QTc Interval Screening in Methadone TreatmentFREE
Publication: Annals of Internal Medicine
Volume 150, Number 6
Submit a Comment
Contributors must reveal any conflict of interest. Comments are moderated. Please see our information for authorsregarding comments on an Annals publication.
Abstract
Description:
An independent panel developed cardiac safety recommendations for physicians prescribing methadone.
Methods:
Expert panel members reviewed and discussed the following sources regarding methadone: pertinent English-language literature identified from MEDLINE and EMBASE searches (1966 to June 2008), national substance abuse guidelines from the United States and other countries, information from regulatory authorities, and physician awareness of adverse cardiac effects.
Recommendation 1 (Disclosure):
Clinicians should inform patients of arrhythmia risk when they prescribe methadone.
Recommendation 2 (Clinical History):
Clinicians should ask patients about any history of structural heart disease, arrhythmia, and syncope.
Recommendation 3 (Screening):
Obtain a pretreatment electrocardiogram for all patients to measure the QTc interval and a follow-up electrocardiogram within 30 days and annually. Additional electrocardiography is recommended if the methadone dosage exceeds 100 mg/d or if patients have unexplained syncope or seizures.
Recommendation 4 (Risk Stratification):
If the QTc interval is greater than 450 ms but less than 500 ms, discuss the potential risks and benefits with patients and monitor them more frequently. If the QTc interval exceeds 500 ms, consider discontinuing or reducing the methadone dose; eliminating contributing factors, such as drugs that promote hypokalemia; or using an alternative therapy.
Recommendation 5 (Drug Interactions):
Clinicians should be aware of interactions between methadone and other drugs that possess QT interval–prolonging properties or slow the elimination of methadone.
Editor's Note: Some members of an expert panel proposed the recommendations presented in this publication. Two panel members declined acknowledgment for the publication. This publication is not a federal guideline. A government agency has recently forwarded draft recommendations related to QTc interval screening in methadone treatment for field review prior to finalization.
Methadone, the most widely used agent for opioid maintenance, may prolong the rate-corrected QT interval (QTc) and result in torsade de pointes (1). This association recently came into focus when the U.S. Food and Drug Administration (FDA) issued a physician safety alert regarding increasing deaths and cardiac arrhythmias (2), which was followed by a manufacturer's black box warning (3). The methadone derivative levacetylmethadol also prolongs the QTc interval; its use requires performance of pretreatment electrocardiography (ECG), and it is no longer actively marketed (4).
Prolongation of the QTc interval is the mandatory substrate for development of torsade de pointes and is the most commonly scrutinized pharmacologic adverse effect evaluated during new drug development and postmarketing surveillance (5, 6). Drug-induced arrhythmia often results from multiple factors, including hypokalemia; structural heart disease; hepatic cytochrome P450 inhibitors; and genetic predisposition, manifested by a prolonged QTc interval at baseline (7). In a meta-analysis of 1288 patients who received the QT interval–prolonging drug sotalol, an increased pretreatment QTc interval was the strongest predictor of arrhythmia (mean QTc interval of 455 ms in those experiencing torsade de pointes versus 428 ms), which occurred in 2% of the overall cohort (8). A study of the antiarrhythmic drug dofetilide found a 2-fold increased risk for sudden death if the pretreatment QTc interval exceeded the upper quartile value of 479 ms, highlighting the importance of pretreatment ECG screening for identifying susceptible patients (9).
Although many drugs prolong the QTc interval, torsade de pointes is associated with fewer drugs and is often accompanied by predisposing risk factors (10), including bradycardia (11, 12). Women have a slightly longer QTc interval than men and are at greater risk for arrhythmia (13). Proposed thresholds for QTc interval prolongation have been set as low as 430 ms for men and as high as 470 ms for women (14–16). Despite these varying definitions, the international regulatory guidance for drug development suggests a sex-independent categorical threshold for QTc interval prolongation of 450 ms (6). A QTc interval greater than 500 ms is an accepted threshold for significant arrhythmia risk (17). The paucity of long-term studies of QTc interval–prolonging drugs in large populations makes it difficult to assign a relative risk for arrhythmia, although a QTc interval greater than 500 ms was associated with a 4-fold increase in syncope or sudden death, presumably from torsade de pointes, in patients with congenital long QT syndrome (18). Limitations of QTc interval screening include selecting a rate-correction formula at extremes of heart rate, choosing between manual or automated measures, and the limited predictive value for arrhythmia risk at the individual level. Despite these limitations, QTc interval screening is the current standard for assessing drug safety in all domains of medicine: clinical practice, drug development, and regulatory assessment for drug withdrawal or manufacturers' labeling changes (19).
Against this background, an expert panel was convened to address the cardiac effects of methadone. (For a list of acknowledged members of the expert panel, see the Appendix.) Because fewer than half of the physicians surveyed among accredited opioid treatment programs in the United States were aware of the association between methadone and QTc interval prolongation (20), the panel believed a consensus document was warranted. The objectives were to synthesize available evidence regarding methadone's proarrhythmic effects and formulate a clinical practice guideline, while being mindful that methadone is a niche medication with few therapeutic alternatives (21) and is associated with a substantial reduction in mortality among treated versus untreated heroin addicts (22).
Methods
Expert Panel
In May 2003, the Center for Substance Abuse Treatment (CSAT) of the Substance Abuse and Mental Health Services Administration convened a meeting, “National Assessment of Methadone-Associated Mortality,” where preliminary evidence suggesting the proarrhythmic properties of methadone was presented (23). This meeting reconvened on 20 July 2007 as “Methadone Mortality—A Reassessment” (24). One recommendation that emerged was the formation of a multidisciplinary expert panel on the cardiac effects of methadone. This panel included electrophysiologists, pain-management specialists, and epidemiologists. Representatives from the FDA, the National Institute on Drug Abuse, the American Association for the Treatment of Opioid Dependence, and the American Society of Addiction Medicine were also present.
The panel met on 19 and 20 December 2007 and reviewed selected articles solicited from members before the meeting. All members disclosed any conflicts of interest. We used a standard consensus decision-making approach that was inclusive (all key stakeholders were invited), participatory, and solution-oriented. Specifically, we collectively established the need for a clinical practice guideline regarding cardiac safety. We then drafted guideline recommendations that were iteratively modified and agreed to on the second day. The committee chair selected a writing group to perform a more in-depth literature review and craft a guidance document. This manuscript was circulated in advance of a second expert panel meeting on 15 and 16 July 2008, at which time, participating members reviewed, refined, and then approved the recommendations, which were sent to CSAT.
Literature Review
Two reviewers from the writing group with expertise in cardiology and electrophysiology independently searched MEDLINE and EMBASE (1966 to June 2008) to identify publications that addressed the cardiac effects of oral and intravenous methadone. We limited our searches to English-language articles but not to humans. We reviewed these articles along with mortality data retrieved from the aforementioned meetings of the CSAT, national opioid treatment guidelines from the United States and other countries, and background articles on QTc interval prolongation (Figure). We did not prespecify critical appraisal criteria, although we paid particular attention to larger clinical studies in terms of validity and relevance. We sorted literature according to the following topical or study design categories: experimental (in vitro) data, clinical case series of QT interval prolongation or torsade de pointes related to methadone, forensic series, cross-sectional investigations, and prospective cohort studies or randomized trials. When available, we extracted information regarding the relationship between methadone dose and cardiac repolarization. Finally, 2 reviewers independently evaluated the association between methadone and both QTc interval prolongation and torsade de pointes by adapting a quantitative method for estimating the probability of adverse drug reactions (25) to assess whether the likelihood of direct causation was definite, probable, possible, or doubtful.
Figure. Study flow diagram.
CSAT = Center for Substance Abuse and Treatment; QTc = rate- corrected QT interval.
Role of the Funding Source
The CSAT of the Substance Abuse and Mental Health Services Administration sponsored the 2 expert panel meetings. It had no role in the design, data collection, analysis, or manuscript preparation. Moreover, the views presented in this document are those of the authors and other referenced sources. They do not necessarily reflect the views or policies of the Department of Defense, the CSAT, the Substance Abuse and Mental Health Services Administration, or any other part of the U.S. Department of Health and Human Services.
Evidence Linking Methadone With QTc Interval Prolongation and Torsade de Pointes
We evaluated published data on the relationship between oral and intravenous methadone hydrochloride and QTc interval prolongation and torsade de pointes. A summary of that evidence follows.
Experimental
The most common mechanism of drug-induced QT prolongation and torsade de pointes is blockade of the human cardiac ether à go-go–related gene (hERG), which encodes Ikr, the delayed-rectifier potassium ion current (26). Blockade of this cardiac ion channel prolongs the terminal portion of the cardiac action potential and causes delayed repolarization, which manifests as QTc interval prolongation on the surface ECG. Methadone has been shown to be a potent inhibitor of the hERG channel, capable of achieving 50% in vitro inhibitory concentration of Ikr at approximately 1 to 10 µM (27). The ratio of the 50% in vitro inhibitory concentration of Ikr to maximal serum concentration, a strong predictor of arrhythmia risk, is identical for methadone and levacetylmethadol and an order of magnitude more potent than buprenorphine, another synthetic opioid approved for substance-abuse treatment. Kornick and colleagues (28) observed that intravenous methadone is associated with greater QTc interval prolongation than the oral preparation. This formulation, which contains 0.5% chlorobutanol as a preservative, resulted in a mean increase in QTc interval from baseline of 41.7 ms (SD, 7.8). The investigators also performed an in vitro study that demonstrated that chlorobutanol potentiated the impact of methadone on hERG channel blockade, which may account for the magnitude of the intravenous formulation's effect on repolarization (28).
de Vos and colleagues (29) reported peak plasma methadone levels in the µM range, which would overlap with concentrations that produce hERG channel blockade in vitro. A priori prediction of QTc interval effects are problematic because of interindividual variability in serum levels for any given dose due to differences in hepatic clearance (30). Specifically, methadone is metabolized by the cytochrome P450 system, and inhibitors of this enzyme can markedly increase plasma area-under-curve measurements (31). In addition, 2% of the population have unsuspected polymorphisms in the hERG channel gene that may be associated with increased sensitivity to hERG channel blockade by methadone or similar compounds (32).
Beyond its effect on cardiac repolarization via blockade of hERG channels, methadone has additional properties that may predispose to development of torsade de pointes. Risk for torsade de pointes is enhanced in the setting of bradycardia, and methadone seems to exhibit negative chronotropic effects through 2 key mechanisms: calcium-channel antagonism (33, 34) and anticholinesterase properties (35–37). This in vitro potential for bradycardia has been confirmed clinically (38–40).
Clinical Case Series
In 1973, a series of patients addicted to heroin was evaluated for predisposing risk factors for sudden cardiac death (41). The investigators observed QTc interval prolongation more commonly among persons with urine toxicology documenting the presence of methadone. However, no scientific evidence had established that methadone possessed cardiac toxicity, and analysis was limited by the presence of multiple drugs of abuse in the patients. It was not until almost 30 years later that a study of a North American series of 17 patients (1) found an association between very high doses of methadone and torsade de pointes. Since then, a growing body of evidence (42–63) has demonstrated an association between methadone and QTc interval prolongation and torsade de pointes. Evaluation of these cases suggests that many occurred in the setting of additional contributing factors and were often associated with relatively high doses of methadone.
The largest series to date was derived from a search of the FDA MedWatch system, which identified 59 cases of QTc interval prolongation or torsade de pointes associated with methadone (64). Eight percent were fatal, and most involved dosages of methadone exceeding 100 mg/d. Because only a fraction of drug-related serious adverse events are voluntarily reported to FDA MedWatch (65), the number of arrhythmia episodes attributable to methadone may be substantially higher. A more recent series described 8 patients receiving methadone maintenance therapy who presented with aborted sudden death or torsade de pointes and required implantable cardioverter–defibrillator placement (66). Patients were receiving high doses of methadone (mean, 204 mg/d [SD, 173]) and were followed longitudinally for a mean of 27 months. Six of 8 patients continued methadone therapy; 1 died and 3 others received shocks for recurrent torsade de pointes. This suggests that patients who experience overt torsade de pointes are at substantial risk for recurrent arrhythmia if methadone therapy is continued.
Forensic Series
In addition to the clinical case series that link methadone with arrhythmia, a growing number of medical examiner investigations (67–70) report unexplained methadone-associated deaths. Although it is prescribed much less frequently than other opioids, methadone seems to be disproportionately involved in opioid-related deaths (71). Deaths associated with methadone in these autopsy series have increased over time and have occurred in multiple geographic regions, thereby providing insight into the scope and extent of the problem. However, given the inherent limitations of autopsy data, these series cannot distinguish the cause of death as arrhythmic or attributable to respiratory depression from overdose.
Information has recently emerged on a possible link between the increasing incidence of sudden death associated with methadone and its proarrhythmic properties. Chugh and colleagues (72) found 72 cases of sudden death over 4 years in which methadone was detectable in serum and another 106 cases in which it was not. A detailed cardiac autopsy was performed in 22 patients with therapeutic methadone levels of 0.1 to 0.9 mg/L, of whom only 23% had evidence of structural heart disease. By contrast, most (60%) patients who had sudden death without detectable methadone had structural heart disease. Sudden death in the absence of detectable cardiac disease is often attributable to a catastrophic arrhythmia. The critical implication of this study is that methadone is associated with sudden cardiac death even after elimination of obvious overdose deaths. It should be emphasized that this study is only inferential, although its findings are consistent with methadone's potent proarrhythmic effects in vitro, the large number of reported cases of torsade de pointes, and the likelihood that a small proportion of arrhythmic events will be fatal (73, 74).
Cross-sectional Data
We found cross-sectional studies comprising 4 ambulatory cohorts and 1 inpatient cohort. An analysis of 83 patients receiving methadone maintenance therapy in Italy (75) noted that most (83%) had a baseline QTc interval that exceeded the population-expected value based on age and sex; 2 patients had a QTc interval that exceeded 500 ms. A larger cross-sectional study of 138 patients by Peles and colleagues (76) observed that 16% had QTc interval prolongation, defined as greater than 450 ms. All patients with prolonged QTc interval were receiving methadone dosages exceeding 120 mg/d. Three (2%) patients had a QTc interval that exceeded 500 ms. Over 2 years of follow-up, 2 patients died, both of whom had a QTc interval greater than 500 ms. Ehret and colleagues (77) retrospectively analyzed 247 hospitalized patients with a history of intravenous drug use, including 167 patients receiving long-term methadone therapy. The investigators found marked QTc prolongation (defined as >500 ms) among 16% of patients who received methadone. In contrast, no QTc interval measurement exceeded 500 ms among the 80 intravenous drug users not receiving methadone. Factors predicting QTc interval prolongation according to multivariate regression analysis included hypokalemia, liver disease, and concomitant use of hepatic cytochrome P450 inhibitors.
The largest cross-sectional comparative study to date (78) analyzed 393 patients receiving methadone and 43 patients receiving buprenorphine maintenance therapy in Copenhagen, Denmark. The investigators observed QTc interval prolongation (>440 ms) among 32% of patients who received methadone, whereas no patient who received buprenorphine had QTc interval prolongation. Similar to Peles and colleagues' findings, 8 (2%) patients who received methadone had a QTc interval greater than 500 ms and all were receiving more than 100 mg/d. Similar findings were also documented in a cohort of 104 patients with chronic pain (79) receiving methadone; 33% had QTc interval prolongation, defined as greater than 430 ms in men and 450 ms in women.
Prospective and Randomized Trial Data
One small study (80) noted a mean increase in QTc interval of 20 ms on initiation of methadone treatment. In the largest prospective cohort study to date, Martell and colleagues (81) evaluated 167 new entrants into methadone maintenance therapy. The investigator who interpreted ECGs was blinded to dose and time interval. Oral methadone induction resulted in a statistically significant increase in the mean QTc interval of 12.4 ms (SD, 23) at 6 months, which persisted at 12 months. Krantz and colleagues (82) observed a similar increase in QT interval dispersion (9.5 ms [SD, 18.6]), a marker of heterogeneous cardiac repolarization, from baseline to 6 months among the study cohort. Two percent of patients exceeded a QTc threshold of 500 ms at 6 and 12 months.
Wedam and colleagues (83) reported ECG safety data from a prospective randomized trial that compared the effect of levacetylmethadol, methadone, and buprenorphine on the QTc interval. They observed QTc interval prolongation in 23% of patients who received methadone with a normal QTc interval at baseline. They conservatively defined QTc prolongation as greater than 470 ms in men and 490 ms in women. Of note, 10% of participants had a QTc interval that exceeded 500 ms during the study. In addition, the investigators observed progressive QTc interval prolongation from baseline at 4, 8, and 16 weeks.
Dose Effects on Cardiac Repolarization
As with most QT interval–prolonging drugs, the effects of methadone on cardiac repolarization are dose-dependent and evident in case reports as well as cross-sectional and prospective studies. Methadone dosages exceeding 100 mg/d have frequently been noted in published cases of torsade de pointes, and some case reports (43, 47, 55) highlight QTc-interval normalization after methadone discontinuation or dose reduction. Furthermore, many studies, including those of oral and intravenous methadone, demonstrate a positive correlation between dose and delayed cardiac repolarization (28, 75–79, 81, 84) among both addiction treatment and pain management cohorts. In Peles and colleagues' study (76), the correlation achieved statistical significance in the subset of patients abusing cocaine, which is consistent with a synergistic effect of methadone and cocaine on hERG channel blockade (85). In Fanoe and colleagues' study (78), the QTc interval increased by 10 ms for every 50-mg increase in methadone dose, which corresponded to a higher risk for syncope (odds ratio, 1.2 [CI, 1.1 to 1.4]).
With regard to serum levels, Martell and colleagues (81) prospectively demonstrated that the increase in QTc interval from baseline to 12 months after methadone initiation correlated with both trough and peak serum concentrations. Huber and colleagues (86) observed similar relationships with the methadone derivative levacetylmethadol. Taken in aggregate, the available literature supports a dose-dependent effect of methadone and levacetylmethadol on cardiac repolarization (Appendix Table). This creates a safety–efficacy paradox, because higher doses of methadone may reduce illicit opioid use (or diminish chronic pain) yet place patients at greater arrhythmia risk (87). It is important for clinicians to recognize that sudden cardiac death associated with methadone has been described at dosages as low as 29 mg/d, which suggests that arrhythmia can occur across a wide therapeutic range that includes dosages commonly used in both chronic pain and addiction treatment (64). This in turn suggests that methadone dosage is just one consideration with regard to limiting arrhythmia risk.
Expert Panel Recommendations
We judged that available evidence definitely suggests that both oral and intravenous methadone hydrochloride cause QTc interval prolongation and torsade de pointes (Table 1).
We then deliberated and arrived at 5 recommendations for physicians prescribing methadone (Table 2). We concluded that arrhythmia risk associated with methadone is a direct consequence of its effect on cardiac repolarization. Hence, our recommendations are applicable to patients either receiving current treatment with methadone or being considered for initiation of methadone treatment for addiction or pain management. Electrocardiographic screening may also be performed on an individual basis in patients receiving methadone with multiple risk factors for QTc prolongation, including a family history of the long QT syndrome or early sudden cardiac death or electrolyte depletion, and on initiation of therapy with a cytochrome P450 inhibitor or other QTc interval–prolonging drug, including cocaine. Moreover, urgent evaluation that includes ECG screening is warranted for patients receiving methadone who have unexplained syncope or generalized seizures; if marked QTc interval prolongation is documented, torsade de pointes should be suspected. Panel recommendations are not intended to supplant clinical judgment or patient preferences and may not apply to patients with terminal, intractable cancer pain.
Other Recommendations and Guidelines
Warnings about the proarrhythmic potential of methadone are catalogued in Thompson's MICROMEDEX (available at www.thomsonhc.com) and a Web site (10) that dynamically archives QTc interval–prolonging drugs. Although the revised product label for methadone suggests careful monitoring among patients with prolonged QTc intervals, it does not specify the form of monitoring. Thompson's MICROMEDEX is more declarative and advises ECG monitoring among patients with cardiac conduction abnormalities or those at increased risk; however, no definition of conduction abnormalities or the population at risk is provided.
The Medicines and Healthcare products Regulatory Agency in the United Kingdom highlights the risk for QT prolongation with methadone and recommends monitoring patients receiving high dosages (defined as >100 mg/d) but does not detail the monitoring approach (88). The United Kingdom guideline on clinical management of drug misuse and dependence incorporates this approach and suggests that patients be informed of the reasons for monitoring if screening is considered (89). The Canadian Methadone Maintenance Guideline is more specific and suggests performing ECG when methadone dosages exceed 150 mg/d and repeating ECG when the dosage approaches 180 to 200 mg/d (90). This guideline further proposes tapering the methadone dose and referring the patient to a cardiologist if the QTc interval exceeds 470 ms. A recently published U.S. consensus guideline on parenteral methadone use in pain and palliative care (91), which principally focuses on inpatient therapy, recommends pretreatment ECG followed by repeated measurement after 24 hours and again after 4 days, when steady-state levels are achieved. This consensus document, however, provides no guidance on risk stratification or subsequent clinical actions on the basis of the measured QTc interval.
Implementation of Recommendations
We acknowledge challenges in screening and arrhythmia risk stratification of patients. Identifying clinically relevant QTc interval prolongation remains difficult because of intraindividual temporal variability, different formulas for the QTc interval (such as the Bazett versus the Fridericia formula), and difficulty in defining the actual risk for arrhythmia that a prolonged QTc interval portends for any given individual. The QTc interval is most often calculated by using the Bazett formula (92): QTc = QT interval (in ms) divided by the square root of the preceding RR interval (in seconds). Although this formula is likely to overcorrect in the setting of high heart rates (6), it is nonetheless a reasonable method for screening purposes with the proviso that patients remain supine for approximately 5 minutes before ECG acquisition.
We discussed practical considerations for implementing our recommendation. First, to estimate the number of potential patients in opioid treatment programs who might be identified by QTc interval screening as being at very high risk for torsade de pointes (QTc >500 ms), we reviewed the 3 available ambulatory cohort studies that focused solely on opioid treatment programs (76, 78, 81). Of note, each documented an identical proportion of patients (2%) in whom the QTc interval exceeded 500 ms, although data from 1 randomized trial (83) suggested a higher proportion. Assuming that these 3 studies are representative of the population receiving methadone maintenance therapy in the United States, we project that approximately 5000 of the 250 000 patients in opioid treatment programs (93) would exceed this threshold and constitute the principal target for risk-reduction interventions.
Second, we discussed the question of automated versus manual interpretation of the QTc interval. Automated (computer-generated) measurements are more standardized and probably offer reasonable estimates of arrhythmia risk because most patients in opioid treatment programs do not have structural heart disease. In support of this, Martell and colleagues (81) prospectively evaluated both blinded manual readings performed by a cardiologist and automated readings and found essentially identical mean values for automated and blinded manual QTc measurements (418 ms [SD, 22] vs. 419 ms [SD, 23]; r = 0.8; P < 0.001). Another cross-sectional study (76) corroborated this finding: Blinded manual QTc readings performed by a cardiologist were strongly correlated with the automated readings (r = 0.997, P < 0.001). Because these data were derived directly from opioid-dependent populations, we believe that practitioners may use automated readings as a screening tool for risk stratification. Practitioners who are uncertain about whether clinically significant QTc interval prolongation is present should repeat ECG or have the tracing interpreted by a cardiologist. Regardless, ECG screening for QTc interval prolongation does not require specialty care and has been judged appropriate in primary care settings (15). Therefore, we deem ECG screening with risk stratification feasible in opioid treatment programs and in the treatment of chronic pain in ambulatory and hospital settings.
Summary
A large body of evidence suggests that oral and intravenous methadone is associated with QTc interval prolongation and torsade de pointes. Opioid treatment programs in the United States are accordingly challenged with integrating cardiac arrhythmia risk assessment into routine care process without reducing access to vital addiction treatment services. We believe that increased clinical vigilance will reduce sudden cardiac death among the approximately 250 000 patients receiving methadone in opioid treatment programs (93) as well as the nearly 720 000 patients receiving methadone for chronic pain through U.S. retail pharmacies (94). These recommendations may inform both the product labeling for methadone as well as practice standards for opioid treatment programs. Currently, among patients receiving methadone who develop marked QTc interval prolongation or torsade de pointes, clinicians have just 1 FDA-approved alternative therapy (buprenorphine). However, (R) methadone seems to exhibit less hERG- channel blockade than standard (R,S) methadone (95). Although currently unavailable in the United States, (R) methadone could prove to be a safe therapeutic alternative compared with the standard racemic mixture, pending larger prospective studies. Nonetheless, with regard to cardiac arrhythmia risk, standard methadone can be safely administered as long as the potential for QTc interval prolongation is recognized through ECG screening and appropriate clinical actions are taken in the presence of QTc interval prolongation.
Appendix: Cardiac Expert Panel Contributing Members
The following cardiac expert panel members are acknowledged*: Dr. Barry Stimmel (Chair), Dr. Mark Haigney, Dr. Margaret Kotz, Dr. Robert Rappaport, Dr. Mori Krantz, Dr. Frank Vocci, Dr. Judith Martin, Dr. Davendra Mehta, and Mr. Charles O'Keeffe.
Barry Stimmel, MD, FASAM, Dean of Graduate Medical Education, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1076, New York, NY 10029-6500; e-mail, [email protected]. (Potential Financial Conflicts of Interest: None disclosed.)
Mark C.P. Haigney, MD, FAHA, Director of Cardiology and Electrophysiology and Professor of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, A3060, Bethesda, MD 20814; e-mail, [email protected]. (Potential Financial Conflicts of Interest: Travel funding sponsored by Reckitt Benckiser.)
Margaret Kotz, DO, Director, Addiction Recovery Services, Case Western Reserve University School of Medicine, 1100 Euclid Avenue, Cleveland, OH 44106-1704; e-mail, [email protected]. (Potential Financial Conflicts of Interest: None disclosed.)
Robert Rappaport, MD, Director, Division of Anesthesia, Analgesia, and Rheumatology Products, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Building 22, Silver Spring, MD 20993; e-mail, [email protected]. (Potential Financial Conflicts of Interest: None disclosed.)
Mori J. Krantz, MD, FACC, Associate Professor of Medicine, University of Colorado, Director, ECG Core Laboratory and CV Prevention Department, Colorado Prevention Center, 789 Sherman Street Suite, 200, Denver, CO 80203; e-mail, [email protected]. (Potential Financial Conflicts of Interest: Former physician for Western Clinical Health Services, where he regularly prescribed methadone for addiction; has lectured at conferences/forums sponsored/hosted by Reckitt Benckiser, CSAT, and the American Association for the Treatment of Opioid Dependency.)
Frank Vocci, PhD, Director, Division of Pharmacotherapies & Medical Consequences of Drug Abuse, National Institute on Drug Abuse, 6001 Executive Boulevard, Room 4133, MSC 9551, Bethesda, MD 20892; e-mail, [email protected], [email protected]. (Potential Financial Conflicts of Interest: None disclosed.)
Judith Martin, MD, Medical Director, BAART Turk Street Clinic, 433 Turk Street, San Francisco, CA 94102; e-mail, [email protected]. (Potential Financial Conflicts of Interest: None disclosed.)
Davendra Mehta, MD, Director of Electrophysiology, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029-6500;e-mail, [email protected]. (Potential Financial Conflicts of Interest: Speakers' bureau for Medtronic, Boston Scientific, and St. Jude's.)
Charles O'Keeffe, Professor, Department of Epidemiology and Community Health, Virginia Commonwealth University School of Medicine, MCV Campus, Leigh House, 1000 East Clay Street, PO Box 980212, Richmond, VA 23298-0212; e-mail, [email protected]. (Potential Financial Conflicts of Interest: Board of Directors, Human Resources, Friends of NIDA, and Catalyst Pharmaceutical Partners; Consultant, Reckitt Benckiser Pharmaceuticals and Purdue Pharma; retired President and CEO of Reckitt Benckiser Pharmaceuticals.)
*Two panel members declined to be acknowledged.
References
1.
Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, Robertson AD, Mehler PS. Torsade de pointes associated with very-high-dose methadone. Ann Intern Med. 2002;137:501-4. [PMID: 12230351]
2.
Methadone hydochloride (marketed as Dolophine) information: death, narcotic overdose, and serious cardiac arryhythmias. [FDA Alert]. Rockville, MD: U.S. Food and Drug Administration; November 2006. Accessed at www.fda.gov/cder/drug/infopage/methadone/default.htm on 12 November 2008.
3.
Dolophine Hydrochloride CII (Methadone Hydrochloride Tablets, USP) 5 mg, 10 mg, Rx Only. Columbus, OH: Roxane Laboratories; 2006. Accessed at www.fda.gov/cder/foi/label/2006/006134s028lbl.pdf on 12 November 2008.
4.
Product Discontinuation Notice: Orlaam (Levomethadyl Hydrochloride Acetate) Oral Solution, 10 mg/mL, CII. Columbus, OH: Roxane Laboratories; 23 August 2003. Accessed at www.fda.gov/cder/drug/shortages/orlaam.htm on 12 November 2008.
5.
Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc Res. 2003;58:32-45. [PMID: 12667944]
6.
U.S. Food and Drug Administration. Guidance for Industry: E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Rockville, MD: Center for Drug Evaluation and Research; 2005.
7.
Viskin S. Long QT syndromes and torsade de pointes. Lancet. 1999;354:1625-33. [PMID: 10560690]
8.
Soyka LF, Wirtz C, Spangenberg RB. Clinical safety profile of sotalol in patients with arrhythmias. Am J Cardiol. 1990;65:74A-81A; discussion 82A-83A. [ 2403737]
9.
Brendorp B, Elming H, Jun L, Køber L, Malik M, Jensen GB, et al; DIAMOND Study Group. QTc interval as a guide to select those patients with congestive heart failure and reduced left ventricular systolic function who will benefit from antiarrhythmic treatment with dofetilide. Circulation. 2001;103:1422-7. [PMID: 11245647]
10.
Drugs with risk of torsade de pointes. Tucson: University of Arizona Center for Education and Research on Therapeutics; 2008. Accessed at www.azcert.org/medical-pros/drug-lists/bycategory.cfm on 12 November 2008.
11.
Kurita T, Ohe T, Shimizu W, Hotta D, Shimomura K. Early afterdepolarization in a patient with complete atrioventricular block and torsades de pointes. Pacing Clin Electrophysiol. 1993;16:33-8. [PMID: 7681173]
12.
Wesley RC Jr, Turnquest P. Torsades de pointe after intravenous adenosine in the presence of prolonged QT syndrome. Am Heart J. 1992;123:794-6. [PMID: 1539535]
13.
Ebert SN, Liu XK, Woosley RL. Female gender as a risk factor for drug-induced cardiac arrhythmias: evaluation of clinical and experimental evidence. J Womens Health. 1998;7:547-57. [PMID: 9650155]
14.
Committee for Proprietary Medicinal Products. Points to Consider: The Assessment of the Potential for QT Interval Prolongation by Non-Cardiovascular Medicinal Products. vol. CPMP 986/96. London: The European Agency for the Evaluation of Medicinal Products; 1997.
15.
Al-Khatib SM, LaPointe NM, Kramer JM, Califf RM. What clinicians should know about the QT interval. JAMA. 2003;289:2120-7. [PMID: 12709470]
16.
Garson A Jr. How to measure the QT interval—what is normal? Am J Cardiol. 1993;72:14B-16B. [PMID: 8256749]
17.
Bednar MM, Harrigan EP, Ruskin JN. Torsades de pointes associated with nonantiarrhythmic drugs and observations on gender and QTc. Am J Cardiol. 2002;89:1316-9. [PMID: 12031739]
18.
Brink PA, Crotti L, Corfield V, Goosen A, Durrheim G, Hedley P, et al. Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population. Circulation. 2005;112:2602-10. [PMID: 16246960]
19.
De Ponti F, Poluzzi E, Cavalli A, Recanatini M, Montanaro N. Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: an overview. Drug Saf. 2002;25:263-86. [PMID: 11994029]
20.
Krantz MJ, Rowan SB, Schmittner J, Bucher Bartelson B. Physician awareness of the cardiac effects of methadone: results of a national survey. J Addict Dis. 2007;26:79-85. [PMID: 18032235]
21.
Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350:1013-22. [PMID: 14999113]
22.
Langendam MW, van Brussel GH, Coutinho RA, van Ameijden EJ. The impact of harm-reduction-based methadone treatment on mortality among heroin users. Am J Public Health. 2001;91:774-80. [PMID: 11344886]
23.
Methadone-Associated Mortality: Report of a National Assessment. Rockville, MD: Substance Abuse and Mental Health Services Administration; 8-9 May 2003. Accessed at www.csdp.org/research/methadone.samhsa204.pdf on 12 November 2008.
24.
Methadone Mortality—A Reassessment. Rockville, MD: Substance Abuse and Mental Health Services Administration; 20 July 2007. Accessed at www.dpt.samhsa.gov/pdf/Methadone_Report_10%2018%2007_Brief%20w%20attch.pdf on 12 November 2008.
25.
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239-45. [PMID: 7249508]
26.
Chiang CE, Roden DM. The long QT syndromes: genetic basis and clinical implications. J Am Coll Cardiol. 2000;36:1-12. [PMID: 10898405]
27.
Katchman AN, McGroary KA, Kilborn MJ, Kornick CA, Manfredi PL, Woosley RL, et al. Influence of opioid agonists on cardiac human ether-a-go-go-related gene K(+) currents. J Pharmacol Exp Ther. 2002;303:688-94. [PMID: 12388652]
28.
Kornick CA, Kilborn MJ, Santiago-Palma J, Schulman G, Thaler HT, Keefe DL, et al. QTc interval prolongation associated with intravenous methadone. Pain. 2003;105:499-506. [PMID: 14527710]
29.
de Vos JW, Geerlings PJ, van den Brink W, Ufkes JG, van Wilgenburg H. Pharmacokinetics of methadone and its primary metabolite in 20 opiate addicts. Eur J Clin Pharmacol. 1995;48:361-6. [PMID: 8641323]
30.
Eap CB, Buclin T, Baumann P. Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41:1153-93. [PMID: 12405865]
31.
Benmebarek M, Devaud C, Gex-Fabry M, Powell Golay K, Brogli C, Baumann P, et al. Effects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone. Clin Pharmacol Ther. 2004;76:55-63. [PMID: 15229464]
32.
Ackerman MJ, Tester DJ, Jones GS, Will ML, Burrow CR, Curran ME. Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome. Mayo Clin Proc. 2003;78:1479-87. [PMID: 14661677]
33.
Seyler DE, Borowitz JL, Maickel RP. Calcium channel blockade by certain opioids. Fundam Appl Toxicol. 1983;3:536-42. [PMID: 6662295]
34.
Lee CH, Berkowitz BA. Calcium antagonist activity of methadone, l-acetylmethadol and l-pentazocine in the rat aortic strip. J Pharmacol Exp Ther. 1977;202:646-53. [PMID: 894527]
35.
Eikenburg DC, Stickney JL. Anti-cholinesterase activity of 1-alpha-acetylmethadol: relationship to bradycardia. Gen Pharmacol. 1979;10:195-200. [PMID: 467958]
36.
Rendig SV, Amsterdam EA, Henderson GL, Mason DT. Comparative cardiac contractile actions of six narcotic analgesics: morphine, meperidine, pentazocine, fentanyl, methadone and l-alpha-acetylmethadol (LAAM). J Pharmacol Exp Ther. 1980;215:259-65. [PMID: 6109016]
37.
Stickney JL. Cardiac effects of 1-alpha-acetylmethadol. I. Chronotropic effects in vitro. Toxicol Appl Pharmacol. 1977;40:23-32. [PMID: 867429]
38.
Wheeler AD, Tobias JD. Bradycardia during methadone therapy in an infant. Pediatr Crit Care Med. 2006;7:83-5. [PMID: 16395081]
39.
Karir V. Bradycardia associated with intravenous methadone administered for sedation in a patient with acute respiratory distress syndrome. Pharmacotherapy. 2002;22:1196-9. [PMID: 12222559]
40.
Ashwath ML, Ajjan M, Culclasure T. Methadone-induced bradycardia. J Emerg Med. 2005;29:73-5. [PMID: 15961013]
41.
Lipski J, Stimmel B, Donoso E. The effect of heroin and multiple drug abuse on the electrocardiogram. Am Heart J. 1973;86:663-8. [PMID: 4743335]
42.
De Bels D, Staroukine M, Devriendt J. Torsades de pointes due to methadone [Letter]. Ann Intern Med. 2003;139:156. [PMID: 12859181]
43.
Gil M, Sala M, Anguera I, Chapinal O, Cervantes M, Guma JR, et al. QT prolongation and torsades de pointes in patients infected with human immunodeficiency virus and treated with methadone. Am J Cardiol. 2003;92:995-7. [PMID: 14556883]
44.
Krantz MJ, Rowan SB, Mehler PS. Cocaine-related torsade de pointes in a methadone maintenance patient. J Addict Dis. 2005;24:53-60. [PMID: 15774410]
45.
Atkinson D, Dunne A, Parker M. Torsades de pointes and self-terminating ventricular fibrillation in a prescription methadone user. Anaesthesia. 2007;62:952-5. [PMID: 17697226]
46.
George S. Methadone-associated QT prolongation and torsades de pointes [Letter]. Br J Hosp Med (Lond). 2007;68:221. [PMID: 17465110]
47.
Krantz MJ, Garcia JA, Mehler PS. Effects of buprenorphine on cardiac repolarization in a patient with methadone-related torsade de pointes. Pharmacotherapy. 2005;25:611-4. [PMID: 15977920]
48.
Walker PW, Klein D, Kasza L. High dose methadone and ventricular arrhythmias: a report of three cases. Pain. 2003;103:321-4. [PMID: 12791438]
49.
Wong SC, Roberts JR. Case files of the Drexel University Medical Toxicology Fellowship: methadone-induced QTc prolongation. J Med Toxicol. 2007;3:190-4. [PMID: 18072176]
50.
Routhier DD, Katz KD, Brooks DE. QTc prolongation and torsades de pointes associated with methadone therapy. J Emerg Med. 2007;32:275-8. [PMID: 17394991]
51.
Iskandar SB, Abi-Saleh BS, Mechleb BK, Fahrig SA. Methadone and torsade de pointes: case report and review of the literature. Tenn Med. 2007;100:35-7, 42. [PMID: 17378505]
52.
Falconer M, Molloy D, Ingerhaug J, Barry M. Methadone induced torsade de pointes in a patient receiving antiretroviral therapy. Ir Med J. 2007;100:631-2. [PMID: 18277734]
53.
Lamont P, Hunt SC. A twist on torsade: a prolonged QT interval on methadone. J Gen Intern Med. 2006;21:C9-C12. [PMID: 17026725]
54.
Sticherling C, Schaer BA, Ammann P, Maeder M, Osswald S. Methadone-induced torsade de pointes tachycardias. Swiss Med Wkly. 2005;135:282-5. [PMID: 15986265]
55.
Piguet V, Desmeules J, Ehret G, Stoller R, Dayer P. QT interval prolongation in patients on methadone with concomitant drugs [Letter]. J Clin Psychopharmacol. 2004;24:446-8. [PMID: 15232338]
56.
Lucchini A, Barbaro G, Barbarini G. Methadone and QT prolongation in HIV-infected patients [Letter]. Am J Cardiol. 2004;94:147-8. [PMID: 15219532]
57.
Lüthi B, Huttner A, Speck RF, Mueller NJ. Methadone-induced torsade de pointes after stopping lopinavir-ritonavir. Eur J Clin Microbiol Infect Dis. 2007;26:367-9. [PMID: 17440756]
58.
Ower K, Morley-Forster P, Moulin D. Fluctuating QTc interval in an asymptomatic patient treated with methadone for chronic pain. J Opioid Manag. 2005;1:73-6. [PMID: 17319250]
59.
Porter BO, Coyne PJ, Smith WR. Methadone-related torsades de pointes in a sickle cell patient treated for chronic pain [Letter]. Am J Hematol. 2005;78:316-7. [PMID: 15795907]
60.
Rademacher S, Dietz R, Haverkamp W. QT prolongation and syncope with methadone, doxepin, and a beta-blocker [Letter]. Ann Pharmacother. 2005;39:1762-3. [PMID: 16144878]
61.
Decerf JA, Gressens B, Brohet C, Liolios A, Hantson P. Can methadone prolong the QT interval? [Letter]. Intensive Care Med. 2004;30:1690-1. [PMID: 15185068]
62.
Pimentel L, Mayo D. Chronic methadone therapy complicated by torsades de pointes: a case report. J Emerg Med. 2008;34:287-90. [PMID: 18022786]
63.
Almehmi A, Malas AM, Yousufuddin M, Rosencrance JG. Methadone-induced torsade de pointes in a patient with normal baseline QT interval. W V Med J. 2004;100:147-8. [PMID: 15471174]
64.
Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmacoepidemiol Drug Saf. 2005;14:747-53. [PMID: 15918160]
65.
Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU, Wolfe SM, Bor DH. Timing of new black box warnings and withdrawals for prescription medications. JAMA. 2002;287:2215-20. [PMID: 11980521]
66.
Patel AM, Singh JP, Ruskin JN. Role of implantable cardioverter-defibrillators in patients with methadone-induced long QT syndrome. Am J Cardiol. 2008;101:209-11. [PMID: 18178408]
67.
Ballesteros MF, Budnitz DS, Sanford CP, Gilchrist J, Agyekum GA, Butts J. Increase in deaths due to methadone in North Carolina [Letter]. JAMA. 2003;290:40. [PMID: 12837709]
68.
Sorg MH, Greenwald M. Maine drug-related mortality patterns: 1997–2002. Augusta, ME: State of Maine Office of Substance Abuse; 2003. Accessed at www.maine.gov/dhhs/osa/pubs/osa/2003/drugreport.pdf on 12 November 2008.
69.
Gagajewski A, Apple FS. Methadone-related deaths in Hennepin County, Minnesota: 1992-2002. J Forensic Sci. 2003;48:668-71. [PMID: 12762545]
70.
Shah N, Lathrop SL, Landen MG. Unintentional methadone-related overdose death in New Mexico (USA) and implications for surveillance, 1998-2002. Addiction. 2005;100:176-88. [PMID: 15679747]
71.
Drug Abuse Warning Network. The DAWN Report. Opiate-Related Drug Misuse Deaths in Six States: 2003. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2006.
72.
Chugh SS, Socoteanu C, Reinier K, Waltz J, Jui J, Gunson K. A community-based evaluation of sudden death associated with therapeutic levels of methadone. Am J Med. 2008;121:66-71. [PMID: 18187075]
73.
Salle P, Rey JL, Bernasconi P, Quiret JC, Lombaert M. [Torsades de pointe. Apropos of 60 cases]. Ann Cardiol Angeiol (Paris). 1985;34:381-8. [PMID: 4026164]
74.
Milon D, Daubert JC, Saint-Marc C, Gouffault J. [Torsade de pointes. Apropos of 54 cases]. Ann Fr Anesth Reanim. 1982;1:513-20. [PMID: 7184347]
75.
Maremmani I, Pacini M, Cesaroni C, Lovrecic M, Perugi G, Tagliamonte A. QTc interval prolongation in patients on long-term methadone maintenance therapy. Eur Addict Res. 2005;11:44-9. [PMID: 15608471]
76.
Peles E, Bodner G, Kreek MJ, Rados V, Adelson M. Corrected-QT intervals as related to methadone dose and serum level in methadone maintenance treatment (MMT) patients: a cross-sectional study. Addiction. 2007;102:289-300. [PMID: 17222284]
77.
Ehret GB, Voide C, Gex-Fabry M, Chabert J, Shah D, Broers B, et al. Drug-induced long QT syndrome in injection drug users receiving methadone: high frequency in hospitalized patients and risk factors. Arch Intern Med. 2006;166:1280-7. [PMID: 16801510]
78.
Fanoe S, Hvidt C, Ege P, Jensen GB. Syncope and QT prolongation among patients treated with methadone for heroin dependence in the city of Copenhagen. Heart. 2007;93:1051-5. [PMID: 17344330]
79.
Cruciani RA, Sekine R, Homel P, Lussier D, Yap Y, Suzuki Y, et al. Measurement of QTc in patients receiving chronic methadone therapy. J Pain Symptom Manage. 2005;29:385-91. [PMID: 15857742]
80.
Fredheim OM, Borchgrevink PC, Hegrenaes L, Kaasa S, Dale O, Klepstad P. Opioid switching from morphine to methadone causes a minor but not clinically significant increase in QTc time: A prospective 9-month follow-up study. J Pain Symptom Manage. 2006;32:180-5. [PMID: 16877186]
81.
Martell BA, Arnsten JH, Krantz MJ, Gourevitch MN. Impact of methadone treatment on cardiac repolarization and conduction in opioid users. Am J Cardiol. 2005;95:915-8. [PMID: 15781034]
82.
Krantz MJ, Lowery CM, Martell BA, Gourevitch MN, Arnsten JH. Effects of methadone on QT-interval dispersion. Pharmacotherapy. 2005;25:1523-9. [PMID: 16232014]
83.
Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MC. QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial. Arch Intern Med. 2007;167:2469-75. [PMID: 18071169]
84.
Krantz MJ, Kutinsky IB, Robertson AD, Mehler PS. Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy. 2003;23:802-5. [PMID: 12820821]
85.
Ferreira S, Crumb WJ Jr, Carlton CG, Clarkson CW. Effects of cocaine and its major metabolites on the HERG-encoded potassium channel. J Pharmacol Exp Ther. 2001;299:220-6. [PMID: 11561083]
86.
Huber A, Ling W, Fradis J, Charuvastra VC. Comparison of the effects of methadone and LAAM on the electrocardiogram [Abstract]. Drug Alcohol Depend. 2001;63:S70.
87.
Krantz MJ, Mehler PS. QTc prolongation: methadone's efficacy-safety paradox. Lancet. 2006;368:556-7. [PMID: 16905001]
88.
Current Problems in Pharmacovigilance. vol 31. London: Medicines and Healthcare products Regulatory Agency; May 2006.
89.
Department of Health (England) and the devolved administrations. Drug Misuse and Dependence: UK Guidelines on Clinical Management. London: Department of Health (England), the Scottish Government, Welsh Assembly Government, and Northern Ireland Executive; 2007.
90.
Methadone Maintenance Guidelines. Toronto, Ontario: Coll of Physicians of Ontario; 2005.
91.
Shaiova L, Berger A, Blinderman CD, Bruera E, Davis MP, Derby S, et al. Consensus guideline on parenteral methadone use in pain and palliative care. Palliat Support Care. 2008;6:165-76. [PMID: 18501052]
92.
Bazett HC. An analysis of the time-relations of electrocardiograms. Heart. 1920;7:353-70.
93.
The DASIS Report. Facilities Operating Opioid Treatment Programs: 2005. Rockville, MD: Substance Abuse and Mental Health Services Administration Office of Applied Studies; 2006. Accessed at www.drugabusestatistics.samhsa.gov/2k6/OTP/OTP.pdf on 12 November 2008.
94.
Verispan Total Patient Tracker, Year 2007. Yardley, PA: Verispan; 2008.
95.
Eap CB, Crettol S, Rougier JS, Schläpfer J, Sintra Grilo L, Déglon JJ, et al. Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers. Clin Pharmacol Ther. 2007;81:719-28. [PMID: 17329992]
Information & Authors
Information
Published In
Annals of Internal Medicine
Volume 150 • Number 6 • 17 March 2009
Pages: 387 - 395
History
Published online: 17 March 2009
Published in issue: 17 March 2009
Keywords
Copyright
© 2009 American College of Physicians.
Authors
Metrics & Citations
Metrics
Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. For an editable text file, please select Medlars format which will download as a .txt file. Simply select your manager software from the list below and click Download.
For more information or tips please see 'Downloading to a citation manager' in the Help menu.
Download article citation data for:
QTc Interval Screening in Methadone Treatment. Ann Intern Med.2009;150:387-395. [Epub 17 March 2009]. doi:10.7326/0003-4819-150-6-200903170-00103
QTc Interval Screening in Methadone Treatment. Ann Intern Med.2009;150:387-395. [Epub 17 March 2009]. doi:10.7326/0003-4819-150-6-200903170-00103
View More
Login Options:
Purchase
You will be redirected to acponline.org to sign-in to Annals to complete your purchase.
Access to EPUBs and PDFs for FREE Annals content requires users to be registered and logged in. A subscription is not required. You can create a free account below or from the following link. You will be redirected to acponline.org to create an account that will provide access to Annals. If you are accessing the Free Annals content via your institution's access, registration is not required.
Create your Free Account
You will be redirected to acponline.org to create an account that will provide access to Annals.
Comments
0 Comments