buprenorphine and Arrhythmias--Cardiac

Almost 3 million Americans have abused heroin. The most effective treatment for this concerning epidemic is opioid replacement therapy. Although, from a historical perspective, acceptance of this therapy has been slow, growing evidence supports its efficacy. There are 3 approved medications for opioid maintenance therapy: methadone hydrochloride, levomethadyl acetate, and buprenorphine hydrochloride. Each has unique characteristics that determine its suitability for an individual patient. Cardiac arrhythmias have been reported with methadone and levomethadyl, but not with buprenorphine. Due to concerns about cardiac risk, levomethadyl use has declined and the product may ultimately be discontinued. These recent safety concerns, specifics about opioid detoxification and maintenance, and new federal initiatives were studied. Opioid detoxification has a role in both preventing acute withdrawal and maintaining long-term abstinence. Although only a minority of eligible patients are engaged in treatment, opioid maintenance therapy appears to offer the greatest public health benefits. There is growing interest in expanding treatment into primary care, allowing opioid addiction to be managed like other chronic illnesses. This model has gained wide acceptance in Europe and is now being implemented in the United States. The recent Drug Addiction Treatment Act enables qualified physicians to treat opioid-dependent patients with buprenorphine in an office-based setting. Mainstreaming opioid addiction treatment has many advantages; its success will depend on resolution of ethical and delivery system issues as well as improved and expanded training of physicians in addiction medicine.

Topics: Analgesics, Opioid; Arrhythmias, Cardiac; Buprenorphine; Europe; Humans; Methadone; Methadyl Acetate; Opioid-Related Disorders; Prevalence; Primary Health Care; Substance Withdrawal Syndrome; United States

To study the effect of transdermal buprenorphine on QTc prolongation at dose levels of 10, 40, and 80 mcg/h, (BTDS 10, BTDS 40, BTDS 80).. Two randomized, placebo- and positive-controlled, parallel-group, dose-escalating clinical studies evaluated healthy adult subjects randomized to BTDS, placebo, or moxifloxacin in the first study; and to BTDS only, BTDS plus naltrexone, naltrexone alone at the same dose, placebo, or moxifloxacin in the second study. QT intervals were corrected for heart rate using data from each individual subject (QTcI).. In the first study (n = 44), the maximum upper bounds of the 90% confidence interval (CI) for mean placebo-corrected change from baseline in QTcI across 13 time points over 24 h were: 10.0 msec for BTDS 10 (Day 6) and 13.3 msec for BTDS 40 (Day 13); and 17.0 msec (Day 6) and 15.5 msec (Day 13) for moxifloxacin, respectively.  Similarly, in the second study (n = 66), the upper bound of the 90% CI for mean placebo-corrected change from baseline for QTcI was under 10 msec at all time points for BTDS 10 (maximum upper bound, 5.63 msec), over 10 msec at 5 time points for BTDS 40 (maximum 11.81 msec) and over 10 msec at all 13 time points for BTDS 80 (maximum, 14.14 msec). Naltrexone administered with BTDS eliminated the QTcI prolongation seen with supratherapeutic BTDS doses (BTDS 40, BTDS 80) administered without naltrexone.. At the therapeutic dose of 10 mcg/h, BTDS has no clinically significant effect on QTc. At supratherapeutic doses of 40 and 80 mcg/h, BTDS treatment produces prolongation of QTcI similar in magnitude to that produced by a 400 mg dose of moxifloxacin. Despite the modest, dose-dependent increase in QTcI noted in these studies, transdermal buprenorphine has not been associated with proarrhythmic effects.

Topics: Administration, Cutaneous; Adult; Arrhythmias, Cardiac; Aza Compounds; Buprenorphine; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fluoroquinolones; Healthy Volunteers; Heart Rate; Humans; Male; Middle Aged; Moxifloxacin; Naltrexone; Pain; United States; Young Adult

Epidemic increases in opioid deaths prompted policies limiting access to prescription opioids in North America. Consequently, the over-the-counter opioids loperamide (Imodium A-D) and mitragynine, the herbal ingredient in kratom, are increasingly used to avert withdrawal or induce euphoria. Arrhythmia events related to these nonscheduled drugs have not been systematically studied.. In this study, we sought to explore opioid-associated arrhythmia reporting in North America.. The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS), and Canada Vigilance Adverse Reaction (CVAR) databases were searched (2015-2021). Reports involving nonprescription drugs (loperamide, mitragynine) and diphenoxylate/atropine (Lomotil) were identified. Methadone, a prescription opioid (full agonist), served as a positive control owing to its established arrhythmia risk. Buprenorphine (partial agonist) and naltrexone (pure antagonist), served as negative controls. Reports were classified according to Medical Dictionary for Regulatory Activities terminology. Significant disproportionate reporting required a proportional reporting ratio (PRR) of ≥2, ≥3 cases, and chi-square ≥4. Primary analysis used FAERS data, whereas CAERS and CVAR data were confirmatory.. Methadone was disproportionately associated with ventricular arrhythmia reports (PRR: 6.6; 95% CI: 6.2-7.0; n = 1,163; chi-square = 5,456), including 852 (73%) fatalities. Loperamide was also significantly associated with arrhythmia (PRR: 3.2; 95% CI: 3.0-3.4; n = 1,008; chi-square = 1,537), including 371 (37%) deaths. Mitragynine demonstrated the highest signal (PRR: 8.9; 95% CI: 6.7-11.7; n = 46; chi-square = 315), with 42 (91%) deaths. Buprenorphine, diphenoxylate, and naltrexone were not associated with arrhythmia. Signals were similar in CVAR and CAERS.. The nonprescription drugs loperamide and mitragynine are associated with disproportionate reports of life-threatening ventricular arrhythmia in North America.

Topics: Analgesics, Opioid; Arrhythmias, Cardiac; Buprenorphine; Diphenoxylate; Humans; Loperamide; Methadone; Naltrexone; Nonprescription Drugs

No data exist on comparative risk of cardiac arrhythmias among 3 Medication-Assisted Therapy (MAT) medications in patients with opioid use disorder. Understanding MAT medications with the least risk of arrhythmia can guide clinical decision-making.. A multicenter retrospective cohort study was performed of patients 18 years or older diagnosed with opioid use disorder by the International Classification of Diseases, 10th revision, Clinical Modification without baseline arrhythmia in 2018-2019, using Clinformatics Data Mart Database (Optum, Eden Prairie, Minn). Everyone required 1 year of continuous enrollment prior to and after the diagnosis. Patients with MAT were propensity score-matched to those without MAT. Primary outcome was rate of arrhythmia across MAT (methadone, naltrexone, and buprenorphine). A multivariable logistic regression model was built to examine the outcome difference across 3 medications adjusted for patient's demographic and comorbidity.. Only 14.1% of the 66,083 patients with opioid use disorder received MAT prescriptions in the 12 months after diagnosis. New-onset arrhythmia diagnoses occur more frequently among MAT vs non-MAT users (4.86% vs 3.92%), with 29% risk of incident arrhythmias among MAT users, even after adjusting relevant confounders (adjusted odds ratio [aOR] 1.29; 95% confidence interval [CI], 1.11-1.52). Incidence of arrhythmia varied by drugs: naltrexone (9.57%), methadone (5.71%), and buprenorphine (3.81%). Difference among the MAT drugs in incidence of arrhythmia remained significant even after adjusting covariates (aOR 2.44; 95% CI, 1.63-3.64 and buprenorphine aOR 0.77; 95% CI, 0.59-1.00, with methadone as reference).. MAT users had higher risk of cardiac arrhythmia than non-users. Naltrexone is associated with the highest risk of arrhythmia, suggesting caution with naltrexone use, especially in opioid use disorder patients with pre-existing heart conditions.

Topics: Analgesics, Opioid; Arrhythmias, Cardiac; Buprenorphine; Humans; Methadone; Naltrexone; Opiate Substitution Treatment; Opioid-Related Disorders; Retrospective Studies

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

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

Topics: Animals; Arrhythmias, Cardiac; Buprenorphine; Coronary Vessels; Dogs; Dose-Response Relationship, Drug; Female; Ligation; Male; Morphinans; Myocardial Infarction; Naloxone

Topics: Adult; Anesthesia, General; Arrhythmias, Cardiac; Buprenorphine; Cardiac Surgical Procedures; Female; Humans; Male; Middle Aged; Morphinans