Impact of patient-specific factors on clozapine metabolism in individuals with treatment-resistant schizophrenia or schizoaffective disorder.

BACKGROUND: There is high inter-individual variability in clozapine metabolism due to genetic and non-genetic differences. Patient-specific factors such as smoking, inflammation indicated by elevated C-reactive protein (CRP), and certain concurrent medications have a significant influence on clozapine metabolism. AIM: To assess which patient-specific factors best explain variability in clozapine metabolism estimated by clozapine concentration to dose (C/D) ratios. METHODS: A retrospective cohort analysis using electronic medical data was conducted on 172 inpatients at the BC Psychosis Program. Patients with normal renal and liver function were included if they were on clozapine and had at least one steady-state plasma concentration. The degree of influence of each factor on the variability of clozapine metabolism in the entire cohort and subgroups stratified by fluvoxamine use was evaluated using multiple linear regression analysis of C/D ratios. RESULTS: Model fit testing showed that the entire cohort model accounts for 52.7% of C/D ratio variability, while the no fluvoxamine and fluvoxamine models accounted for 40.8% and 43.8%. In the entire cohort (n = 172), fluvoxamine use explained the highest variance, and C/D ratios were higher by 30.6% on average. The second strongest predictor was elevated CRP > 10 mg/L, and C/D ratios were higher by 22.9% on average. Subsequently, obesity, nonsmoker status, and female sex explained a significant but modest proportion of variance. Among participants on fluvoxamine (n = 58), only fluvoxamine dose was associated with an increase, and for every 25 mg increase in dose, C/D ratios increased by 5% on average. CONCLUSION: In a clinical population, this study replicated the relationship between reduced rate of clozapine metabolism and the use of fluvoxamine, elevated CRP, obesity, nonsmoking status, and female sex; and the magnitude of the effects were large enough to be clinically relevant.

Adult self-reported childhood maltreatment types are associated with treatment satisfaction and alcohol relapse in patients with comorbid substance use and mental health disorders.

BACKGROUND AND OBJECTIVES: Individuals with comorbid substance use and mental health disorders (concurrent disorders; CD) report poor treatment outcomes, high prevalence of childhood maltreatment, and mostly negative experiences with treatment. No studies to date have examined childhood maltreatment and treatment outcomes in CD. This study investigated self-reported childhood maltreatment as it relates to treatment satisfaction and substance use relapse among CD patients. METHODS: The 258 CD inpatients completed a self-report questionnaire package, comprising the Childhood Trauma Questionnaire and the Inpatient Consumer Survey (ICS). Childhood maltreatment was assessed according to five subtypes and self-perceived treatment satisfaction was rated across six ICS domains. Psychiatric diagnoses, substance use status and relapse data were retrieved via patient medical charts. RESULTS: Emotional neglect was associated with lower ratings across all ICS domains and physical neglect was associated with a lower rating for 'outcome of care'. Childhood sexual abuse was associated with a greater likelihood of alcohol relapse. No other relationships were statistically significant. DISCUSSION AND CONCLUSIONS: The presence of childhood neglect (but not abuse) was more associated with overall treatment dissatisfaction, and sexual abuse alone increased the likelihood of alcohol relapse. These findings suggest some early adverse experiences in CD patients may increase negative experiences in treatment while others contribute to the risk of substance use. Broader longitudinal research is needed to examine the trajectory leading to negative outcomes. SCIENTIFIC SIGNIFICANCE: This is the first study to report differential patterns of association by type of childhood maltreatment on negative outcomes in treatment among CD patients.

Prescription psychostimulants for the treatment of amphetamine-type stimulant use disorder: A systematic review and meta-analysis of randomized placebo-controlled trials.

BACKGROUND AND AIMS: There is currently no standard of care for pharmacological treatment of amphetamine-type stimulant (ATS) use disorder (ATSUD). This systematic review with meta-analysis (PROSPERO CRD42022354492) aimed to pool results from randomized placebo-controlled trials (RCTs) to evaluate efficacy and safety of prescription psychostimulants (PPs) for ATSUD. METHODS: Major indexing sources and trial registries were searched to include records published before 29 August 2022. Eligible studies were RCTs evaluating efficacy and safety of PPs for ATSUD. Risk of bias (RoB) was assessed using the Cochrane RoB 2 tool. Risk ratio (RR) and risk difference were calculated for random-effect meta-analysis of dichotomous variables. Mean difference and standardized mean difference (SMD) were calculated for random-effect meta-analysis of continuous variables. RESULTS: Ten RCTs (n = 561 participants) were included in the meta-analysis. Trials studied methylphenidate (n = 7), with daily doses of 54-180 mg, and dextroamphetamine (n = 3), with daily doses of 60-110 mg, for 2-24 weeks. PPs significantly decreased end-point craving [SMD  -0.29; 95% confidence interval (CI) = -0.55, -0.03], while such a decrease did not reach statistical significance for ATS use, as evaluated by urine analysis (UA) (RR = 0.93; 95% CI = 0.85-1.01). No effect was observed for self-reported ATS use, retention in treatment, dropout following adverse events, early-stage craving, withdrawal and depressive symptoms. In a sensitivity analysis, treatment was associated with a significant reduction in UA positive for ATS (RR = 0.89; 95% CI = 0.79-0.99) after removing studies with a high risk of bias. In subgroup analyses, methylphenidate and high doses of PPs were negatively associated with ATS use by UA, while higher doses of PPs and treatment duration (≥ 20 weeks) were positively associated with longer retention. CONCLUSIONS: Among individuals with amphetamine-type stimulant use disorder, treatment with prescription psychostimulants may decrease ATS use and craving. While effect size is limited, it may increase with a higher dosage of medications.

Blood Oxygenation and Heart Rate Changes After Diamorphine Intravenous Injection During Opioid Agonist Treatment for Outpatients With Heroin Dependence.

OBJECTIVES: More than 60 million people use opioids each year, and many countries have declared an opioid overdose crisis. Heroin, one of the most commonly used opioids, has depressant effects on autonomic functioning; however, few studies have been able to examine the effects of heroin or its pharmaceutically prepared equivalent, diamorphine, in human clinical populations. The present study examined heart rate and oxygen saturation in the minutes immediately after acute diamorphine administration in outpatients with heroin dependence. METHODS: The sample was a subset of participants (N = 36) in the German Project of Heroin Assisted Treatment of Opiate Dependent Patients Trial in Bonn, Germany. Patients were given 3 daily doses of intravenous diamorphine. Doses were determined on an individual basis by study physicians. Pulse oximetry was recorded at baseline and at 30-second intervals from 0 to 450 seconds after diamorphine administration. RESULTS: Heart rate was significantly higher than baseline at 30 seconds after diamorphine administration and significantly lower than baseline at 270 seconds onward. Oxygen saturation was significantly lower than baseline at 60 seconds onward. CONCLUSIONS: Results are consistent with other studies in which depressant effects of opioids were observed. Our findings suggest that even therapeutic doses of diamorphine may have rapid and significant-predominantly depressant-effects on oxygenation and heart rate in populations that frequently use opioids. Monitoring of potential adverse opioid effects would be beneficial even in populations presumed to have developed physiological tolerance.

Bupropion for treatment of amphetamine-type stimulant use disorder: A systematic review and meta-analysis of placebo-controlled randomized clinical trials.

BACKGROUND: This meta-analysis (PROSPERO-ID: CRD42022362962), pooled effect estimates of outcomes, from placebo-controlled randomized clinical trials (RCTs) examining bupropion efficacy and safety for amphetamine-type stimulant use disorder (ATSUD) treatment. METHOD: Electronic databases were searched for records published to October 31st, 2022, including MEDLINE, CINAHL, PsycINFO, EBM Reviews, EMBASE, PubMed, Web of Science, trial registries. Inclusion criteria were RCTs comparing bupropion to placebo in ATSUD. Cochrane RoB2 tool and GRADE evidence certainty assessment were employed. Outcomes included amphetamine-type stimulant (ATS) use by urinalysis, retention in treatment, treatment adherence, ATS craving, addiction severity, depressive symptom severity, drop-out following adverse events (AEs), and serious AEs. Random-effect meta-analysis was conducted presenting standardized mean difference (SMD), risk ratio (RR), and risk difference (RD). RESULTS: Eight RCTs (total N=1239 participants) were included. Bupropion compared to placebo was associated with reduced ATS use (RR: 0.90; 95% CI: 0.84, 0.96), end-of-treatment ATS craving (SMD: -0.38; 95%CI: -0.63, -0.13), and adherence (RR: 0.91; 95%CI: 0.84, 0.99). Subgroup analysis showed greater reduction in ATS use with longer trial duration (12 weeks) (RR: 0.85; 95%CI: 0.78, 0.93) and greater reduction in end-of-treatment ATS craving in studies with mixed ATS use frequency (SMD: -0.46; 95%CI: -0.70, -0.22) and male-only samples (SMD: -1.26; 95%CI: -1.87, -0.65). CONCLUSION: Bupropion showed a significant modest reduction in ATS use and ATS craving (both rated as very low-quality evidence), larger in males (craving), and with longer treatment (ATS use). These results may inform future studies. More research is warranted on who might benefit from bupropion as ATSUD treatment.

Associations of the P300 Event-Related Potentials and Self-Reported Craving in Substance Use Disorders: A Systematic Review.

INTRODUCTION: The phenomenon of craving and attention bias towards drug cues is theorized to operate cooperatively, owing to the principles of associative learning. In this context, the conditioned response to drug-related stimuli activates reward mechanisms within the brain, consequently inducing craving and fostering the underlying mechanisms that contribute to relapse in individuals with substance use disorders. Multiple studies have assessed the relationship between attention to substance-related cues and subjective craving through electroencephalography (EEG), but their findings have yet to be synthesized and examined. This review summarizes the association between the amplitude of the P300 event-related potential (ERP) and substance use craving, compares discrepancies in results by type of substance, and discusses gaps in the literature to inform future research. METHODS: A systematic search was conducted on Embase, Web of Science, CINAHL, and PsychINFO databases. Studies were published in English and included peer-reviewed human research investigating the relationship between EEG P300 ERP and self-reported substance use craving. The included study samples comprised of in treatment or non-treatment-seeking participants who use substances. The primary outcomes of interest were those derived from inferential statistics assessing P300 amplitude and substance use craving. RESULTS: Ten studies were included in the final search and were organized by substance type: three alcohol, three cocaine, two tobacco, one heroin, and one cannabis. Results were mixed for alcohol and cocaine. Studies on tobacco, heroin, and cannabis use were congruent for associations between the P300 amplitude and craving. CONCLUSIONS: Overall findings are mixed between studies addressing the association of the EEG P300 amplitude and craving. These results should be considered in the context of the limited sample size, underpowered analyses, and methodological differences that potentially contribute to discrepancies in outcomes. Further research is required to assess the role of craving assessment, EEG methodology, and substance-related factors on the association between P300 amplitude and self-reported craving.

Association of clozapine treatment and rate of methamphetamine or amphetamine relapses and abstinence among individuals with concurrent schizophrenia spectrum and amphetamine use disorder: A retrospective cohort study.

BACKGROUND: Preliminary evidence suggest clozapine is associated with more favorable impact on concurrent substance use disorder related outcomes in patients with concurrent schizophrenia spectrum disorders (SSD). At the same time, there is a dearth of evidence with regards to clozapine outcomes in the context of concurrent methamphetamine or amphetamine use disorder (MAUD). AIMS: To examine whether clozapine use decreases rate of methamphetamine or amphetamine (MA) relapses and increases the likelihood of maintaining abstinence from any MA use. METHODS: A descriptive-analytic retrospective cohort study was conducted on individuals with SSD-MAUD in an inpatient provincial treatment and rehabilitation center for concurrent disorders. Antipsychotic exposure was categorized as "on clozapine" or "on other antipsychotic(s)." Data were collected using electronic health records. Logistic regression was used to examine association of clozapine treatment with likelihood of complete abstinence from MA use for the duration of antipsychotic exposure. Negative binomial regression was used to examine association of clozapine treatment with rate of MA relapses for the duration of antipsychotic exposure. RESULTS: The majority of the 87 included patients were male. Ethnicity was diverse, with the largest groups self-identifying as Indigenous and European. Clozapine use was both associated with increased likelihood of maintaining abstinence from MA use (adjusted odds ratio (aOR) = 3.05, 95% confidence intervals (CI) = 1.15-8.1, p = 0.025), and decreased rate of MA relapses (aRR = 0.45, 95% CI = 0.25-0.82, p = 0.009) for the duration of antipsychotic exposure. Co-prescription of psychostimulants was associated with increased rate of MA relapses (aRR = 2.43, 95% CI = 1.16-5.10, p = 0.019). CONCLUSION(S): In this study, clozapine use compared with other antipsychotics in SSD was associated with improved outcomes related to severe concurrent MAUD. Co-prescription of psychostimulant medications was associated with a poor outcome.

The effectiveness of oxytocin in the treatment of stimulant use disorders: a systematic review.

OBJECTIVES: The purpose of this review is to examine human study evidence on the effectiveness of oxytocin in this patient population. Despite stimulant use disorder being a major public health concern, there are no validated pharmacological treatments. Psychosocial interventions show limited effectiveness especially in the more severe cases of stimulant use disorder, whereas animal models suggest that oxytocin may be a useful treatment. METHODS: A literature search using Medline, Embase, and PsychInfo was undertaken. Search results were subsequently imported into Covidence to identify relevant studies. RESULTS: Six studies were included in this review, two of which were pilot studies. Although oxytocin was well tolerated across studies, no study showed a statistically significant reduction in reported cocaine use or cravings. One study suggested oxytocin increased the desire to use cocaine, although the population of participants should be taken into consideration. In contrast, one study showed a trend towards reduced self-reported cocaine use. CONCLUSION: Available research does not support the use of oxytocin in the management of stimulant use disorder; however, included studies are small in sample size and limited in number. There were several noteworthy findings unrelated to this review's primary and secondary outcomes, which are of interest and warrant further research. We provide suggestions for future studies in this area of research. Considering the limited data available at this time, further studies are required before any definitive conclusions can be made regarding the use of oxytocin in stimulant use disorder management.

Developing A Rapid Transfer from Opioid Full Agonist to Buprenorphine: "Ultrarapid Micro-Dosing" Proof of Concept.

Buprenorphine/naloxone has been shown to be effective for treating opioid use disorder (OUD). However, the traditional method of induction requires a patient to be in moderate-to-severe withdrawal, which is challenging, time-consuming, and a common reason for leaving against medical advice. Induction strategies that minimize the severity and duration of patient discomfort while enabling patients to reach therapeutic doses during short hospital admissions can mitigate difficulties when inducing a patient on buprenorphine/naloxone. This case-series illustrates two patients with OUD using illicit fentanyl, who were successfully started on buprenorphine/naloxone using 24-hour and 6-hour micro-dosing induction protocol. During induction, the patients were up-titrated to a therapeutic dose through ultrarapid micro-dosing with ongoing use of short-acting opioids. Both patients reached therapeutic doses experiencing minimal levels of withdrawal. This case-series is a proof of concept for the use of a buprenorphine/naloxone ultrarapid micro-induction protocol for inpatients with OUD. By reducing the length of induction and precluding the need for withdrawal, this method offers several advantages over previously published inductions protocols and can improve the accessibility of buprenorphine/naloxone to patients with OUD.

Effects of clozapine treatment on the improvement of substance use disorders other than nicotine in individuals with schizophrenia spectrum disorders: A systematic review and meta-analysis.

BACKGROUND: Antipsychotic medications are the mainstay of treatment for schizophrenia and are associated with a reduction in psychiatric hospitalization and overall mortality. Some evidence suggest that antipsychotic medications might have a varying effect on the improvement of comorbid substance use disorders (SUDs), with clozapine showing more favorable outcomes. AIM: We systematically reviewed all available evidence on effects of clozapine on the improvement of SUDs other than nicotine. METHODS: Electronic searches of MEDLINE, Embase, PsycINFO, and CINHAL were conducted up to March 1, 2022. Studies of any methodological design involving two concepts: (1) clozapine and (2) SUD terms (excluding nicotine) were included. For SUD outcomes with three or more comparative studies with available raw data meta-analysis was performed. SUD outcomes not meeting criteria for meta-analysis were described qualitatively. Risk of bias was examined using "Downs and Black," and "Q-Coh" instruments. RESULTS: The majority of individuals in the included 31 studies were male and of European ancestry. Abstinence was the most common outcome. Most of the studies were of low-to-moderate quality, and none of the studies met all the quality criteria. Pooled findings from four observational studies in samples of patients with predominantly comorbid alcohol use disorder showed that clozapine treatment is associated with significantly higher odds of remaining abstinent. In addition clozapine was associated with decreased odds of psychiatric hospitalization in all but one observational study. CONCLUSIONS: Our systematic review and meta-analysis builds upon previous reviews, and it suggests the association of clozapine treatment with significantly higher odds of remaining abstinent from substance use and decreased likelihood of psychiatric hospitalization, compared with continuing treatment with other antipsychotic medications. Still, the validity of this association needs greater exploration and providing recommendations for the utility of clozapine in individuals without treatment-resistant psychosis and comorbid SUDs would be premature.

Sleep and Rest-Activity Rhythms in Recovering Patients with Severe Concurrent Mental and Substance Use Disorder: A Pilot Study.

Objective: Mental health and substance use disorders are commonly associated with disrupted sleep and circadian rest-activity rhythms. How these disorders in combination relate to sleep and circadian organization is not well studied. We provide here the first quantitative assessment of sleep and rest-activity rhythms in inpatients with complex concurrent disorders, taking into account categories of substance use (stimulant vs. stimulant and opioid use) and psychiatric diagnosis (psychotic disorder and mood disorder). We also explore how sleep and rest-activity rhythms relate to psychiatric functioning. Methods: A total of 44 participants (10 female) between the age of 20-60 years (median = 29 years) wore wrist accelerometers over 5-70 days and completed standardized questionnaires assessing chronotype and psychiatric functioning (fatigue, psychiatric symptom severity, and impulsiveness). To examine potential influences from treatment, we computed (1) length of stay; (2) days of abstinence from stimulants and opioids as a measure of withdrawal; and (3) a sedative load based on prescribed medications. Results: Participants exhibited a sustained excessive sleep duration, frequent nighttime awakenings, and advanced rest-activity phase related to sedative load. Sleep disruptions were elevated in participants with a history of opioid use. Patients with a psychotic disorder showed the longest sleep and most fragmented and irregular rest-activity patterns. Non-parametric circadian rhythm analysis revealed a high rhythm amplitude by comparison with population norms, and this was associated with greater psychiatric symptom severity. Psychiatric symptom severity was also associated with greater fatigue and later MCTQ chronotype. Conclusions: This pilot study provides initial information on the prevalence and severity of sleep and circadian rhythm disturbances in individuals with severe concurrent disorders. The results underline the need for further studies to start to understand the role of sleep in the disease and recovery process in this understudied population.

Primary care for individuals with serious mental illness (PriSMI): protocol for a convergent mixed methods study.

INTRODUCTION: People with serious mental illness (SMI) have poor health outcomes, in part because of inequitable access to quality health services. Primary care is well suited to coordinate and manage care for this population; however, providers may feel ill-equipped to do so and patients may not have the support and resources required to coordinate their care. We lack a strong understanding of prevention and management of chronic disease in primary care among people with SMI as well as the context-specific barriers that exist at the patient, provider and system levels. This mixed methods study will answer three research questions: (1) How do primary care services received by people living with SMI differ from those received by the general population? (2) What are the experiences of people with SMI in accessing and receiving chronic disease prevention and management in primary care? (3) What are the experiences of primary care providers in caring for individuals with SMI? METHODS AND ANALYSIS: We will conduct a concurrent mixed methods study in Ontario and British Columbia, Canada, including quantitative analyses of linked administrative data and in-depth qualitative interviews with people living with SMI and primary care providers. By comparing across two provinces, each with varying degrees of mental health service investment and different primary care models, results will shed light on individual and system-level factors that facilitate or impede quality preventive and chronic disease care for people with SMI in the primary care setting. ETHICS AND DISSEMINATION: This study was approved by the University of Ottawa Research Ethics Board and partner institutions. An integrated knowledge translation approach brings together researchers, providers, policymakers, decision-makers, patient and caregiver partners and knowledge users. Working with this team, we will develop policy-relevant recommendations for improvements to primary care systems that will better support providers and reduce health inequities.

The relationship between outpatient service use and emergency department visits among people treated for mental and substance use disorders: analysis of population-based administrative data in British Columbia, Canada.

BACKGROUND: Research findings on the association between outpatient service use and emergency department (ED) visits for mental and substance use disorders (MSUDs) are mixed and may differ by disorder type. METHODS: We used population-based linked administrative data in British Columbia, Canada to examine associations between outpatient primary care and psychiatry service use and ED visits among people ages 15 and older, comparing across people treated for three disorder categories: common mental disorders (MDs) (depressive, anxiety, and/or post-traumatic stress disorders), serious MDs (schizophrenia spectrum and/or bipolar disorders), and substance use disorders (SUDs) in 2016/7. We used hurdle models to examine the association between outpatient service use and odds of any ED visit for MSUDs as well count of ED visits for MSUDs, stratified by cohort in 2017/8. RESULTS: Having had one or more MSUD-related primary care visit was associated with lower odds of any ED visit among people treated for common MDs and SUDs but not people treated for serious MDs. Continuity of primary care was associated with slightly lower ED use in all cohorts. One or more outpatient psychiatrist visits was associated with lower odds of ED visits among people treated for serious MDs and SUDs, but not among people with common MDs. CONCLUSION: Findings highlight the importance of expanded access to outpatient specialist mental health services, particularly for people with serious MDs and SUDs, and collaborative models that can support primary care providers treating people with MSUDs.

The Utility of Research Domain Criteria in Diagnosis and Management of Dual Disorders: A Mini-Review.

The Research Domain Criteria (RDoC) initiative has been considered a comprehensive alternative classification framework for understanding neuropsychiatric ailments, as opposed to the longstanding, traditional DSM framework. Where the DSM categorizes neuropsychiatric disorders as each being distinct and diagnostically defined by the presence of specified symptoms, RDoC provides a multidimensional conceptualization of psychiatric disorders with neurobiological roots. By taking a multidimensional approach, RDoC overcomes two major constraints of the DSM framework: that is, that the DSM is categorical in its approach to psychiatric disorders to the point of understating the intersectionality between concomitant disorders, and that the DSM focuses mainly on clinical features. RDoC seems to better account for the intersection between dual disorders and considers a range of factors, from the more microscopic (e.g., genetics or molecular functions) to the more macroscopic (e.g., environmental influences). The multidimensional approach of RDoC is particularly appealing in the context of dual disorders. Dual disorders refers to a concurrent psychiatric disorder with an addiction disorder. RDoC accounts for the fact that there is often overlap in symptoms across and bidirectional influence between various disorders. However, to date, there is limited research into the clinical utility of RDoC, and less so in the context of the clinical management of dual disorders. In this Mini-Review, we discuss how RDoC differs from the DSM, what outcomes have been reported in utilizing RDoC clinically, the utility of RDoC for the diagnosis, management, and monitoring of psychopathology, and the limitations of RDoC as well as avenues for future research.

Emergency department use for mental and substance use disorders: descriptive analysis of population-based, linked administrative data in British Columbia, Canada.

OBJECTIVES: Information on emergency department (ED) visits for mental and substance use disorders (MSUDs) is important for planning services but has not been explored in British Columbia (BC), Canada. We describe all MSUD ED visits for people ages 15 and older in the province of BC in 2017/2018 and document trends in MSUD ED visits between 2007/2008 and 2017/2018 by disorder group. DESIGN: Population-based linked administrative data comprised of ED records and physician billings capturing all MSUD ED visits in BC. SETTING: BC is Canada's westernmost province with a population of approximately 5 million. Permanent residents receive first-dollar coverage for all medically necessary services provided by licensed physicians or in hospitals, including ED services. POPULATION: All people age >15 with MSUD ED visits during the study period. MEASURES: All claims with a service location in the ED or corresponding to fee items billed only in the ED were examined alongside ED visits reported through a national reporting system. Patient characteristics (sex/gender, age, location of residence, income, treated disorders and comorbidities) and previous outpatient service use for all ED visits by visit diagnosis are also described. RESULTS: A total of 72 363 people made 134 063 visits to the ED in 2017/2018 for needs related to MSUD. MSUD ED visits have increased since 2010, particularly visits for substance use and anxiety disorders. People with more frequent visits were more likely to be male, on public prescription drug plans for income assistance, prescribed psychiatric medications, and living in lower-income neighbourhoods. They used more community-based primary care and psychiatry services and had lower continuity of primary care. CONCLUSIONS: MSUD ED visits are substantial and growing in BC. Findings underscore a need to strengthen and target community healthcare services and adequately resource and support EDs to manage growing patient populations.

Prescription-related risk factors for opioid-related overdoses in the era of fentanyl contamination of illicit drug supply: A retrospective case-control study.

Background:We sought to quantify the association between clinical, physiological, and contextual factors and opioid-related overdose, specifically focusing on current and past use of select prescription medications. Methods: We conducted a case-control study of individuals who experienced a non-fatal opioid-related overdose between January 2015 and November 2016 in British Columbia, Canada. We matched 8,831 cases to 44,155 controls on birth year, sex, and local health area of residence and examined 5-year prescribing history for opioids for pain, medications for opioid use disorder (MOUD), benzodiazepines/z-drugs, and other psychoactive medications. Results: The overall prevalence of prescription opioid drug use was generally low in the study population. Cases had a relatively higher use of selected prescription medications, a higher physical and mental morbidity burden, and were less connected to health services compared with controls. For opioids for pain, current therapy was associated with experiencing an overdose (OR = 8.5, 95%CI: 7.3-10); history of long-term use had a stronger association than history of short-term use (OR = 2.9, 95%CI: 2.6-3.3 vs OR = 1.7, 95%CI: 1.5-1.8, respectively). While persons on MOUD were more likely to overdose compared to persons who were not on therapy (OR = 2.0, 95%CI 1.7-2.4), recent discontinuation of MOUD greatly increased the likelihood of overdose (OR = 25.6, 95%CI 17.5-37.4). Active therapy of benzodiazepines/z-drugs and other sedating medications also significantly increased the likelihood of overdose. Conclusions: While this study supports expansion of efforts to prevent overdoses among individuals actively using opioids for pain and improve retention among those on MOUD, it is also important to address other clinical, physiological, and contextual risk and protective factors to help curb the current overdose crisis.

Impact of opioid agonist treatment on mental health in patients with opioid use disorder: a systematic review and network meta-analysis of randomized clinical trials.

Background: There is a knowledge gap in systematic reviews on the impact of opioid agonist treatments on mental health.Objectives: We compared mental health outcomes between different opioid agonist treatments and placebo/waitlist, and between the different opioids themselves.Methods: This meta-analysis of randomized clinical trials (RCTs) was pre-registered at PROSPERO (CRD42018109375). Embase, MEDLINE, PsychInfo, CINAHL Complete, and Web of Science Core Collection were searched from inception to May 2020. RCTs were included if they compared opioid agonists with each other or with placebo/waitlist in the treatment of patients with opioid use disorder and reported at least one mental health outcome after 1-month post-baseline. Studies with psychiatric care, adjunct psychotropic medications, or unbalanced psychosocial services were excluded. The primary outcome was overall mental health symptomatology, e.g. Symptom Checklist 90 total score, between opioids and placebo/waitlist. Random effects models were used for all the meta-analyses.Results: Nineteen studies were included in the narrative synthesis and 15 in the quantitative synthesis. Hydromorphone, diacetylmorphine (DAM), methadone, slow-release oral morphine, buprenorphine, and placebo/waitlist were among the included interventions. Based on the network meta-analysis for primary outcomes, buprenorphine (SMD (CI95%) = -0.61 (-1.20, -0.11)), DAM (-1.40 (-2.70, -0.23)), and methadone (-1.20 (-2.30, -0.11)) were superior to waitlist/placebo on overall mental health. Further direct pairwise meta-analysis indicated that overall mental health improved more in DAM compared to methadone (-0.23 (-0.34, -0.13)).Conclusions: Opioid agonist treatments used for the treatment of opioid use disorder improve mental health independent of psychosocial services.

Comparing rapid micro-induction and standard induction of buprenorphine/naloxone for treatment of opioid use disorder: protocol for an open-label, parallel-group, superiority, randomized controlled trial.

BACKGROUND: Buprenorphine/naloxone (Suboxone) is a current first-line treatment for opioid use disorder (OUD). The standard induction method of buprenorphine/naloxone requires patients to be abstinent from opioids and therefore experience withdrawal symptoms prior to induction, which can be a barrier in starting treatment. Rapid micro-induction (micro-dosing) involves the administration of small, frequent does of buprenorphine/naloxone and removes the need for a period of withdrawal prior to the start of treatment. This study aims to compare the effectiveness and safety of rapid micro-induction versus standard induction of buprenorphine/naloxone in patients with OUD. METHODS: This is a randomized, open-label, two-arm, superiority, controlled trial comparing the safety and effectiveness of rapid micro-induction versus standard induction of buprenorphine/naloxone for the treatment of OUD. A total of 50 participants with OUD will be randomized at one Canadian hospital. The primary outcome is the completion of buprenorphine/naloxone induction with low levels of withdrawal. Secondary outcomes are treatment retention, illicit drug use, self-reported drug use behaviour, craving, pain, physical health, safety, and client satisfaction. DISCUSSION: This is the first randomized controlled trial to compare the effectiveness and safety of rapid micro-induction versus standard induction of buprenorphine/naloxone. This study will thereby generate evidence for a novel induction method which eliminates substantial barriers to the use of buprenorphine/naloxone in the midst of the ongoing opioid crisis. Trial registration ClinicalTrials.gov, NCT04234191; date of registration: January 21, 2020; https://clinicaltrials.gov/ct2/show/NCT04234191.