No Evidence to Support QTc-Interval Screening in Methadone Maintenance Treatment: Cochrane Review

EKG“Methadone represents today the gold standard of efficacy for the pharmacological treatment of opioid dependence,” states the newly published (June 20) Cochrane Review on QTc interval screening for cardiac risk in methadone treatment. The review goes on to say that “methadone, like many other medications, has been implicated in the prolongation of the [QTc] interval of the electrocardiogram (ECG), which is considered a marker for arrhythmias such as torsade de pointes (TdP).” It further notes that the recommendations and consensus statements regarding QTc screening developed for patients receiving methadone maintenance treatment (MMT) have been questioned

At times, that questioning has been contentious (see issues of the AT Forum newsletter: Spring 2009, Summer 2009, and Winter 2012 ).

Cochrane investigators undertook a review study “to evaluate the efficacy and acceptability of QTc screening” to prevent cardiac-related morbidity and mortality in MMT. The authors performed an extensive search of MEDLINE, EMBASE, other databases, and electronic sources of ongoing trials, and identified 872 pertinent records.

Their finding: “No evidence has been found to support the use of the electrocardiogram (ECG) for preventing cardiac arrhythmias in methadone-treated opioid dependents.”

Gold Standards

Just as methadone is considered the gold standard in treating opioid dependence, Cochrane reviews are internationally recognized as the gold standard in evidence-based medical information. Using predefined criteria, Cochrane researchers conduct meticulous statistical data analyses to determine the efficacy of medical interventions. Cochrane Reviews are published by The Cochrane Collaboration, an independent nonprofit organization with 28,000 volunteers in more than 100 countries.

Existing Screening Recommendations

Screening guidelines recommended several years ago by an Expert Panel (Krantz, 2009) were a pretreatment ECG for all patients being considered for methadone treatment, to measure the QTc interval; a follow-up ECG within 30 days and annually; and additional ECGs if the daily methadone dosage exceeds 100 mg, or if unexplained syncope (loss of consciousness) or seizures occur.

A different Expert Panel (Martin, 2011) recommended instead a baseline ECG at the time of admission and within 30 days only for patients with significant risk factors for QT prolongation, and additional ECGs annually, or whenever the daily dose exceeds 120 mg.

Untoward Consequences of ECG Screening

The Cochrane study points out that the procedures involved in ECG screening may be “too demanding and stressful,” and “may expose patients to health consequences of untreated opioid addiction, including increased mortality risk.”

Untoward health consequences can occur when unnecessary evaluations and false-positive findings result in delays for additional studies and other treatments. In the meantime, some patients’ opioid addiction goes untreated, with potentially fatal outcomes—a factor that “does not seem to have been appropriately ruled out” by those drafting the screening guidelines, according to the authors.

Key Points in the Review

  • QTc prolongation is “not a safety concern per se,” but a “sharply imperfect” surrogate marker for the risk of TdP. A QTc longer than 500 milliseconds—considered the threshold of increased danger—is found in about 2 percent to 16 percent of MMT patients. But the prolongation isn’t necessarily due to methadone; liver disease, low potassium levels, and therapy with a variety of drugs also prolong QTc in MMT patients.
  • Estimated mortality for TdP is about 10 percent to 17 percent. But the “supposed involvement of methadone in TdP-related mortality” is thought to be only 6 deaths per 10,000 patient-years. Studies typically do not rule out other known risk factors, such as heart disease and various medications, so the true figure is probably lower. In contrast, mortality of untreated heroin dependence is estimated to be far higher: 100 to 300 per 10,000 person-years. Methadone maintenance, with an annual mortality rate of 0.1 percent, reduces by 2 to 11 times the mortality risk of people with opioid dependence.
  • The benefits of methadone treatment include increased retention in treatment, and a reduction in opioid use, HIV transmission, and mortality.
  •  Other treatments for opioid dependence with substantially lower risk of cardiac complications, such as buprenorphine, are available, but “their pharmacological profile, efficacy and acceptability by patients do not allow them to be thought of as an easy alternative to methadone.”
  •  ”Undue focus on QTc prolongation,” which may not be an appropriate way to screen for TdP, may decrease patient safety by diverting attention from other risk factors.
  •  Planning and performing ECG screenings isn’t easy; most physicians and many cardiologists cannot correctly calculate a QTc and identify a long QTc.

Unable to find any study that fulfilled methodological criteria for their review, The Cochrane authors said “it is not possible to draw any conclusions about the effectiveness of ECG-based screening strategies for preventing cardiac morbidity/mortality in methadone-treated opioid addicts.” Their recommendation: “Research efforts should focus on strengthening the evidence about the effectiveness of widespread implementation of such strategies and clarifying associated benefits and harms.”

In summing up, the authors note the lack of scientific evidence supporting ECG-based screening, and point out that “many examples of screening tests that were believed to be efficacious and recommended until rigorous evaluation showed their disadvantages are reported in the literature.” So, this appears to be another case of recommendations and guidelines being enacted “without the scientific rigour applied to other areas of medicine.”

The Cochrane study, with a complete description of study methods and results, is available for purchase through the Wiley Online Library at


Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MC. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150(6):387-395. doi:10.7326/0003-4819-150-6-200903170-00103.

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. doi: 10.1080/10550887.2011.610710.

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