Mood and Anxiety Symptoms in Persons Taking Prescription Opioids: A Systematic Review with Meta-Analyses of Longitudinal Studies.

OBJECTIVE: To review evidence from longitudinal studies on the association between prescription opioid use and common mood and anxiety symptoms. DESIGN: We conducted a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. METHODS: We searched PubMed, Embase, and PsycINFO for search terms related to opioids AND (depression OR bipolar OR anxiety OR post-traumatic stress disorder [PTSD]). Findings were summarized narratively, and random-effects meta-analyses were used to pool effect sizes. RESULTS: We identified 10,290 records and found 10 articles that met our inclusion criteria. Incidence studies showed that people who used prescription opioids had an elevated risk of any mood outcome (adjusted effect size [aES] = 1.80 [95% confidence interval = 1.40-2.30]) and of an anxiety outcome (aES = 1.40 [1.20-1.80]) compared with those who did not use prescription opioids. Associations with depression were small and not significant after adjustment for potential confounders (aES = 1.18 [0.98-1.41]). However, some studies reported an increased risk of depressive symptoms after increased (aES = 1.58 [1.30-1.93]) or prolonged opioid use (aES = 1.49 [1.19-1.86]). CONCLUSIONS: Mental health should be considered when opioids are prescribed because some patients could be vulnerable to adverse mental health outcomes.

Association Between Opioid Agonist Therapy and Testing, Treatment Uptake, and Treatment Outcomes for Hepatitis C Infection Among People Who Inject Drugs: A Systematic Review and Meta-analysis.

BACKGROUND: People who inject drugs (PWID) experience barriers to accessing testing and treatment for hepatitis C virus (HCV) infection. Opioid agonist therapy (OAT) may provide an opportunity to improve access to HCV care. This systematic review assessed the association of OAT and HCV testing, treatment, and treatment outcomes among PWID. METHODS: Bibliographic databases and conference presentations were searched for studies that assessed the association between OAT and HCV testing, treatment, and treatment outcomes (direct-acting antiviral [DAA] therapy only) among PWID (in the past year). Meta-analysis was used to pool estimates. RESULTS: Of 9877 articles identified, 22 studies conducted in Australia, Europe, North America, and Thailand were eligible and included. Risk of bias was serious in 21 studies and moderate in 1 study. Current/recent OAT was associated with an increased odds of recent HCV antibody testing (4 studies; odds ratio (OR), 1.80; 95% confidence interval [CI], 1.36-2.39), HCV RNA testing among those who were HCV antibody-positive (2 studies; OR, 1.83; 95% CI, 1.27-2.62), and DAA treatment uptake among those who were HCV RNA-positive (7 studies; OR, 1.53; 95% CI, 1.07-2.20). There was insufficient evidence of an association between OAT and treatment completion (9 studies) or sustained virologic response following DAA therapy (9 studies). CONCLUSIONS: OAT can increase linkage to HCV care, including uptake of HCV testing and treatment among PWID. This supports the scale-up of OAT as part of strategies to enhance HCV treatment to further HCV elimination efforts.

All-Cause and Overdose Mortality Risk Among People Prescribed Opioids: A Systematic Review and Meta-analysis.

OBJECTIVE: To estimate all-cause and overdose crude mortality rates and standardized mortality ratios among people prescribed opioids for chronic noncancer pain and risk of overdose death in this population relative to people with similar clinical profiles but not prescribed opioids. DESIGN: Systematic review and meta-analysis. METHODS: Medline, Embase, and PsycINFO were searched in February 2018 and October 2019 for articles published beginning 2009. Due to limitations in published studies, we revised our inclusion criteria to include cohort studies of people prescribed opioids, excluding those studies where people were explicitly prescribed opioids for the treatment of opioid use disorder or acute cancer or palliative pain. We estimated pooled all-cause and overdose crude mortality rates using random effects meta-analysis models. No studies reported standardized mortality ratios or relative risks. RESULTS: We included 13 cohorts with 6,029,810 participants. The pooled all-cause crude mortality rate, based on 10 cohorts, was 28.8 per 1000 person-years (95% CI = 17.9-46.4), with substantial heterogeneity (I2 = 99.9%). The pooled overdose crude mortality rate, based on six cohorts, was 1.1 per 1000 person-years (95% CI = 0.4-3.4), with substantial heterogeneity (I2 = 99.5%), but indications for opioid prescribing and opioid exposure were poorly ascertained. We were unable to estimate mortality in this population relative to clinically similar populations not prescribed opioids. CONCLUSIONS: Methodological limitations in the identified literature complicate efforts to determine the overdose mortality risk of people prescribed opioids. There is a need for large-scale clinical trials to assess adverse outcomes in opioid prescribing, especially for chronic noncancer pain.

Antidepressant Use Among People Prescribed Opioids for Chronic Noncancer Pain.

OBJECTIVE: Although depression and chronic pain often coexist, few studies have examined antidepressant use among people with pain. This study examines the prevalence and characteristics associated with antidepressant use among people prescribed opioids for chronic noncancer pain (CNCP). DESIGN: Baseline data from a prospective cohort study. SETTING: Australian community. SUBJECTS: A total of 1166 people prescribed opioids for CNCP. METHODS: Baseline data collection consisted of a self-completed seven-day medication diary and telephone interview to collect information on sociodemographic characteristics and mental/physical health using validated questionnaires. Logistic regression was used to examine characteristics associated with antidepressant use, reporting adjusted odds ratios (AORs) and 95% confidence intervals (CIs). RESULTS: Of the 1166 participants, 668 (57.3%) were female, and the median (interquartile range) age was 59 (49-68) years. About half the cohort (N = 637, 54.6%) used antidepressants. Of these, 329 (51.7%) reported moderate to severe depression. Amitriptyline was the most commonly used antidepressant (17.3%). Factors independently associated with antidepressant use were being female (AOR = 1.47, 95% CI = 1.13-1.92), more years lived in pain (AOR = 1.01, 95% CI = 1.00-1.02), and use of nonopioid analgesics (AOR = 1.34, 95% CI = 1.01-1.78), benzodiazepines and related drugs (AOR = 1.84, 95% CI = 1.36-2.49), antiepileptics (AOR = 1.86, 95% CI = 1.38-2.51), and antipsychotics (AOR = 2.15, 95% CI = 1.22-3.77). CONCLUSIONS: Antidepressant use is common among people with CNCP prescribed opioids. Those using antidepressants were more likely to use other psychotropic medicines concurrently, highlighting that they are a high-risk population requiring comprehensive assessment to optimize outcomes and reduce potential harms from polypharmacy.

Prevalence of comorbid substance use disorders among people with opioid use disorder: A systematic review & meta-analysis.

BACKGROUND: Comorbid substance use disorders (SUDs) among people with opioid use disorder (OUD) contribute to poor clinical outcomes, including overdose and mortality. We present the first systematic review and meta-analysis to estimate the prevalence of specific non-opioid SUDs among people with OUD. METHODS: We searched Embase, PsycINFO, and MEDLINE from 1990 to 2022 for studies that used Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD) criteria to assess the prevalence of non-opioid SUDs among individuals with OUD. We used random-effects meta-analyses with 95% Confidence Intervals (CIs) to pool current and lifetime prevalence estimates separately. Meta-regressions and stratified meta-analyses were used to examine differences in prevalence estimates by sample characteristics and methodological factors. RESULTS: Of the 36,971 publications identified, we included data from 194 studies and 77,212 participants with OUD. The prevalence of any comorbid SUD among people with OUD was 59.5% (95%CI 49.1-69.5%) for current non-opioid SUDs, with 72.0% (95%CI 52.5-87.9%) experiencing a comorbid SUD in their lifetime. Of the studies that examined current comorbid SUDs, cocaine use disorder (30.5%, 95%CI 23.0-38.7%) was most common, followed by alcohol (27.1%, 95%CI 24.4- 30.0%), cannabis (22.7%, 95%CI 19.0-26.6%), sedative (16.1%, 95%CI 13.1-19.3%), and methamphetamine (11.4%, 95%CI 6.8-17.1%) use disorders. Substantial heterogeneity (I2>90%) across estimates was observed. Substantial heterogeneity (I2>90%) was observed across estimates, with significant variations in prevalence identified across geographic locations, recruitment settings, and other study-level factors. CONCLUSION: Findings from this study emphasize the importance of comorbid SUD treatment access for people with OUD. Our estimates can inform the provision of treatment and harm reduction strategies for people with OUD and specific subpopulations.

The effects of childhood trauma and mental disorders on treatment engagement, contact with the criminal justice system, and mortality among people with opioid dependence.

BACKGROUND: Childhood trauma and mental disorders increase the risk of opioid dependence. We aimed to examine whether childhood trauma and mental disorders are associated with opioid agonist treatment (OAT) engagement, contact with the criminal justice system, and mortality among people with opioid dependence. METHODS: This observational study linked survey data from 1482 people receiving OAT in Sydney, Australia (2004-2008) to administrative data on OAT, crime, and mortality through 2017. We used survey data to assess childhood trauma, depression, panic disorder, post-traumatic stress disorder (PTSD), borderline personality disorder, anti-social personality disorder (ASPD), and comorbid substance dependence. We used discrete-time analysis to examine time from opioid dependence onset to OAT entry and mortality. Poisson regressions were used to analyze time receiving OAT and number of charges. RESULTS: Participants with extensive childhood trauma histories and ASPD were less likely to enter OAT and those with depression were more likely to enter OAT in any given year after opioid dependence onset. Panic disorder, PTSD, and borderline personality disorder were associated with less time in OAT. Extensive histories of childhood trauma, PTSD, ASPD, and comorbid substance dependence increased risk of charges for any offence. There were no significant associations between the exposure variables and mortality. CONCLUSIONS: Our findings suggest that childhood trauma and mental disorders increase the risk of adverse treatment and social outcomes among people with opioid dependence. Interventions that aim to reduce harm among people with opioid dependence may consider the effect of childhood trauma and mental disorders on OAT engagement and crime.

Incidence of suicide and self-harm among people with opioid use disorder and the impact of opioid agonist treatment: A retrospective data linkage study.

BACKGROUND: Rates of suicide and self-harm are elevated among people with opioid use disorder (OUD). This study examined incidence of self-harm and suicide among people who have entered OAT and assessed the impact of different OAT exposure periods on these events. METHOD: We conducted a retrospective population-based cohort study of all OAT recipients (N = 45,664) in New South Wales, Australia (2002-2017), using linked administrative data. Incidence rates of self-harm hospitalisations and suicide deaths were estimated per 1000 person-years (PY). The first 28 days of an OAT episode, ≥ 29 days on OAT, the first 28 days off OAT, and ≥ 29 days off OAT (maximum four years post-OAT) were exposure periods. Poisson regression models with generalised estimating equations estimated the adjusted incidence rate ratios (ARR) of self-harm and suicide by OAT exposure periods, adjusting for covariates. RESULTS: There were 7482 hospitalisations (4148 individuals) for self-harm and 556 suicides, equating to incidence rates of 19.2 (95% confidence intervals [CI]=18.8-19.7) and 1.0 (95%CI=0.9-1.1) per 1000 PY, respectively. Opioid overdose was implicated in 9.6% of suicides and 28% of self-harm hospitalisations. Compared to ≥ 29 days on OAT, the incidence rate of suicide was elevated in the 28 days following OAT cessation (ARR=17.4 [95%CI=11.7-25.9]), and the rate of self-harm hospitalisations was elevated during the first 28 days of OAT (ARR=2.2 [95%CI=1.9-2.6]) and the 28 days after leaving OAT (ARR=2.7 [95%CI=2.3-3.2]). CONCLUSIONS: OAT may reduce suicide and self-harm risk among people with OUD; however, OAT initiation and cessation are critical periods for targeting self-harm and suicide prevention interventions.

Exposure to childhood trauma increases risk of opioid use disorder among people prescribed opioids for chronic non-cancer pain.

BACKGROUND: Little is known about childhood trauma exposure and Opioid Use Disorder (OUD) among people prescribed opioids for chronic non-cancer pain (CNCP). We aimed to (1) describe childhood trauma exposure among this population, and (2) examine if childhood trauma exposure was an independent risk factor for OUD among people prescribed opioids for CNCP. METHODS: This study used baseline data from 1514 people prescribed opioids for CNCP in Australia. We used latent class analysis to characterise participants by five indicators of childhood trauma exposure and logistic regression to characterise class membership. We used discrete-time survival analysis to determine whether there was an independent association between childhood trauma exposure and risk of OUD according to adjusted odds ratios (AOR). RESULTS: We identified three classes of childhood trauma exposure: (1) 'low exposure' (n = 765; 54.0%), (2) 'emotional & sexual abuse' (n = 324; 22.9%), and (3) 'high all' (n = 329; 23.2%). 'Emotional & sexual abuse' or 'high all' childhood trauma exposure class membership was associated with higher rates of pain difficulties, mental disorders, and substance use disorders, compared to 'low exposure' class membership. After we adjusted for previously identified OUD risk factors, participants in the 'emotional & sexual abuse' (AOR 1.51; 95%CI 1.09-2.12; p = 0.016) and 'high all' (AOR 1.77; 95%CI 1.28-2.45; p = 0.001) childhood trauma exposure classes were at increased risk of OUD. CONCLUSIONS: Among people prescribed opioids for CNCP, childhood trauma exposure was a common, independent risk factor for OUD. Availability of trauma-informed services for those prescribed opioids for CNCP may reduce risk of transition to OUD.

Prevalence of mental disorders among people with opioid use disorder: A systematic review and meta-analysis.

BACKGROUND: Opioid use disorder (OUD) and mental disorders are major public health issues and comorbidity is common. Among people with OUD, comorbid mental disorders are associated with poorer health outcomes. To our knowledge, this is the first systematic review and meta-analysis to estimate prevalence of specific mental disorders among people with OUD. METHODS: We searched Embase, MEDLINE, and PsycInfo from 1990 to 2021 for observational studies of depression, anxiety, post-traumatic stress disorder (PTSD), bipolar, personality, and other pre-specified mental disorders among people with OUD. We pooled current and lifetime estimates of each disorder using random-effects meta-analyses with 95% Confidence Intervals (CIs). Meta-regressions and stratified analyses were used to assess heterogeneity of prevalence estimates by methodological factors and sample characteristics. FINDINGS: Of the 36,971 publications identified, we included data from 345 studies and 104,135 people with OUD in at least one pooled estimate. Among people with OUD, the prevalence of current depression was 36.1% (95%CI 32.4-39.7%), anxiety was 29.1% (95%CI 24.0-33.3%), attention-deficit/hyperactivity disorder was 20.9% (95%CI 15.7-26.2%), PTSD was 18.1% (95%CI 15.4-20.9%), and bipolar disorder was 8.7% (95%CI 6.7-10.7%). Lifetime prevalence of anti-social personality disorder was 33.6% (95%CI 29.1-38.0%) and borderline personality disorder was 18.2% (95% CI 13.4-23.1%). Sample characteristics and methodological factors, including sex, were associated with variance of multiple prevalence estimates. INTERPRETATION: Our findings emphasise the need for access to mental disorder treatment among people with OUD. Specific mental disorder estimates may inform clinical guidelines, treatment services, and future research for people with OUD, including subpopulations with distinct treatment needs.

Examining the cost and impact of dosing fees among clients in opioid agonist treatment: Results from a cross-sectional survey of Australian treatment clients.

INTRODUCTION: Opioid agonist treatment (OAT) clients frequently bear costs associated with their treatment, including dosing fees. This study aimed to explore the financial and social impact of dosing fees upon clients. METHODS: Cross-sectional survey of people who use opioids regularly (N = 402) between December 2017 and March 2018, conducted in Australia. Dosing fees were calculated and expressed as percentage of income, by OAT type. Consequences and strategies for difficulties making payments were examined as proportions. RESULTS: A total of N = 360 participants had ever been in OAT and N = 245 participants currently engaged in OAT reported data on dosing fees, of them 53% (n = 129) reported paying dosing fees. Compared to clients with high levels of dosing supervision, those with moderate or low levels of supervision were more likely to pay dosing fees. The median 28-day dosing fee was AUD$110 (interquartile range AUD$80); median 28-day income was AUD$1520 (interquartile range AUD$700). For those who paid dosing fees, the fee comprised <10% of total monthly income for 70% of participants; however, 23% of participants paid fees comprising 10% to <20%, and 7% of participants paid fees comprising 20% or more of monthly income. Among those that had ever been in OAT, 72% experienced difficulties in paying treatment costs; 36% left treatment earlier than intended and 25% had been excluded due to payment difficulties. DISCUSSION AND CONCLUSIONS: Negative consequences of treatment costs to clients, particularly dosing fees, are evident. These costs impact treatment access and retention that may negatively impact clients' physical health, mental health and social wellbeing.

Economic analysis of out-of-pocket costs among people in opioid agonist treatment: A cross-sectional survey in three Australian jurisdictions.

BACKGROUND: Out-of-pocket costs for opioid agonist treatment (OAT) constitute a barrier to treatment entry and retention.This study examines OAT clients' total out-of-pocket costs (including dispensing fees, travel costs and OAT-related appointment costs) in different treatment settings (public clinics, community pharmacies, and private clinics). METHODS: Cross-sectional survey of 402 people with opioid drug use (OUD) in New South Wales (NSW), Victoria (VIC), Tasmania (TAS), Australia; 266 clients (66%) currently receiving methadone, buprenorphine or buprenorphine-naloxone treatment were asked about dispensing fees, travel costs and OAT-related appointment costs in the past 28 days. A two-part regression model was used to deal with non-normal distributions of costing data (right skew and excess zeros). RESULTS: Among clients currently receiving OAT, 87% paid out-of-pocket costs. Among those who paid out-of-pocket costs (N=194), travel costs accounted for more than half of total costs (52%), followed by dispensing fees (44%). The mean monthly total out-of-pocket costs were AU$135 (SD: AU$121) for public clinics, AU$161 (SD: AU$110) to AU$214 (SD: AU$166) for community pharmacies and AU$355 (SD: AU$159) for private clinics. Compared to participants in NSW private clinics, those at public clinics paid one third the total out-of-pocket costs (coefficient = 0.33; 95%CI = 0.23-0.48) and those at NSW, TAS, VIC pharmacies paid approximately half the costs (coefficient = 0.58; 95%CI = 0.42-0.79; coefficient = 0.51; 95%CI = 0.36-0.72; coefficient = 0.47; 95%CI = 0.34-0.66, respectively). People in OAT for more than a year paid half the total out-of-pocket costs, compared with those in OAT less than a year (coefficient = 0.49, 95%CI = 0.31-0.77). CONCLUSIONS: Participants in the current study spent one-eighth of their income on out-of-pocket costs associated with OAT representing a substantial financial burden. Total out-of-pocket costs disproportionately affects those who are newer in treatment and receiving fewer unsupervised doses. Considering and addressing total out-of-pocket costs, especially travel costs and dispensing fees, to clients is critical to prevent cost from being a barrier from receiving effective care.

Prevalence of childhood maltreatment among people with opioid use disorder: A systematic review and meta-analysis.

BACKGROUND: Experience of childhood maltreatment (CM) is a risk factor for opioid use disorder (OUD). CM is also associated with comorbid mental disorders and poor treatment outcomes among people with OUD. To our knowledge, this is the first systematic review and meta-analysis to estimate the prevalence of CM among people with OUD. METHODS: We searched MEDLINE, EMBASE, and PsycINFO to identify observational studies that evaluated CM among people with OUD from January 1990 to June 2020. Prevalence of each CM type, sample characteristics, and methodological factors were extracted from each eligible study. Random-effects meta-analyses were used to pool prevalence estimates. Stratified meta-analyses were used to assess heterogeneity. RESULTS: Of the 6,438 publications identified, 113 studies reported quantitative CM data among people with OUD and 62 studies (k = 62; N = 21,871) were included in primary analyses. Among people with OUD, the estimated prevalence of sexual abuse was 41% (95% CI 36-47%; k = 38) among women and 16% (95% CI 12-20%; k = 25) among men. Among all people with OUD, prevalence estimates were 38% (95% CI 33-44%; k = 48) for physical abuse, 43% (95% CI 38-49%; k = 31) for emotional abuse, 38% (95% CI 30-46%; k = 17) for physical neglect, and 42% (95% CI 32-51%; k = 17) for emotional neglect. Sex, history of injecting drug use, recruitment methods, and method of assessing CM were associated with substantial heterogeneity. CONCLUSIONS: People with OUD frequently report the experience of CM, supporting the need for trauma-informed interventions among this population. Future research should consider the impact of CM on OUD presentations and when assessment is appropriate, use of validated instruments.

All-cause and cause-specific mortality among people with regular or problematic cocaine use: a systematic review and meta-analysis.

AIMS: To estimate pooled all-cause and cause-specific mortality risk for people with regular or problematic cocaine use. METHODS: Systematic review and meta-analysis of prospective or retrospective cohort studies or clinical trials (n ≥30) of people with regular or problematic cocaine use with data on all-cause or cause-specific mortality. Of 2808 papers, 28 were eligible and reported on 21 cohorts, with a total 170 019 individuals. Cohorts identified based on acute care for drug poisoning or other severe health presentation were excluded. Title/abstract screening was conducted by one reviewer; a second reviewer independently checked 10% of excluded studies. Two reviewers conducted full-text screening. Data were extracted by one reviewer and checked by a second. A customized review-specific study reporting quality/risk of bias tool was used. Data on crude mortality rates (CMR) and standardized mortality ratios were extracted for both all-cause and cause-specific mortality. Standardized mortality ratios were imputed where not provided by the author using extracted data and information from the Global Burden of Disease Study 2017. Data were pooled using a random-effects model. RESULTS: The pooled all-cause crude mortality rate was 1.24 per 100 person-years [95% confidence interval (CI) = 0.86, 1.78; n = 16 cohorts], but with considerable heterogeneity (I2  = 98.8%). The pooled all-cause standardized mortality ratio (SMR) was 6.13 (95% CI = 4.15, 9.05; n = 16 cohorts). Suicide (SMR = 6.26, 95% CI = 2.84, 13.80), accidental injury (SMR = 6.36, 95% CI = 4.18, 9.68), homicide (SMR = 9.38, 95% CI 3.45-25.48) and AIDS-related mortality (SMR = 23.12, 95% CI = 11.30, 47.31) were all elevated compared with age and sex peers in the general population. CONCLUSIONS: There are elevated rates of mortality among people with regular or problematic cocaine use for traumatic deaths and deaths attributable to infectious disease.

Association between opioid agonist therapy use and HIV testing uptake among people who have recently injected drugs: a systematic review and meta-analysis.

BACKGROUND AND AIM: Globally, nearly one in five people who inject drugs (PWID) are living with HIV, and the rate of new HIV infections in PWID is increasing in some settings. Early diagnosis is crucial for effective HIV control. We reviewed the evidence on the association between opioid agonist therapy (OAT) and HIV testing uptake among PWID. METHODS: We conducted a systematic review searching MEDLINE, Scopus, Web of Science, Cochrane Central Register of Controlled Trials and PsycINFO for studies published from January 2000 to March 2019. Reference lists and conference proceedings were hand-searched. Observational and intervention studies were eligible for inclusion. Risk of bias was assessed using the Risk of Bias in Non-Randomised Studies of Interventions (ROBINS-I) tool. Meta-analyses were conducted using random-effects models. RESULTS: Of 13 373 records identified, 11 studies from Australia, Europe, Malaysia and the United States were included. All studies had at least a serious risk of bias, largely due to confounding and selection bias, making it difficult to draw causal conclusions from the evidence. Ten studies provided data on the association between current OAT use and recent HIV testing. Six showed a positive association, while four provided little evidence of an association: pooled odds ratio (OR) = 1.71, 95% confidence interval (CI) = 1.28-2.27. Looking at having ever been on OAT and having ever been HIV tested, seven studies showed a positive association and three showed either weak or no evidence of an association: pooled OR = 3.82, 95% CI = 2.96-4.95. CONCLUSIONS: Opioid agonist therapy may increase uptake of HIV testing among people who inject drugs, providing further evidence that opioid agonist therapy improves the HIV treatment care cascade.

Association of Opioid Agonist Treatment With All-Cause Mortality and Specific Causes of Death Among People With Opioid Dependence: A Systematic Review and Meta-analysis.

Importance: Mortality among people with opioid dependence is higher than that of the general population. Opioid agonist treatment (OAT) is an effective treatment for opioid dependence; however, there has not yet been a systematic review on the relationship between OAT and specific causes of mortality. Objective: To estimate the association of time receiving OAT with mortality. Data Sources: The Embase, MEDLINE, and PsycINFO databases were searched through February 18, 2020, including clinical trial registries and previous Cochrane reviews. Study Selection: All observational studies that collected data on all-cause or cause-specific mortality among people with opioid dependence while receiving and not receiving OAT were included. Randomized clinical trials (RCTs) were also included. Data Extraction and Synthesis: This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Data on study, participant, and treatment characteristics were extracted; person-years, all-cause mortality, and cause-specific mortality were calculated. Crude mortality rates and rate ratios (RRs) were pooled using random-effects meta-analyses. Main Outcomes and Measures: Overall all-cause and cause-specific mortality both by setting and by participant characteristics. Methadone and buprenorphine OAT were evaluated specifically. Results: Fifteen RCTs including 3852 participants and 36 primary cohort studies including 749 634 participants were analyzed. Among the cohort studies, the rate of all-cause mortality during OAT was more than half of the rate seen during time out of OAT (RR, 0.47; 95% CI, 0.42-0.53). This association was consistent regardless of patient sex, age, geographic location, HIV status, and hepatitis C virus status and whether drugs were taken through injection. Associations were not different for methadone (RR, 0.47; 95% CI, 0.41-0.54) vs buprenorphine (RR, 0.34; 95% CI, 0.26-0.45). There was lower risk of suicide (RR, 0.48; 95% CI, 0.37-0.61), cancer (RR, 0.72; 95% CI, 0.52-0.98), drug-related (RR, 0.41; 95% CI, 0.33-0.52), alcohol-related (RR, 0.59; 95% CI, 0.49-0.72), and cardiovascular-related (RR, 0.69; 95% CI, 0.60-0.79) mortality during OAT. In the first 4 weeks of methadone treatment, rates of all-cause mortality and drug-related poisoning were almost double the rates during the remainder of OAT (RR, 2.01; 95% CI, 1.55-5.09) but not for buprenorphine (RR, 0.58; 95% CI, 0.18-1.85). All-cause mortality was 6 times higher in the 4 weeks after OAT cessation (RR, 6.01; 95% CI, 4.32-8.36), remaining double the rate for the remainder of time not receiving OAT (RR, 1.81; 95% CI, 1.50-2.18). Opioid agonist treatment was associated with a lower risk of mortality during incarceration (RR, 0.06; 95% CI, 0.01-0.46) and after release from incarceration (RR, 0.09; 95% CI, 0.02-0.56). Conclusions and Relevance: This systematic review and meta-analysis found that OAT was associated with lower rates of mortality. However, access to OAT remains limited, and coverage of OAT remains low. Work to improve access globally may have important population-level benefits.

Correlates of indicators of potential extra-medical opioid use in people prescribed opioids for chronic non-cancer pain.

INTRODUCTION AND AIMS: The opioid-related behaviours in treatment (ORBIT) scale are a measure of recent indicators of potential extra-medical opioid use. Indicators of potential extra-medical opioid use are divergent practices among people prescribed opioids that may place them at risk of harm. This study aimed to examine the correlates of indicators of potential extra-medical opioid use in people prescribed opioids for chronic non-cancer pain (CNCP). DESIGN AND METHODS: The Pain and Opioids IN Treatment (POINT) study is a prospective cohort study of people prescribed opioids for CNCP in Australia. People prescribed opioids solely for opioid dependence were excluded. This cross-sectional study utilised logistic regression to determine the characteristics associated with reporting any indicators of potential extra-medical opioid use. RESULTS: Of the 1505 participants, 38% reported at least one indicator of potential extra-medical opioid use, most commonly asking for an increase in prescribed opioid dose (21%) and early prescription renewal (12%). Indicators of potential extra-medical opioid use were associated with younger age (adjusted odds ratio [AOR] = 0.98; 95% confidence interval [CI] = 0.92, 0.99), male sex (AOR = 1.53; 95% CI = 1.15, 2.04), lifetime pharmaceutical opioid use disorder (AOR = 1.87; 95% CI = 1.31, 2.66) and lifetime illicit drug use disorder (AOR = 1.72; 95% CI = 1.18, 2.52). DISCUSSION AND CONCLUSIONS: Over one-third of the POINT cohort reported one or more indicators of potential extra-medical opioid use. Lifetime substance use disorders were associated these divergent practices, highlighting the importance of clinical monitoring and patient education for this patient group. Longitudinal studies are needed to investigate whether indicators of potential extra-medical opioid use predict opioid use disorders in this population.

All-Cause and Cause-Specific Mortality Among People Using Extramedical Opioids: A Systematic Review and Meta-analysis.

Importance: Extramedical opioid use has escalated in recent years. A better understanding of cause-specific mortality in this population is needed to inform comprehensive responses. Objective: To estimate all-cause and cause-specific crude mortality rates (CMRs) and standardized mortality ratios (SMRs) among people using extramedical opioids, including age- and sex-specific estimates when possible. Data Sources: For this systematic review and meta-analysis, MEDLINE, PsycINFO, and Embase were searched for studies published from January 1, 2009, to October 3, 2019, and an earlier systematic review on this topic published in 2011. Study Selection: Cohort studies of people using extramedical opioids and reporting mortality outcomes were screened for inclusion independently by 2 team members. Data Extraction and Synthesis: Data were extracted by a team member and checked by another team member. Study quality was assessed using a custom set of items that examined risk of bias and quality of reporting. Data were pooled using random-effects meta-analysis models. Heterogeneity was assessed using stratified meta-analyses and meta-regression. Main Outcomes and Measures: Outcome measures were all-cause and cause-specific CMRs and SMRs among people using extramedical opioids compared with the general population of the same age and sex. Results: Of 8683 identified studies, 124 were included in this analysis (100 primary studies and 24 studies providing additional data for primary studies). The pooled all-cause CMR, based on 99 cohorts of 1 262 592 people, was 1.6 per 100 person-years (95% CI, 1.4-1.8 per 100 person-years), with substantial heterogeneity (I2 = 99.7%). Heterogeneity was associated with the proportion of the study sample that injected opioids or was living with HIV infection or hepatitis C. The pooled all-cause SMR, based on 43 cohorts, was 10.0 (95% CI, 7.6-13.2). Excess mortality was observed across a range of causes, including overdose, injuries, and infectious and noncommunicable diseases. Conclusions and Relevance: The findings suggest that people using extramedical opioids experience significant excess mortality, much of which is preventable. The range of causes for which excess mortality was observed highlights the multiplicity of risk exposures experienced by this population and the need for comprehensive responses to address these. Better data on cause-specific mortality in this population in several world regions appear to be needed.

Perceptions of extended-release buprenorphine injections for opioid use disorder among people who regularly use opioids in Australia.

AIMS: To examine perceptions of extended-release (XR) buprenorphine injections among people who regularly use opioids in Australia. DESIGN: Cross-sectional survey prior to implementation. XR-buprenorphine was registered in Australia in November 2018. SETTING: Sydney, Melbourne and Hobart. Participants A total of 402 people who regularly use opioids interviewed December 2017 to March 2018. MEASUREMENTS: Primary outcome concerned the proportion of participants who believed XR-buprenorphine would be a good treatment option for them, preferred weekly versus monthly injections and perceived advantages/disadvantages of XR-buprenorphine. Independent variables concerned the demographic characteristics and features of current opioid agonist treatment (OAT; medication-type, dose, prescriber/dosing setting, unsupervised doses, out-of-pocket expenses and travel distance). FINDINGS: Sixty-eight per cent [95% confidence interval (CI) = 63-73%] believed XR-buprenorphine was a good treatment option for them. They were more likely to report being younger [26-35 versus > 55 years; odds ratio (OR) = 3.16, 95% CI = 1.12-8.89; P = 0.029], being female (OR = 1.67, 95% CI = 1.04-2.69; P = 0.034), < 10 years school education (OR = 1.87, 95% CI = 1.12-3.12; P = 0.016) and past-month heroin (OR = 1.81, 95% CI = 1.15-2.85; P = 0.006) and methamphetamine use (OR = 1.90, 95% CI = 1.20-3.01; P = 0.006). Fifty-four per cent reported no preference for weekly versus monthly injections, 7% preferred weekly and 39% preferred monthly. Among OAT recipients (n = 255), believing XR-buprenorphine was a good treatment option was associated with shorter treatment episodes (1-2 versus ≥ 2 years; OR = 3.93, 95% CI = 1.26-12.22; P = 0.018), fewer unsupervised doses (≤ 8 doses past-month versus no take-aways; OR = 0.50; 95% CI = 0.27-0.93; P = 0.028) and longer travel distance (≥ 5 versus < 5 km; OR = 2.10, 95% CI = 1.20-3.65; P = 0.009). Sixty-nine per cent reported 'no problems or concerns' with potential differences in availability, flexibility and location of XR-buprenorphine. CONCLUSIONS: Among regular opioid users in Australia, perceptions of extended-release buprenorphine as a good treatment option are associated with being female, recent illicit drug use and factors relating to the (in)convenience of current opioid agonist treatment.

Mortality among people with regular or problematic use of amphetamines: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Amphetamines are the second most commonly used class of illicit drugs. We aimed to produce pooled estimates of mortality risks among people with regular or dependent use of amphetamines, with a focus upon all-cause mortality as well as specific causes of death. DESIGN: Systematic review and meta-analysis of cohorts of people with problematic use or dependence on amphetamines with data on all-cause or cause-specific mortality. SETTING AND PARTICIPANTS: Of 4240 papers, 30 were eligible, reporting on 25 cohorts that measured all-cause mortality, drug poisoning, suicide, accidental injuries, homicide and cardiovascular mortality. Cohorts (n = 35-74 139) were in North America, several Nordic countries and Asia Pacific. MEASUREMENT: Titles/abstracts were independently screened by one reviewer and excluded those reviewed by a second reviewer. Full-text screening was by two reviewers with discrepancies resolved via a third reviewer. We extracted data on crude mortality rates (CMR) per 100 person-years (py), standardized mortality ratios (SMRs). We imputed SMRs where possible if not reported by study authors. We also calculated mortality relative risks. Data were pooled using random-effects models; potential reasons for heterogeneity were explored using subgroup analyses and meta-regressions. FINDINGS: Twenty-three cohorts contributed data for the pooled all-cause CMR: 1.14 per 100 py [95% confidence interval (CI) = 0.92-1.42]. Pooled cause-specific mortality rates were: drug poisoning, 0.14 per 100 py (95% CI = 0.06-0.34); cardiovascular disease, 0.13 per 100 py (95% CI = 0.06-0.29); suicide, 0.20 per 100 py (95% CI = 0.07-0.55); accidental injury, 0.20 per 100 py (95% CI = 0.08-0.47) and homicide, 0.03 per 100 py (95% CI = 0.02-0.06). There was substantial heterogeneity for all pooled CMR estimates except homicide. The pooled all-cause SMR was 6.83 (95% CI = 5.27-8.84). Pooled cause-specific SMRS were: poisoning, 24.70 (95% CI = 16.67, 36.58); homicide, 11.90 (95% CI = 7.82-18.12); suicide, 12.20 (95% CI = 4.89-30.47); cardiovascular disease, 5.12 (95% CI = 3.74-7.00) and accidental injury, 5.12 (95% CI = 2.88-9.08). CONCLUSIONS: People with regular or dependent amphetamine use are at elevated risk of a range of causes of mortality compared with people without regular or dependent amphetamine use.