In recent years the safety of methadone has been questioned by data indicating a large rise in the number of methadone-associated overdose deaths occurring at the same time as a marked increase in methadone use to treat chronic pain.
Between 2008 and 2011, several medical groups issued methadone safety guidelines to address the increased mortality. Published in BMJ Supportive & Palliative Care, Annals of Internal Medicine, and Journal of Addictive Diseases, these guidelines focused on preventing cardiac arrhythmias. None addressed other methadone safety issues; nor did they grade the strength of their recommendations or the quality of the evidence.
The American Pain Society and the College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society, commissioned a 16-member interdisciplinary expert panel to address these shortcomings. The panel’s careful review of the evidence led to specific guidelines for methadone use for treating opioid addiction in licensed opioid treatment programs, and for treating chronic pain in primary care or specialty settings. The Journal of Pain published the guidelines in April.
The new guidelines focus on promoting patient safety and mitigating avoidable harms. They include patient risk assessment, patient education and counseling, selective use of electrocardiography, dose initiation and titration, diligent monitoring and follow-up, and medication interactions.
Zeroing in on the risk of respiratory depression, a major cause of methadone-associated deaths, the panel stressed safety issues—low initial methadone doses, careful titration, and the use of alternative opioids for selected patients. Panelists concluded that the safe use of methadone “requires clinical skills and knowledge to mitigate potential risks, including serious risks related to overdose and cardiac arrhythmias.”
Methadone-Associated Deaths: Overdoses or Arrhythmias?
The panel noted factors that make it difficult to identify the cause of methadone-associated deaths, among them prescribed vs. illicit methadone use, concurrent use of other medications or substances, and uncertainty about links between increased methadone prescribing and a rise in the death rate. In the vast majority of cases, the panel could not determine whether death was due to “respiratory depression related to overdose, or to other factors, such as arrhythmia.”
The characteristics of methadone present special challenges. Methadone has a long and variable half-life, and can interact with many medications. It is difficult to adjust methadone dosages safely when switching patients from a different opioid. Methadone is associated with a prolonged QTc interval, “which may predispose patients to the ventricular arrhythmia known as torsades de pointes [TdP].” Also, “the proportion of methadone-associated deaths related to arrhythmia is likely to be small relative to the proportion related to accidental overdose,” the panelists found.
The panel gave each recommendation a separate grade for the strength of the recommendation and the quality of the evidence. This Addiction Treatment Forum article includes only the strong recommendations. The published guidelines include additional recommendations and practice advice. The table below describes the grading system.
| Strength of Recommendation | Quality of Evidence |
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Strong: The panel believes that the potential benefits of following the recommendation “clearly outweigh potential harms and burdens” (or vice versa); most clinicians and patients would choose to follow a strong recommendation.
Weak: Benefits outweigh potential harms and burdens (or vice versa), “but the balance of benefits to harms is smaller or evidence is weaker.” Clinical circumstances or patient preferences could affect the decision.
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The type, number, size, and quality of studies, strengths of associations, and comparative consistency of results determine the quality of the evidence that supports a recommendation.
High: A low probability exists that new evidence would affect the recommendation.
Low: A high probability exists that new evidence would affect the recommendation.
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Because of a lack of published evidence-based studies on methadone safety, panelists were obliged to base their recommendations on what they had—evidence they considered to be of generally low quality. Panelists reviewed more than 3,700 abstracts and 168 primary studies, solicited input from more than 20 external peer reviewers, and eliminated the lowest-ranked recommendations. All of the approved recommendations received unanimous or near-unanimous consensus. In contrast, as the authors point out, two of guidelines published earlier “were not fully endorsed by a professional society or government entity, and the third was endorsed by the Substance Abuse and Mental Health Services Administration.”
The following provides highlights of this panel’s recommendations for adult patients.
Patient Assessment and Selection – When considering methadone treatment, perform an individualized medical and behavioral risk-and-benefits evaluation (low-quality evidence).
Patient Education and Counseling – Before prescribing methadone, educate and counsel patients about the indications for treatment, goals of therapy, availability of other therapies, ongoing management, and other factors (low-quality evidence).
Baseline Electrocardiograms – On the controversial key topic of baseline ECGs, the panel has two strong recommendations, both based on low-quality evidence.
- Obtain an ECG before starting methadone in patients with risk factors for QTc interval prolongation, any previous ECG showing a QTc > 450 ms, or a history suggesting previous ventricular arrhythmia. In patients without new risk factors for QTc interval prolongation, an ECG within the previous 3 months with a QTc < 450 ms can serve as the baseline study.
In contrast, some previous guidelines required a baseline ECG screening for all patients.
- The panel recommends against methadone use in patients with a baseline QTc interval > 500 ms.
Some previous guidelines allowed methadone use in selected patients in this category.
Panelists provided a lengthy discussion of ECGs and risk factors for TdP and for QTc interval prolongation.
Initiating Methadone Therapy – The panel offers two strong recommendations:
- Start with low doses, based on treatment indication and the patient’s previous opioid exposure; titrate slowly; and monitor for sedation (moderate-quality evidence). The panel’s emphasis on low initial dosing and careful titration echoes previous guidelines. It prioritizes patient safety and takes into consideration methadone’s long, variable half-life—usually assumed to be about one day, but, according to some reports, occasionally as long as 120 hours. The panel stresses the need to withhold the dose temporarily if patients show evidence of sedation, and to restart treatment cautiously.
- When restarting methadone, consider patients who have not taken opioids for 1 to 2 weeks to be opioid-naïve (low-quality evidence).
Monitoring and Follow-up ECGs
Three strong recommendations for follow-up ECGs, all with low-quality evidence:
- Base follow-up ECGs on baseline ECG findings, methadone dose changes, and other risk factors for QTc interval prolongation.
- Switch patients with a QTc interval ≥ 500 ms to a different opioid, or immediately lower the methadone dose; evaluate and correct reversible causes of QTc interval prolongation; repeat the ECG after lowering the methadone dose.
- In patients with a QTc interval ≥ 450 ms but < 500 ms, consider switching to an alternative opioid or lowering the methadone dose (otherwise, discuss with the patient the potential risks of continuing methadone therapy); evaluate and correct reversible causes of QTc interval prolongation; repeat the ECG after lowering the methadone dose.
Adverse Events – Two recommendations:
- Monitor patients for common opioid adverse effects and toxicities; consider adverse-effects management to be part of routine therapy (moderate-quality evidence).
- The panel recommends discussing adverse events with patients—either face-to-face or by phone—within 3 to 5 days after starting methadone and within 3 to 5 days after each dose increase (low-quality evidence).
Urine Drug Testing – Two recommendations, both low-quality evidence:
- Obtain urine drug screens before starting methadone treatment for opioid addiction and again at regular intervals.
- Consider urine drug testing in all patients, regardless of risk status, before starting therapy and at regular intervals; the panel recommends such testing for patients who are prescribed methadone for chronic pain and have risk factors for drug abuse (low-quality evidence).
Medication Interactions – Use methadone with care in patients taking other medications that may have additive side effects or pharmacologic interactions with methadone (low-quality evidence).
Methadone Treatment During Pregnancy – Monitor neonates whose mothers received methadone; if neonatal abstinence syndrome occurs, provide appropriate treatment (moderate-quality evidence).
Need for Additional Research
Two related articles appear in the same issue of The Journal of Pain. One discusses in more detail methadone overdose and cardiac arrhythmia potential; the second highlights research gaps related to methadone safety. These gaps include lack of enough evidence to evaluate the comparative mortality associated with of methadone treatment versus treatment with other opioids, and to determine the effectiveness of ECG monitoring and other risk-mitigation steps.
A clear need exists for additional randomized clinical trials and large, well-controlled observational studies to provide additional data. This would allow the expert panel to update the guidelines and provide additional recommendations. The panel plans an update by 2018; earlier, if critical new evidence becomes available.
The article is available online at: http://www.jpain.org/article/S1526-5900(14)00522-7/fulltext
Links to Resources Mentioned in This Article
Chou R, Cruciani RA, Fiellin DA, et al. Methadone safety: A clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. J Pain. 2014;15(4):321-337. http://www.jpain.org/article/S1526-5900(14)00522-7/abstract. Accessed June 3, 2014.
Chou R, Weimer M, Dana T. Methadone overdose and cardiac arrhythmia potential: Findings from a review of the evidence for an American Pain Society and College on Problems of Drug Dependence clinical practice guideline. J Pain. 2014;15(4):338-365. http://www.ncbi.nlm.nih.gov/pubmed/24685459?dopt=Abstract. Accessed June 3, 2014.
Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MD. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150(6):387-395. doi:10.7326/0003-4819-150-6-200903170-00103. http://annals.org/article.aspx?articleid=744382. Accessed June 3, 2014.
Martin JA, Campbell A, Killip T, et al. QT interval screening in methadone maintenance treatment: Report of a SAMHSA expert panel. J Addict Dis. 2011; Oct;30(4):283-306. http://www.tandfonline.com/doi/pdf/10.1080/10550887.2011.610710. Accessed June 3, 2014.
Shaiova L, Berger A, Blinderman CD, et al. Consensus guideline on parenteral methadone use in pain and palliative care. Palliat Support Care. 2008;6:165-176. http://journals.cambridge.org/action/displayFulltext?type=1&fid=1885936&jid=PAX&volumeId=6&issueId=02&aid=1885928&bodyId=&membershipNumber=&societyETOCSession=. Accessed June 3, 2014.
Weimer MB, Chou R. Research gaps on methadone harms and comparative harms: Findings from a review of the evidence for an American Pain Society and College on Problems of Drug Dependence clinical practice guideline. J Pain. 2014;15(4):366-376. doi:10.1016/j.jpain.2014.01.496. PMID:24685460. http://www.ncbi.nlm.nih.gov/pubmed/24685460. Accessed June 3, 2014.
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