Children had increased risks of impaired motor and visual-motor skills after prenatal exposure to opioid maintenance therapy.

AIM: Preschool children prenatally exposed to opioid maintenance therapy (OMT) have an increased risk of neurodevelopmental impairments. We aimed to investigate long-term motor and visual-motor integration outcome in children aged 5-13 Years, born to mothers in OMT. METHODS: From January 2018 to June 2021, 63 children prenatally exposed to OMT and 63 comparison children matched for age and gender, were examined at two Norwegian hospitals. Motor skills were assessed by the Movement-ABC test and visual-motor integration by the Beery VMI test. A motor function neurological assessment test was used to examine neuromotor soft signs. RESULTS: In the OMT-exposed group, 16% had motor impairment, 35% had motor problems and 19% had visual-motor integration problems. Forty-three percent of the exposed children had neuromotor soft signs. Strabismus had some influence on motor and visual-motor outcomes but could not explain the group differences. CONCLUSION: Children prenatally exposed to opioid maintenance therapy have an increased risk of long-term motor impairment and visual-motor problems. In addition, they exhibit significantly more neuromotor soft signs, which may affect general well-being, leisure activities and school performance.

Medications for opioid use disorder associated with reduced readmissions for patients with severe injection-related infections: A matched cohort study.

INTRODUCTION: Hospitalizations due to severe injection-related infections (SIRIs) and patient-directed discharge (PDD) in people who inject drugs (PWID) are increasing, but research on readmission outcomes at PDD is limited. In this retrospective, matched cohort study we evaluated predictors of 30-day readmission by discharge status among PWID. METHODS: Among patients diagnosed with SIRIs at a tertiary hospital, Fisher's exact tests assessed differences in readmission rates by discharge status. Medications for opioid use disorder (MOUD) at discharge was defined as either having a buprenorphine dose dispensed within 24 h of discharge and buprenorphine being included in the discharge summary as a prescription, or a methadone dose dispensed inpatient within 24 h of discharge. Logistic regression analyses evaluated predictors of readmission outcomes. RESULTS: Among 148 PWID with SIRI diagnosis, 30-day readmission rate following PDD was higher than standard discharge (25.7 % vs. 9.5 %, p = 0.016) and MOUD decreased odds of 30-day readmission (OR = 0.32, 95 % CI: 0.12,0.83, p = 0.012). >7 missed days of antibiotic treatment increased odds of 30-day readmission (OR 4.65, 95 % CI: 1.14, 31.72, p = 0.030) within PDD patients. CONCLUSIONS: PDD carries higher 30-day readmission rate compared to standard discharge. Strategies to reduce PDD rates and increase MOUD initiation may improve readmission outcomes.

Effects of Bundling Medication for Opioid Use Disorder With an mHealth Intervention Targeting Addiction: A Randomized Clinical Trial.

OBJECTIVE: Medication for opioid use disorder (MOUD) improves treatment retention and reduces illicit opioid use. A-CHESS is an evidence-based smartphone intervention shown to improve addiction-related behaviors. The authors tested the efficacy of MOUD alone versus MOUD plus A-CHESS to determine whether the combination further improved outcomes. METHODS: In an unblinded parallel-group randomized controlled trial, 414 participants recruited from outpatient programs were assigned in a 1:1 ratio to receive either MOUD alone or MOUD+A-CHESS for 16 months and were followed for an additional 8 months. All participants were on methadone, buprenorphine, or injectable naltrexone. The primary outcome was abstinence from illicit opioid use; secondary outcomes were treatment retention, health services use, other substance use, and quality of life; moderators were MOUD type, gender, withdrawal symptom severity, pain severity, and loneliness. Data sources were surveys comprising multiple validated scales, as well as urine screens, every 4 months. RESULTS: There was no difference in abstinence between participants in the MOUD+A-CHESS and MOUD-alone arms across time (odds ratio=1.10, 95% CI=0.90-1.33). However, abstinence was moderated by withdrawal symptom severity (odds ratio=0.95, 95% CI=0.91-1.00) and MOUD type (odds ratio=0.57, 95% CI=0.34-0.97). Among participants without withdrawal symptoms, abstinence rates were higher over time for those in the MOUD+A-CHESS arm than for those in the MOUD-alone arm (odds ratio=1.30, 95% CI=1.01-1.67). Among participants taking methadone, those in the MOUD+A-CHESS arm were more likely to be abstinent over time (b=0.28, SE=0.09) than those in the MOUD-alone arm (b=0.06, SE=0.08), although the two groups did not differ significantly from each other (∆b=0.22, SE=0.11). MOUD+A-CHESS was also associated with greater meeting attendance (odds ratio=1.25, 95% CI=1.05-1.49) and decreased emergency department and urgent care use (odds ratio=0.88, 95% CI=0.78-0.99). CONCLUSIONS: Overall, MOUD+A-CHESS did not improve abstinence relative to MOUD alone. However, MOUD+A-CHESS may provide benefits for subsets of patients and may impact treatment utilization.

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.

Associations of methadone and buprenorphine-naloxone doses with unregulated opioid use, treatment retention, and adverse events in prescription-type opioid use disorders: Exploratory analyses of the OPTIMA study.

BACKGROUND AND OBJECTIVES: Buprenorphine/naloxone (BUP-NX) and methadone are used to treat opioid use disorder (OUD), yet there is insufficient evidence on the impact of doses on interventions' effectiveness and safety when treating OUD attributable to other opioids than heroin. METHODS: We explored associations between methadone and BUP-NX doses and treatment outcomes using data from OPTIMA, a 24-week, pragmatic, open-label, multicenter, pan-Canadian, randomized controlled, two-arm parallel trial with participants (N = 272) with OUD who primarily use opioids other than heroin. Participants were randomized to receive flexible take-home BUP-NX (n = 138) or standard supervised methadone treatment (n = 134). We examined associations between highest BUP-NX and methadone doses, and (1) percentage of opioid-positive urine drug screens (UDS); (2) retention in the assigned treatment; and (3) adverse events (AEs). RESULTS: The mean (SD) highest BUP-NX and methadone dose were 17.31 mg/day (8.59) and 67.70 mg/day (34.70). BUP-NX and methadone doses were not associated with opioid-positive UDS percentages or AEs. Methadone dose was associated with higher retention in treatment (odds ratio [OR]: 1.025; 95% confidence interval [CI]: 1.010; 1.041), while BUP-NX dose was not (OR: 1.055; 95% CI: 0.990; 1.124). Higher methadone doses (70-110 mg/day) offered higher odds of treatment retention. DISCUSSION AND CONCLUSION: Methadone dose was associated with higher retention, which may be related to its full µ-opioid receptor agonism. Future research should notably ascertain the effect of pace of titration on a wide range of outcomes. SCIENTIFIC SIGNIFICANCE: Our results extend previous findings of high doses of methadone increasing retention to be applied in our population using opioids other than heroin, including highly potent opioids.

Outcomes of a mobile medical unit for low-threshold buprenorphine access targeting opioid overdose hot spots in Chicago.

INTRODUCTION: Opioid overdoses in Chicago are unevenly distributed, affecting medically underserved neighborhoods most acutely. Innovations in reaching patients perceived to be hard-to-reach (e.g., unstably housed, marginalized), especially in these underserved neighborhoods, are urgently needed to combat the overdose crisis. This study characterizes the pilot year of a mobile medical unit partnership between a large urban academic center and a community-based harm reduction organization in Chicago. METHODS: This is a retrospective cohort study of all patients who were seen on a mobile medical unit focused on providing low-threshold buprenorphine and primary care in areas with high opioid overdose rates on Chicago's West Side. Treatment episodes were accrued between July 1, 2021, and June 30, 2022 in the first year of operation. The main outcomes were number of patients seen, demographic characteristics of patients, and reason(s) for visit over time. RESULTS: The study saw 587 unique patients on the mobile medical unit between July 1, 2021, and June 30, 2022. Approximately 64.6 % were African American, and more than half lacked active insurance or could not confirm insurance status at the time of visit. The most common reason for initial visit was COVID-19 vaccination (42.4 %), and the most common reason for follow-up visit was buprenorphine treatment (51.0 %). Eleven patients initially presented for other health concerns and later returned to initiate buprenorphine. CONCLUSIONS: The mobile medical unit successfully reached nearly 600 patients in traditionally medically underserved Chicago neighborhoods with the highest overdose rates. The mobile unit's integrated approach met a variety of health needs, including buprenorphine initiation, with a unique opportunity for postoverdose initiation. Several patients initiated buprenorphine after presenting for different health concerns, showing the potential of an integrated approach to build on past mobile outreach programs and reach people with opioid use disorder who are not yet ready to initiate treatment.

Risk of motor vehicle collisions after methadone use: A systematic review and meta-analysis.

INTRODUCTION: Methadone maintenance therapy is a leading treatment strategy for stabilizing and rehabilitating patients with opioid dependence; however, findings related to the risk of motor vehicle collisions after methadone use have been conflicting. In the present study, we compiled the available evidence on the risk of motor vehicle collisions after methadone use. METHODS: We completed a systematic review and meta-analysis of studies identified on six databases. Two reviewers independently screened the identified epidemiological studies, extracted data, and used the Newcastle-Ottawa Scale to assess the quality of the studies. Risk ratios were retrieved for analysis, conducted using random-effects model. Sensitivity analyses, subgroup analyses, and tests for publication bias were conducted. RESULTS: Among 1446 identified relevant studies, a total of 7 epidemiological studies enrolling 33226142 participants met the inclusion criteria. Overall, study participants with methadone use had a higher risk of motor vehicle collisions than did those without methadone use (pooled relative risk 1.92, 95% CI 1.25-2.95; number needed to harm 11.3, 95% CI 5.3-41.6); the I2 statistic was 95.1%, indicating substantial heterogeneity. Subgroup analyses revealed that database type explained 95.36% of the between-study variance (p = 0.008). Egger's (p = 0.376) and Begg's (p = 0.293) tests revealed no evidence of publication bias. Sensitivity analyses indicated that the pooled results were robust. CONCLUSION: The present review revealed that methadone use is significantly associated with a nearly doubled risk of motor vehicle collisions. Therefore, clinicians should exercise caution in implementing methadone maintenance therapy for drivers.

Comparative Safety Analysis of Opioid Agonist Treatment in Pregnant Women with Opioid Use Disorder: A Population-Based Study.

INTRODUCTION AND OBJECTIVE: Receipt of opioid agonist treatment during early and late pregnancy for opioid use disorder may relate to varying perinatal risks. We aimed to assess the effect of time-varying prenatal exposure to opioid agonist treatment using buprenorphine or methadone on adverse neonatal and pregnancy outcomes. METHODS: We conducted a retrospective cohort study of pregnant women with opioid use disorder using Rhode Island Medicaid claims data and vital statistics during 2008-16. Time-varying exposure was evaluated in early (0-20 weeks) and late (≥ 21 weeks) pregnancy. Marginal structural models with inverse probability of treatment weighting were applied. RESULTS: Of 400 eligible pregnancies, 85 and 137 individuals received buprenorphine and methadone, respectively, during early pregnancy. Compared with 152 untreated pregnancies with opioid use disorders, methadone exposure in both periods was associated with an increased risk of preterm birth (adjusted odds ratio [aOR]: 2.52; 95% confidence interval [CI] 1.07-5.95), low birth weight (aOR: 2.99; 95% CI 1.34-6.66), neonatal intensive care unit admission (aOR, 5.04; 95% CI 2.49-10.21), neonatal abstinence syndrome (aOR: 11.36; 95% CI 5.65-22.82), respiratory symptoms (aOR, 2.71; 95% CI 1.17-6.24), and maternal hospital stay > 7 days (aOR, 14.51; 95% CI 7.23-29.12). Similar patterns emerged for buprenorphine regarding neonatal abstinence syndrome (aOR: 10.27; 95% CI 4.91-21.47) and extended maternal hospital stay (aOR: 3.84; 95% CI 1.83-8.07). However, differences were found favoring the use of buprenorphine for preterm birth versus untreated pregnancies (aOR: 0.17; 95% CI 0.04-0.77), and for several outcomes versus methadone. CONCLUSIONS: Methadone and buprenorphine prescribed for the treatment of opioid use disorder during pregnancy are associated with varying perinatal risks. However, buprenorphine may be preferred in the setting of pregnancy opioid agonist treatment. Further research is necessary to confirm our findings and minimize residual confounding.

Management of surgical patients on opioid replacement therapy: An audit of current practice.

Patients on opioid replacement therapy hospitalised with acute pain represent a clinical challenge and have poorer perioperative outcomes. There is limited evidence relating to acute pain management of this complex cohort. The primary objectives of this retrospective audit was to establish the number of patients who are admitted on opioid replacement therapy with an acute pain condition under surgical services and evaluate the management of these patients to determine consistency of pain management practices. Secondarily, we aimed to evaluate the documentation of opioid replacement therapy in clinical notes to determine adherence to operational protocols and record clinically relevant outcomes including infection or postoperative complication rates. Forty-four episodes of care for buprenorphine patients and 19 episodes of care for methadone patients were included. There was significant variability in inpatient opioid prescribing, including practice of dose modification, and there was high utilisation of additional opioids, although agent choice varied. Multimodal analgesia was utilised, especially following acute pain service review. There was an 11% readmission rate for complications of the initial presentation. Documentation at transitions of care was poor. There is a need for further clinical studies into specific acute pain management strategies, and their effect on clinically relevant outcomes, to guide consistent management practices.

Systematic review on the clinical management of chronic pain and comorbid opioid use disorder. / Revisión sistemática sobre el manejo clínico del dolor crónico y el trastorno por uso de opioides simultáneo.

The crisis caused by prescribed opioids and their related side effects are a public health problem worldwide. Most of these are prescribed for coping with chronic pain. The coexistence of opioid use disorder (OUD) in patients with chronic pain represents a complex challenge due to the need for managing both pain and OUD. The aim of this systematic review is to evaluate the efficacy of feasible treatments for this population with OUD and comorbid chronic pain for both conditions. A systematic database search has been performed using Cochrane Library, MEDLINE, PsycINFO and ClinicalTrials.gov in compliance with PRISMA guidelines. Eligible articles addressed the outcomes in chronic pain patients with comorbid opioid use disorder after treatment interventions were applied. Of 593 identified articles, nine were eligible for qualitative review (n = 7 pharmacological interventions; n = 2 psychological interventions). Methadone, buprenorphine, cognitive-behavioral and mindfulness showed promising results, but data were inconclusive (<2 RCT with low risk of bias). It is unclear whether the opioid agonist treatment should be maintained or tapered and which drug should be prescribed for the opioid substitution therapy (methadone or buprenorphine/naloxone). Mindfulness and cognitive behavioral therapy have a discrete effect on improving negative affect but not pain. The therapeutic approach might be individualized under a shared decision-making basis.

La crisis causada por los opioides recetados y sus efectos secundarios relacionados son un problema de salud pública en todo el mundo. La mayoría de estos medicamentos se recetan para el afrontamiento del dolor crónico. La coexistencia del trastorno por uso de opioides (TUO) en pacientes con dolor crónico representa un desafío complejo debido a la necesidad de controlar tanto el dolor como el TUO. El objetivo de esta revisión sistemática es evaluar la eficacia de los tratamientos posibles para dicha población con TUO y dolor crónico. Se ha realizado una revisión sistemática usando las bases de datos Cochrane Library, MEDLINE, PsycINFO y ClinicalTrials.gov, conforme a las pautas PRISMA. Los artículos elegibles abordaron los resultados en pacientes con dolor crónico y diagnóstico comórbido de TUO, después de aplicar una intervención. De 593 artículos identificados, nueve eran elegibles para la revisión cualitativa (n = 7 intervenciones farmacológicas; n = 2 intervenciones psicológicas). La metadona, la buprenorfina, la terapia cognitivo-conductual y el mindfulness mostraron resultados prometedores, pero los datos no eran concluyentes (<2 ECA con bajo riesgo de sesgo). No está claro si el tratamiento con agonistas opioides debe mantenerse o disminuirse y qué fármaco debe prescribirse para la terapia de sustitución de opioides (metadona o buprenorfina/naloxona). El mindfulness y la terapia cognitivo-conductual tienen un efecto discreto en la mejora del afecto negativo, pero no del dolor. El enfoque terapéutico podría individualizarse sobre la base de una toma de decisiones conjunta.

Buprenorphine versus Methadone for Opioid Use Disorder in Pregnancy.

BACKGROUND: Opioid agonist therapy is strongly recommended for pregnant persons with opioid use disorder. Buprenorphine may be associated with more favorable neonatal and maternal outcomes than methadone, but existing data are limited. METHODS: We conducted a cohort study involving pregnant persons who were enrolled in public insurance programs in the United States during the period from 2000 through 2018 in which we examined outcomes among those who received buprenorphine as compared with those who received methadone. Exposure to the two medications was assessed in early pregnancy (through gestational week 19), late pregnancy (gestational week 20 through the day before delivery), and the 30 days before delivery. Risk ratios for neonatal and maternal outcomes were adjusted for confounders with the use of propensity-score overlap weights. RESULTS: The data source for the study consisted of 2,548,372 pregnancies that ended in live births. In early pregnancy, 10,704 pregnant persons were exposed to buprenorphine and 4387 to methadone. In late pregnancy, 11,272 were exposed to buprenorphine and 5056 to methadone (9976 and 4597, respectively, in the 30 days before delivery). Neonatal abstinence syndrome occurred in 52.0% of the infants who were exposed to buprenorphine in the 30 days before delivery as compared with 69.2% of those exposed to methadone (adjusted relative risk, 0.73; 95% confidence interval [CI], 0.71 to 0.75). Preterm birth occurred in 14.4% of infants exposed to buprenorphine in early pregnancy and in 24.9% of those exposed to methadone (adjusted relative risk, 0.58; 95% CI, 0.53 to 0.62); small size for gestational age in 12.1% and 15.3%, respectively (adjusted relative risk, 0.72; 95% CI, 0.66 to 0.80); and low birth weight in 8.3% and 14.9% (adjusted relative risk, 0.56; 95% CI, 0.50 to 0.63). Delivery by cesarean section occurred in 33.6% of pregnant persons exposed to buprenorphine in early pregnancy and 33.1% of those exposed to methadone (adjusted relative risk, 1.02; 95% CI, 0.97 to 1.08), and severe maternal complications developed in 3.3% and 3.5%, respectively (adjusted relative risk, 0.91; 95% CI, 0.74 to 1.13). Results of exposure in late pregnancy were consistent with results of exposure in early pregnancy. CONCLUSIONS: The use of buprenorphine in pregnancy was associated with a lower risk of adverse neonatal outcomes than methadone use; however, the risk of adverse maternal outcomes was similar among persons who received buprenorphine and those who received methadone. (Funded by the National Institute on Drug Abuse.).

Identifying Clinically Relevant Drug-Drug Interactions With Methadone and Buprenorphine: A Translational Approach to Signal Detection.

Methadone and buprenorphine have pharmacologic properties that are concerning for a high risk of drug-drug interactions (DDIs). We performed high-throughput screening for clinically relevant DDIs with methadone or buprenorphine by combining pharmacoepidemiologic and pharmacokinetic approaches. We conducted pharmacoepidemiologic screening via a series of self-controlled case series studies (SCCS) in Optum claims data from 2000 to 2019. We included persons 18 years or older who experienced an outcome of interest during target drug treatment. Exposures were all overlapping medications (i.e., the candidate precipitants) during target drug treatment. Outcomes were opioid overdose, non-overdose adverse effects, and cardiac arrest. We used conditional Poisson regression to calculate rate ratios, accounting for multiple comparisons with semi-Bayes shrinkage. We explored the impact of key study design choices in analyses that varied the exposure definitions of the target drugs and the candidate precipitant drugs. Pharmacokinetic screening was conducted by incorporating published data on CYP enzyme metabolism into an equation-based static model. In SCCS analysis, 1,432 events were included from 248,069 new users of methadone or buprenorphine. In the primary analysis, statistically significant DDIs included gabapentinoids with either methadone or buprenorphine; baclofen with methadone; and benzodiazepines with methadone. In sensitivity analysis, additional statistically significant DDIs included methocarbamol, quetiapine, or simvastatin with methadone. Pharmacokinetic screening identified two moderate-to-strong potential DDIs (clonidine and fluconazole with buprenorphine). The combination of clonidine and buprenorphine was also associated with a significantly increased risk of opioid overdose in pharmacoepidemiologic screening. These DDI signals may be the most important targets for future confirmation studies.

Verbal and nonverbal memory in school-aged children born to opioid-dependent mothers.

BACKGROUND: The potential long-term developmental effects of prenatal methadone and buprenorphine exposure during pregnancy are still largely unknown. AIMS: We investigated memory function in school-aged children of women enrolled in opioid maintenance therapy (OMT) during pregnancy. STUDY DESIGN: Prospective longitudinal cohort study. SUBJECTS: Participants included 41 children (aged 9-11 years), 20 of which had histories of prenatal methadone or buprenorphine exposure. OUTCOME MEASURES: Verbal and non-verbal memory function was assessed using four subtests from the Test of Memory and Learning - Second edition (TOMAL-2). RESULTS: The OMT group scored lower on both the two non-verbal as well as the two verbal memory tasks, all p-values <.05. Group differences remained for three out of the four subtests after controlling for general IQ. Including maternal tobacco use during pregnancy increased the explanatory power of the model, R2 change of 0.07, p = .04. CONCLUSIONS: Children prenatally exposed to methadone or buprenorphine had significantly lower memory performance, however, this association may in part be explained by maternal tobacco use during pregnancy. Consequently, smoking cessation programs should be systematically integrated into opioid maintenance therapy programs for pregnant women.

Solar maculopathy and dissociative symptoms: a case report on a patient on buprenorphine opioid replacement therapy.

Solar maculopathy refers to thermal and photochemical macular damage caused by excessive exposure to light.1 Risk factors include behaviour (eg welding, sunbathing), refraction, pupillary size and clarity of ocular media.2 Drugs, both prescribed and recreational, can contribute to solar maculopathy through analgesic, photosensitization and psychiatric effects.2 We report a case of solar retinopathy associated with a brief dissociative episode. Written informed consent was obtained from the participant.

Association of Medication-Assisted Therapy with New Onset of Cardiac Arrhythmia in Patients Diagnosed with Opioid Use Disorders.

BACKGROUND: 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. METHOD: 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. RESULT: 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). CONCLUSION: 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.

A genetic-based population PK/PD modeling of methadone in Chinese opiate dependence patients.

PURPOSE: The full potential of methadone maintenance treatment (MMT) is often limited by the large inter-individual variability in both pharmacokinetics (PK) and pharmacodynamics (PD), and by the risk of torsade de pointes, a severe adverse effect caused by QTc prolongation. The current study aims to quantitate the contribution of genetic polymorphisms and other variables in PK/PD variability, and their contribution to the QTc interval prolongation in Chinese MMT patients. METHODS: Population PK models were developed to fit (R)- and (S)-methadone PK data. Hierarchical models were tested to characterize the PK profile, the concentration-QTc relationship, and concentration-urinalysis illicit drug testing relationship, with demographics and genetic variants being included as covariates. Simulation based on the developed PK/PD models was performed to assess the effect of methadone dose and genetic variants on QTc interval prolongation. RESULTS: The PK data were best-fit by a one-compartment, first-order absorption model. Clearance of (R)- and (S)-methadone was both affected by the weighted activity score derived from genetic variants. A linear model was used to describe both the methadone concentration-urinalysis illicit drug testing relationship and the methadone concentration-QTc relationship. Concentration of (R)- and (S)-methadone exhibits a comparable effect on QTc prolongation. Simulation showed that the percentage of QTc higher than 450 ms was almost doubled in the lowest clearance group as compared the highest when methadone dose was greater than 120 mg. CONCLUSIONS: The large variability in PK/PD profiles can be partially explained by the genetic variants in an extent different from other population, which confirmed the necessity to conduct such a study in the specific Chinese patients.

A retrospective, observational study on medication for opioid use disorder during pregnancy and risk for neonatal abstinence syndrome.

OBJECTIVES: The prevalence of opioid use disorder (OUD) among pregnant women is increasing. Research consistently demonstrates the efficacy of medications for OUD (MOUD); however, researchers have called for additional studies evaluating the safety of MOUD during pregnancy, particularly the relative safety of two commonly used MOUD medications-methadone and buprenorphine. This study aimed to evaluate the consequences of MOUD exposure during pregnancy on risk for neonatal abstinence syndrome (NAS). METHODS: In a clinical sample of infants born to women with OUD, we evaluated the risk of NAS among those exposed to (i) methadone and (ii) buprenorphine compared with those unexposed to MOUD, as well as the risk of NAS among those exposed to (i) methadone compared with those exposed to (ii) buprenorphine. RESULTS: Compared with buprenorphine-exposed infants (n = 37), methadone-exposed infants (n = 27) were at increased risk for NAS (odds ratio [OR] = 4.67, 95% confidence interval [CI]: 1.03, 21.17). Compared with unexposed infants (n = 43), buprenorphine-exposed infants were at decreased risk for NAS (OR = 0.45, 95% CI: 0.14, 1.39) and methadone-exposed infants were at increased risk for NAS (OR = 2.64, 95% CI: 0.79, 8.76), though these associations were not statistically significant. CONCLUSIONS: Our study suggests that when methadone and buprenorphine are equally appropriate options for the treatment of OUD in pregnant women, buprenorphine may add the additional benefit of reduced risk of newborn NAS.

Medications for opioid use disorder (MOUD), such as buprenorphine and methadone, are effective in reducing the significant harms associated with untreated opioid use disorder (OUD) in nonpregnant and pregnant adults. While previous research clearly documents that the risks of MOUD in pregnancy are less than the risks of untreated OUD in pregnancy, researchers have called for additional studies evaluating the safety of MOUD during pregnancy, particularly the relative safety of methadone and buprenorphine. In a clinical sample of infants born to women with OUD, we showed that buprenorphine-exposed infants were at significantly reduced risk for neonatal abstinence syndrome compared with methadone-exposed infants. Our study adds to the growing body of evidence supporting the use of buprenorphine over methadone for the treatment of OUD among pregnant women.

Self-harm and suicide during and after opioid agonist treatment among primary care patients in England: a cohort study.

BACKGROUND: The first 4 weeks after initiation and cessation of opioid agonist treatment for opioid dependence are associated with an increased risk of all-cause mortality and overdose. We aimed to investigate whether the rate of self-harm and suicide among people who were prescribed opioid agonist treatment differs during initiation, cessation, and the remainder of time on and off treatment. METHODS: We did a retrospective cohort study and used health-care records from UK Clinical Practice Research Datalink, linked to mortality and hospital admission data, for adults (age 18-75 years at cohort entry) who were prescribed opioid agonist treatment at least once in primary care in England between Jan 2, 1998, and Nov 30, 2018. We estimated rates and adjusted risk ratios (aRRs) of hospital admissions for self-harm and death by suicide, comparing time during and after treatment, as well as comparing stable periods of time on treatment with treatment initiation, cessation, and the remaining time off treatment. FINDINGS: Between Jan 2, 1998, and Nov 30, 2018, 8070 patients (5594 [69·3%] men and 2476 [30·7%] women) received 17 004 episodes of opioid agonist treatment over 40 599 person-years. Patients were mostly of White ethnicity (7006 [86·8%] patients). 807 episodes of self-harm (1·99 per 100 person-years) and 46 suicides (0·11 per 100 person-years) occurred during the study period. The overall age-standardised and sex-standardised mortality ratio for suicide was 7·5 times (95% CI 5·5-10·0) higher in the study cohort than in the general population. Opioid agonist treatment was associated with a reduced risk of self-harm (aRR in periods off treatment 1·50 [95% CI 1·21-1·88]), but was not significantly associated with suicide risk (aRR in periods off treatment 1·21 [0·64-2·28]). Risk of self-harm (aRR 2·60 [95% CI 1·83-3·70]) and suicide (4·68 [1·63-13·42]) were both elevated in the first 4 weeks after stopping opioid agonist treatment compared with stable periods on treatment. INTERPRETATION: Stable periods of opioid agonist treatment are associated with reduced risk of self-harm, emphasising the importance of improving retention of patients in treatment. The first month following cessation of opioid agonist treatment is a period of increased risk of suicide and self-harm, during which additional psychosocial support is required. FUNDING: Medical Research Council.

Risk of motor vehicle collisions after methadone use.

Methadone maintenance treatment (MMT) can alleviate opioid dependence. However, MMT possibly increases the risk of motor vehicle collisions. The current study investigated preliminary estimation of motor vehicle collision incidence rates. Furthermore, in this population-based retrospective cohort study with frequency-matched controls, opiate adults receiving MMT (cases) and those not receiving MMT (controls) were identified at a 1:2 ratio by linking data from several nationwide administrative registry databases. From 2009 to 2016, the crude incidence rate of motor vehicle collisions was the lowest in the general adult population, followed by that in opiate adults, and it was the highest in adults receiving MMT. The incidence rates of motor vehicle collisions were significantly higher in opiate users receiving MMT than in those not receiving MMT. Kaplan-Meier curves of the incidence of motor vehicle collisions differed significantly between groups, with a significant increased risk during the first 90 days of follow-up. In conclusion, drivers receiving MMT have higher motor vehicle collision risk than those not receiving MMT in opiate users, and it is worthy of noticing road safety in such drivers, particularly during the first 90 days of MMT.

In 2019, 58 million people were estimated to use opioids ­ a group of substances that include drugs like heroin and morphine. Dependence on opioids can be managed using a prescribed dose of an opioid called methadone, which is administered through a controlled treatment plan. This so-called methadone maintenance treatment manages withdrawal symptoms in opioid-dependent individuals and can reduce the occurrences of overdose, criminal activity and transmission of diseases such as HIV. However, methadone acts on the same brain receptors as other opioids, and individuals receiving methadone may experience impaired motoric and cognitive functioning, including reduced driving ability. It is therefore important to know whether methadone maintenance treatment may increase an individual's risk to cause road accidents. To assess motor vehicle collision risk associated with individuals receiving methadone maintenance treatment, Yang et al. analysed data from the Taiwan National Health Insurance Research Database and six Taiwanese administrative registries, including the ministries of health and welfare, interior and justice, and registries in substitution maintenance therapy, road accidents and the National Police Agency. Initial analyses found that individuals receiving treatment had a higher risk to be involved in car accidents than the general adult population or those without methadone maintenance treatment. Further tests showed that individuals receiving treatment were at three times higher risk of collisions than individuals not receiving treatment, particularly in the first 90 days. These findings may help individuals undergoing methadone maintenance treatment manage their risk of motor vehicle collisions. Further investigation is needed to reveal the underlying mechanisms of methadone-related impairment of driving ability.

Polyvinylpyrrolidone deposition disease in patients with intravenous opioid use: a case series.

The polymer polyvinylpyrrolidone (PVP) is an excipient widely used in prescription drugs. Depending on the molecular weight (MW), parenterally administered PVP may accumulate in various tissues. Consequently, moderate and high MW PVP have only been used in oral preparations since the late 1970s. Surprisingly, starting in 2009, pathology departments in Norway received biopsies revealing PVP deposition, all from patients with a history of intravenous drug use. We identified 13 patients with PVP deposition and re-evaluated 31 biopsies and two autopsies. Common indications for biopsy were renal insufficiency, anemia, pathological fractures, and abdominal complaints. We observed PVP deposits in all biopsies (kidney, hematopoietic bone marrow, bone, gastrointestinal tract, lymph node, and skin) and all sampled tissue from the autopsies. Overall, the clinical findings could be related to PVP deposits in the biopsies. In the most seriously affected patients, PVP deposition caused severe organ dysfunction and contributed to the fatal outcomes of two patients. All patients except for one were prescribed opioid substitution drugs (OSDs), and most of the patients admitted to having injected such medications. Several OSDs contain PVP. One methadone formulation that was marketed in Norway from 2007 to 2014 contained large amounts of very high MW PVP, making it the most likely source of PVP deposition. Although the presumed source of PVP in these patients has now been withdrawn from the market, pathologists should be aware of PVP deposits when evaluating biopsies from this patient group.