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 http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008939.pub2/abstract

Resources

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. http://www.tandfonline.com/doi/abs/10.1080/10550887.2011.610710#.UdL01zssnj4

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. http://www.tandfonline.com/doi/pdf/10.1080/10550887.2011.610710

Comments

  1. It is very negligent to NOT perform and ecg at least on high risk patients starting methadone. Ecg machines are very inexpensive and only takes about five minutes to run a test. Is it really too much to ask doctors to be trained on how to recognize long QTc intervals? If nurses and paramedics can be trained to recognized issues…..why can’t doctors?
    This article states they are concerned about health consequences of the untreated opioid addiction…….
    If methadone is given to a patient with a long QTc interval that turns into a TdP death that could have been identified had an ECG been done prior to starting methadone, what has been accomplished? The “treatment” becomes the “killer”A dead addict never recovers!

    I can understand why the Cochrane Collaboration compare their studies to the gold standard of treatment like methadone……..neither are looking a the whole picture and many of the studies used have a vested interested in keeping methadone on the market. There were 5000 methadone related deaths in 2009. At least 25% of these were related to methadone clinics used to treat addiction and I’m sure this is a low number. How many people have to die?

  2. Peter Klimon Szabo says:

    If there is no conclusive evidence that links the two together what is the logic?

    If you go with that theory why not also do blood tests, XRays and any other dozens of tests that may or may not have a significance? At what point does common sense come into play? I am always amused by recommendations that begin with “what will it hurt” or “the costs are negligible” etc. I am not a believer in “hail-mary pass” medical treatments that have no basis in fact. You are correct that the actual ECG test is probably inexpensive in relation to other medical tests but you forget to mention the wasted time it takes to administer the test, then have a doctor spend wasted time analysing the results and then wasting the patients time in consultations scaring the patient with a non-existant possible medical problem!

    Personally as a long time methadone patient I feel the committee that pushed this ridiculous theory could have spent more productive and meaningful analysis and research on why after 40 years the medical community has yet to come up with a viable treatment that could help addicts detox without the horrible side effects associated with opiate withdrawal. I am especially curious to know why methadone was pushed as a treatment option knowing that it is hundreds of times more addictive than the heroin? Who gains to benefit from the insane war on drugs that has generated billions for the medical industry, the illicite drug trades and the criminal justice system that feeds of the misery of addicts around the world!

    These are much more profound questions begging for honest assessment and viable solutions, not how a 30sec ecg test just maybe might prevent a – a rare at best 2% – possibilty of a link to methadone and torsade de pointes. Give me a break – what ever happened to common sense…

  3. My concern is that if there is an unrecognized QTc prolongation in a patient receiving high-dose (above the 100mg/day) methadone as a part of an Opioid Treatment Program and the patient is forced into abrupt withdrawal, is death a possible outcome of abrupt QTc shortening with corresponding VF. Next, the question becomes what type of compensatory cardiac mechanisms come into play with high-dose methadone treatment and does the abrupt discontinuation of treatment with methadone incite cardiac distress? There is an abundance of anecdotal evidence that the abrupt cessation of high-dose methadone can lead to sudden death. Any comment or reference to this subject are welcomed.

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