Buprenorphine versus methadone for the treatment of opioid dependence: a systematic review and meta-analysis of randomised and observational studies.

BACKGROUND: Opioid dependence is associated with substantial health and social burdens, and opioid agonist treatment (OAT) is highly effective in improving multiple outcomes for people who receive this treatment. Methadone and buprenorphine are common medications provided as OAT. We aimed to examine buprenorphine compared with methadone in the treatment of opioid dependence across a wide range of primary and secondary outcomes. METHODS: We did a systematic review and meta-analysis in accordance with GATHER and PRISMA guidelines. We searched Embase, MEDLINE, CENTRAL, and PsycINFO from database inception to Aug 1, 2022; clinical trial registries and previous relevant Cochrane reviews were also reviewed. We included all RCTs and observational studies of adults (aged ≥18 years) with opioid dependence comparing treatment with buprenorphine or methadone. Primary outcomes were retention in treatment at 1, 3, 6, 12, and 24 months, treatment adherence (measured through doses taken as prescribed, dosing visits attended, and biological measures), or extra-medical opioid use (measured by urinalysis and self-report). Secondary outcomes were use of benzodiazepines, cannabis, cocaine, amphetamines, and alcohol; withdrawal; craving; criminal activity and engagement with the criminal justice system; overdose; mental and physical health; sleep; pain; global functioning; suicidality and self-harm; and adverse events. Single-arm cohort studies and RCTs that collected data on buprenorphine retention alone were also reviewed. Data on study, participant, and treatment characteristics were extracted. Study authors were contacted to obtain additional data when required. Comparative estimates were pooled with use of random-effects meta-analyses. The proportion of individuals retained in treatment across multiple timepoints was pooled for each drug. This study is registered with PROSPERO (CRD42020205109). FINDINGS: We identified 32 eligible RCTs (N=5808 participants) and 69 observational studies (N=323 340) comparing buprenorphine and methadone, in addition to 51 RCTs (N=11 644) and 124 observational studies (N=700 035) that reported on treatment retention with buprenorphine. Overall, 61 studies were done in western Europe, 162 in North America, 14 in north Africa and the Middle East, 20 in Australasia, five in southeast Asia, seven in south Asia, two in eastern Europe, three in central Europe, one in east Asia, and one in central Asia. 1 040 827 participants were included in these primary studies; however, gender was only reported for 572 111 participants, of whom 377 991 (66·1%) were male and 194 120 (33·9%) were female. Mean age was 37·1 years (SD 6·0). At timepoints beyond 1 month, retention was better for methadone than for buprenorphine: for example, at 6 months, the pooled effect favoured methadone in RCTs (risk ratio 0·76 [95% CI 0·67-0·85]; I·=74·2%; 16 studies, N=3151) and in observational studies (0·77 [0·68-0·86]; I·=98·5%; 21 studies, N=155 111). Retention was generally higher in RCTs than observational studies. There was no evidence suggesting that adherence to treatment differed with buprenorphine compared with methadone. There was some evidence that extra-medical opioid use was lower in those receiving buprenorphine in RCTs that measured this outcome by urinalysis and reported proportion of positive urine samples (over various time frames; standardised mean difference -0·20 [-0·29 to -0·11]; I·=0·0%; three studies, N=841), but no differences were found when using other measures. Some statistically significant differences were found between buprenorphine and methadone among secondary outcomes. There was evidence of reduced cocaine use, cravings, anxiety, and cardiac dysfunction, as well as increased treatment satisfaction among people receiving buprenorphine compared with methadone; and evidence of reduced hospitalisation and alcohol use in people receiving methadone. These differences in secondary outcomes were based on small numbers of studies (maximum five), and were often not consistent across study types or different measures of the same constructs (eg, cocaine use). INTERPRETATION: Evidence from trials and observational studies suggest that treatment retention is better for methadone than for sublingual buprenorphine. Comparative evidence on other outcomes examined showed few statistically significant differences and was generally based on small numbers of studies. These findings highlight the imperative for interventions to improve retention, consideration of client-centred factors (such as client preference) when selecting between methadone and buprenorphine, and harmonisation of data collection and reporting to strengthen future syntheses. FUNDING: Australian National Health and Medical Research Council.

Acceptability of, and barriers and facilitators to, a pilot physical health service for people who inject drugs: A qualitative study with service users and providers.

BACKGROUND: People who inject drugs may experience difficulty accessing or maintaining involvement with traditional healthcare services. This is associated with increased health inequalities and bio-psychosocial difficulties. Embedding physical healthcare services within community-based drug services may provide a practical and feasible approach to increase access and delivery of healthcare. This study explored the acceptability of, and barriers and facilitators to, embedding a pilot physical healthcare service within a community-based drug service in the United Kingdom (Bristol, England). METHODS: Semi-structured interviews were conducted with service users (people who inject drugs) (n = 13), and a focus group was conducted with service providers (n = 11: nine harm reduction workers, two nurses, one service manager). Topic guides included questions to explore barriers and facilitators to using and delivering the service (based on the COM-B Model), and acceptability of the service (using the Theoretical Framework of Acceptability). Transcripts were analysed using a combined deductive framework and inductive thematic analysis approach. RESULTS: The service was viewed as highly acceptable. Service users and providers were confident they could access and provide the service respectively, and perceived it to be effective. Barriers included competing priorities of service users (e.g. drug use) and the wider service (e.g. equipment), and the potential impact of the service being removed in future was viewed as a barrier to overall healthcare access. Both service users and providers viewed embedding the physical health service within an existing community-based drug service as facilitating accessible and holistic care which reduced stigma and discrimination. CONCLUSIONS: The current study demonstrated embedding a physical health service within an existing community-drug based and alcohol service was acceptable and beneficial. Future studies are required to demonstrate cost-effectiveness and ensure long-term sustainability, and to determine transferability of findings to other settings, organisations and countries.

Prevalence of steatosis and fibrosis in young adults in the UK: a population-based study.

BACKGROUND: The estimated worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) in adults is 25%; however, prevalence in young adults remains unclear. We aimed to identify the prevalence of steatosis and fibrosis in young adults in a sample of participants recruited through the Avon Longitudinal Study of Parents and Children (ALSPAC), based on transient elastography and controlled attenuation parameter (CAP) score. METHODS: In this population-based study, we invited active participants of the ALSPAC cohort to our Focus@24+ clinic at the University of Bristol (Bristol, UK) between June 5, 2015, and Oct 31, 2017, for assessment by transient elastography with FibroScan, to determine the prevalence of steatosis and fibrosis. FibroScan data were collected on histologically equivalent fibrosis stage (F0-F4) and steatosis grade (S0-S3); results with an IQR to median ratio of 30% or greater were excluded for median fibrosis results greater than 7·1 kPa, and CAP scores for steatosis were excluded if less than ten valid readings could be obtained. Results were collated with data on serology (including alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transferase) and exposures of interest: alcohol consumption (via the Alcohol Use Disorder Identification Test for Consumption [AUDIT-C] and the Diagnostic and Statistical Manual of Mental Disorders-5 criteria for alcohol use disorder), body-mass index (BMI), waist-to-height ratio, socioeconomic status (based on predefined ALSPAC markers), and sex. We used logistic regression models to calculate odds ratios (ORs) for the effect of exposures of interest on risk of steatosis and fibrosis, after dichotomising the prevalences of fibrosis and steatosis and adjusting for covariates (excessive alcohol intake [hazardous drinking, AUDIT-C score ≥5; or harmful drinking, evidence of alcohol use disorder], social class, smoking, and BMI). FINDINGS: 10 018 active ALSPAC participants were invited to our Focus@24+ clinic, and 4021 attended (1507 men and 2514 women), with a mean age of 24·0 years (IQR 23·0-25·0). 3768 CAP scores were eligible for analysis. 780 (20·7% [95% CI 19·4-22·0]) participants had suspected steatosis (S1-S3; ≥248 dB/m), with 377 (10·0%) presenting with S3 (severe) steatosis (≥280 dB/m). A BMI in the overweight or obese range was positively associated with steatosis when adjusted for excessive alcohol consumption, social class, and smoking (overweight BMI: OR 5·17 [95% CI 4·11-6·50], p<0·0001; obese BMI: 27·27 [20·54-36·19], p<0·0001). 3600 participants had valid transient elastography results for fibrosis analysis. 96 participants (2·7% [95% CI 2·2-3·2]) had transient elastography values equivalent to suspected fibrosis (F2-F4; ≥7·9 kPa), nine of whom had values equivalent to F4 fibrosis (≥11·7 kPa). Individuals with alcohol use disorder and steatosis had an increased risk of fibrosis when adjusted for smoking and social class (4·02 [1·24-13·02]; p=0·02). INTERPRETATION: One in five young people had steatosis and one in 40 had fibrosis around the age of 24 years. The risk of fibrosis appears to be greatest in young adults who have harmful drinking patterns and steatosis. A holistic approach to the UK obesity epidemic and excessive drinking patterns is required to prevent an increasing health-care burden of adults with advanced liver disease in later life. FUNDING: Medical Research Council UK, Alcohol Change UK, David Telling Charitable Trust.

Long-Chain ω-3 Levels Are Associated With Increased Alcohol Sensitivity in a Population-Based Sample of Adolescents.

BACKGROUND: The levels of the ω-3 long-chain polyunsaturated fatty acids (ω-3 LC-PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been associated with alcohol sensitivity in vertebrate and invertebrate model systems, but prior studies have not examined this association in human samples despite evidence of associations between ω-3 LC-PUFA levels and alcohol-related phenotypes. Both alcohol sensitivity and ω-3 LC-PUFA levels are impacted by genetic factors, and these influences may contribute to observed associations between phenotypes. Given the potential for using EPA and DHA supplementation in adjuvant care for alcohol misuse and other outcomes, it is important to clarify how ω-3 LC-PUFA levels relate to alcohol sensitivity. METHODS: Analyses were conducted using data from the Avon Longitudinal Study of Parents and Children. Plasma ω-3 LC-PUFA levels were measured at ages 15.5 and 17.5. Participants reported on their initial alcohol sensitivity using the early drinking Self-Rating of the Effects of Alcohol (SRE-5) scale, for which more drinks needed for effects indicates lower levels of response per drink, at ages 15.5, 16.5, and 17.5. Polygenic liability for alcohol consumption, alcohol problems, EPA levels, and DHA levels was derived using summary statistics from large, publicly available datasets. Linear regressions were used to examine the cross-sectional and longitudinal associations between ω-3 LC-PUFA levels and SRE scores. RESULTS: Age 15.5 ω-3 LC-PUFA levels were negatively associated with contemporaneous SRE scores and with age 17.5 SRE scores. One modest association (p = 0.02) between polygenic liability and SRE scores was observed, between alcohol problems-based polygenic risk scores (PRS) and age 16.5 SRE scores. Tests of moderation by genetic liability were not warranted. CONCLUSIONS: Plasma ω-3 LC-PUFA levels may be related to initial sensitivity to alcohol during adolescence. These data indicate that diet-related factors have the potential to impact humans' earliest responses to alcohol exposure.

Pathways to optimising antibiotic use in rural China: identifying key determinants in community and clinical settings, a mixed methods study protocol.

INTRODUCTION: This study aims to investigate patterns of antibiotic treatment-seeking, describe current levels of and drivers for antibiotic use for common infections (respiratory tract and urinary tract infections) and test the feasibility of determining the prevalence and epidemiology of antimicrobial resistance (AMR) in rural areas of Anhui province, in order to identify potential interventions to promote antibiotic stewardship and reduce the burden of AMR in China. METHODS AND ANALYSIS: We will conduct direct observations, structured and semistructured interviews in retail pharmacies, village clinics and township health centres to investigate treatment-seeking and antibiotic use. Clinical isolates from 1550 sputum, throat swab and urine samples taken from consenting patients at village and township health centres will be analysed to identify bacterial pathogens and ascertain antibiotic susceptibilities. Healthcare records will be surveyed for a subsample of those recruited to the study to assess their completeness and accuracy. ETHICS AND DISSEMINATION: The full research protocol has been reviewed and approved by the Biomedical Ethics Committee of Anhui Medical University (reference number: 20170271). Participation of patients and doctors is voluntary and written informed consent is sought from all participants. Findings from the study will be disseminated through academic routes including peer-reviewed publications and conference presentations, via tailored research summaries for health professionals, health service managers and policymakers and through an end of project impact workshop with local and regional stakeholders to identify key messages and priorities for action.

Mortality rates among individuals diagnosed with hepatitis C virus (HCV); an observational cohort study, England, 2008 to 2016.

BackgroundMonitoring trends in mortality for individuals diagnosed with hepatitis C virus (HCV) infection are important as we expand treatment and move towards World Health Organization elimination targets.AimTo estimate mortality rates for individuals aged ≥ 15 years diagnosed with HCV infection in England 2008-16.MethodsAn observational cohort study whereby death certificate information was linked to the Sentinel Surveillance of Blood Borne Virus Testing in England. Age-sex standardised mortality rates (ASMR) for individuals diagnosed with HCV infection (2008-16) were calculated and compared to the general population.ResultsOf 43,895 individuals with HCV infection, 2,656 (6.3%) died. All-cause ASMRs were 2,834.2 per 100,000 person years (PY), 2.3 times higher than in the general population. In individuals aged 30-69 years, all-cause mortality rates were 1,768.9 per 100,000 PY among individuals with HCV, 4.7 times higher than in the general population. ASMRs had not decreased between 2010 (2,992) and 2016 (2,340; p=0.10), with no change from 2014 (p = 0.058). ASMRs were 441.0 times higher for hepatitis, 34.4 times higher for liver cancer, 8.1 times higher for end stage liver disease and 6.4 times higher for external causes than in the general population.ConclusionsMortality was higher in individuals with diagnosed HCV infection compared to the general population, highlighting health inequalities. There is a need to improve HCV diagnosis, engagement in care and treatment rates. The high mortality from external causes highlights the importance of integrated health and social care strategies and addressing the needs of this vulnerable population.

Risk to heroin users of polydrug use of pregabalin or gabapentin.

AIM: To examine the risk to heroin users of also using gabapentin or pregabalin (gabapentoids). DESIGN: Multi-disciplinary study: we (a) examined trends in drug-related deaths and gabapentoid prescription data in England and Wales to test for evidence that any increase in deaths mentioning gabapentin or pregabalin is associated with trends in gabapentoid prescribing and is concomitant with opioid use; (b) interviewed people with a history of heroin use about their polydrug use involving gabapentin and pregabalin; and (c) studied the respiratory depressant effects of pregabalin in the absence and presence of morphine in mice to determine whether concomitant exposure increased the degree of respiratory depression observed. SETTING: England and Wales. PARTICIPANTS: Interviews were conducted with 30 participants (19 males, 11 female). MEASUREMENTS: (a) Office of National Statistics drug-related deaths from 1 January 2004 to 31 December 2015 that mention both an opioid and pregabalin or gabapentin; (b) subjective views on the availability, use, interactions and effects of polydrug use involving pregabalin and gabapentin; and (c) rate and depth of respiration. RESULTS: Pregabalin and gabapentin prescriptions increased approximately 24% per year from 1 million in 2004 to 10.5 million in 2015. The number of deaths involving gabapentoids increased from fewer than one per year prior to 2009 to 137 in 2015; 79% of these deaths also involved opioids. The increase in deaths was correlated highly with the increase in prescribing (correlation coefficient 0.94; 5% increase in deaths per 100 000 increase in prescriptions). Heroin users described pregabalin as easy to obtain. They suggested that the combination of heroin and pregabalin reinforced the effects of heroin but were concerned it induced 'blackouts' and increased the risk of overdose. In mice, a low dose of S-pregabalin (20 mg/kg) that did not itself depress respiration reversed tolerance to morphine depression of respiration (resulting in 35% depression of respiration, P < 0.05), whereas a high dose of S-pregabalin (200 mg/kg) alone depressed respiration and this effect summated with that of morphine. CONCLUSIONS: For heroin users, the combination of opioids with gabapentin or pregabalin potentially increases the risk of acute overdose death through either reversal of tolerance or an additive effect of the drugs to depress respiration.

A Novel Triazolopyridine-Based Spleen Tyrosine Kinase Inhibitor That Arrests Joint Inflammation.

Autoantibodies and the immunoreceptors to which they bind can contribute to the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). Spleen Tyrosine Kinase (Syk) is a non-receptor tyrosine kinase with a central role in immunoreceptor (FcR) signaling and immune cell functionality. Syk kinase inhibitors have activity in antibody-dependent immune cell activation assays, in preclinical models of arthritis, and have progressed into clinical trials for RA and other autoimmune diseases. Here we describe the characterization of a novel triazolopyridine-based Syk kinase inhibitor, CC-509. This compound is a potent inhibitor of purified Syk enzyme, FcR-dependent and FcR-independent signaling in primary immune cells, and basophil activation in human whole blood. CC-509 is moderately selective across the kinome and against other non-kinase enzymes or receptors. Importantly, CC-509 was optimized away from and has modest activity against cellular KDR and Jak2, kinases that when inhibited in a preclinical and clinical setting may promote hypertension and neutropenia, respectively. In addition, CC-509 is orally bioavailable and displays dose-dependent efficacy in two rodent models of immune-inflammatory disease. In passive cutaneous anaphylaxis (PCA), CC-509 significantly inhibited skin edema. Moreover, CC-509 significantly reduced paw swelling and the tissue levels of pro-inflammatory cytokines RANTES and MIP-1α in the collagen-induced arthritis (CIA) model. In summary, CC-509 is a potent, moderately selective, and efficacious inhibitor of Syk that has a differentiated profile when compared to other Syk compounds that have progressed into the clinic for RA.

How ideology shapes the evidence and the policy: what do we know about cannabis use and what should we do?

In the United Kingdom, as in many places, cannabis use is considered substantially within a criminal justice rather than a public health paradigm with prevention policy embodied in the Misuse of Drugs Act. In 2002 the maximum custodial sentence tariff for cannabis possession under the Act was reduced from 5 to 2 years. Vigorous and vociferous public debate followed this decision, centred principally on the question of whether cannabis use caused schizophrenia. It was suggested that new and compelling evidence supporting this hypothesis had emerged since the re-classification decision was made, meaning that the decision should be reconsidered. The re-classification decision was reversed in 2008. We consider whether the strength of evidence on the psychological harms of cannabis has changed substantially and discuss the factors that may have influenced recent public discourse and policy decisions. We also consider evidence for other harms of cannabis use and public health implications of preventing cannabis use. We conclude that the strongest evidence of a possible causal relation between cannabis use and schizophrenia emerged more than 20 years ago and that the strength of more recent evidence may have been overstated--for a number of possible reasons. We also conclude that cannabis use is almost certainly harmful, mainly because of its intimate relation to tobacco use. The most rational policy on cannabis from a public health perspective would seem to be one able to achieve the benefit of reduced use in the population while minimizing social and other costs of the policy itself. Prohibition, whatever the sentence tariff associated with it, seems unlikely to fulfil these criteria.