First Trimester Use of Buprenorphine or Methadone and the Risk of Congenital Malformations.

Importance: Use of buprenorphine or methadone to treat opioid use disorder is recommended in pregnancy; however, their teratogenic potential is largely unknown. Objective: To compare the risk of congenital malformations following in utero exposure to buprenorphine vs methadone. Design, Setting, and Participants: This population-based cohort study used health care utilization data from publicly insured Medicaid beneficiaries in the US from 2000 to 2018. A total of 13 360 pregnancies with enrollment from 90 days prior to pregnancy start through 1 month after delivery and first trimester use of buprenorphine or methadone were included and linked to infants. Data were analyzed from July to December 2022. Exposure: A pharmacy dispensing of buprenorphine or a code for administration of methadone in the first trimester. Main Outcomes and Measures: Primary outcomes included major malformations overall and malformations previously associated with opioids (any cardiac malformations, ventricular septal defect, secundum atrial septal defect/nonprematurity-related patent foramen ovale, neural tube defects, clubfoot, and oral clefts). Secondary outcomes included other organ system-specific malformations. Risk differences and risk ratios (RRs) were estimated comparing buprenorphine with methadone, adjusting for confounders with propensity score overlap weights. Results: The cohort included 9514 pregnancies with first-trimester buprenorphine exposure (mean [SD] maternal age, 28.4 [4.6] years) and 3846 with methadone exposure (mean [SD] maternal age, 28.8 [4.7] years). The risk of malformations overall was 50.9 (95% CI, 46.5-55.3) per 1000 pregnancies for buprenorphine and 60.6 (95% CI, 53.0-68.1) per 1000 pregnancies for methadone. After confounding adjustment, buprenorphine was associated with a lower risk of malformations compared with methadone (RR, 0.82; 95% CI, 0.69-0.97). Risk was lower with buprenorphine for cardiac malformations (RR, 0.63; 95% CI, 0.47-0.85), including both ventricular septal defect (RR, 0.62; 95% CI, 0.39-0.98) and secundum atrial septal defect/nonprematurity-related patent foramen ovale (RR, 0.54; 95% CI, 0.30-0.97), oral clefts (RR, 0.65; 95% CI, 0.35-1.19), and clubfoot (RR, 0.55; 95% CI, 0.32-0.94). Results for neural tube defects were uncertain given low event counts. In secondary analyses, buprenorphine was associated with a decreased risk of central nervous system, urinary, and limb malformations but a greater risk of gastrointestinal malformations compared with methadone. These findings were consistent in sensitivity and bias analyses. Conclusions and Relevance: In this cohort study, the risk of most malformations previously associated with opioid exposure was lower in buprenorphine-exposed infants compared with methadone-exposed infants, independent of measured confounders. Malformation risk is one factor that informs the individualized patient decision regarding medications for opioid use disorder in pregnancy.

Routine Monitoring of QTc Interval as a Barrier for Efficient Use of Methadone in Palliative Care.

BACKGROUND: Methadone is a commonly prescribed opioid amongst cancer patients. It has unique pharmacological properties which can benefit in treating complex pain syndromes and neuropathic pain. However, strict guidelines have been created in a generalized manner for chronic pain and long-term survival patients. These guidelines, such as QT interval monitoring can lead to limitations for methadone use in patients with comfort-associated goals. We present two cases of patients with metastatic cancer who were treated for pain with methadone and had to undergo opioid rotation due to abnormal QT intervals. CASE DESCRIPTION: Case one was a female with open ulcerated wounds due to metastatic breast cancer who presented with uncontrolled pain on her current opioid regimen. She achieved pain relief when rotated to methadone but a repeat electrocardiogram a few months later showed QTc prolongation. She underwent opioid rotation with different medications, but her pain remained poorly controlled. Case two was a female with poorly controlled pain in the setting of bilateral breast cancer. She presented with concerns for opioid-induced neurotoxicity and was rotated to methadone. She achieved optimal pain relief. A few weeks later, her machine read QT interval was prolonged and she was rotated off methadone. The electrocardiogram was manually read which showed a normal QT interval and she was restarted on methadone with pain relief. CONCLUSION: In the palliative care setting, monitoring QTc per chronic pain guidelines may lead to uncontrolled pain and a significant impact on quality of life.

Transplacental methadone exposure and risk of Neonatal Opioid Withdrawal Syndrome.

STUDY OBJECTIVE: Neonatal opioid withdrawal syndrome (NOWS) is a condition that often occurs in neonates born to mothers who received methadone treatment for opioid use disorder during pregnancy. Early identification and treatment of infants at risk of NOWS may improve clinical outcomes. The purpose of this study was to evaluate whether maternal and umbilical cord plasma concentrations of methadone and its metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), could predict the need for NOWS treatment. DESIGN: Single-center prospective study. SETTING: University of Michigan Neonatal Intensive Care Unit. PATIENTS: The study included 11 opioid-dependent mother-infant dyads, where the mothers were treated with methadone at 34 weeks' gestation or later. INTERVENTION: Maternal and cord blood samples were collected from the study participants. MEASUREMENTS AND MAIN RESULTS: Maternal and cord plasma concentrations of methadone and EDDP were determined. Six out of the 11 infants required treatment for NOWS. Maternal methadone plasma concentrations were comparable between infants requiring and not requiring NOWS treatment (329.1 ± 229.7 ng/mL vs. 413.2 ± 329.8 ng/mL). However, the average cord plasma methadone concentration in infants who did not require NOWS treatment was 2.9-fold higher than in those who required the treatment (120.0 ± 88.6 ng/mL vs. 40.9 ± 24.4 ng/mL), although the difference was not statistically significant. The ratios of maternal-to-cord methadone plasma concentrations were significantly higher in patients who required treatment for NOWS compared with those who did not (7.7 ± 1.9 vs. 3.5 ± 1.6, p = 0.003). Maternal and cord plasma EDDP concentrations and the maternal-to-cord plasma EDDP concentration ratios did not differ between patients who required and did not require treatment for NOWS. CONCLUSIONS: The results suggest that methadone permeability across the blood-placental barrier may affect in utero exposure to methadone, and the maternal-to-cord methadone plasma concentration ratio could be a potential biomarker for predicting the need for NOWS treatment.

Impaired vision in children prenatally exposed to methadone: an observational cohort study.

BACKGROUND/OBJECTIVES: To examine prevalence of failed visual assessment at 8-10 years in children born to methadone-maintained opioid dependent (MMOD) mothers and relate this to known in utero substance exposure. SUBJECTS/METHODS: Follow up of observational cohort study of methadone-exposed and comparison children matched for birthweight, gestation and postcode of residence at birth. Participants were 144 children (98 exposed, 46 comparison). Prenatal drug exposure was previously established via comprehensive maternal and neonatal toxicology. Children were invited to attend for visual assessment and casenotes were reviewed. Presence of acuity poorer than 0.2 logMAR, strabismus, nystagmus and/or impaired stereovision constituted a 'fail'. Fail rates were compared between methadone-exposed and comparison children after adjusting for known confounding variables. RESULTS: 33 children attended in person: data were also derived from casenote review for all children. After controlling for maternal reported tobacco use, methadone-exposed children were more likely to have a visual 'fail' outcome, adjusted odds ratio 2.6, 95% CI 1.1-6.2; adjusted relative risk 1.8 (95% CI 1.1-3.4). Visual 'fail' outcome rates did not differ between methadone-exposed children who had (n = 47) or had not (n = 51) received pharmacological treatment for neonatal abstinence/opioid withdrawal syndrome (NAS/NOWS); fail rate 62% vs 53% (95% CI of difference-11-27%). CONCLUSIONS: Children born to MMOD mothers are almost twice as likely as unexposed peers to have significant visual abnormalities at primary school age. Prenatal methadone exposure should be considered in the differential diagnosis of nystagmus. Findings support visual assessment prior to school entry for children with any history of prenatal opioid exposure. TRIAL REGISTRATION: The study was prospectively registered on ClinicalTrials.gov (NCT03603301), https://clinicaltrials.gov/ct2/show/NCT03603301 .

Initiation and rapid titration of methadone and slow-release oral morphine (SROM) in an acute care, inpatient setting: a case series.

BACKGROUND: Methadone titration in an outpatient setting typically involves initiation with subtherapeutic doses with slow titration to mitigate the risks of respiratory depression and overdose. In pregnancy, and generally, subtherapeutic doses of methadone and slow titrations are associated with poorer outcomes in terms of treatment retention and ongoing illicit opioid use. We aim to describe rapid titration of OAT in an inpatient setting for pregnant injection opioid users with high opioid tolerance secondary to a fentanyl-based illicit drug supply. METHODS: Retrospective case series of patients admitted to a tertiary center with a primary indication of opioid withdrawal and treatment for severe opioid use disorder in pregnancy. RESULTS: Twelve women received rapid methadone titrations with or without slow-release oral morphine for opioid use disorder during a total of fifteen hospital admissions. All women included in the study were active fentanyl users (12/12). Methadone dosing was increased rapidly with no adverse events with a median dose at day 7 of 65 mg (IQR 60-70 mg) and median discharge dose of 85 mg (IQR 70-92.5 mg) during their admission for titration. Slow-release oral morphine was used in half of the titration admissions (8/15) with a median dose of 340 mg (IQR 187.5-425 mg) at discharge. The median length of admission was 12 days (IQR 9.5-15). CONCLUSIONS: A rapid titration of methadone was completed in an inpatient setting with or without slow-release oral morphine, without adverse events showing feasibility of this protocol for a pregnant population in an inpatient setting. Patients achieved therapeutic doses of methadone (and/or SROM) faster than outpatient counterparts with no known adverse events.

Large variations in all-cause and overdose mortality among >13,000 patients in and out of opioid maintenance treatment in different settings: a comparative registry linkage study.

Background: Opioid maintenance treatment (OMT) has the potential to reduce mortality rates substantially. We aimed to compare all-cause and overdose mortality among OMT patients while in or out of OMT in two different countries with different approaches to OMT. Methods: Two nation-wide, registry-based cohorts were linked by using similar analytical strategies. These included 3,637 male and 1,580 female patients enrolled in OMT in Czechia (years 2000-2019), and 6,387 male and 2,078 female patients enrolled in OMT in Denmark (years 2007-2018). The direct standardization method using the European (EU-27 plus EFTA 2011-2030) Standard was employed to calculate age-standardized rate to weight for age. All-cause and overdose crude mortality rates (CMR) as number of deaths per 1,000 person years (PY) in and out of OMT were calculated for all patients. CMRs were stratified by sex and OMT medication modality (methadone, buprenorphine, and buprenorphine with naloxone). Results: Age-standardized rate for OMT patients in Czechia and Denmark was 9.7/1,000 PY and 29.8/1,000 PY, respectively. In Czechia, the all-cause CMR was 4.3/1,000 PY in treatment and 10.8/1,000 PY out of treatment. The overdose CMR was 0.5/1,000 PY in treatment and 1.2/1,000 PY out of treatment. In Denmark, the all-cause CMR was 26.6/1,000 PY in treatment and 28.2/1,000 PY out of treatment and the overdose CMR was 7.3/1,000 PY in treatment and 7.0/1,000 PY out of treatment. Conclusion: Country-specific differences in mortality while in and out of OMT in Czechia and Denmark may be partly explained by different patient characteristics and treatment systems in the two countries. The findings contribute to the public health debate about OMT management and may be of interest to practitioners, policy and decision makers when balancing the safety and accessibility of OMT.

Rapid Methadone Induction in a General Hospital Setting: A Retrospective, Observational Analysis.

BACKGROUND: Outpatient methadone guidelines recommend starting at a low dose and titrating slowly. As fentanyl prevalence and opioid-related mortality increases, there is a need for individuals to rapidly achieve a therapeutic methadone dose. Hospitalization offers a monitored setting for methadone initiation, however dosing practices and safety are not well described. METHODS: Retrospective, observational analysis of hospitalized patients with opioid use disorder seen by an inpatient addiction consult team in an academic medical center who were newly initiated on methadone between 2016 and 2022. We calculated initial daily dose, maximum daily dose, timing interval of dose escalation, whether patients were connected to an opioid treatment program (OTP) prior to discharge, whether adverse effects or safety events occurred during the hospitalization, and whether such events were definitely or probably related versus possibly related or unrelated to methadone. RESULTS: One hundred twelve patients were included. The mean initial daily methadone dose administered was 32 mg (range: 10-90 mg). The mean maximum dose reached was 76.8 mg (range 30-165 mg). The mean number of days from initial to peak dose was 5.6 days (range 1-19 days). Overall, 30% of patients experienced a safety event, most commonly sedation. Only 4 safety events were deemed probably or definitely related to methadone. In regression analyses, there was no significant difference between starting doses among patients with or without sedation but there was a relationship between last dose and the likelihood of any possibly related event, with those ending at a dose of 100 mg or higher having a higher likelihood event, compared to those ending at lower doses (47.8% vs 12.4%, P < .001). Seventy-six percent were connected to OTP before discharge. CONCLUSION: Among hospitalized patients initiating methadone, rapid dose titration was infrequently associated with related safety events and most were connected to community-based methadone treatment before discharge.

Levomethadone Therapeutic Drug Monitoring to Aid Opioid Withdrawal Therapy: A Short Communication.

BACKGROUND: Therapeutic drug monitoring (TDM) is recommended for opioid maintenance therapy with levomethadone. However, TDM has not yet been applied to monitor opioid withdrawal therapy clinically, although tools to improve it are required. METHODS: In this observational cohort study, repeated TDM with levomethadone was performed according to a prospective opioid withdrawal study protocol. Objective and subjective opioid withdrawal symptoms were measured using validated rating scales and correlated to levomethadone plasma concentrations. Plasma levels were measured using high-pressure liquid chromatography with column switching and spectroscopic detection of methadone and its major metabolite. RESULTS: This study included 31 opioid-dependent patients who participated in standardized opioid withdrawal therapy. The serum levels of levomethadone were found to be highly variable and below the recommended therapeutic reference range of 250 ng/mL for maintenance therapy. These serum levels were positively correlated with dosage (r = 0.632; P < 0.001) and inversely correlated with subjective (r = -0.29; P = 0.011) and objective (r = -0.28; P = 0.014) withdrawal symptoms. CONCLUSIONS: The evidence provided sheds light on how to improve levomethadone withdrawal therapy in patients with opioid dependence. It seems likely that higher initial doses at the beginning and lower dose reductions would have been advantageous. TDM can enhance the safety of opioid withdrawal therapies, minimize withdrawal symptoms, and reduce dropout rates.

Sublingual/Buccal buprenorphine and dental problems: a pharmacovigilance study.

BACKGROUND: The association between dental problems and sublingual/buccal buprenorphine is unclear. We conducted an analysis of dental adverse drug reactions reported with sublingual/buccal buprenorphine in VigiBase®, the pharmacovigilance database of the World Health Organization. RESEARCH DESIGN AND METHODS: We performed disproportionality analyses to compare the reporting rates of dental problems with sublingual/buccal buprenorphine, compared to other buprenorphine formulations and methadone. Significant signals were considered if the lower boundary of the 95% confidence interval of the Reporting Odds Ratio (ROR) was > 1; cases were ≥ 3 and p-value <0.05. We conducted sensitivity analyses by calculating the ROR according to the reporter's qualification and the reporting continent (United States of America and Europe). RESULTS: We included 30,769 reports with all buprenorphine forms. We found 20 cases of dental problems with sublingual/buccal buprenorphine. Sublingual/buccal buprenorphine was associated with an overreporting of dental problems compared to other buprenorphine formulations (ROR = 15.10; 95% CI [7.50-30.39]; p < 0.005) and compared to methadone (ROR = 6.02; 95% CI [3.21-11.30]; p < 0.005). Overreporting of dental problems was consistent in sensitivity analyses, except in Europe compared with other buprenorphine formulations and with methadone. CONCLUSIONS: Sublingual/buccal buprenorphine might increase the risk of reporting dental problems. However, these results do not modify the benefits of sublingual/buccal buprenorphine in the treatment of opioid use disorders.

Long-Term Visual and Neurodevelopmental Outcomes in Two Children with Congenital Nystagmus Secondary to Methadone Exposure In utero.

Methadone is used as a substitute for illicit opioids during pregnancy. However, the real effect of this molecule on visual and neurodevelopmental outcomes of the children exposed is not fully understood, since studies considered subjects born to polydrug-dependent mothers and followed for few months/years. We report the long-term outcomes of two infants with congenital nystagmus solely exposed to methadone in utero. Neurological and neurovisual evaluations were performed every year from the first year of life to 11 years of age. One child was diagnosed with developmental coordination disorder. Both cases presented with ophthalmologic (refractive errors), oculomotor (nystagmus and fixation, smooth pursuit, and saccades dysfunctions), and perceptive problems (reduced visual acuity and contrast sensitivity). While nystagmus and other oculomotor dysfunctions remained stable over time, visual acuity and contrast sensitivity improved; refractive errors worsened and required corrective lenses. Both children showed normal neurodevelopmental and cognitive profile. This report highlights the long-term visual and developmental outcomes of two children exclusively exposed to methadone underlining the possibility of a visual dysfunction and motor coordination disorder. These observations prompt the need to investigate prenatal drug exposure as a cause of congenital nystagmus.

Short-acting versus long-acting opioids for pediatric postoperative pain management.

INTRODUCTION: Opioids are potent analgesics commonly used to manage children's moderate to severe perioperative pain in children. A wide range of short and long-acting opioids are used to treat surgical pain and will be reviewed in this article. AREAS COVERED: Both short- and long-acting opioids contain unique therapeutic benefits and adverse effects; however, due to the side effect profile and safety concerns, lack of familiarity, and evidence with long-acting opioids to treat surgical pain, shorter-acting opioids have traditionally been used in children. Almost all opioids work by binding to the mu receptor. Methadone, a long-acting opioid, is an exception because it also has beneficial N-methyl-D-aspartate antagonist properties. Clinically methadone's properties could translate to improved analgesic outcomes, reduced risk of adverse events, less risk for acute hyperalgesia, tolerance and abuse potential, faster recovery, and reduced risk for chronic persistent surgical pain. This review article summarizes and compares the evidence of commonly used short and long-acting opioids for perioperative pain control in the pediatric population. EXPERT OPINION: Individualized methadone therapy using pharmacogenomics has the potential to transform opioid use in pain management by improving patient safety and analgesic outcomes, thereby addressing the gaps in current standardized ERAS protocols.

Neonatal opioid toxicity: opioid withdrawal (abstinence) syndrome with emphasis on pharmacogenomics and respiratory depression.

The increasing use of opioids in pregnant women has led to an alarming rise in the number of cases of neonates with drug-induced withdrawal symptoms known as neonatal opioid withdrawal syndrome (NOWS). NOWS is a toxic heterogeneous condition with many neurologic, autonomic, and gastrointestinal symptoms including poor feeding, irritability, tachycardia, hypertension, respiratory defects, tremors, hyperthermia, and weight loss. Paradoxically, for the management of NOWS, low doses of morphine, methadone, or buprenorphine are administered. NOWS is a polygenic disorder supported by studies of genomic variation in opioid-related genes. Single-nucleotide polymorphisms (SNPs) in CYP2B6 are associated with variations in NOWS infant responses to methadone and SNPs in the OPRM1, ABCB1, and COMT genes are associated with need for treatment and length of hospital stay. Epigenetic gene changes showing higher methylation levels in infants and mothers have been associated with more pharmacologic treatment in the case of newborns, and for mothers, longer infant hospital stays. Respiratory disturbances associated with NOWS are not well characterized. Little is known about the effects of opioids on developing neonatal respiratory control and respiratory distress (RD), a potential problem for survival of the neonate. In a rat model to test the effect of maternal opioids on the developing respiratory network and neonatal breathing, maternal-derived methadone increased apneas and lessened RD in neonates at postnatal (P) days P0 and P1. From P3, breathing normalized with age suggesting reorganization of respiratory rhythm-generating circuits at a time when the preBötC becomes the dominant inspiratory rhythm generator. In medullary slices containing the preBötC, maternal opioid treatment plus exposure to exogenous opioids showed respiratory activity was maintained in younger but not older neonates. Thus, maternal opioids blunt centrally controlled respiratory frequency responses to exogenous opioids in an age-dependent manner. In the absence of maternal opioid treatment, exogenous opioids abolished burst frequencies at all ages. Prenatal opioid exposure in children stunts growth rate and development while studies of behavior and cognitive ability reveal poor performances. In adults, high rates of attention deficit disorder, hyperactivity, substance abuse, and poor performances in intelligence and memory tests have been reported.

Pragmatic, randomized, blinded trial to shorten pharmacologic treatment of newborns with neonatal opioid withdrawal syndrome (NOWS).

BACKGROUND: The incidence of maternal opioid use in the USA has increased substantially since 2000. As a consequence of opioid use during pregnancy, the incidence of neonatal opioid withdrawal syndrome (NOWS) has increased fivefold between 2002 and 2012. Pharmacological therapy is indicated when signs of NOWS cannot be controlled, and the objective of pharmacological therapy is to control NOWS signs. Once pharmacologic therapy has started, there is great variability in strategies to wean infants. An important rationale for studying weaning of pharmacological treatment for NOWS is that weaning represents the longest time interval of drug treatment. Stopping medications too early may not completely treat NOWS symptoms. METHODS: This will be a pragmatic, randomized, blinded trial of opioid weaning to determine whether more rapid weaning, compared to slow wean, will reduce the number of days of opioid treatment in infants receiving morphine or methadone as the primary treatment for NOWS. DISCUSSION: The proposed study is a pragmatic trial to determine whether a rapid-weaning intervention reduces the number of days of opioid treatment, compared to a slow-weaning intervention, and we powered the proposed study to detect a 2-day difference in the length of treatment. Hospitals will be able to use either morphine or methadone with the knowledge that we may find a positive treatment effect for both, one, or neither drugs. TRIAL REGISTRATION: NCT04214834. Registered January 2, 2020.

Assessment of the potential of novel and classical opioids to induce respiratory depression in mice.

BACKGROUND AND PURPOSE: Opioid-induced respiratory depression limits the use of µ-opioid receptor agonists in clinical settings and is the main cause of opioid overdose fatalities. The relative potential of different opioid agonists to induce respiratory depression at doses exceeding those producing analgesia is understudied despite its relevance to assessments of opioid safety. Here we evaluated the respiratory depressant and anti-nociceptive effects of three novel opioids and relate these measurements to their in vitro efficacy. EXPERIMENTAL APPROACH: Respiration was measured in awake, freely moving male CD-1 mice using whole body plethysmography. Anti-nociception was measured using the hot plate test. Morphine, oliceridine and tianeptine were administered intraperitoneally, whereas methadone, oxycodone and SR-17018 were administered orally. Receptor activation and arrestin-3 recruitment were measured in HEK293 cells using BRET assays. KEY RESULTS: Across the dose ranges examined, all opioids studied depressed respiration in a dose-dependent manner, with similar effects at the highest doses, and with tianeptine and oliceridine showing reduced duration of effect, when compared with morphine, oxycodone, methadone and SR-17018. When administered at doses that induced similar respiratory depression, all opioids induced similar anti-nociception, with tianeptine and oliceridine again showing reduced duration of effect. These data were consistent with the in vitro agonist activity of the tested compounds. CONCLUSION AND IMPLICATIONS: In addition to providing effective anti-nociception, the novel opioids, oliceridine, tianeptine and SR-17018 depress respiration in male mice. However, the different potencies and kinetics of effect between these novel opioids may be relevant to their therapeutic application in different clinical settings.

Ventricular Arrhythmias Associated With Over-the-Counter and Recreational Opioids.

BACKGROUND: 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. OBJECTIVES: In this study, we sought to explore opioid-associated arrhythmia reporting in North America. METHODS: 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. RESULTS: 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. CONCLUSIONS: The nonprescription drugs loperamide and mitragynine are associated with disproportionate reports of life-threatening ventricular arrhythmia in North America.