Association Between Prenatal Opioid Exposure and Neurodevelopmental Outcomes in Children

Introduction: Several studies have reported increasing prevalence of prescription opioid use among pregnant women. However, little is known regarding the effects of maternal opioid use on neurodevelopmental disorders in early childhood in pregnant women with no evidence of opioid use disorders or drug dependence. Objective: The aim of this study was to quantify the association between prenatal opioid exposure from maternal prescription use and neurodevelopmental outcomes in early childhood. Methods: This retrospective study included pregnant women aged 12–55 years and their live-birth infants born from 2010 to 2012 present in Optum’s deidentified Clinformatics® Data Mart database. Eligible infants born to mothers without opioid use disorders or drug dependence were followed till occurrence of neurodevelopmental disorders, loss to follow-up, or study end (December 31, 2017), whichever came first. Propensity score by fine stratification was applied to adjust for confounding by demographic characteristics, obstetric characteristics, maternal comorbid mental and pain conditions, and measures of burden of illnesses and to obtain adjusted hazard ratios (HR) and 95% confidence intervals (CI). Exposed and unexposed infants were compared on the incidence of neurodevelopmental disorders. Results: Of 24,910 newborns, 7.6% (1899) were prenatally exposed to prescription opioids. Overall, 1562 children were diagnosed with neurodevelopmental disorders, with crude incidence rates of 2.9 per 100 person-years in exposed children versus 2.5 per 100 person-years in unexposed children. After adjustment, we observed no association between fetal opioid exposure and the risk of neurodevelopmental disorders (HR 1.10; 95% CI 0.92–1.32). However, increased risk of neurodevelopmental disorders were observed in children with longer cumulative exposure duration (HR 1.70; 95% CI 1.05–2.96) or high cumulative opioid doses (HR 1.22; 95% CI 1.01–1.54). Conclusion and Relevance: In pregnant women without opioid use disorders or drug dependence, maternal opioid use was not associated with increased risk of neurodevelopmental disorders in early childhood. However, increased risks of early neurodevelopmental disorders were observed in children born to women receiving prescription opioids for longer duration and at higher doses during pregnancy

Rate and Risk Factors Associated With Prolonged Opioid Use After Surgery: A Systematic Review and Meta-analysis

Importance: Prolonged opioid use after surgery may be associated with opioid dependency and increased health care use. However, published studies have reported varying estimates of the magnitude of prolonged opioid use and risk factors associated with the transition of patients to long-term opioid use. Objectives: To evaluate the rate and characteristics of patient-level risk factors associated with increased risk of prolonged use of opioids after surgery. Data Sources: For this systematic review and meta-analysis, a search of MEDLINE, Embase, and Google Scholar from inception to August 30, 2017, was performed, with an updated search performed on June 30, 2019. Key words may include opioid analgesics, general surgery, surgical procedures, persistent opioid use, and postoperative pain. Study Selection: Of 7534 articles reviewed, 33 studies were included. Studies were included if they involved participants 18 years or older, evaluated opioid use 3 or more months after surgery, and reported the rate and adjusted risk factors associated with prolonged opioid use after surgery. Data Extraction and Synthesis: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed. Two reviewers independently assessed and extracted the relevant data. Main Outcomes and Measures: The weighted pooled rate and odds ratios (ORs) of risk factors were calculated using the random-effects model. Results: The 33 studies included 1 922 743 individuals, with 1 854 006 (96.4%) from the US. In studies with available sex and age information, participants were mostly female (1 031 399; 82.7%) and had a mean (SD) age of 59.3 (12.8) years. The pooled rate of prolonged opioid use after surgery was 6.7% (95% CI, 4.5%-9.8%) but decreased to 1.2% (95% CI, 0.4%-3.9%) in restricted analyses involving only opioid-naive participants at baseline. The risk factors with the strongest associations with prolonged opioid use included preoperative use of opioids (OR, 5.32; 95% CI, 2.94-9.64) or illicit cocaine (OR, 4.34; 95% CI, 1.50-12.58) and a preoperative diagnosis of back pain (OR, 2.05; 95% CI, 1.63-2.58). No significant differences were observed with various study-level factors, including a comparison of major vs minor surgical procedures (pooled rate: 7.0%; 95% CI, 4.9%-9.9% vs 11.1%; 95% CI, 6.0%-19.4%; P = .20). Across all of our analyses, there was substantial variability because of heterogeneity instead of sampling error. Conclusions and Relevance: The findings suggest that prolonged opioid use after surgery may be a substantial burden to public health. It appears that strategies, such as proactively screening for at-risk individuals, should be prioritized

Venous thromboembolism, chronic liver disease and anticoagulant choice: effectiveness and safety of direct oral anticoagulants versus warfarin

Background Little to no data exist to guide treatment decision in patients with venous thromboembolism (VTE) and chronic liver disease. Objectives To assess the effectiveness and safety of direct oral anticoagulants (DOACs)—individually and as a class—vs warfarin and between 2 DOACs in patients with acute VTE and chronic liver disease. Methods We conducted a retrospective, US claims–based, propensity score–matched cohort study in adults with acute VTE and chronic liver disease who had newly initiated oral anticoagulants between 2011 and 2017. The primary outcome was a composite of hospitalization for recurrent VTE and hospitalization for major bleeding. Results The cohorts included 2361 DOAC-warfarin, 895 apixaban-warfarin, 2161 rivaroxaban-warfarin, and 895 apixaban-rivaroxaban matched pairs. Lower risk of the primary outcome was seen with DOACs (hazard ratio [HR], 0.72; 95% CI, 0.61-0.85), apixaban (HR, 0.48; 95% CI, 0.35-0.66) or rivaroxaban (HR, 0.73; 95% CI, 0.61-0.88) vs warfarin but not apixaban-rivaroxaban (HR, 0.68; 95% CI, 0.43-1.08). The HRs of hospitalization for major bleeding were 0.69 (95% CI, 0.57-0.84) for DOAC-warfarin, 0.43 (95% CI, 0.30-0.63) for apixaban-warfarin, 0.72 (95% CI, 0.58-0.89) for rivaroxaban-warfarin, and 0.60 (95% CI, 0.35-1.06) for apixaban-rivaroxaban. Recurrent VTE risk was lower with apixaban (HR, 0.47; 95% CI, 0.26-0.86), but not DOACs (HR, 0.81; 95% CI, 0.59-1.12) or rivaroxaban vs warfarin (HR, 0.81; 95% CI, 0.57-1.14) or apixaban-rivaroxaban (HR, 0.92; 95% CI, 0.42-2.02). Conclusion While the magnitude of clinical benefit varied across individual DOACs, in adults with acute VTE and chronic liver disease, oral factor Xa inhibitors (as a class or individually) were associated with lower risk of recurrent VTE and major bleeding

Accurate pain reporting training diminishes the placebo response: Results from a randomised, double-blind, crossover trial

Analgesic trials frequently fail to demonstrate efficacy of drugs known to be efficacious. Poor pain reporting accuracy is a possible source for this low essay-sensitivity. We report the effects of Accurate-Pain-Reporting-Training (APRT) on the placebo response in a trial of Pregabalin for painful-diabetic-neuropathy. The study was a two-stage randomized, double-blind trial: In Stage-1 (Training) subjects were randomized to APRT or No-Training. The APRT participants received feedback on the accuracy of their pain reports in response to mechanical stimuli, measured by R-square score. In Stage-2 (Evaluation) all subjects entered a placebo-controlled, cross-over trial. Primary (24-h average pain intensity) and secondary (current, 24-h worst, and 24-h walking pain intensity) outcome measures were reported. Fifty-one participants completed the study. APRT patients (n = 28) demonstrated significant (p = 0.036) increases in R-square scores. The APRT group demonstrated significantly (p = 0.018) lower placebo response (0.29 ± 1.21 vs. 1.48 ± 2.21, mean difference ± SD = -1.19±1.73). No relationships were found between the R-square scores and changes in pain intensity in the treatment arm. In summary, our training successfully increased pain reporting accuracy and resulted in a diminished placebo response. Theoretical and practical implications are discussed

Addressing Posttreatment Selection Bias in Comparative Effectiveness Research, Using Real-World Data and Simulation

To examine methodologies that address imbalanced treatment switching and censoring, 6 different analytical approaches were evaluated under a comparative effectiveness framework: intention-to-treat, as-treated, intention-to-treat with censor-weighting, as-treated with censor-weighting, time-varying exposure, and time-varying exposure with censor-weighting. Marginal structural models were employed to address time-varying exposure, confounding, and possibly informative censoring in an administrative data set of adult patients who were hospitalized with acute coronary syndrome and treated with either clopidogrel or ticagrelor. The effectiveness endpoint included first occurrence of death, myocardial infarction, or stroke. These methodologies were then applied across simulated data sets with varying frequencies of treatment switching and censoring to compare the effect estimate of each analysis. The findings suggest that implementing different analytical approaches has an impact on the point estimate and interpretation of analyses, especially when censoring is highly unbalanced

Improved experimental pain reporting accuracy.

<p>* = P<0.05.</p

CONSORT participant flow diagram.

<p>CONSORT participant flow diagram.</p

The placebo response in the entire cohort, trained and untrained subjects—Primary outcome measure.

<p>Change in placebo was calculated as difference between pain scores in the placebo arm (pre-minus post treatment). Black bars represent changes in pain in the entire cohort. White and Black bars represent changes in pain in the trained (n = 28) and untrained (n = 23) sub-cohorts, respectively. * = P<0.05; Error bars are Standard Error of the Mean (SEM).</p