Methadone is highly effective for opioid dependency, but it is associated with Torsade de pointes. Although electrocardiography (ECG) has been proposed, its utility is uncertain, because an ECG-based intervention has not been described. An ECG-based cardiac safety program in methadone maintenance patients was evaluated in a single opioid treatment program from September 1, 2009, to August 31, 2011, in the United States. Time from pretreatment to repeat ECG in new entrants was assessed. The proportion with marked rate-corrected QT (QTc) interval prolongation (>500 ms) and the effect of the intervention on the QTc interval in this group were evaluated. Multivariate predictors of QTc interval change were assessed using a mixed-effects model. Of 531 new entrants, 436 (82%) underwent ≥1 electrocardiographic assessment, and 186 (35%) underwent pretreatment ECG. Median time to follow-up ECG was 43 days but decreased over time (p <0.0001). In 21 patients with QTc intervals >500 ms, the mean QTc interval from peak to final ECG decreased significantly (−55.5 ms, 95% confidence interval −77.0 to −33.9, p = 0.001), and 12 of 21 (57.1%) decreased to lower than the 500-ms threshold. In new entrants with serial ECG, only methadone dose (p = 0.009) and pretreatment QTc interval (p <0.0001) were associated with the magnitude of QTc interval change. In conclusion, this study suggests that the implementation of an ECG-based intervention in methadone maintenance can decrease the QTc interval in high-risk patients; clinical characteristics alone were inadequate to identify patients in need of electrocardiographic screening.
Methadone is a long-acting μ-opioid agonist that is highly effective for the treatment of opioid dependency. Within the opioid drug class, methadone is prescribed to a minority of patients, but it is disproportionately implicated in opioid-related deaths. Although the higher lethality of methadone likely reflects its potency and long half-life, it is known to block the cardiac delayed-rectifier potassium ion current and has been associated with prolongation of the rate-corrected QT (QTc) interval and Torsade de pointes. On a morphine-equivalent basis, the mortality rate for methadone is higher than those of all other prescription opioids, which might in part reflect methadone’s proarrhythmic properties. Recent data from the US Food and Drug Administration from 2004 to 2011 suggest that methadone is currently the most frequently reported drug associated with QTc interval prolongation and Torsade de pointes.
The US Substance Abuse and Mental Health Services Administration’s (SAMHSA) Center for Substance Abuse Treatment convened a cardiac expert panel, which in 2009 published a guideline recommending electrocardiography (ECG) for QTc interval assessment in opioid treatment programs (OTPs). However, controversy regarding the potential of ECG to increase costs and create barriers to care and uncertainty about feasibility have limited its adoption. In response to qualitative field review, SAMHSA reconstituted the expert panel and revised the guideline. The revised SAMHSA guidance and the American Association for the Treatment of Opioid Dependence QTc interval screening policy and guidance statement suggest ECG only for patients with multiple clinical risk factors for arrhythmia, despite a paucity of evidence for a risk factor–based approach. The SAMHSA panel noted concerns regarding the potential of an ECG-based intervention to restrict access to limited therapeutic options, potential challenges due to insufficient support staffing, and uncertainty regarding the appropriateness of computerized (automated) QTc interval measurements. Most important, a real-world demonstration of an outpatient intervention to mitigate risk has not been described for methadone or other QTc interval–prolonging drugs. Given this background, we assessed the feasibility and impact of implementing a pilot ECG-based cardiac safety program using computer-generated QTc interval measurements in methadone maintenance patients.
Methods
The study was approved by the local institutional review board (protocol #11-1168) to evaluate the impact of a cardiac safety program. The program was initiated in an outpatient OTP that provides opioid substitution for a predominantly indigent population affiliated with an urban public hospital. Other than the purchase of a single ECG cart ($4,600), no additional staff hires or institutional resources were provided to support the program. The implementation team consisted of an addiction psychiatrist, an addiction fellow, and an internal medicine physician. Support staff members included the program director, behavioral health technicians, and registered nurses. Nurses and technicians were trained in electrocardiographic acquisition by the hospital cardiology division. No regular cardiology oversight was provided. Methadone was dispensed under direct nursing supervision, and dose tracking was performed using Creative Socio-Medics M4 Patient Workbench (Netsmart Technologies, Great River, New York). All doses were titrated to achieve abstinence from illicit opioids. Preliminary implementation commenced September 1, 2009.
The following recommendations from published cardiac safety guidelines for methadone were considered: (1) disclose arrhythmia risk, (2) assess for a history of heart disease, arrhythmia, and syncope, (3) perform pretreatment ECG in new entrants and perform follow-up ECG within 30 days, (4) if the QTc interval is >500 ms, consider discontinuation or reduction of the methadone dose and elimination of contributing factors, (5) consider interactions between methadone and other QTc interval–prolonging drugs, (6) provide patient educational materials that explain cardiac risk, and (7) educate OTP clinical staff members about QTc interval prolongation. Formal patient and provider education was not instituted. The decision to perform additional ECG in patients with doses exceeding 100 (or 120) mg/day occurred at the discretion of treating physicians. The program was integrated into routine care, and all electrocardiographic studies were performed on site before dosing. No algorithms specifying clinical actions or methadone dose adjustments were used by physicians. Patients were verbally informed of the rationale for ECG to ensure safety. The behavioral health technician scheduled pretreatment and follow-up ECG in coordination with the dosing nurse.
Trough-concentration electrocardiographic measurements were acquired with a Pagewriter Trim III electrocardiograph (Philips Medical Systems, Best, The Netherlands) and a computer-generated QTc interval was calculated by superimposed median complexes. To assess differences between computer-generated QTc intervals and manual readings in patients in whom the cardiac safety program was applicable, a single electrophysiologist manually reviewed all tracings with any computer-generated QTc intervals ≥450 ms. Measurements were performed retrospectively using on-screen digital calipers (Xcelera; Philips Medical Systems). Tracings were reclassified if the manual and computer-generated QTc intervals differed by >10 ms or if the automated heart rate calculation was spurious because of high-frequency artifacts. The QTc interval was defined as the time between the initial deflection from the isoelectric PR interval to the return of the T wave derived from the longest measurement in any lead. The QTc interval was calculated using Bazett’s formula for automated and manually derived values because this formula has been recommended as the standard rate correction method in clinical practice.
Data were collected using a secure Web-based application (Research Electronic Data Capture version 4.8.2). Pertinent medical history and clinical data were abstracted for patients with initial QTc intervals >450 ms by a single abstractor. Categorical variables are summarized as frequency distributions and continuous variables as mean, median, SD, and interquartile range. All tests were 2 sided, and p values <0.05 were considered statistically significant. Statistical analyses were performed using SAS version 9.3 (SAS Institute Inc., Cary, North Carolina).
Baseline clinical characteristics were analyzed among 3 prespecified groups, including the complete cohort, those with QTc intervals of 450 to 499 ms, and those with marked QTc interval prolongation (≥1 value ≥500 ms). Concomitant medications were categorized by therapeutic class and grouped as QTc prolonging or not. The groups with QTc intervals of 450 to 499 ms and marked QTc interval prolongation were compared. Student’s t test was used for comparing mean age and Fisher’s exact tests for categorical variables. For analysis of median time to repeat ECG, patients were grouped into 4 sequential 6-month periods on the basis of the date of initial ECG. Time to repeat ECG for each period was calculated and compared using the Kruskal-Wallis test. To evaluate similarity between computer-generated and manual electrocardiograms, an intraclass correlation coefficient was calculated in patients with any QTc interval >450 ms. In those with marked QTc interval prolongation who had dose reductions, we determined whether the change in dose and QTc interval were linearly related. Clinical interventions performed in patients with marked QTc interval prolongation were tabulated, and the mean change from peak to final QTc interval values were assessed. QTc interval changes from initial measurement were analyzed with demographics (age, gender), clinical characteristics (cardiovascular disease, hypertension, and liver disease), pretreatment QTc interval, and methadone dose as covariates in a mixed-effects model.
Results
During the study period, a total of 953 unique patients were enrolled, of whom 568 (60%) had ≥1 electrocardiographic tracing obtained, and 531 were new entrants. Among new entrants, 436 (82%) underwent ECG and 143 (27%) had >1 electrocardiographic tracing obtained. A total of 186 new entrants (35%) underwent pretreatment ECG, 68 (37%) of whom underwent follow-up ECG. The distribution of patients with decreases or increases in QTc interval is depicted in Figure 1 . Most experienced increases (69%) in QTc interval on methadone, whereas 31% had decreases. This in part reflected undercorrection using Bazett’s formula, because only 22% of patients experienced decreases in QTc interval using Fridericia’s formula. Overall, the mean pretreatment QTc interval was 433.7 ± 16 ms, which increased to 449.2 ± 23 ms after methadone induction, representing an increase of 15.4 ± 25 ms (p <0.0001). This resulted in 16 and 2 patients exceeding the 450- and 500-ms thresholds, respectively. The clinical and demographic characteristics of the overall cohort with ECG, stratified by QTc interval range, are listed in Table 1 . The median time to follow-up ECG over the course of the study was 43 days, which decreased significantly over time from a median of 101 to 29 days (p <0.0001) in those with pretreatment and follow-up ECG ( Figure 2 ).
| Variable ∗ | All Patients (n = 568) | QTc Interval 450–499 ms (n = 195) | QTc Interval ≥500 ms (n = 21) | p Value † |
|---|---|---|---|---|
| Age (yrs) | 41.2 ± 13.1 | 43.6 ± 12.3 | 47.6 ± 15.1 | 0.1633 |
| Male | 322 (56.7%) | 95 (48.7%) | 11 (52.4%) | |
| Female | 242 (42.6%) | 97 (49.7%) | 10 (47.6%) | |
| Hispanic/Latino | 167 (29.4%) | 56 (28.7%) | 9 (42.9%) | 0.2118 |
| Black/African-American | 24 (4.2%) | 5 (2.6%) | 1 (4.8%) | 0.4627 |
| American Indian/Alaska Native | 7 (1.2%) | 4 (2.1%) | 0 (0%) | 1.0000 |
| White | 364 (64.1%) | 129 (66.2%) | 9 (42.9%) | 0.0535 |
| Other race ‡ | 4 (0.7%) | 0 (0%) | 2 (9.5%) | 0.0090 |
| Cardiovascular disease § | 13 (2.3%) | 9 (4.6%) | 4 (19.0%) | 0.0267 |
| Diabetes mellitus | 2 (0.4%) | 1 (0.5%) | 1 (4.8%) | 0.1854 |
| Hypertension | 63 (11.1%) | 50 (25.6%) | 12 (57.1%) | 0.0044 |
| Hypokalemia ‖ | 0 (0%) | 0 (0%) | 0 (0%) | 0 |
| Liver Disease ¶ | 93 (16.4%) | 75 (38.5%) | 12 (57.1%) | 0.1067 |
| Human immunodeficiency virus | 3 (0.5%) | 3 (1.5%) | 0 (0%) | 1.000 |
| Medications | ||||
| QTc interval–prolonging drugs # | 7 (1.2%) | 6 (3.1%) | 0 (0%) | 1.000 |
| Benzodiazepines | 4 (0.7%) | 4 (2.1%) | 0 (0%) | 1.000 |
| Psychiatric drugs | 7 (1.2%) | 6 (3.1%) | 0 (0%) | 1.000 |
| Antihypertensive/diuretic agents | 12 (2.1%) | 8 (4.1%) | 3 (14.3%) | 0.0786 |
| Baseline data | ||||
| QTc interval (ms) | 439.5 ± 28.3 | 458.2 ± 19.6 | 499.0 ± 57.3 | NA |
| Methadone dose (mg) | 44.0 ± 46.3 | 50.9 ± 49.7 | 82.5 ± 53.6 | 0.0065 |
∗ Percentages are based on total number of patients in each group.
† Groups with QTc intervals of 450 to 499 ms and QTc intervals >500 ms were compared by applying Student’s t tests for age ( t = −1.4, df = 214), and baseline dose ( t = −2.75, df = 213). Fisher’s exact tests were used to compare categorical variables.
‡ Participants could self-select >1 race and ethnicity, resulting in percentages not totaling 100%.
§ Includes coronary artery disease, myocardial infarction, and heart failure.
¶ Includes hepatitis C virus seropositivity.
# Includes antiemetics, antibiotics, antidepressants, and antipsychotics.
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