7-Deazaguanines in DNA: functional and structural elucidation of a DNA modification system.

The modified nucleosides 2'-deoxy-7-cyano- and 2'-deoxy-7-amido-7-deazaguanosine (dPreQ0 and dADG, respectively) recently discovered in DNA are the products of the bacterial queuosine tRNA modification pathway and the dpd gene cluster, the latter of which encodes proteins that comprise the elaborate Dpd restriction-modification system present in diverse bacteria. Recent genetic studies implicated the dpdA, dpdB and dpdC genes as encoding proteins necessary for DNA modification, with dpdD-dpdK contributing to the restriction phenotype. Here we report the in vitro reconstitution of the Dpd modification machinery from Salmonella enterica serovar Montevideo, the elucidation of the roles of each protein and the X-ray crystal structure of DpdA supported by small-angle X-ray scattering analysis of DpdA and DpdB, the former bound to DNA. While the homology of DpdA with the tRNA-dependent tRNA-guanine transglycosylase enzymes (TGT) in the queuosine pathway suggested a similar transglycosylase activity responsible for the exchange of a guanine base in the DNA for 7-cyano-7-deazaguanine (preQ0), we demonstrate an unexpected ATPase activity in DpdB necessary for insertion of preQ0 into DNA, and identify several catalytically essential active site residues in DpdA involved in the transglycosylation reaction. Further, we identify a modification site for DpdA activity and demonstrate that DpdC functions independently of DpdA/B in converting preQ0-modified DNA to ADG-modified DNA.

Comparative Analysis of Instrumental Variables on the Assignment of Buprenorphine/Naloxone or Methadone for the Treatment of Opioid Use Disorder.

BACKGROUND: Instrumental variable (IV) analysis provides an alternative set of identification assumptions in the presence of uncontrolled confounding when attempting to estimate causal effects. Our objective was to evaluate the suitability of measures of prescriber preference and calendar time as potential IVs to evaluate the comparative effectiveness of buprenorphine/naloxone versus methadone for treatment of opioid use disorder (OUD). METHODS: Using linked population-level health administrative data, we constructed five IVs: prescribing preference at the individual, facility, and region levels (continuous and categorical variables), calendar time, and a binary prescriber's preference IV in analyzing the treatment assignment-treatment discontinuation association using both incident-user and prevalent-new-user designs. Using published guidelines, we assessed and compared each IV according to the four assumptions for IVs, employing both empirical assessment and content expertise. We evaluated the robustness of results using sensitivity analyses. RESULTS: The study sample included 35,904 incident users (43.3% on buprenorphine/naloxone) initiated on opioid agonist treatment by 1585 prescribers during the study period. While all candidate IVs were strong (A1) according to conventional criteria, by expert opinion, we found no evidence against assumptions of exclusion (A2), independence (A3), monotonicity (A4a), and homogeneity (A4b) for prescribing preference-based IV. Some criteria were violated for the calendar time-based IV. We determined that preference in provider-level prescribing, measured on a continuous scale, was the most suitable IV for comparative effectiveness of buprenorphine/naloxone and methadone for the treatment of OUD. CONCLUSIONS: Our results suggest that prescriber's preference measures are suitable IVs in comparative effectiveness studies of treatment for OUD.

Rethinking Substance Use as Social History: Charting a Way Forward.

Physicians have traditionally asked about substance use within the Social History section of the consultation note. Drawing on social science theory and using the authors' own experiences as generalists and addiction scholars, we consider the possible unintended harms associated with this approach. The inclusion of the substance use history within the Social History reproduces the discourse of substance use disorders as "life-style choices" rather than medical conditions, and reinforces stigma among healthcare workers through the attribution of personal responsibility for complications associated with problematic substance use. The ongoing placement of the substance use history within the Social History may lead to a failure to diagnose and make appropriate management plans for clients with substance use disorders. These missed opportunities may include inadequate withdrawal management leading to discharge before medically advised, insufficient use of evidence-based pharmacotherapy and psychotherapy, polypharmacy, medical complications, and repeated admissions to hospital. We argue instead that the Substance Use History should be a stand-alone section within the consultation note. This new section would reduce the invisibility of substance use disorders within our medical systems and model that these chronic medical conditions are amenable to prevention, treatment and harm reduction through the application of evidence-based practices.

Does This Patient Have Alcohol Use Disorder?: The Rational Clinical Examination Systematic Review.

Importance: The accuracy of screening tests for alcohol use disorder (defined as a problematic pattern of alcohol use leading to clinically significant impairment or distress) requires reassessment to align with the latest definition in the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5). Objective: To assess the diagnostic accuracy of screening tools in identifying individuals with alcohol use disorder as defined in the DSM-5. Data Sources and Study Selection: The databases of MEDLINE and Embase were searched (January 2013-February 2023) for original studies on the diagnostic accuracy of brief screening tools to identify alcohol use disorder according to the DSM-5 definition. Because diagnosis of alcohol use disorder does not include excessive alcohol use as a criterion, studies of screening tools that identify excessive or high-risk drinking among younger (aged 9-18 years), older (aged ≥65 years), and pregnant persons also were retained. Data Extraction and Synthesis: Sensitivity, specificity, and likelihood ratios (LRs) were calculated. When appropriate, a meta-analysis was performed to calculate a summary LR. Results: Of 4303 identified studies, 35 were retained (N = 79 633). There were 11 691 individuals with alcohol use disorder or a history of excessive drinking. Across all age categories, a score of 8 or greater on the Alcohol Use Disorders Identification Test (AUDIT) increased the likelihood of alcohol use disorder (LR, 6.5 [95% CI, 3.9-11]). A positive screening result using AUDIT identified alcohol use disorder better among females (LR, 6.9 [95% CI, 3.9-12]) than among males (LR, 3.8 [95% CI, 2.6-5.5]) (P = .003). An AUDIT score of less than 8 reduced the likelihood of alcohol use disorder similarly for both males and females (LR, 0.33 [95% CI, 0.20-0.52]). The abbreviated AUDIT-Consumption (AUDIT-C) has sex-specific cutoff scores of 4 or greater for males and 3 or greater for females, but was less useful for identifying alcohol use disorder (males: LR, 1.8 [95% CI, 1.5-2.2]; females: LR, 2.0 [95% CI, 1.8-2.3]). The AUDIT-C appeared useful for identifying measures of excessive alcohol use in younger people (aged 9-18 years) and in those older than 60 years of age. For those younger than 18 years of age, the National Institute on Alcohol Abuse and Alcoholism age-specific drinking thresholds were helpful for assessing the likelihood of alcohol use disorder at the lowest risk threshold (LR, 0.15 [95% CI, 0.11-0.21]), at the moderate risk threshold (LR, 3.4 [95% CI, 2.8-4.1]), and at the highest risk threshold (LR, 15 [95% CI, 12-19]). Among persons who were pregnant and screened within 48 hours after delivery, an AUDIT score of 4 or greater identified those more likely to have alcohol use disorder (LR, 6.4 [95% CI, 5.1-8.0]), whereas scores of less than 2 for the Tolerance, Worried, Eye-Opener, Amnesia and Cut-Down screening tool and the Tolerance, Annoyed, Cut-Down and Eye-Opener screening tool identified alcohol use disorder similarly (LR, 0.05 [95% CI, 0.01-0.20]). Conclusions and Relevance: The AUDIT screening tool is useful to identify alcohol use disorder in adults and in individuals within 48 hours postpartum. The National Institute on Alcohol Abuse and Alcoholism youth screening tool is helpful to identify children and adolescents with alcohol use disorder. The AUDIT-C appears useful for identifying various measures of excessive alcohol use in young people and in older adults.

Canadian guideline for the clinical management of high-risk drinking and alcohol use disorder.

BACKGROUND: In Canada, low awareness of evidence-based interventions for the clinical management of alcohol use disorder exists among health care providers and people who could benefit from care. To address this gap, the Canadian Research Initiative in Substance Misuse convened a national committee to develop a guideline for the clinical management of high-risk drinking and alcohol use disorder. METHODS: Development of this guideline followed the ADAPTE process, building upon the 2019 British Columbia provincial guideline for alcohol use disorder. A national guideline committee (consisting of 36 members with diverse expertise, including academics, clinicians, people with lived and living experiences of alcohol use, and people who self-identified as Indigenous or Métis) selected priority topics, reviewed evidence and reached consensus on the recommendations. We used the Appraisal of Guidelines for Research and Evaluation Instrument (AGREE II) and the Guidelines International Network's Principles for Disclosure of Interests and Management of Conflicts to ensure the guideline met international standards for transparency, high quality and methodological rigour. We rated the final recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) tool; the recommendations underwent external review by 13 national and international experts and stakeholders. RECOMMENDATIONS: The guideline includes 15 recommendations that cover screening, diagnosis, withdrawal management and ongoing treatment, including psychosocial treatment interventions, pharmacotherapies and community-based programs. The guideline committee identified a need to emphasize both underused interventions that may be beneficial and common prescribing and other practice patterns that are not evidence based and that may potentially worsen alcohol use outcomes. INTERPRETATION: The guideline is intended to be a resource for physicians, policymakers and other clinical and nonclinical personnel, as well as individuals, families and communities affected by alcohol use. The recommendations seek to provide a framework for addressing a large burden of unmet treatment and care needs for alcohol use disorder within Canada in an evidence-based manner.

Time-Series Analysis of Fentanyl Concentration in the Unregulated Opioid Drug Supply in a Canadian Setting.

North America has been contending with an unregulated street drug supply in which opioids are often adulterated with illicitly manufactured fentanyl. The unpredictability of composition may result in an increased risk of overdose due to unexpected elevated concentrations of the high-potency drug. Using data from a community-based drug-checking project, we evaluated trends in fentanyl concentration of illicit opioids in the context of an overdose epidemic. Using a quantification model for fentanyl hydrochloride, historical Fourier-transform infrared spectra from opioid drug-checking samples were analyzed to determine fentanyl concentrations. Median monthly fentanyl concentrations were plotted, and polynomial and autoregressive time-series analyses were performed to examine trends over time. A total of 3,621 fentanyl-positive samples were included in the study, spanning November 2017 to December 2019. Monthly median fentanyl concentrations ranged from 4.5% to 10.4%. Time-series analyses indicated that a third-degree polynomial model fit the data well (R2 = 0.639), suggesting a cyclical pattern in median concentration over time. Notably, absolute variance in fentanyl concentration decreased by an average 0.1% per month (P < 0.001). Future research should explore the relationship between fentanyl concentration and overdose to identify potential targeted harm-reduction interventions that can respond to changes in observed fentanyl concentration.

Increasing preference for fentanyl among a cohort of people who use opioids in Vancouver, Canada, 2017-2018.

Background: Despite increasing prevalence of illicit fentanyl use in the US and Canada, preference for fentanyl over other illicit opioids has not been fully characterized. Therefore, we sought to describe changes in illicit opioid preferences over time among people who inject drugs (PWID). Methods: Data were obtained from two prospective cohort studies between 2017 and 2018. Trends in opioid preference over time were examined using bivariable generalized estimating equation (GEE) analysis. Multivariable models were used to identify factors associated with fentanyl preference. Results: Among 732 eligible participants, including 425 (58%) males, the prevalence of preference for fentanyl increased from 4.4% in 2017 to 6.6% in 2018 (Odds Ratio [OR] = 1.27, 95% Confidence Interval [CI]: 1.05-1.52). In a multivariable analysis, younger age (Adjusted Odds Ratio [AOR] = 0.94, 95% CI: 0.92-0.96) and daily crystal methamphetamine injection (AOR = 1.68, 95% CI: 1.01-2.78) were independently associated with preference for fentanyl. The most common reasons for preferring fentanyl included "better high than other opioids" (45%), and "lasts longer than heroin" (27%). Conclusions: The current study has demonstrated that preference for fentanyl has been increasing over time among our sample of PWID who use opioids. Further work is needed to clarify risk factors surrounding transitions to illicit fentanyl.

Impact of the international collaborative addiction medicine research fellowship on physicians' future engagement in addiction research.

Background: To evaluate how an international one-year intensive research training program for addiction medicine physicians contributed to subsequent research involvement and productivity. Methods: We prospectively compared addiction medicine physician fellows admitted to a one-year training program with non-admitted controls, using baseline questionnaire and peer-reviewed publication data. Participants' publication activity was assessed from fellowship application date onwards using biomedical databases (e.g., PubMed, Embase). Results: Between July 2014 and June 2020, which is six years of cohorts, 56 (39 women) physicians, both fellows (n = 25) and non-admitted applicants (n = 31), were observed and included in the study, contributing 261 person-years of observation. At baseline, in the fellows' cohort: 76% of participants (19/25) reported past research involvement, 24% (6/25) had one or more advanced graduate degrees (e.g., MPH), and the median number of peer-reviewed, first author publications was one (Interquartile Range [IQR] = 0-2). At baseline, in the controls' cohort: 84% of participants (26/31) reported past research involvement, 39% (12/31) had one or more advanced graduate degrees, and the median number of peer-reviewed, first author publications was zero. The physicians' training included internal medicine (n = 8), family medicine (n = 33), psychiatry (n = 5) and others (n = 4). At follow up, there was a significant difference between fellows (n = 25) and controls (n = 31) in total number of publications (Rate Ratio [RR] = 13.09, 95% Confidence Interval [CI], 5.01 - 34.21, p < 0.001), as well as first author publications (RR = 5.59, 95% CI, 2.23 - 14.06, p < 0.001). Conclusion: In the six-year observation period, fellows' productivity indicates undertaking this fellowship was associated with significant research outputs in comparison to controls, signaling successful training of addiction physicians to help recruit addiction medicine physicians to participate in addiction research.

Prevalence and correlates of intentional substance use to reduce illicit opioid use in a Canadian setting.

Background: While preliminary evidence has begun to document intentional use of one substance to reduce the use of another, the phenomenon of drug substitution among people who use illicit opioids remains understudied. Therefore, we sought to estimate the prevalence and correlates of intentional substance use to reduce illicit opioid use among persons who use drugs (PWUD). Methods: We analysed data from three prospective cohorts of PWUD in Vancouver, Canada, using multivariable generalized estimating equations (GEE). Results: Between June 2012 and June 2016, 1527 participants were recruited and contributed 4991 interviews. Of those, 336 (22%) illicit opioid-using participants self-reported substitution to reduce illicit opioid use at least once during study period contributing 467 (9.4%) interviews. Among those interviews, substances substituted for opioids were alcohol (15 participants, 3.2%), stimulants (235, 50.3%), cannabis (129, 27.6%), benzodiazepines (21, 4.5%), and others (20, 4.3%). In multivariable GEE model adjusted for socio-demographic factors, reporting substitution to reduce illicit opioid use was positively associated with greater likelihood of daily cannabis use (Adjusted Odds Ratio = 1.56, 95% Confidence Interval: 1.24-1.96]. Conclusions: While daily cannabis use was associated with reporting opioid substitution attempts, additional study is needed to examine potential of cannabis/cannabinoids to reduce illicit opioid use.

Pain and Barriers to Accessing Health Services Among People Who Use Drugs.

BACKGROUND: The opioid overdose crisis underscores the need for health services among people who use drugs (PWUD) with concurrent pain. AIMS: Investigating the effect of pain on barriers to accessing health services among PWUD. DESIGN: Prospective cohort study. SETTINGS: A setting of universal access to no-cost medical care in Vancouver, Canada from June 2014 to May 2016. PARTICIPANTS/SUBJECTS: PWUD who completed at least one study interview. METHODS: Data derived from interviewer-administered questionnaires were used for multivariable generalized linear mixed-effects multiple regression (GLMM) analyses. RESULTS: Among 1,348 PWUD, 469 (34.8%) reported barriers to accessing health services at least once during the study period. The median average pain severity was 3 (IQR: 0-6) out of 10. A dose-response relationship was observed between greater pain and increased odds of reporting barriers to accessing health services (adjusted odds ratio [AOR]: 1.59, 95% confidence interval [CI]: 1.15-2.21, p = .005 for mild versus no pain; AOR: 1.76, 95% CI: 1.30-2.37, p < .001 for moderate versus no pain; AOR: 2.55, 95% CI: 1.92-3.37, p < .001 for severe versus no pain). Common barriers included poor treatment by health professionals, socio-structural barriers such as transportation or mobility, and long wait lists or wait times. CONCLUSIONS: Pain may be a significant risk factor associated with increased barriers to accessing health services among PWUD. Attention to pain management may improve access to health services, and reducing barriers to health services may conversely improve pain management and its related risks and harms.

Is expected substance type associated with timing of drug checking service utilization?: A cross-sectional study.

BACKGROUND: Drug checking is a harm reduction intervention aiming to reduce substance use-related risks by improving drug user knowledge of the composition of unregulated drugs. With increasing fears of fentanyl adulteration in unregulated drugs, this study sought to examine whether the expected type of drug checked (stimulant vs. opioid) was associated with timing of drug checking service utilization (pre-consumption vs. post-consumption). METHODS: Data were derived from drug checking sites in British Columbia between October 31, 2017 and December 31, 2019. Pearson's Chi-square test was used to examine the relationship between expected sample type (stimulant vs. opioid) and timing of service utilization. Odds ratios (OR) were calculated to assess the strength of this relationship. The Mantel-Haenszel (MH) test was used to adjust for service location. RESULTS: A total of 3561 unique stimulant and opioid samples were eligible for inclusion, including 691 (19.40%) stimulant samples; and 2222 (62.40%) samples that were tested pre-consumption. Results indicated a positive association between testing stimulant samples and testing pre-consumption (OR = 1.45; 95% CI 1.21-1.73). Regions outside of the epicenter of the province's drug scene showed a stronger association with testing pre-consumption (ORMH = 2.33; 95% CI 1.51-3.56) than inside the epicenter (ORMH = 1.33; 95% CI 1.09-1.63). CONCLUSION: Stimulant samples were more likely to be checked pre-consumption as compared with opioid samples, and stimulant samples were more likely to be tested pre-consumption in regions outside the epicenter of the province's drug scene. This pattern may reflect a concern for fentanyl-adulterated stimulant drugs.

High-intensity cannabis use and hospitalization: a prospective cohort study of street-involved youth in Vancouver, Canada.

BACKGROUND: There is concern that cannabis use negatively affects vulnerable groups such as youth; however, the relationship between cannabis use and health care utilization has not been well characterized in this population. We longitudinally evaluated the association between daily cannabis use and hospitalization among a prospective cohort of street-involved youth. METHODS: Data were collected from the At-Risk Youth Study (ARYS) in Vancouver, Canada, from September 2005 to May 2015. Participants were interviewed semi-annually and multivariable generalized estimating equation (GEE) logistic regression was used to examine the relationship between daily cannabis use and hospitalization. RESULTS: A total of 1216 participants (31.2% female) were included in this analysis, and 373 (30.7%) individuals reported hospitalization at some point during the study period. In a multivariable GEE analysis, daily cannabis use was not significantly associated with hospitalization (Adjusted Odds Ratio [AOR] = 1.17, 95% Confidence interval [CI] = 0.84, 1.65). We did observe a significant interaction between daily cannabis use and sex (AOR = 0.51, 95% CI = 0.34, 0.77), whereby cannabis use was associated with a decreased odds of hospitalization among males (AOR = 0.60, 95% CI = 0.47, 0.78), yet was not significantly associated with hospitalization among females (AOR = 1.19, 95% CI = 0.84, 1.67). CONCLUSIONS: The finding that daily cannabis use was not associated with hospitalization among street-involved youth is encouraging given the high rates of cannabis use in this population and the expansion of cannabis legalization and regulation. Future studies, however, are warranted to monitor possible changes in the consequences of cannabis use as cannabis legalization and regulation increase internationally.

The utility of visual appearance in predicting the composition of street opioids.

Background: With the emergence of unregulated fentanyl, people who use unregulated opioids are increasingly relying on appearance in an effort to ascertain the presence of fentanyl and level of drug potency. However, the utility of visual inspection to identify drug composition in the fentanyl era has not been assessed. Methods: We assessed client expectation, appearance, and composition of street drug samples being presented for drug checking. Results of a visual screening test were compared to fentanyl immunoassay strip testing. We calculated sensitivity, specificity and likelihood ratios (LR) to assess the accuracy of the common assumption that samples with a "pebbles" appearance contain fentanyl. Results: In total, of the 2502 unregulated opioid samples tested, 1820 (73.5%) appeared as "pebbles", of which 1729 (95.0%) tested positive for fentanyl for a sensitivity of 75.9% (95% Confidence Interval [CI]: 74.2-77.6) and specificity of 59.4% (95%CI: 57.5-61.3). Although, the odds of samples containing fentanyl was 4.60 (95%CI: 3.47-6.11) times higher among pebbles samples compared to non-pebble samples, the positive LR for pebbles to contain fentanyl was only 1.87 (CI: 1.59-2.19). The negative LR was more useful at 0.41 (95% CI: 0.36-0.46). Conclusions: A positive screening test for pebbles is not strongly enough associated to be used as a proxy for detecting fentanyl. While the absence of the appearance of pebbles does somewhat reduce the likelihood of fentanyl being present in a given sample, the high prevalence of fentanyl and fentanyl analogues in the drug supply and the risks of consumption are such that public health providers should routinely advise people who use unregulated opioids against solely relying on visual characteristics of drugs as a harm reduction strategy.

Inability to access primary care clinics among people who inject drugs in a Canadian health care setting.

OBJECTIVE: To examine the prevalence and correlation of self-reported inability to access community primary care clinics among people who inject drugs (PWID). DESIGN: Self-report questionnaire data. SETTING: Vancouver, BC. PARTICIPANTS: Data were derived from 3 prospective cohort studies of PWID between 2013 and 2016. MAIN OUTCOME MEASURES: Multivariable generalized estimating equations were used to determine prevalence of and reasons for self-reported inability to access primary care, as well as factors associated with inability to access care. RESULTS: Of 1396 eligible participants, including 525 (37.6%) women, 209 (15.0%) persons were unable to access a primary care clinic at some point during the study period. In the multivariable analysis, factors independently associated with inability to access clinics included ever being diagnosed with a mental health disorder (adjusted odds ratio [AOR] = 1.63, 95% CI 1.14 to 2.35), dealing drugs (AOR = 1.60, 95% CI 1.15 to 2.22), using emergency services (AOR = 1.51, 95% CI 1.13 to 2.02), being female (AOR = 1.49, 95% CI 1.08 to 2.08), and testing positive for HIV (AOR = 0.47, 95% CI 0.30 to 0.72) (for all factors, P < .05). CONCLUSION: Specific exposures were linked to challenges in accessing primary care among the sample of PWID, even in a publicly funded health care setting. Notably, models designed for care of people with HIV appear to increase access to primary care among PWID. Further research is needed to determine how to effectively treat accompanying mental illness, how to provide women-centred services, and how to connect people with primary care who would likely otherwise go to the emergency department.

Effect of witnessing an overdose on the use of drug checking services among people who use illicit drugs in Vancouver, Canada.

BACKGROUND: Since 2013, fentanyl-contaminated drugs have been driving North America's opioid-overdose epidemic. Drug checking, which enables people who use illicit drugs (PWUD) to test and receive feedback regarding the contents of their drugs, is being considered as a potential tool to address the toxic drug supply. While some PWUD witness overdoses, little is known about the impact of these experiences on subsequent risk reduction practices. OBJECTIVE: The purpose of this study was to examine the effect of witnessing an overdose on drug checking service use. METHODS: Data were derived from prospective cohorts of PWUD in Vancouver, Canada, a setting with a community-wide fentanyl overdose crisis, between June 1, 2018 and December 1, 2018. Multivariable logistic regression was used to estimate the effect of witnessing an overdose on drug checking service use. RESULTS: 1,426 participants were eligible for the study, including 530 females; 767 (53.8%) participants reported witnessing an overdose and 196 (13.7%) reported using drug checking services in the last 6 months. In multivariable analyses, after adjusting for a range of confounders including the use of fentanyl, witnessing an overdose was positively associated with drug checking service use (adjusted odds ratio = 2.32; 95% confidence interval: 1.57-3.49). CONCLUSION: Our findings suggest that witnessing an overdose may motivate PWUD to use drug checking services. Given that only a small proportion of PWUD in the study reported using drug checking services, our findings highlight the need to continue to scale-up a range of overdose prevention interventions.

Factors associated with drug checking service utilization among people who use drugs in a Canadian setting.

BACKGROUND: The United States and Canada are amidst an opioid overdose crisis, with the Canadian province of British Columbia (BC) among the hardest hit. In response, drug checking services (DCS) have been introduced in this setting as a novel pilot harm reduction intervention though little is known about usage rates. Therefore, we sought to identify factors associated with drug checking uptake among people who use drugs (PWUD) in Vancouver, BC. METHODS: Data were derived from three ongoing prospective cohort studies of PWUD in Vancouver between June and November 2018. Multivariable logistic regression was used to determine factors associated with self-reported DCS utilization in the past 6 months among participants at high risk of fentanyl exposure (i.e., those self-reporting illicit opioid use or testing positive for fentanyl via urine drug screen). RESULTS: Among 828 eligible participants, including 451 (55%) males, 176 (21%) reported recent use of DCS. In multivariable analyses, factors significantly associated with DCS utilization included: homelessness (Adjusted Odds Ratio [AOR] 1.47; 95% Confidence Interval [CI] 1.01-2.13) and involvement in drug dealing (AOR 1.59; 95% CI 1.05-2.39). CONCLUSIONS: In our sample of PWUD, uptake of DCS was low, although those who were homeless, a sub-population known to be at a heightened risk of overdose, were more likely to use the services. Those involved in drug dealing were also more likely to use the services, which may imply potential for improving drug market safety. Further evaluation of drug checking is warranted.

Temporal changes in non-fatal opioid overdose patterns among people who use drugs in a Canadian setting.

Background and Aims: Little is known about how the expansion of opioid agonist therapy (OAT) and emergence of fentanyl in the illicit drug supply in North America has influenced non-fatal opioid overdose (NFOD) risk. Therefore, we sought to identify patterns of substance use and addiction treatment engagement (i.e., OAT, other inpatient or outpatient treatment) prior to NFOD, as well as the trends and correlates of each pattern among people who use drugs (PWUD) in Vancouver, Canada. Methods: Data were derived from participants in three prospective cohorts of PWUD in Vancouver in 2009-2016. Observations from participants reporting opioid-related NFOD in the previous six months were included. A latent class analysis was used to identify classes based on substances used at the time of last NFOD and addiction treatment engagement in the month prior to the last NFOD. Multivariable generalized estimating equations estimated the correlates of each class membership. Results: In total, 889 observations from 570 participants were included. Four distinct classes were identified: (1) polysubstance use (PSU) and addiction treatment engagement; (2) PSU without treatment engagement; (3) exposure to unknown substances, mostly without treatment engagement; and (4) primary heroin users without treatment engagement. The class of exposure to unknown substances appeared in 2015 and became the dominant group (76.9%) in 2016. In multivariable analyses, the odds of membership in the class of primary heroin users decreased over time (adjusted odds ratio [AOR]: 0.74, 95% confidence interval [CI]: 0.68-0.81). Conclusions: Changing profiles of PWUD reporting opioid-related NFOD were seen over time. Notably, there was a sudden increase in reports of overdose following exposure to unknown substances since 2015, the majority of whom reported no recent addiction treatment engagement. Further study into patterns of substance use and strategies to improve addiction treatment engagement is needed to improve and focus overdose prevention efforts.

Supervised injection facility use and all-cause mortality among people who inject drugs in Vancouver, Canada: A cohort study.

BACKGROUND: People who inject drugs (PWID) experience elevated rates of premature mortality. Although previous studies have demonstrated the role of supervised injection facilities (SIFs) in reducing various harms associated with injection drug use, including accidental overdose death, the possible impact of SIF use on all-cause mortality is unknown. Therefore, we examined the relationship between frequent SIF use and all-cause mortality among PWID in Vancouver, Canada. METHODS AND FINDINGS: Data were derived from 2 prospective cohort studies of PWID in Vancouver, Canada, between December 2006 and June 2017. Every 6 months, participants completed questionnaires that elicited information regarding sociodemographic characteristics, substance use patterns, social-structural exposures, and use of health services including SIFs. These data were confidentially linked to the provincial vital statistics database to ascertain mortality rates and causes of death. We used multivariable extended Cox regression analyses to estimate the independent association between frequent (i.e., at least weekly) SIF use and all-cause mortality. Of 811 participants, 278 (34.3%) were women, and the median age was 39 years (IQR 33-46) at baseline. In total, 432 (53.3%) participants reported frequent SIF use at baseline, and 379 (46.7%) did not. At baseline, frequent SIF users were on average younger than nonfrequent users, and a higher proportion of frequent SIF users than nonfrequent users were unstably housed, resided in the Downtown Eastside neighbourhood, injected in public, had a recent non-fatal overdose, used prescription opioids at least daily, injected heroin at least daily, injected cocaine at least daily, and injected crystal methamphetamine at least daily. A lower proportion of frequent SIF users than nonfrequent users were HIV positive and enrolled in addiction treatment at baseline. The median duration of follow-up among study participants was 72 months (IQR 24-123). In total, 112 participants (13.8%) died during the study period, yielding a crude mortality rate of 22.7 (95% CI 18.7-27.4) deaths per 1,000 person-years. The median years of potential life lost per death was 34 (IQR 27-42) years. In a time-updated multivariable model, frequent SIF use was inversely associated with risk of all-cause mortality after adjusting for potential confounders, including age, sex, HIV seropositivity, unstable housing, at least daily cocaine injection, public injection, incarceration, enrolment in addiction treatment, and calendar year of interview (adjusted hazard ratio 0.46, 95% CI 0.26-0.80, p = 0.006). The main study limitations are the limited generalizability of findings due to non-random sampling, the potential for reporting biases due to reliance on some self-reported information, and the possibility that residual confounding influenced findings. CONCLUSIONS: We observed a high burden of premature mortality among a community-recruited cohort of PWID. Frequent SIF use was associated with a lower risk of death, independent of relevant confounders. These findings support efforts to enhance access to SIFs as a strategy to reduce mortality among PWID. Further analyses of individual-level data are needed to determine estimates of, and potential causal pathways underlying, associations between SIF use and specific causes of death.

Frequency of cannabis and illicit opioid use among people who use drugs and report chronic pain: A longitudinal analysis.

BACKGROUND: Ecological research suggests that increased access to cannabis may facilitate reductions in opioid use and harms, and medical cannabis patients describe the substitution of opioids with cannabis for pain management. However, there is a lack of research using individual-level data to explore this question. We aimed to investigate the longitudinal association between frequency of cannabis use and illicit opioid use among people who use drugs (PWUD) experiencing chronic pain. METHODS AND FINDINGS: This study included data from people in 2 prospective cohorts of PWUD in Vancouver, Canada, who reported major or persistent pain from June 1, 2014, to December 1, 2017 (n = 1,152). We used descriptive statistics to examine reasons for cannabis use and a multivariable generalized linear mixed-effects model to estimate the relationship between daily (once or more per day) cannabis use and daily illicit opioid use. There were 424 (36.8%) women in the study, and the median age at baseline was 49.3 years (IQR 42.3-54.9). In total, 455 (40%) reported daily illicit opioid use, and 410 (36%) reported daily cannabis use during at least one 6-month follow-up period. The most commonly reported therapeutic reasons for cannabis use were pain (36%), sleep (35%), stress (31%), and nausea (30%). After adjusting for demographic characteristics, substance use, and health-related factors, daily cannabis use was associated with significantly lower odds of daily illicit opioid use (adjusted odds ratio 0.50, 95% CI 0.34-0.74, p < 0.001). Limitations of the study included self-reported measures of substance use and chronic pain, and a lack of data for cannabis preparations, dosages, and modes of administration. CONCLUSIONS: We observed an independent negative association between frequent cannabis use and frequent illicit opioid use among PWUD with chronic pain. These findings provide longitudinal observational evidence that cannabis may serve as an adjunct to or substitute for illicit opioid use among PWUD with chronic pain.