buprenorphine and Long-QT-Syndrome

Cardiac arrhythmias have been linked to treatment with methadone and levacetylmethadol. HIV-positive patients often have conditions that place them at risk for QT interval prolongation including HIV-associated dilated cardiomyopathy, coronary artery disease as a consequence of highly active antiretroviral (ARV) therapy-associated metabolic syndrome, and uncorrected electrolyte abnormalities. As of February 14, 2006, no cases of adverse events related to QT interval prolongation have been reported in patients receiving buprenorphine, an opioid partial agonist and the newest drug approved for the treatment of opioid dependence.. To evaluate the effects of buprenorphine/naloxone alone and in combination with 1 of 5 ARV agents (efavirenz, nelfinavir, delavirdine, ritonavir, lopinavir/ritonavir) on the QT interval.. This study was prospective, open-label, and within-subject in design, with subjects serving as their own controls. In 50 HIV-negative, opioid-dependent subjects, electrocardiogram recordings were obtained at baseline, after receiving buprenorphine/naloxone for 2 weeks, and then following buprenorphine/naloxone plus ARV administration for 5-15 days at steady-state. QTc interval measurements were compared using mixed-model, repeated-measures ANOVA. Recent cocaine use and gender were considered covariates.. Buprenorphine/naloxone alone and often in the presence of evidence for recent use of cocaine did not significantly alter the QT interval (p = 0.612). Buprenorphine/naloxone in combination with ARVs caused a statistically, but not clinically, significant increase (p = 0.005) in the QT interval. Subjects receiving buprenorphine/naloxone in combination with either delavirdine or ritonavir had the greatest increase in QTc intervals.. Prolonged QT intervals were not observed in opioid-dependent subjects receiving buprenorphine/naloxone alone. QT interval increases were observed with buprenorphine/naloxone in combination with either delavirdine or ritonavir, which inhibit CYP3A4.

Topics: Adult; Analgesics, Opioid; Antiretroviral Therapy, Highly Active; Buprenorphine; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Electrocardiography; Female; Humans; Long QT Syndrome; Male; Middle Aged; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Prospective Studies

More than 109,000 Americans died of drug overdose in 2022, with 81,231 overdose deaths involving opioids. Methadone, buprenorphine and naltrexone are the most widely used medications for opioid use disorders (MOUD) and the most effective intervention for preventing overdose deaths. However, there is a concern that methadone results in long QT syndrome, which increases the risk for fatal cardiac arrythmias. Currently few studies have systematically evaluated both the short-term and long-term differences in cardiac and mortality outcomes between MOUD.. To compare the risks of cardiac arrythmias, long QT syndrome and overall mortality between patients with opioid use disorders (OUD) who were prescribed methadone, buprenorphine or naltrexone.. Retrospective cohort study based on a multicenter and nationwide database of electronic health records (EHRs) in the United States. The study population was comprised of 144,141 patients who had medical encounters for OUD in 2016-2022, were prescribed MOUD within 1 month following a medical encounter for OUD diagnosis and had no diagnosis of cardiac arrythmias or long QT syndrome before any MOUD prescription. The study population was divided into three cohorts: (1) Methadone cohort (n = 40,938)-who were only prescribed methadone. (2) Buprenorphine cohort (n = 80,055)-who were only prescribed buprenorphine. (3) Naltrexone cohort (n = 5,738)-who were only prescribed naltrexone.. methadone, buprenorphine, or naltrexone.. Cardiac arrythmias, long QT syndrome, and death. Hazard ratio (HR) and 95% confidence interval (CI) of outcomes at six different follow-up time frames (1-month, 3-month, 6-month, 1-year, 3-year, and 5-year) by comparing propensity-score matched cohorts using Kaplan-Meier survival analysis.. Patients with OUD who were prescribed methadone had significantly higher risks of cardiac arrhythmias, long QT syndrome and death compared with propensity-score matched patients with OUD who were prescribed buprenorphine or naltrexone. For the 1-month follow-up, the overall risk for cardiac arrythmias was 1.03% in the Methadone cohort, higher than the 0.87% in the matched Buprenorphine cohort (HR: 1.20, 95% CI: 1.04-1.39); The overall risk for long QT syndrome was 0.35% in the Methadone cohort, higher than the 0.15% in the matched Buprenorphine cohort (HR: 2.40, 95% CI: 1.75-3.28); The overall mortality was 0.59% in the Methadone cohort, higher than the 0.41% in the matched Buprenorphine cohort (HR: 1.48, 95% CI: 1.21-1.81). The increased risk persisted for 5 years: cardiac arrhythmias (HR: 1.31, 95% CI: 1.23-1.38), long QT syndrome (HR: 3.14, 95% CI: 2.76-3.58), death (HR: 1.50, 95% CI: 1.41-1.59).. Methadone was associated with a significantly higher risk for cardiac and mortality outcomes than buprenorphine and naltrexone. These findings are relevant to the development of guidelines for medication selection when initiating MOUD treatment and inform future medication development for OUD that minimizes risks while maximizing benefits.

Topics: Buprenorphine; Humans; Long QT Syndrome; Methadone; Naltrexone; Opiate Substitution Treatment; Opioid-Related Disorders; Prescriptions; Retrospective Studies; United States

Extensive 12-lead electrocardiogram monitoring and drug concentrations were obtained during development of BUP-XR, a monthly subcutaneous injection for the treatment of opioid use disorder (OUD). Matched QT and plasma drug concentrations (11,925) from 1,114 subjects were pooled from 5 studies in OUD. A concentration-QT model was developed, which accounted for confounding factors (e.g., comedications) affecting heart rate and heart rate-corrected QT interval (QTc). Bias-corrected nonparametric two-sided 90% confidence intervals (CIs) were derived for the mean predicted effect of BUP-XR on QTc (ΔQTc) at therapeutic and supratherapeutic doses. Changes in QTc were associated with age, central vs. noncentral reading, sex, methadone, and barbiturates. The upper 90% CI of ΔQTc was 0.29, 0.67, and 1.34 ms at the steady-state peak concentration (C

Topics: Adult; Age Factors; Aged; Barbiturates; Buprenorphine; Delayed-Action Preparations; Dose-Response Relationship, Drug; Electrocardiography; Female; Humans; Injections, Subcutaneous; Long QT Syndrome; Male; Methadone; Middle Aged; Opiate Substitution Treatment; Opioid-Related Disorders; Sex Factors; Young Adult

Methadone is a widely used opioid agonist treatment associated with QT prolongation and torsades de pointes. We investigated the QT interval in patients treated with methadone or buprenorphine using continuous 12-lead Holter recordings.. We prospectively made 24-h Holter recordings in patients prescribed methadone or buprenorphine, compared to controls. After their normal dose a continuous 12-lead Holter recorder was attached for 24 h. Digital electrocardiograms were extracted hourly from the Holter recordings. The QT interval was measured automatically (H-scribe software, Mortara Pty Ltd) and checked manually. The QT interval was plotted against heart rate (HR) on the QT nomogram to determine abnormality. Demographics, dosing, medical history and laboratory investigations were recorded.. Methadone is associated with prolonged QT intervals, but there was no association with dose. Buprenorphine did not prolong the QT interval. Twenty four-hour Holter recordings using the QT nomogram is a feasible method to assess the QT interval in patients prescribed methadone.

Topics: Adult; Analgesics, Opioid; Buprenorphine; Dose-Response Relationship, Drug; Electrocardiography; Female; Humans; Long QT Syndrome; Male; Methadone; Middle Aged; Opiate Substitution Treatment; Opioid-Related Disorders; Prospective Studies; Torsades de Pointes; Young Adult

Topics: Analgesics, Opioid; Arrhythmias, Cardiac; Buprenorphine; Dose-Response Relationship, Drug; Humans; Long QT Syndrome; Methadone; Opioid-Related Disorders; United States Food and Drug Administration

Topics: Arrhythmias, Cardiac; Buprenorphine; Electrocardiography; Humans; Long QT Syndrome; Methadone; Torsades de Pointes; United States Food and Drug Administration

To assess the relative frequency of reporting of adverse events involving ventricular arrhythmia, cardiac arrest, corrected QT interval (QTc) prolongation or torsade de pointes to the US Food and Drug Administration (FDA) between buprenorphine and methadone.. Retrospective pharmacoepidemiological study.. Adverse drug events reported spontaneously to the FDA between 1969 and June 2011 originating in 196 countries (71% events from the United States).. Adverse event cases mentioning methadone (n = 14 915) or buprenorphine (n = 7283) were evaluated against all other adverse event cases (n = 4 796 017).. The primary outcome was the composite of ventricular arrhythmia or cardiac arrest. The secondary outcome was the composite of QTc prolongation or torsade de pointes. The proportional reporting ratio (PRR) was used to identify disproportionate reporting defined as a PRR > 2, χ(2) error > 4, with ≥ 3 cases.. There were 132 (1.8%) ventricular arrhythmia/cardiac arrest and 19 (0.3%) QTc prolongation/torsade de pointes cases associated with buprenorphine compared with 1729 (11.6%) ventricular arrhythmia/cardiac arrest and 390 (2.6%) QTc prolongation/torsade de pointes cases involving methadone. PRRs associated with buprenorphine were not significant for ventricular arrhythmia/cardiac arrest (1.10, 95%, confidence interval (0.93-1.31, χ(2)  = 1.2) or QTc prolongation/torsade de pointes (1.03, 95% CI = 0.66-1.62, χ(2)  = 0.01), but were for methadone (7.20, 95% CI = 6.88-7.52, χ(2)  = 8027; 10.7, 95% CI = 9.66-11.8, χ(2)  = 1538, respectively).. In spontaneously reported adverse events, methadone is associated with disproportionate reporting of cardiac arrhythmias, whereas buprenorphine is not. Although these findings probably reflect clinically relevant differences, a causal connection cannot be presumed and disproportionality analysis cannot quantify absolute risk per treatment episode. Population-based studies to definitively quantify differential incidence rates are warranted.

Topics: Adult; Arrhythmias, Cardiac; Buprenorphine; Female; Heart Arrest; Humans; Long QT Syndrome; Male; Methadone; Narcotic Antagonists; Retrospective Studies; Torsades de Pointes; United States; United States Food and Drug Administration

The authors investigated whether patients receiving buprenorphine maintenance treatment (BMT) will have corrected QT (QTc) prolongation after taking buprenorphine for an extended period of time. They also compared QTc prolongation for patients in methadone maintenance treatment (MMT) versus BMT to determine which medication is the better option for patients with heart disease. A retrospective chart review study of 73 patients in BMT and 55 patients in MMT was performed. A linear regression model with a one-sided P value was used for data analysis. The MMT group had statistically significant prolongation of QTc compared with the BMT group (F = 3.94, P = .0001). Being diagnosed with congestive heart failure and taking methadone were the only individual variables that showed a statistically significant association with a QTc prolongation > 500 ms. The model as a whole showed statistical significance (F = 5.203, P = .007). Being diagnosed with congestive heart failure was the only individual variable that showed a statistically significant association with mortality. The model as a whole also showed statistical significance (F = 17.15, P = .000). This study supports previous findings that methadone may be associated with QTc prolongation, whereas buprenorphine may not. This study has the advantage of confirming that QTc prolongation persists in patients in MMT but not in those in BMT over an extended period of time (i.e., 5 years). Buprenorphine might a better first-line opioid maintenance treatment for patients with heart disease because buprenorphine was not associated with QTc prolongation. Patients in BMT may not need to be screened routinely for QTc prolongation.

Topics: Adult; Aged; Buprenorphine; Comorbidity; Dose-Response Relationship, Drug; Electrocardiography; Epidemiologic Methods; Female; Heart Failure; Humans; Long QT Syndrome; Male; Methadone; Middle Aged; Opiate Substitution Treatment; Opioid-Related Disorders; Outcome Assessment, Health Care; Time Factors

Methadone and buprenorphine are widely used in the treatment of opioid addiction. Some study results suggest that methadone can be associated with QT interval prolongation and torsades de pointes ventricular arrhythmias, whereas no such risk has been observed for buprenorphine. The aim of this study is to determine the risk of corrected QT interval (QTc) increase among patients treated with these medications in an opioid maintenance treatment (OMT) programme, and to study possible associations between QTc changes and serum concentrations of methadone or buprenorphine.. Eighty patients enrolled in the OMT programme were followed after start of treatment with methadone (n=45) or buprenorphine (n=35). QTc interval was assessed by electrocardiography (ECG) at baseline and after 1 month (n=79) and 6 months (n=66) in the OMT programme. Blood samples were obtained for the analysis of serum concentrations of buprenorphine, (R)-methadone, (S)-methadone and total methadone.. No patients had QTc prolongation (defined as a QTc value above 450 ms) at baseline or after 1 or 6 months. When analysed in a linear mixed effects model, QTc was not associated with the serum concentrations of buprenorphine or methadone. However, low serum potassium levels increased QTc significantly.. These results support and extend previous findings that treatment with methadone in modest doses (i.e. below 100mg/d) is not associated with clinically significant QTc increases, and that buprenorphine in commonly used doses is a suitable alternative to methadone with regard to the risk of QTc prolongation.

Topics: Adult; Arrhythmias, Cardiac; Buprenorphine; Electrocardiography; Female; Humans; International Classification of Diseases; Linear Models; Long QT Syndrome; Longitudinal Studies; Male; Methadone; Middle Aged; Narcotics; Opioid-Related Disorders; Potassium; Risk; Sex Characteristics; Torsades de Pointes; Young Adult

Illicit drugs such as cocaine, and methadone can induce acquired long QT syndrome.. The aim of this study was to evaluate the prevalence of cardiovascular disease and to assess the risk of torsades de pointes in substance abuse patients either with methadone or buprenorphine maintenance therapy, or without any specific therapy for opiate addiction.. From November 2008 to December 2009, 190 patients (153 men, mean age 38.2 years, 22-56 years) with a substance use disorder according to DSM IV TR criteria were included in the study. All patients underwent blood tests, serial electrocardiogram (ECG) and, when necessary, additional testing, including echocardiogram, exercise test and Holter monitoring. Age and sex-matched healthy controls were also evaluated and compared with the cases.. One hundred and twenty-five patients (65.7%) had associated diseases. The prevalence of coronary artery disease and hypertension was, respectively, 2.1 and 5.2% in the addicted population. The percentage of abnormal ECGs was 34.2% in the addicted population and 4.7% in the nonaddicted population (P < 0.001). Twenty-five addicted patients had a QT interval prolongation (10 patients ≥ 480 ms). There were no sudden deaths or major cardiac events during the observation period.. Our results indicate that the QT interval prolongation is not a negative prognostic marker in the addicted population, even with associated diseases. ECG should be performed when other drugs potentially prolonging QT interval are associated. Substance abuse patients should be followed by multidisciplinary teams, and blood tests and ECGs should be performed regularly.

Topics: Adult; Buprenorphine; Cardiovascular Diseases; Electrocardiography; Female; Humans; Hypertension; Long QT Syndrome; Male; Methadone; Middle Aged; Observation; Opiate Substitution Treatment; Opioid-Related Disorders; Substance Abuse Detection; Torsades de Pointes; Young Adult

This study investigates opioid maintenance treatment (OMT) patients found to have corrected QT (QTc) interval above 500 ms, with particular focus on past medical history, genetic testing and cardiac investigations.. Detailed medical and cardiac history was obtained, with particular focus upon risk factors. Cardiac investigations, including genetic testing for the five most common long QT syndrome (LQTS) mutations, exercise electrocardiography (ECG) and 24-h ECG recordings, were performed.. Of 200 OMT patients assessed with ECG, seven methadone maintained patients identified with QTc interval above 500 ms participated in this study. Two were identified as heterozygous LQTS mutation carriers. Both had experienced cardiac symptoms prior to and during OMT. No other risk factors for QTc prolongation were detected among the seven patients. Six of the seven patients underwent further cardiac investigations. QTc intervals fluctuated widely over 24h and during exercise for all patients. Only one of the LQTS mutation carriers switched to buprenorphine and started on a beta-blocker. Despite strong medical advice and information, none of the other patients wanted to switch to buprenorphine or take other cardiac protective measures.. Findings indicate the importance of recording a thorough past medical history, focusing specifically on previous cardiac symptoms, and on other known risk factors for QTc prolongation, prior to initiating patients on methadone.

Topics: Adult; Analgesics, Opioid; Buprenorphine; Electrocardiography; Female; Genetic Testing; Heterozygote; Humans; Long QT Syndrome; Male; Methadone; Middle Aged; Mutation; Opiate Substitution Treatment; Risk Factors

To determine the prevalence of corrected QT interval (QTc) prolongation among patients in opioid maintenance treatment (OMT) and to investigate mortality potentially attributable to QTc prolongation in the Norwegian OMT programme.. Two hundred OMT patients in Oslo were recruited to the QTc assessment study between October 2006 and August 2007. The Norwegian register of all patients receiving OMT in Norway (January 1997-December 2003) and the national death certificate register were used to assess mortality. Mortality records were examined for the 90 deaths that had occurred among 2382 patients with 6450 total years in OMT.. The QTc interval was assessed by electrocardiography (ECG). All ECGs were examined by the same cardiologist, who was blind to patient history and medication. Mortality was calculated by cross-matching the OMT register and the national death certificate register: deaths that were possibly attributable to QTc prolongation were divided by the number of patient-years in OMT.. In the QTc assessment sample (n = 200), 173 patients (86.5%) received methadone and 27 (13.5%) received buprenorphine. In the methadone group, 4.6% (n = 8) had a QTc above 500 milliseconds; 15% (n = 26) had a QTc interval above 470 milliseconds; and 28.9% (n = 50) had a QTc above 450 milliseconds. All patients receiving buprenorphine (n = 27) had QTc results <450 milliseconds. A positive dose-dependent association was identified between QTc length and dose of methadone, and all patients with a QTc above 500 milliseconds were taking methadone doses of 120 mg or more. OMT patient mortality, where QTc prolongation could not be excluded as the cause of death, was 0.06/100 patient-years. Only one death among 3850 OMT initiations occurred within the first month of treatment.. Of the methadone patients, 4.6% had QTc intervals above 500 milliseconds. The maximum mortality attributable to QTc prolongation was low: 0.06 per 100 patient-years.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Buprenorphine; Female; Humans; Long QT Syndrome; Male; Methadone; Middle Aged; Narcotic Antagonists; Norway; Opioid-Related Disorders; Prevalence; Young Adult

There has been recent concern about the association between high dose methadone and prolongation of QTc in the electrocardiogram. QTc is the time from the beginning of the QRS complex to the end of the T have as measured on an electrocardiogram and corrected for heart rate. To date, no association has been made between methadone and buprenorphine in commonly used doses and prolonged QTc. Electrocardiograms were performed on groups of methadone (n = 35, mean daily dose +/- standard deviation, 69 +/- 29 mg) and buprenorphine (n = 19, mean daily dose 11 +/- 5 mg) subjects and a group of non-opioid dependent controls (n = 17). Mean QTc did not differ (p = 0.45) between methadone, buprenorphine, or controls. Methadone subjects were significantly (odds ratio of 7.8) more likely to have U waves than buprenorphine and controls combined. Methadone subjects with U waves were maintained on higher (p = 0.004) doses (89 +/- 29 mg/day) than methadone subjects without U waves (60 +/- 24 mg/day). Methadone subjects taking 60 mg and above had higher (p = 0.02) QTc (405 +/- 29 milliseconds) than methadone subjects taking less than 60 mg per day (381 +/- 27 milliseconds). Although an association is thought to exist between high methadone doses and elongated QTc, methadone and buprenorphine, at commonly used daily doses, remain safe agents for opioid substitution therapy.

Topics: Adult; Buprenorphine; Dose-Response Relationship, Drug; Electrocardiography; Female; Humans; Long QT Syndrome; Long-Term Care; Male; Methadone; Middle Aged; Narcotics; Opioid-Related Disorders; Risk Factors

Methadone is prescribed to heroin addicts to decrease illicit opioid use. Prolongation of the QT interval in the ECG of patients with torsade de pointes (TdP) has been reported in methadone users. As heroin addicts sometimes faint while using illicit drugs, doctors might attribute too many episodes of syncope to illicit drug use and thereby underestimate the incidence of TdP in this special population, and the high mortality in this population may, in part, be caused by the proarrhythmic effect of methadone.. In this cross-sectional study interview, ECGs and blood samples were collected in a population of adult heroin addicts treated with methadone or buprenorphine on a daily basis. Of the patients at the Drug Addiction Service in the municipal of Copenhagen, 450 (approximately 52%) were included. The QT interval was estimated from 12 lead ECGs. All participants were interviewed about any experience of syncope. The association between opioid dose and QT, and methadone dose and reporting of syncope was assessed using multivariate linear regression and logistic regression, respectively.. Methadone dose was associated with longer QT interval of 0.140 ms/mg (p = 0.002). No association between buprenorphine and QTc was found. Among the subjects treated with methadone, 28% men and 32% women had prolonged QTc interval. None of the subjects treated with buprenorphine had QTc interval >0.440 s((1/2)). A 50 mg higher methadone dose was associated with a 1.2 (95% CI 1.1 to 1.4) times higher odds for syncope.. Methadone is associated with QT prolongation and higher reporting of syncope in a population of heroin addicts.

Topics: Adult; Buprenorphine; Cross-Sectional Studies; Dose-Response Relationship, Drug; Electrocardiography; Female; Heroin Dependence; Humans; Long QT Syndrome; Male; Methadone; Middle Aged; Narcotics; Syncope