Assessing fragility of statistically significant findings from randomized controlled trials assessing pharmacological therapies for opioid use disorders: a systematic review.

BACKGROUND: The fragility index is a statistical measure of the robustness or "stability" of a statistically significant result. It has been adapted to assess the robustness of statistically significant outcomes from randomized controlled trials. By hypothetically switching some non-responders to responders, for instance, this metric measures how many individuals would need to have responded for a statistically significant finding to become non-statistically significant. The purpose of this study is to assess the fragility index of randomized controlled trials evaluating opioid substitution and antagonist therapies for opioid use disorder. This will provide an indication as to the robustness of trials in the field and the confidence that should be placed in the trials' outcomes, potentially identifying ways to improve clinical research in the field. This is especially important as opioid use disorder has become a global epidemic, and the incidence of opioid related fatalities have climbed 500% in the past two decades. METHODS: Six databases were searched from inception to September 25, 2021, for randomized controlled trials evaluating opioid substitution and antagonist therapies for opioid use disorder, and meeting the necessary requirements for fragility index calculation. Specifically, we included all parallel arm or two-by-two factorial design RCTs that assessed the effectiveness of any opioid substitution and antagonist therapies using a binary primary outcome and reported a statistically significant result. The fragility index of each study was calculated using methods described by Walsh and colleagues. The risk of bias of included studies was assessed using the Revised Cochrane Risk of Bias tool for randomized trials. RESULTS: Ten studies with a median sample size of 82.5 (interquartile range (IQR) 58, 179, range 52-226) were eligible for inclusion. Overall risk of bias was deemed to be low in seven studies, have some concerns in two studies, and be high in one study. The median fragility index was 7.5 (IQR 4, 12, range 1-26). CONCLUSIONS: Our results suggest that approximately eight participants are needed to overturn the conclusions of the majority of trials in opioid use disorder. Future work should focus on maximizing transparency in reporting of study results, by reporting confidence intervals, fragility indexes, and emphasizing the clinical relevance of findings. TRIAL REGISTRATION: PROSPERO CRD42013006507. Registered on November 25, 2013.

Genetics of cannabis use in opioid use disorder: A genome-wide association and polygenic risk score study.

BACKGROUND: Individuals with an Opioid Use Disorder (OUD) have increased rates of cannabis use in comparison to the general population. Research on the short- and long-term impacts of cannabis use in OUD patients has been inconclusive. A genetic component may contribute to cannabis cravings. AIMS: Identify genetic variants associated with cannabis use through Genome-wide Association Study (GWAS) methods and investigate a Polygenic Risk Score (PRS). In addition, we aim to identify any sex differences in effect size for genetic variants reaching or nearing genome-wide significance in the GWAS. METHODS: The study outcomes of interest were: regular cannabis use (yes/no) (n = 2616), heaviness of cannabis use (n = 1293) and cannabis cravings (n = 836). Logistic and linear regressions were preformed, respectively, to test the association between genetic variants and each outcome, regular cannabis use and heaviness of cannabis use. GWAS summary statistics from a recent large meta-GWAS investigating cannabis use disorder were used to conduct PRS's. Findings are limited to a European ancestry sample. RESULTS: No genome-wide significant associations were found. Rs1813412 (chromosome 17) for regular cannabis use and rs62378502 (chromosome 5) for heaviness of cannabis use were approaching genome-wide significance. Both these SNPs were nominally significant (p<0.05) within males and females, however sex did not modify the association. The PRS identified statistically significant association with cannabis cravings. The variance explained by all PRSs were less than 1.02x10-2. CONCLUSION: This study provides promising results in understanding the genetic contribution to cannabis use in individuals living with OUD.

Cannabis use and opioid relapse: An exploratory survival analysis of prospectively collected data.

Importance: It is known that only minority of patients with opioid use disorder (OUD) receive treatment, of which only a fraction successfully complete treatment as intended. Factors associated with poor treatment outcomes remain unclear, and there is emerging but conflicting evidence that cannabis use may mitigate opioid use. Objective: To analyze predictors of relapse amongst patients receiving buprenorphine-naloxone for OUD and identify the association between cannabis use and time to relapse. Design: Data were prospectively collected between May 2018 and October 2020, and patients were followed for 12 months. Setting: Thirty-one outpatient opioid agonist treatment clinics across Ontario, Canada. Participants: All patients 16 years of age or older receiving buprenorphine-naloxone for OUD who had a urine toxicology screen negative for opioids at baseline were eligible for inclusion. Of the 488 patients consecutively sampled, 466 were included. Exposure: Cannabis use. Main outcome and measure: Relapse to opioid use assessed using urine toxicology screens. We employed a multivariable Cox-proportional hazard model for our analyses. Results: We found that cannabis use was not protective against relapse [hazard ratio (HR) = 1.03, 95% confidence interval (CI): 0.78, 1.36, p = 0.84]. We found that participants who have been in treatment for at least two years had a 44% decrease in the hazard of relapse compared to those in treatment for less than a year (HR = 0.56, 95% CI: 0.34, 0.92, p = 0.021). We also found that the hazard of relapse was 2.6 times higher for participants who were intravenous drug users (HR = 2.61, 95% CI: 1.74, 3.91, p < 0.001), and that for every 1mg increase in the participants' buprenorphine-naloxone dose, the hazard of relapse is 2% greater (HR = 1.02, 95% CI: 1.01, 1.03, p < 0.001). Conclusion: Our analysis failed to show cannabis to be protective against relapse to opioid use in patients receiving buprenorphine-naloxone for OUD. We identified that individuals who inject drugs, are on higher doses of buprenorphine-naloxone, or have been in treatment for less than two years have a higher hazard for relapse. The presence of such factors may thus warrant closer patient follow-up and more stringent treatment protocols to mitigate risk of relapse and potential overdose.

Sex-Specific Risk Factors and Health Disparity Among Hepatitis C Positive Patients Receiving Pharmacotherapy for Opioid Use Disorder: Findings From a Propensity Matched Analysis.

BACKGROUND: The incidence of opioid-related fatality has reached unparalleled levels across North America. Patients with comorbid hepatitis C virus (HCV) remain the most vulnerable and difficult to treat. Considering the unique challenges associated with this population, we aimed to re-examine the impact of HCV on response to medication assistant treatment for opioid use disorder and establish sex-specific risk factors affecting care. METHODS: This study employs a multi-center prospective cohort design, with 1-year follow-up. Patients aged ≥18, receiving methadone for opioid use disorder were recruited from a network of outpatient opioid addiction treatment centers across Southern Ontario, Canada. Patients with ≥50% positive opioid urine screens over 1 year of follow-up were classified as poor responders. The prognostic impact of HCV on response was established using a propensity score matched analysis. Sex-specific regression models were constructed to evaluate risk factors for treatment response. RESULTS: Among participants eligible for inclusion (n = 1234), HCV was prevalent in 25% (n = 307). HCV patients exhibited significantly higher rates of high-risk opioid consumption patterns 35.29% (standard deviation 0.478). Sex-specific examination revealed females with HCV incur a 2 times increased risk for high-risk opioid consumption behaviors (female odds ratio: 1.95, 95% confidence interval 1.23, 3.10; P = 0.01). CONCLUSIONS: Findings from this study establish the link between HCV and poor treatment response, with differentially higher risk among female patients. In light of the high potential for overdose among this population, concerted efforts are required for distinguishing the source for sex-based disparities, in addition to establishing trauma and gender informed treatment protocols.

Delirium and other neuropsychiatric manifestations of COVID-19 infection in people with preexisting psychiatric disorders: a systematic review.

BACKGROUND: Psychiatric disorders increase risk of neuropsychiatric disease and poor outcomes, yet little is known about the neuropsychiatric manifestations of COVID-19 in the psychiatric population. The primary objective is to synthesize neuropsychiatric outcomes of COVID-19 in people with preexisting psychiatric disorders. METHODS: Data were collected during an ongoing review of the impact of pandemics on people with existing psychiatric disorders. All study designs and gray literature were included. Medline, PsychInfo, CINAHL, EMBASE, and MedRx were searched from inception to September 1 2020. Risk of bias was assessed using a published tool that can accommodate all study types. Two independent authors screened the studies and extracted data. Data were narratively synthesized, as there were insufficient data to meta-analyze. Evidence was appraised according to GRADE. RESULTS: Four case reports were included, comprising 13 participants from three countries. Many large-sample, relevant papers were omitted for not reporting psychiatric history, despite reporting other comorbidities. Included participants (n = 13) were hospitalized with COVID-19 and appeared to meet criteria for delirium. Myoclonus, rigidity, and alogia were also reported. The most commonly reported preexisting psychiatric diagnoses were mood disorders, schizophrenia, and alcohol use disorder. CONCLUSIONS: People with preexisting psychiatric disorders may experience delirium, rigidity, myoclonus, and alogia during COVID-19 infection; although higher quality and longitudinal data are needed to better understand these phenomena. Relevant COVID-19 literature does not always report psychiatric history, despite heightened neuropsychiatric vulnerability within this population. TRIAL REGISTRATION:  PROSPERO (CRD42020179611).

Implications of OPRM1 and CYP2B6 variants on treatment outcomes in methadone-maintained patients in Ontario: Exploring sex differences.

Genetic variants in the OPRM1 and CYP2B6 genes, respectively coding for an opioid receptor and methadone metabolizers, have been linked to negative treatment outcomes in patients undergoing methadone maintenance treatment, with little consensus on their effect. This study aims to test the associations between pre-selected SNPs of OPRM1 and CYP2B6 and outcomes of continued opioid use, relapse, and methadone dose. It also aims to observe differences in associations within the sexes. 1,172 participants treated with methadone (nMale = 666, nFemale = 506) were included in this study. SNPs rs73568641 and rs7451325 from OPRM1 and all the tested CYP2B6 SNPs were detected to be in high linkage disequilibrium. Though no associations were found to be significant, noteworthy differences were observed in associations of OPRM1 rs73568641 and CYP2B6 rs3745274 with treatment outcomes between males and females. Further research is needed to determine if sex-specific differences are present.

A systematic review of GWAS identified SNPs associated with outcomes of medications for opioid use disorder.

BACKGROUND: Patients with opioid use disorder (OUD) display an interindividual variability in their response to medications for opioid use disorder (MOUD). A genetic basis may explain the variability in this response. However, no consensus has been reached regarding which genetic variants significantly contribute to MOUD outcomes. OBJECTIVES: This systematic review aims to summarize genome-wide significant findings on MOUD outcomes and critically appraise the quality of the studies involved. METHODS: Databases searched from inception until August 21st, 2020 include: MEDLINE, Web of Science, EMBASE, CINAHL and Pre-CINAHL, GWAS Catalog and GWAS Central. The included studies had to be GWASs that assessed MOUD in an OUD population. All studies were screened in duplicate. The quality of the included studies was scored and assessed using the Q-Genie tool. Quantitative analysis, as planned in the protocol, was not feasible, so the studies were analyzed qualitatively. RESULTS: Our search identified 7292 studies. Five studies meeting the eligibility criteria were included. However, only three studies reported results that met our significance threshold of p ≤ 1.0 × 10-7. In total, 43 genetic variants were identified. Variants corresponding to CNIH3 were reported to be associated with daily heroin injection in Europeans, OPRM1, TRIB2, and ZNF146 with methadone dose in African Americans, EYS with methadone dose in Europeans, and SPON1 and intergenic regions in chromosomes 9 and 3 with plasma concentrations of S-methadone, R-methadone, and R-EDDP, respectively, in Han Chinese. LIMITATIONS: The limitations of this study include not being able to synthesize the data in a quantitative way and a conservative eligibility and data collection model. CONCLUSION: The results from this systematic review will aid in highlighting significant genetic variants that can be replicated in future OUD pharmacogenetics research to ascertain their role in patient-specific MOUD outcomes. Systematic review registration number CRD42020169121.

The Role of Perceived Social Support in the Association Between Stressful Life Events and Suicidal Behavior.

Background: Suicide is a serious public health concern for which there have been well-established protective and risk factors reported in literature. There is a lack of evidence on the indirect effects of other variables on these factors. Specifically, the association between stressful life events and suicidal behavior may be affected by perceived social support, but its role in this association is largely uninvestigated. Objectives: Thus, this paper aims to explore the role of perceived social support in the association between stressful life events and suicidal behavior. Perceived social support will be explored as a mediator and as a moderator in this association. Methods: Data were obtained from the Determinants of Suicidal Behavior Conventional and Emergent Risk (DISCOVER), a study conducted to identify risk factors of suicidal behavior. The study participants are individuals with suicide attempts admitted to hospital. Participants (n = 343) were recruited from hospital setting. Suicidal behavior was measured using two outcomes (1) the occurrence of a suicide attempt (2) level of suicide intent as measured by the Pierce Suicide Intent Scale. Perceived social support was measured using the Sarason Social Support Questionnaire. Results: Stressful life events were significantly associated with suicide attempts (OR 1.440, 95% CI 1.440, 1.682, p < 0.001) and perceived social support (B -0.785, 95% CI -1.501, -0.068, p = 0.032). There was no significant mediation effect by perceived social support in the association between stressful life events and suicide attempts (Sobel's test statistic 1.64, p = 0.100). Perceived social support did not moderate the relationship between stressful life events and suicide attempts [(OR 1.007, 95% CI 0.987, 1.027, p = 0.514] or the relationship between stressful life events and level of suicidal intent (B -0.043, 95% CI -0.132, 0.046, p = 0.343). Conclusion: Stressful life events are associated with increased risk of suicide attempts. The study also identified an inverse relationship between stressful life events and perceived social support. These associations were independent of perceived social support. This study highlights the effects of stressful life events on suicide risk is not affected by perceived social support, requiring further investigation into measures to reduce the impact of social stressors on people with risk of suicide.

Factors affecting participant recruitment and retention in borderline personality disorder research: a feasibility study.

BACKGROUND: Previous studies have shown that stigma is a major barrier to participation in psychiatric research and that individuals who participate in psychiatric research may differ clinically and demographically from non-participants. However, few studies have explored research recruitment and retention challenges in the context of personality disorders. AIM: To provide an analysis of the factors affecting participant recruitment and retention in a study of borderline personality disorder among general psychiatric inpatients. METHODS: Adult inpatients in a tertiary psychiatric hospital were approached about participating in a cross-sectional study of borderline personality disorder. Recruitment rates, retention rates, and reasons for declining participation or withdrawing from the study were collected. Demographic characteristics were compared between participants and non-participants and between patients who remained in the study and those who withdrew. RESULTS: A total of 71 participants were recruited into the study between January 2018 and March 2020. Recruitment and retention rates were 45% and 70%, respectively. Lack of interest was the most commonly cited reason for non-participation, followed by scheduling conflicts and concerns regarding mental/physical well-being. Age and sex were not predictors of study participation or retention. CONCLUSIONS: More research is needed to explore patients' perspectives and attitudes towards borderline personality disorder diagnosis and research, determine effects of different recruitment strategies, and identify clinical predictors of recruitment and retention in personality disorder research.

Genetic basis of cannabis use: a systematic review.

BACKGROUND: With the increase in cannabis use rates, cannabis use disorder is being reported as one of the most common drug use disorders globally. Cannabis use has several known physical, psychological, and social adverse events, such as altered judgement, poor educational outcomes, and respiratory symptoms. The propensity for taking cannabis and the development of a cannabis use disorder may be genetically influenced for some individuals. Heritability estimates suggest a genetic basis for cannabis use, and several genome-wide association studies (GWASs) have identified possible regions of association, albeit with inconsistent findings. This systematic review aims to summarize the findings from GWASs investigating cannabis use and cannabis use disorder. METHODS: This systematic review incorporates articles that have performed a GWAS investigating cannabis use or cannabis use disorder. MEDLINE, Web of Science, EMBASE, CINAHL, GWAS Catalog, GWAS Central, and NIH Database of Genotype and Phenotype were searched using a comprehensive search strategy. All studies were screened in duplicate, and the quality of evidence was assessed using the quality of genetic association studies (Q-Genie) tool. All studies underwent qualitative synthesis; however, quantitative analysis was not feasible. RESULTS: Our search identified 5984 articles. Six studies met our eligibility criteria and were included in this review. All six studies reported results that met our significance threshold of p ≤ 1.0 × 10-7. In total 96 genetic variants were identified. While meta-analysis was not possible, this review identified the following genes, ANKFN1, INTS7, PI4K2B, CSMD1, CST7, ACSS1, and SCN9A, to be associated with cannabis use. These regions were previously reported in different mental health conditions, however not in relation to cannabis use. CONCLUSION: This systematic review summarized GWAS findings within the field of cannabis research. While a meta-analysis was not possible, the summary of findings serves to inform future candidate gene studies and replication efforts. Systematic Review Registration PROSPERO CRD42020176016.

Factors associated with opioid overdose during medication-assisted treatment: How can we identify individuals at risk?

BACKGROUND: Due to the loss of tolerance to opioids during medication-assisted treatment (MAT), this period may represent a time of heightened risk for overdose. Identifying factors associated with increased risk of overdose during treatment is therefore paramount to improving outcomes. We aimed to determine the prevalence of opioid overdoses in patients receiving MAT. Additionally, we explored factors associated with opioid overdose during MAT and the association between length of time enrolled in MAT and overdose. METHODS: Data were collected prospectively from 2360 participants receiving outpatient MAT in Ontario, Canada. Participants were divided into three groups by overdose status: no history of overdose, any lifetime history of overdose, and emergency department visit for opioid overdose in the last year. We used a multivariate multinomial regression model to assess demographic and clinical factors associated with overdose status. RESULTS: Twenty-four percent of participants reported a lifetime history of overdose (n = 562), and 8% reported an emergency department (ED) visit for opioid overdose in the last year (n = 179). Individuals with a recent ED visit for opioid overdose were in treatment for shorter duration (odds ratio [OR] 0.92, 95% confidence interval [CI] 0.87, 0.97, p = 0.001). Individuals with a lifetime or recent history of overdose were more likely to be younger in age (OR 0.93, 95% CI 0.89, 0.98, p = 0.007 and OR 0.84, 95% CI 0.77, 0.92, p < 0.001, respectively), report more physical symptoms (OR 1.02, 95% CI 1.01, 1.03, p = 0.005 and OR 1.03, 95% CI 1.01, 1.05, p = 0.005, respectively), and had higher rates of non-prescription benzodiazepine use (OR 1.87, 95% CI 1.32, 2.66, p < 0.001 and OR 2.34, 95% CI 1.43, 3.81, p = 0.001, respectively) compared to individuals with no history of overdose. CONCLUSIONS: A considerable number of patients enrolled in MAT have experienced overdose. Our study highlights that there are identifiable factors associated with a patient's overdose status that may represent areas for intervention. In particular, longer duration in MAT is associated with a decreased risk of overdose.

The future of precision medicine in opioid use disorder: inclusion of patient-important outcomes in clinical trials

Opioid use has reached an epidemic proportion in Canada and the United States that is mostly attributed to excess availability of prescribed opioids for pain. This excess in opioid use led to an increase in the prevalence of opioid use disorder (OUD) requiring treatment. The most common treatment recommendations include medication-assisted treatment (MAT) combined with psychosocial interventions. Clinical trials investigating the effectiveness of MAT, however, have a limited focus on effectiveness measures that overlook patient-important outcomes. Despite MAT, patients with OUD continue to suffer negative consequences of opioid use. Patient goals and personalized medicine are overlooked in clinical trials and guidelines, thus missing an opportunity to improve prognosis of OUD by considering precision medicine in addiction trials. In this mixed-methods study, patients with OUD receiving MAT (n=2,031, mean age 39.1 years [SD 10.7], 44% female) were interviewed to identify patient goals for MAT. The most frequently reported patient-important outcomes were to stop treatment (39%) and to avoid all drugs (25%). These results are inconsistent with treatment recommendations and trial outcome measures. We discuss theses inconsistencies and make recommendations to incorporate these outcomes to achieve patient-centered and personalized treatment strategies.

The future of precision medicine in opioid use disorder: inclusion of patient-important outcomes in clinical trials.

Opioid use has reached an epidemic proportion in Canada and the United States that is mostly attributed to excess availability of prescribed opioids for pain. This excess in opioid use led to an increase in the prevalence of opioid use disorder (OUD) requiring treatment. The most common treatment recommendations include medication-assisted treatment (MAT) combined with psychosocial interventions. Clinical trials investigating the effectiveness of MAT, however, have a limited focus on effectiveness measures that overlook patient-important outcomes. Despite MAT, patients with OUD continue to suffer negative consequences of opioid use. Patient goals and personalized medicine are overlooked in clinical trials and guidelines, thus missing an opportunity to improve prognosis of OUD by considering precision medicine in addiction trials. In this mixed-methods study, patients with OUD receiving MAT (n=2,031, mean age 39.1 years [SD 10.7], 44% female) were interviewed to identify patient goals for MAT. The most frequently reported patient-important outcomes were to stop treatment (39%) and to avoid all drugs (25%). These results are inconsistent with treatment recommendations and trial outcome measures. We discuss theses inconsistencies and make recommendations to incorporate these outcomes to achieve patient-centered and personalized treatment strategies.

Treatment Outcomes in Patients With Opioid Use Disorder Who Were First Introduced to Opioids by Prescription: A Systematic Review and Meta-Analysis.

OBJECTIVE: Prescription opioid misuse has led to a new cohort of opioid use disorder (OUD) patients who were introduced to opioids through a legitimate prescription. This change has caused a shift in the demographic profile of OUD patients from predominantly young men to middle age and older people. The management of OUD includes medication-assisted treatment (MAT), which produces varying rates of treatment response. In this study, we will examine whether the source of first opioid use has an effect on treatment outcomes in OUD. Using a systematic review of the literature, we will investigate the association between source of first opioid introduction and treatment outcomes defined as continuing illicit opioid use and poly-substance use while in MAT. METHODS: Medline, EMBASE, CINHAL, and PsycInfo were searched from inception to December 31st, 2019 inclusive using a comprehensive search strategy. Five pairs of reviewers conducted screening and data extraction independently in duplicate. The review is conducted and reported according to the PRISMA guidelines. A random-effects model was used for meta analyses assuming heterogeneity among the included studies. RESULTS: The initial search results in 27,345 articles that were screened, and five observational studies were included in the qualitative and quantitative analyses. Our results found that those who were introduced to opioids through a legitimate prescription were significantly less likely to have illicit opioid use (0.70, 95% CI 0.50, 0.99) while on MAT. They were also less likely to use cannabis (0.54, 95% CI 0.32, 0.89), alcohol (0.75, 95% CI 0.59, 0.95), cocaine (0.50, 95% CI 0.29, 0.85), and injection drug use (0.25, 95% CI 0.14, 0.43) than those introduced to opioids through recreational means. CONCLUSION: This study shows that the first exposure to opioids, whether through a prescription or recreationally, influences prognosis and treatment outcomes of opioid use disorder. Although the increased pattern of prescribing opioids may have led to increased OUD in a new cohort of patients, these patients are less likely to continue to use illicit drugs and have a different prognostic and clinical profile that requires a tailored approach to treatment. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017058143.

GWAS-identified genetic variants associated with medication-assisted treatment outcomes in patients with opioid use disorder: a systematic review and meta-analysis protocol.

BACKGROUND: The burden of opioid use disorder (OUD) has been increasing in North America. Administration of medication-assisted treatments (MATs) for OUD on an individual-dose basis has been shown to affect patient responses to treatment, proving to be, on occasion, dangerous. A genetic basis has been identified for some MAT responses in a candidate gene context, but consensus has not been reached for any genome-wide significant associations. This systematic review aims to identify and assess any genetic variants associated with MAT patient outcomes at genome-wide significance. METHODS: The databases searched by the authors will be: MEDLINE, Web of Science, EMBASE, CINAHL and Pre-CINAHL, GWAS Catalog, GWAS Central, and NIH Database of Genotypes and Phenotypes. A title and abstract screening, full-text screening, data extraction, and quality assessment will be completed in duplicate for each study via Covidence. Treatment outcomes of interest include continued opioid use or abstinence during treatment or at follow-up, time to relapse, treatment retention rates, opioid overdose, other substance use, comorbid psychiatric disorders, risk taking behaviors, MAT plasma concentrations, and mortality rates. Analysis methods applied, if appropriate, will include random effects meta-analysis with pooled odds ratios for all outcomes. Subgroup analyses will also be implemented, when possible. DISCUSSION: This systematic review can hopefully inform the direction of future research, aiding in the development of a safer and more patient-centered treatment. It will be able to highlight genome-wide significant variants that are replicable and associated with MAT patient outcomes. SYSTEMATIC REVIEW REGISTRATION: This systematic review protocol has been registered with the International Prospective Register of Systematic Reviews (PROSPERO) (registration ID CRD42020169121).

Genetic determinants of cannabis use: a systematic review protocol.

BACKGROUND: With the legalization of cannabis in Canada, there is an increase trend in use. Cannabis has been known to have several health implications, one of which is the development of cannabis use disorder (CUD). CUD is more common in males than females, as well as in certain ethnic groups such as Native Americans. Additionally, both environmental and genetic risk factors have been found for cannabis use. The objective of this systematic review will be to summarize the genetic variants associated with cannabis use which have reached borderline genome-wide significance. METHODS: This systematic review will incorporate articles that have performed a genome-wide association study (GWAS) investigating cannabis use. MEDLINE, Web of Science, EMBASE, GWAS Catalog, GWAS Central, and NIH Database of Genotype and Phenotype will be searched using a comprehensive search strategy. The quality of genetic association studies (Q-Genie) tool will be utilized to assess the quality of the included studies. All screening and data extraction will occur independently by two authors. If feasible, a random-effects meta-analysis will be conducted on pooled odds ratios of single nucleotide polymorphisms reaching borderline genome-wide significance. DISCUSSION: This systematic review will synthesize available GWAS on cannabis use. Results from this review will inform and direct further investigation of genetic variants associated with cannabis use. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020176016.

The impact of chronic liver disease in patients receiving active pharmacological therapy for opioid use disorder: One-year findings from a prospective cohort study.

INTRODUCTION: Despite the demonstrated benefit of methadone, the incidence opioid-related overdose, and its associated mortality continues to rise at an alarming rate. The impact of high prevalence comorbid features such as chronic liver disease (CLD) on methadone treatment response remain unclear. AIM: To determine whether CLD is associated with poor response to methadone treatment. METHODS: Using a well-established multi-center cohort from the Genetics of Opioid Addiction Study (GENOA), we evaluated if presence of CLD among 1234 eligible patients with opioid use disorder receiving methadone treatment impacted health and behavioural responses to treatment. CLD was classified as any liver disorder/dysfunction present for a minimum period of six months. Serial urine toxicology assessments were used to determine treatment response. The effect of CLD was determined using a multi-variable logistic regression model. RESULTS: CLD was present in 25 % (n = 314) of the population. On average, patients with CLD were found to be older (mean age 44 vs 36 years, p < 0.0001), unemployed (81.8 % vs 61 %, p < 0.0001), and receiving government disability benefits at significantly higher rates (21.9 % vs 11 %, p < 0.0001). Increased levels of physical craving, emotional stress, as well as health risk behaviors were noted in CLD patients. Findings from the multi-variable model demonstrate a 68 % increased risk for dangerous opioid consumption behaviors (Odds Ration [OR]: 1.68, 95 % Confidence Interval [CI] 1.22, 2.31, p = 0.001) among patients with CLD. Methadone dose (OR: 0.76, 95 % CI 0.70, 0.81, p < 0.0001) was shown to be protective with a significant risk reduction of 24 % per 20 mg increase in methadone. Duration in treatment was also found to be protective (OR: 0.99, 95 % CI 0.97, 0.99, p < 0.0001). CONCLUSION: CLD poses a distinct risk for patients with opioid addiction. Closer drug monitoring, and substance use contingency management should be considered to reduce mortality risk in these patients.

A call for consensus in defining efficacy in clinical trials for opioid addiction: combined results from a systematic review and qualitative study in patients receiving pharmacological assisted therapy for opioid use disorder.

BACKGROUND: Given the complex nature of opioid addiction treatment and the rising number of available opioid substitution and antagonist therapies (OSAT), there is no 'gold standard' measure of treatment effectiveness, and each successive trial measures a different set of outcomes which reflect success in arbitrary or opportune terms. We sought to describe the variation in current outcomes employed across clinical trials for opioid addiction, as well as determine whether a discrepancy exists between the treatment targets that patients consider important and how treatment effectiveness is measured in the literature. METHODS: We searched nine commonly used databases (e.g., EMBASE, MEDLINE) from inception to August 1, 2015. Outcomes used across trials were extracted and categorized according to previously established domains. To evaluate patient-reported goals of treatment, semi-structured interviews were conducted with 18 adults undergoing methadone treatment. RESULTS: We identified 60 trials eligible for inclusion. Once outcomes were categorized into eight broad domains (e.g., abstinence/substance abuse), we identified 21 specific outcomes with furthermore 53 subdomains and 118 measurements. Continued opioid use and treatment retention were the most commonly reported measures (46%, n = 28). The majority of patients agreed that abstinence from opioids was a primary goal in their treatment, although they also stressed goals under-reported in clinical trials. CONCLUSIONS: There is inconsistency in the measures used to evaluate the effectiveness of OSATs. Individual and population level decision making is being guided by a standard of effect considered useful to researchers yet in direct conflict with what patients deem important. TRIAL REGISTRATION: PROSPERO, CRD42013006507.

The association between health conditions and cannabis use in patients with opioid use disorder receiving methadone maintenance treatment.

BACKGROUND: Cannabis is the most commonly used substance among patients in methadone maintenance treatment (MMT) for opioid use disorder. Current treatment programmes neither screen nor manage cannabis use. The recent legalisation of cannabis in Canada incites consideration into how this may affect the current opioid crisis. AIMS: Investigate the health status of cannabis users in MMT. METHOD: Patients were recruited from addiction clinics in Ontario, Canada. Regression analyses were used to assess the association between adverse health conditions and cannabis use. Further analyses were used to assess sex differences and heaviness of cannabis use. RESULTS: We included 672 patients (49.9% cannabis users). Cannabis users were more likely to consume alcohol (odds ratio 1.46, 95% CI 1.04-2.06, P = 0.029) and have anxiety disorders (odds ratio 1.75, 95% CI 1.02-3.02, P = 0.043), but were less likely to use heroin (odds ratio 0.45, 95% CI 0.24-0.86, P = 0.016). There was no association between cannabis use and pain (odds ratio 0.98, 95% CI 0.94-1.03, P = 0.463). A significant association was seen between alcohol and cannabis use in women (odds ratio 1.79, 95% CI 1.06-3.02, P = 0.028), and anxiety disorders and cannabis use in men (odds ratio 2.59, 95% CI 1.21-5.53, P = 0.014). Heaviness of cannabis use was not associated with health outcomes. CONCLUSIONS: Our results suggest that cannabis use is common and associated with psychiatric comorbidities and substance use among patients in MMT, advocating for screening of cannabis use in this population. DECLARATION OF INTEREST: None.

Adverse Outcomes Associated with Prescription Opioids for Acute Low Back Pain: A Systematic Review and Meta-Analysis.

BACKGROUND: Acute low back pain (ALBP) is a common clinical complaint that can last anywhere from 24 hours to 12 weeks. In recent years, there has been an opioid epidemic which is linked to the increased availability of prescription opioids. Though guidelines recommend that in the treatment of ALBP, opioids should be used when other treatments fail, we have seen an increase in opioid prescriptions for ALBP. With this crisis, it is important to examine if there are any adverse outcomes associated with prescribing opioids for ALBP. OBJECTIVE: We aim to review the published literature to examine the adverse outcomes associated with opioid use for ALBP. STUDY DESIGN: We performed a systematic review with meta-analysis in accordance with our published protocol and PRISMA guidelines. SETTING: The review was conducted at McMaster University. METHODS: Various electronic databases for articles published from inception to September 30, 2017, inclusive. Both randomized clinical trials and observational studies on the impact of opioid use in ALBP in the adult population were included. Eight pairs of independent reviewers performed screening, data extraction, and assessment of methodological quality. The identified articles were assessed for risk of bias using sensitivity analysis. Trials with comparative outcomes were reported in a meta-analysis using a fixed effects model. RESULTS: A total of 13,889 studies were initially screened for the review and a total of 4 studies were included in the full review, of which 2 studies were meta-analyzed. Our results showed that prescribing opioids for ALBP was significantly associated with long-term continued opioid use (1.57, 95% CI, 1.06-2.33). There was no significant association found between unemployment duration and prescribing opioids for ALBP (3.54, 95% CI, -7.57 to 14.66). LIMITATIONS: Due to the limited number of studies that considered unemployment, only an unpooled analysis was conducted. Among the included studies there was both statistical and clinical heterogeneity due to differences in methodology, study design, risk of selection or performance bias. Most of the studies had an unclear or high risk of bias and poorly defined side effects. CONCLUSIONS: Due to the lack of literature examining long-term adverse outcomes associated with prescribing opioids for ALBP, no definitive conclusions can be made. However, with the literature available, there does seem to be risk associated with prescribing opioids for ALBP so there is a great need to conduct further investigations examining these adverse outcomes for ALBP patients. KEY WORDS: Acute low back pain, opioids, prescriptions, low back pain, long-term use, opioid use disorder.