The following evidence-based research reports, guidance documents, and other information focus on factors involved in safer prescribing of effective methadone analgesia.

NOTE: All URL links listed below were valid at the time of posting; however, the Internet is constantly changing and some linked sites may move or become inactive with time. Please notify us of any broken links at: [email protected]


NOTE: All methadone-related documents produced exclusively by Pain Treatment Topics have been reviewed and found in compliance and consistent with the latest FDA-approved findings and recommendations.

 CAUTION: Methadone HCl prescribing instructions (PI) were revised in October 2006. When starting opioid-naïve patients on oral methadone the usual induction dose is 2.5 to 10 mg every 8-12 hours, slowly titrated to effect – 30 mg/day maximum. Vigilance is necessary to avoid overdosage, taking into account methadone’s long elimination half-life. (The older PI allowed induction doses of up to 80 mg/day, which could be hazardous.)

Mathematical Model for Methadone Conversion Examined

By: Fudin J, Marcoux MD, Fudin JA. Practical Pain Management. 2012(Sep):46-51.

PDF available here for download:…Mathematical-Model-2012.pdf

Safely converting opioid analgesics to or from methadone can be challenging because of methadone’s long half-life but relatively shorter analgesic action, plus variable pharmacokinetics and individual patient factors. Therefore, methadone levels can build up in the body to toxic levels when starting the medication, or remain in the body longer than expected when switching to other opioids. This paper discusses the shortcomings of various methadone dose-conversion schemes that have been used in the past and presents a new mathematical model that may facilitate greater safety when combined with a slow and careful dose titration. An online conversion calculator also is available for more easily making necessary calculations <See Details Here>.

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Methadone-Drug Interactions to Watch For

PCSS Guidance – Drug Interactions – Methadone/Buprenorphine

From: Physician Clinical Support System (PCSS); E. McCance-Katz, MD, PhD; updated July 2010.

PDF here:

PCSS is a program through which healthcare providers needing information and mentoring on methadone or buprenorphine can connect with experts in the field. This paper, briefly listing drug interactions with methadone or buprenorphine, is based on an examination of the medical literature (unreferenced) and is more current but less extensive than the paper below regarding methadone from Pain Treatment Topics.

 Methadone-Drug* Interactions (*Medications, illicit drugs, & other substances)

By: Stewart B. Leavitt, MA, PhD; from Pain Treatment Topics, January 2006.

PDF available here for download: Methadone-Drug_Intx_2006.pdf (700 KB; 33 pp)

Each year in the U.S. there are innumerable adverse drug reactions, broadly defined as any unexpected, unintended, undesired, or excessive response to a medicine. Such reactions may require discontinuing or changing medication therapy. Furthermore, greater than 2 million of those are serious reactions resulting in hospitalization and/or permanent disability, and there are more than 100,000 deaths annually attributed to reactions involving prescribed medications.

Three-fourths of those adverse reactions relate to drug interactions, which occur when the amount or action of a drug in the body is altered – usually increased or decreased – by the presence of another drug or multiple drugs. Avoiding these can be difficult and, as the tables in this document indicate, there are more than100 substances – medications, illicit drugs, OTC products, etc. – that can interact in some fashion to affect a patient’s response to methadone.

During extensive clinical study and use, oral methadone analgesia has proven to be a well-tolerated medication with minimal adverse reactions when prescribed appropriately. However, potential methadone-drug interactions sometimes can be difficult to predict. Such interactions may be potentially harmful and/or can lead to treatment failures; although, they can usually be avoided or minimized.

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Follow Directions: How to Use Methadone Safely [Outreach Campaign]

From: SAMHSA and FDA; 2009.

See website: Access checked 4/29/09.

The U.S. Department of Health and Human Services (HHS), the Substance Abuse and Mental Health Administration’s (SAMHSA) Center for Substance Abuse Treatment (CSAT) and the Food and Drug Administration (FDA) launched this collaborative public awareness campaign to deliver the message to consumers that methadone is a safe and effective treatment for opioid addiction and pain management when taken as directed. The campaign will educate consumers, healthcare professionals and clinics about how methadone’s complex pharmacology can have life-threatening interactions when taken with other medications or not as prescribed. Available materials include a patient brochure, information sheet, and poster.

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Oral Methadone Dosing for Chronic Pain: A Practitioner’s Guide

By: James D. Toombs, MD; from Pain Treatment Topics, Updated March 2008; reviewed in 2010.

PDF available here for download: OralMethadoneDosing.pdf (364 KB; 12 pp)

Methadone is a good choice for the management of cancer pain and chronic noncancer pain, both as a first line medication and as a replacement opioid. Particular cautions must be observed as methadone’s pharmacokinetics and pharmacodynamics are unique among opioids. Milligram for milligram, methadone is much more powerful than morphine; however, there is significant interindividual variability in the response to methadone. In the initiation of chronic opioid therapy with methadone or the transition from a different opioid, careful day-to-day monitoring is essential. Furthermore, methadone has potential to interact with a large number of medications, and drug-drug interactions must be considered. Finally, compared with other opioids, methadone can offer a very significant cost advantage.

This paper discusses these vital issues and provides guidance for appropriate methadone analgesia dosing in daily clinical practice.

 Also see, the Pain Treatment Topics Opioid Guidelines section at:

Guidelines for the Use of Methadone in Office-Based Management of Chronic Non-Cancer Pain and A Review of the Use of Methadone for Treatment of Chronic Non-Cancer Pain
From: College of Physicians & Surgeons of Nova Scotia, 2006.

Methadone for Pain Guidelines
From: College of Physicians and Surgeons of Ontario, 2004.

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Methadone Safety Handout for Patients (in English and Spanish)

By: Stewart B. Leavitt, MA, PhD; from Pain Treatment Topics, Updated March 2008.

PDF available here for download: MethadoneHandout.pdf (266 KB; 7 pp)

These special 2-page Handouts for patients and their families or caretakers (in English and Spanish) offer vital instructions for treatment compliance and safety. These can be freely copied and provided to patients at the time they receive their methadone prescription from the healthcare provider. They also can be used effectively for one-on-one counseling of patients on the proper use of methadone, and on warning signs of adverse reactions or overdose.

When appropriately prescribed and used, methadone is a safe medication offering effective and economical relief for chronic pain. However, patients must clearly understand that misuse or abuse of this strong opioid can be fatal. Taking extra doses or mixing methadone with alcohol or other drugs can have dire consequences. They also must appreciate the importance of safeguarding the medication from unauthorized access by other persons, children or adults. It should not be casually stored as other medications might be. NOTE: These instructions do not take the place of practioner-provided guidance or the methadone package insert.

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Keeping Patients Safe from Iatrogenic Methadone Overdoses

From: Institute for Safe Medication Practices (ISMP), February 14, 2008.

HTML document at: Access checked 3/1/08.

Methadone has steadily gained popularity as a treatment option for moderate-to-severe chronic pain. It may be ordered by any healthcare provider licensed to prescribe schedule II controlled substances and dispensed by any licensed pharmacy. This article from the ISMP newsletter is of special importance for all practitioners, pharmacists, and nurses. It discusses important qualities of methadone that may result in dosing errors, including potential mistakes in distribution resulting from confusion with similarly named products. It also presents a number of safe-practice recommendations relating to prescribing, dispensing, and administration that can help prevent life-threatening adverse events involving methadone.

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FDA & DEA Public Health Advisories – Methadone Hydrochloride

From: US Food & Drug Administration and the Drug Enforcement Administration.

Methadone Use Pain Control May Result in Death & Life-Threatening Changes in Breathing and Heart Beat

HTML document at: (Access updated 6/1/09)

The FDA in late 2006 released this special Advisory to alert healthcare providers of reported deaths and life-threatening side effects in patients taking methadone. These occurred in patients newly starting methadone for pain control and in patients who were switched to methadone after being treated for pain with other opioid analgesics. Important safety information is provided in this Advisory and practitioners also are directed to read the revised methadone prescribing instructions (PI).

Also see: FDA Methadone Alert: Death, Narcotic Overdose, and Cardiac Arrhythmias [November 2006]

PDF document at:
 (Access updated 6/1/09)

DEA Advisory – Methadone Hydrochloride Tablets USP 40 mg (Dispersible)

As of January 1, 2008, manufacturers of methadone hydrochloride tablets 40 mg (dispersible) have voluntarily agreed to restrict distribution of this formulation to only those facilities authorized for detoxification and maintenance treatment of opioid addiction, and to hospitals. Wholesale distributors will discontinue supplying this formulation to any facility not meeting the above criteria. The 5mg and 10 mg formulations indicated for the treatment of pain will continue to be available to all authorized registrants, including retail pharmacies. The 40 mg strength is not FDA approved for use in the management of pain.

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Revised Methadone Prescribing Information (PI) — October 2006

PDF of PI available here for download: MethadoneTabs_PI_Oct2006.pdf (136 KB; 21 pp)

In October 2006 the package instructions (PI) were revised to include additional “Black Box” warning information. The PI emphasizes that particular vigilance is necessary during treatment initiation, during conversion from one opioid to another, and during dose titration. A high degree of opioid tolerance does not eliminate the possibility of methadone overdose. Deaths have occurred during methadone induction in opioid-naïve patients and during conversion from other opioids to methadone. Prescribers are urged to carefully read the prescribing instructions.

CAUTION: Methadone HCl prescribing instructions (PI) were revised in October 2006. When starting opioid-naïve patients on oral methadone the usual induction dose is 2.5 to 10 mg every 8-12 hours, slowly titrated to effect – 30 mg/day maximum. Vigilance is necessary to avoid overdosage, taking into account methadone’s long elimination half-life. (The older PI allowed induction doses up to 80 mg/day, which could be hazardous.)

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Methadone-Associated Mortality – U.S. Government Reports

From: CSAT (Center for Substance Abuse Treatment), SAMHSA (Substance Abuse and Mental Health
Services Administration), 2004.

A National Assessment of Methadone-Associated Mortality: Background Briefing Report
PDF available here for download: CSAT_Methadone_Briefing.pdf (658 KB; 77 pp)

Methadone-Associated Mortality: Report of a National Assessment
PDF available here for download: CSAT_Methadone_Report.pdf (422 KB; 60 pp)

During 2002 and 2003, articles appeared in prominent newspapers describing methadone as “widely abused and dangerous.” These alarming reports arose from apparent increases in methadone-associated mortality. However, determining methadone’s role in such deaths was complicated by inconsistencies in methods of determining and reporting causes of death, the coinciding presence of other CNS drugs, and the absence of information about the decedent’s antemortem physical or mental condition and level of opioid tolerance.

In response to the concerns, SAMHSA’s Center for Substance Abuse Treatment convened a large multidisciplinary group of experts for a National Assessment of Methadone-Associated Mortality in May 2003. In preparation for this meeting, a “Background Briefing Report” was issued, containing research data and other information to help establish a common understanding of the problem. The findings and recommendations of the assessment group itself were summarized in a “Report of the National Assessment.” Together, the documents, published in 2004, provide a vital source of information regarding methadone, as well as expert analysis of both anecdotal and statistical reports of methadone-associated mortality.

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Methadone Cardiac Concerns

By: Stewart B. Leavitt, MA, PhD; Mori J. Krantz, MD, FACC – Pain Treatment Topics exclusive, from Addiction Treatment Forum, October 2003.

PDF available here for download: Methadone_Cardiac_Concerns.pdf (200 KB; 6 pp)

Some patients with chronic pain may have conditions associated with increased risks of arrhythmia, including: cardiovascular disease, electrolyte imbalances, and prescribed medications or abuse of cardiotoxic substances that may foster cardiac repolarization disturbances. Furthermore, studies of patients in methadone maintenance therapy (MMT) for opioid addiction suggest that in some individuals methadone – alone or, more commonly, in combination with other drugs and/or cardiac risk factors – can prolong the QT interval, which may contribute to the development of the serious arrhythmia torsade de pointes (TdP) in susceptible patients.

Current evidence, however, does not support altering methadone analgesia dosing practices or requiring electrocardiograms (ECGs) for all patients beginning methadone therapy and should not deter the appropriate use of methadone. The relatively small potential risk of adverse cardiac events with methadone should be weighed against the significant benefits of this analgesic. This paper briefly summarizes the published research concerning methadone effects on cardiac repolarization and TdP. Clinical suggestions are offered for identifying individual patient cardiac risk factors and for optimizing cardiac safety during methadone therapy.

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