they need to use more than 5 breakthrough doses per day.  Example:  if someone took a total of 45 mg methadone on day 7 they would be converted to 15 mg tid scheduled with 5 mg q3 hours prn dose.

Cardiac safety    Due to methadone’s potential to prolong the QTc interval, an independent expert panel developed cardiac safety recommendations for clinicians (4). Of note, for patients with a short prognosis (e.g., less than 2 months) and comfort goals of care, the rationale for ECG monitoring is less sound. 

1. Clinicians should inform patients for the potential risk for arrhythmia before initiating methadone.
2. Clinicians should ask about any history of structural heart disease, arrhythmia or syncope.
3. Clinicians should obtain a pretreatment ECG to measure the QTc interval as well as a follow up ECG within 30 days, annually, for major dose increases, and/or if the dosage exceeds 100 mg/day or an unexplained syncopal event occurs.
4. If the QTc > 500 ms, consider discontinuing methadone, reducing the dose, or eliminating cofactors which may raise the QTc unless prognosis is short (i.e. weeks to months).  If the QTc is between 450 ms to 500 ms, the clinician should discuss the risks and benefits with the patient.
5. Clinicians should be aware of drug interactions with methadone which could slow its metabolism or prolong the QTc even more.

References:   

1. Parsons, Henrique A., et al. “Methadone initiation and rotation in the outpatient setting for patients with cancer pain.” Cancer 116.2 (2010): 520-528.
2. Bruera E, Sweeney C. Methadone use in cancer patients with pain: a review. J Pall Med. 2002; 5:127-138.
3. Bruera E, et al.  Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind Study.  J Clin Oncol.  2004; 22:185-92. 
4. Krantz, Mori J., et al. “QTc interval screening in methadone treatment.” Annals of Internal Medicine 150.6 (2009): 387-395.
5. Palat G, Chary S.  Practical guide for using methadone in pain and palliative care practice. Indian J Palliat Care 2018; 24:S21-S29.

Version History:  This Fast Fact was originally edited by David E Weissman MD. 2nd Edition was edited by Drew A Rosielle and published October 2007; 3rd Edition June 2015; 4th Edition May 2025. 
Conflicts of Interest: None to report.