Monica Bawor

A tutorial on sensitivity analyses in clinical trials: the what, why, when and how

BackgroundSensitivity analyses play a crucial role in assessing the robustness of the findings or conclusions based on primary analyses of data in clinical trials. They are a critical way to assess the impact, effect or influence of key assumptions or variations—such as different methods of analysis, definitions of outcomes, protocol deviations, missing data, and outliers—on the overall conclusions of a study.The current paper is the second in a series of tutorial-type manuscripts intended to discuss and clarify aspects related to key methodological issues in the design and analysis of clinical trials.DiscussionIn this paper we will provide a detailed exploration of the key aspects of sensitivity analyses including: 1) what sensitivity analyses are, why they are needed, and how often they are used in practice; 2) the different types of sensitivity analyses that one can do, with examples from the literature; 3) some frequently asked questions about sensitivity analyses; and 4) some suggestions on how to report the results of sensitivity analyses in clinical trials.SummaryWhen reporting on a clinical trial, we recommend including planned or posthoc sensitivity analyses, the corresponding rationale and results along with the discussion of the consequences of these analyses on the overall findings of the study.

A systematic scoping review of adherence to reporting guidelines in health care literature

Background Reporting guidelines have been available for the past 17 years since the inception of the Consolidated Standards of Reporting Trials statement in 1996. These guidelines were developed to improve the quality of reporting of studies in medical literature. Despite the widespread availability of these guidelines, the quality of reporting of medical literature remained suboptimal. In this study, we assess the current adherence practice to reporting guidelines; determine key factors associated with better adherence to these guidelines; and provide recommendations to enhance adherence to reporting guidelines for future studies. Methods We undertook a systematic scoping review of systematic reviews of adherence to reporting guidelines across different clinical areas and study designs. We searched four electronic databases (Cumulative Index to Nursing and Allied Health Literature, Web of Science, Embase, and Medline) from January 1996 to September 2012. Studies were included if they addressed adherence to one of the following guidelines: Consolidated Standards of Reporting Trials (CONSORT), Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), Quality of Reporting of Meta-analysis (QUOROM), Transparent Reporting of Evaluations with Nonrandomized Designs (TREND), Meta-analysis Of Observational Studies in Epidemiology (MOOSE) and Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). A protocol for this study was devised. A literature search, data extraction, and quality assessment were performed independently by two authors in duplicate. This study reporting follows the PRISMA guidelines. Results Our search retrieved 5159 titles, of which 50 were eligible. Overall, 86.0% of studies reported suboptimal levels of adherence to reporting guidelines. Factors associated with better adherence included journal impact factor and endorsement of guidelines, publication date, funding source, multisite studies, pharmacological interventions and larger studies. Conclusion Reporting guidelines in the clinical literature are important to improve the standards of reporting of clinical studies; however, adherence to these guidelines remains suboptimal. Action is therefore needed to enhance the adherence to these standards. Strategies to enhance adherence include journal editorial policies endorsing these guidelines.

Testosterone suppression in opioid users: A systematic review and meta-analysis ☆

BACKGROUND Whether used for pain management or recreation, opioids have a number of adverse effects including hormonal imbalances. These imbalances have been reported to primarily involve testosterone and affect both males and females to the point of interfering with successful treatment and recovery. We conducted a systematic review and meta-analysis to determine the extent that opioids affect testosterone levels in both men and women, which may be relevant to improved treatment outcomes for opioid dependence and for pain management. METHODS We searched PubMed, EMBASE, PsycINFO, and CINAHL for relevant articles and included studies that examined testosterone levels in men and women while on opioids. Data collection was completed in duplicate. RESULTS Seventeen studies with 2769 participants (800 opioid users and 1969 controls) fulfilled the review inclusion criteria; 10 studies were cross-sectional and seven were cohort studies. Results showed a significant difference in mean testosterone level in men with opioid use compared to controls (MD=-164.78; 95% CI: -245.47, -84.08; p<0.0001). Methadone did not affect testosterone differently than other opioids. Testosterone levels in women were not affected by opioids. Generalizability of results was limited due to high heterogeneity among studies and overall low quality of evidence. CONCLUSIONS Our findings demonstrated that testosterone level is suppressed in men with regular opioid use regardless of opioid type. We found that opioids affect testosterone levels differently in men than women. This suggests that opioids, including methadone, may have different endocrine disruption mechanisms in men and women, which should be considered when treating opioid dependence.

Impact of ABCB1 and CYP2B6 Genetic Polymorphisms on Methadone Metabolism, Dose and Treatment Response in Patients with Opioid Addiction: A Systematic Review and Meta-Analysis

Background Genetic variability may influence methadone metabolism, dose requirements, and risk of relapse. Objectives To determine whether the CYP2B6*6 or ABCB1 (rs1045642) polymorphisms are associated with variation in methadone response (plasma concentration, dose, or response to treatment). Methods Two independent reviewers searched Medline, EMBASE, CINAHL, PsycINFO, and Web of Science databases. We included studies that reported methadone plasma concentration, methadone response, or methadone dose in relation to the CYP2B6*6 or ABCB1 polymorphisms. Results We screened 182 articles and extracted 7 articles for inclusion in the meta-analysis. Considerable agreement was observed between the two independent raters on the title (kappa, 0.82), abstract (kappa, 0.43), and full text screening (kappa, 0.43). Trough (R) methadone plasma concentration was significantly higher in CYP2B6*6 homozygous carriers when compared to non-carriers (standardized mean difference [SMD] = 0.53, 95% confidence interval [CI], 0.05–1.00, p = 0.03) with minimal heterogeneity (I2 = 0%). Similarly, trough (S) methadone plasma concentration was higher in homozygous carriers of the *6 haplotype when compared to non-carriers, (SMD = 1.44, 95% CI 0.27–2.61, p = 0.02) however significant heterogeneity was observed (I2 = 69%). Carriers of the CYP2B6*6 haplotype were not found to be significantly different from non-carriers with respect to dose or response to treatment. We found no significant association between the ABCB1 polymorphism and the trough (R), (S) plasma concentrations, methadone dose, or methadone response. Conclusion Although the number of studies included and sample size were modest, this is the first meta analysis to show participants homozygous for the CYP2B6*6 genotype have higher trough (R) and (S) methadone plasma concentrations, suggesting that methadone metabolism is significantly slower in *6 homozygous carriers.

Sex differences in outcomes of methadone maintenance treatment for opioid addiction: a systematic review protocol

BackgroundUse of methadone for the treatment of opioid addiction is an effective harm-reduction approach, although variability in treatment outcomes among individuals has been reported. Men and women with opioid addiction have been known to differ in factors such as opioid use patterns and characteristics at treatment entry; however, little has been reported about differences in methadone treatment outcomes between men and women. Therefore, we present a protocol for a systematic review which aims to provide a summary of existing literature on sex differences in outcomes of methadone treatment for opioid addiction.Methods/DesignElectronic search of PubMed/MEDLINE, EMBASE, PsycINFO, and CINAHL databases will be conducted using a priori defined search strategy. Two authors (MB and BBD) will independently screen potential articles for eligibility using pre-determined inclusion and exclusion criteria and extract key information using a data extraction form designed for this study. Discrepancies will be resolved using a third party (ZS). The primary outcome will be sex differences in response to treatment defined as abstinence from illicit opioid use. We will also assess sex differences in treatment outcomes including treatment retention, remission status post-treatment, polysubstance abuse, methadone dose, drug-related adverse events, health status, psychological status, mortality, criminal activity, high risk sexual behavior, social support/relations, and employment. A meta-analysis will be conducted if possible; risk of bias and overall quality of evidence will be assessed to determine confidence in the estimates.DiscussionWe anticipate that this review will highlight how men and women differ in methadone treatment outcomes and allow us to generate conclusions that can be applied to treatment in a clinical setting.Systematic review registrationPROSPERO CRD42013006549

The effectiveness of opioid substitution treatments for patients with opioid dependence: a systematic review and multiple treatment comparison protocol

BackgroundOpioids are psychoactive analgesic drugs prescribed for pain relief and palliative care. Due to their addictive potential, effort and vigilance in controlling prescriptions is needed to avoid misuse and dependence. Despite the effort, the prevalence of opioid use disorder continues to rise. Opioid substitution therapies are commonly used to treat opioid dependence; however, there is minimal consensus as to which therapy is most effective. Available treatments include methadone, heroin, buprenorphine, as well as naltrexone. This systematic review aims to assess and compare the effect of all available opioid substitution therapies on the treatment of opioid dependence.Methods/DesignThe authors will search Medline, EMBASE, PubMed, PsycINFO, Web of Science, Cochrane Library, Cochrane Clinical Trials Registry, World Health Organization International Clinical Trials Registry Platform Search Portal, and the National Institutes for Health Clinical Trials Registry. The title, abstract, and full-text screening will be completed in duplicate. When appropriate, multiple treatment comparison Bayesian meta-analytic methods will be performed to deduce summary statistics estimating the effectiveness of all opioid substitution therapies in terms of retention and response to treatment (as measured through continued opioid abuse).DiscussionUsing evidence gained from this systematic review, we anticipate disseminating an objective review of the current available literature on the effectiveness of all opioid substitution therapies for the treatment of opioid use disorder. The results of this systematic review are imperative to the further enhancement of clinical practice in addiction medicine.Systematic review registrationPROSPERO CRD42013006507.

Genetics of Opioid Dependence: A Review of the Genetic Contribution to Opioid Dependence

This narrative review aims to provide an overview of the impact of opioid dependence and the contribution of genetics to opioid dependence. Epidemiological data demonstrate that opioid dependence is a global trend with far-reaching effects on the social, economic, and health care systems. A review of classical genetic studies of opioid use suggests significant heritability of drug use behavior, however the evidence from molecular genetic studies is inconclusive. Nonetheless, certain genetic variants are important to consider given their role in the pathophysiology of addictive behavior. We undertook a literature review to identify the current state of knowledge regarding the role of genes in opioid dependence. Determining the association of genetic markers could change the current understanding of the various factors contributing to opioid dependence and therefore may improve recognition of individuals at risk for the disorder and prevention and treatment strategies.

Methadone induces testosterone suppression in patients with opioid addiction

Sex hormones may have a role in the pathophysiology of substance use disorders, as demonstrated by the association between testosterone and addictive behaviour in opioid dependence. Although opioid use has been found to suppress testosterone levels in men and women, the extent of this effect and how it relates to methadone treatment for opioid dependence is unclear. The present multi-centre cross-sectional study consecutively recruited 231 patients with opioid dependence from methadone clinics across Ontario, Canada between June and December of 2011. We obtained demographic details, substance use, psychiatric history, and blood and urine samples from enrolled subjects. The control group included 783 non-opioid using adults recruited from a primary care setting in Ontario, Canada. Average testosterone level in men receiving methadone treatment was significantly lower than controls. No effect of opioids including methadone on testosterone level in women was found and testosterone did not fluctuate significantly between menstrual cycle phases. In methadone patients, testosterone level was significantly associated with methadone dose in men only. We recommend that testosterone levels be checked in men prior and during methadone and other opioid therapy, in order to detect and treat testosterone deficiency associated with opioids and lead to successful methadone treatment outcomes.

Genetic influence on methadone treatment outcomes in patients undergoing methadone maintenance treatment for opioid addiction: a pilot study

Introduction Treatment of opioid addiction with methadone is effective; however, it is known to produce interindividual variability. This may be influenced in part by genetic variants, which can increase the initial risk of developing opioid addiction as well as explain differences in response to treatment. This pilot study aimed to assess the feasibility of conducting a full-scale genetic analysis to identify genes that predict methadone treatment outcomes in this population. Methods This was a cross-sectional observational study of patients admitted to a methadone maintenance treatment program for opioid addiction. We obtained demographic and clinical characteristics in addition to blood and urine samples, for the assessment of treatment outcomes. Results The recruitment process yielded 252 patients, representing a 20% recruitment rate. We conducted genetic testing based on a 99.6% rate of provision of DNA samples. The average retention in treatment was 3.4 years, and >50% of the participants reported psychiatric and medical comorbidities. BDNF rs6265 and DRD2 rs1799978 were the common single nucleotide polymorphisms (SNPs) selected for the feasibility study. Discussion This study met our predetermined feasibility criteria; recruitment, response rates, and genetic testing were feasible; treatment duration was sufficient for follow up; and the prevalence of comorbid conditions indicated the need for reliable psychiatric and chronic pain measures. The study strengths included effective collaboration with clinics and the generalizability of sample population. Key learning points show the need for assessment of treatment outcomes on multiple domains, implementation of follow up, and the development of standardized training for the study clinical staff.

Evaluation of clinical and inflammatory profile in opioid addiction patients with comorbid pain: results from a multicenter investigation

Background Chronic pain is the most commonly reported comorbidity among patients with opioid addiction receiving methadone maintenance treatment (MMT), with an estimated prevalence ranging between 30% and 55%. Evidence suggests that patients with comorbid pain are at high risk for poor treatment response, including continued illicit substance use. Due to the important relationship between the presence of pain and illicit substance abuse within the MMT setting, it is imperative that we target our efforts toward understanding the characteristics of this patient population. Methods The primary objective of this study was to explore the clinical and inflammatory profile of MMT patients reporting comorbid pain. This multicenter study enrolled patients (n=235) on MMT for the treatment of opioid dependence. Clinical history and blood and urine data were collected. Blood samples were obtained for estimating the serum levels of inflammatory markers (tumor necrosis factor [TNF]-α, interleukin-1 receptor antagonist [IL-1ra], IL-6, IL-8, IL-10, interferon [IFN]-γ and chemokine (C–C motif) ligand 2 [CCL2]). The study objectives were addressed using a descriptive statistical summary and a multivariable logistic regression model constructed in STATA version 12. Results Among the participants eligible for inclusion (n=235), serum IFN-γ level and substance abuse behavior proved to be important delineating characteristics for the detection of comorbid pain. Analysis of inflammatory profile showed IFN-γ to be significantly elevated among patients reporting comorbid pain (odds ratio [OR]: 2.02; 95% confidence interval [CI]: 1.17, 3.50; P=0.01). Patients reporting comorbid pain were also found to have an increase in positive opioid urine screens (OR: 1.02; 95% CI: 1.00, 1.03; P=0.01), indicating an increase in illicit opioid consumption. Conclusion MMT patients with comorbid pain were shown to have elevated IFN-γ and higher rates of continued opioid abuse. The ability to objectively distinguish between patients with comorbid pain may help to both improve the prediction of poor responders to MMT as well as identify treatment approaches such as anti-inflammatory medications as safe alternatives for MMT patients with comorbid pain.