ECG Screening Prior to Initiating Methadone: Is it Really Necessary?
This issue of Practical Pain Management focuses on the safe use of methadone in pain management. The finding that methadone may prolong the QT interval, cause a condition known as torsades de pointes with ventricular tachycardia, and produce sudden death has rightly caused great concern among pain practitioners.1 Some practitioners have stopped prescribing methadone and others, including federal agencies, have been calling for an electrocardiogram (ECG) screen prior to prescribing methadone.1,2 The point, of course, was to withhold methadone if ECG screening showed a prolonged QT interval (>500 ms).
Another cause of anxiety among physicians has been what to do for patients who are already taking methadone. Should methadone be stopped to protect the patient and reduce the liability risks to the prescriber? The latter is no small issue because some physicians have been sued due to sudden death in pain patients who were taking methadone. I have been consulted on several methadone sudden death cases, all of which occurred in patients who were concomitantly taking benzodiazepines and antidepressants.
In these tough economic times, one of the ironies is the fact that methadone is being encouraged by health plans, including many state Medicaid plans, because it is an effective, low-cost opioid. What may be overlooked is the fact that it is also a very tricky agent to use! Although methadone represents less than 5% of prescribed opioids, it accounts for more than one-third of accidental deaths.3
The question of methadone cardiac risk assessment erupted in 2003 and again in 2007 when the Substance Abuse and Mental Health Services Administration’s (SAMHSA) Federal Center for Substance Abuse Treatment convened a “National Assessment of Methadone Mortality” meeting, which consisted of a panel of substance abuse experts including some cardiologists. These meetings resulted in a report titled, “QT Interval Screening in Methadone Treatment,” which was published in 2009 in the Annals of Internal Medicine.1 This publication recommended that a pretreatment ECG be obtained on all patients undergoing methadone maintenance treatment to measure the QT interval with a follow-up ECG within 30 days and annually thereafter. Additional ECGs were recommended if the methadone dose exceeded 100 mg per day or if patients complained of unexplained syncope or seizures.
The impracticality of these recommendations drew fire from methadone maintenance programs for opioid addiction. Pain practitioners were more sanguine as they had other long-acting opioid choices. Nevertheless, the basic recommendation to perform a pretreatment ECG on every pain patient who was going to receive methadone or risk facing malpractice liability has been preached and presented at many pain conferences and in various publications.2
Since 2009, however, there have been some scientific studies and investigations that have shed light on this subject and caused the expert panel to reconvene and alter its recommendation for a pretreatment ECG. The updated expert panel report was recently published in the Journal of Addictive Diseases.4
New information regarding the link between methadone and torsades de pointes underpins the basic recommendation that routine ECG screening need not be done prior to initiation of methadone treatment except in high-risk patients, particularly those patients with evidence of cardiac disease by history or physical. First and foremost, Anchersen et al from Norway examined the prevalence of QT prolongation in addicts treated with methadone as well as the causes of death in 90 out of 2,382 participants who underwent outpatient methadone treatment.5 These investigators confirmed past reports in that there is a dose-related increase in QT interval in individuals treated with methadone and found that 4.6% had a QT interval greater than 500 milliseconds, a threshold of high concern for arrhythmias. Despite finding evidence of QT prolongation, they concluded that postmortem examination or clinical history excluded torsades de pointes as the cause of death in all but four participants, suggesting that methadone-associated mortality in their cohort was only 0.06 deaths per 100 patient-years.
This study simply points out that although a risk may be present, the benefits of methadone are far greater. Also, it has come to light that a prolonged QT interval on screening doesn’t really predict a higher death rate. For example, the Framingham study found that 4.l4% of adults had a QT interval greater than 440 milliseconds but there was no association between this finding and 25-year risk for total mortality, sudden cardiac death, or even cardiac-related deaths.6
Much to the substance abuse expert panel’s credit, some specific recommendations to reduce the risk for sudden cardiac death with methadone were established. They are summarized in the Table.
It is pointed out in the new guidelines that patients who are treated with methadone for pain rather than addiction may be at greater risk for sudden cardiac death than those in methadone maintenance programs. Why? Dosages of methadone for pain commonly exceed those used in addiction treatment (usually <200 mg per day). In addition, patients with chronic pain take many other drugs, particularly benzodiazepines and antidepressants, which may interfere with cytochrome P450 activity and increase the risks associated with methadone. Please note that duloxetine (Cymbalta), a new and heavily used antidepressant in pain treatment, was not referenced by the expert panel.
In summary, QT screening prior to prescribing methadone is left to the discretion of the practitioner. There is no universal consensus to require screening based on sound scientific evidence. Because we know that sudden cardiac death has occurred in pain patients taking methadone, simple, practical screening measures need to be done (Table). Some patients with chronic pain, particularly those with a cardiac history who are taking older antidepressants or showing physical evidence of cardiovascular disease, may need to be excluded from methadone treatment.