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OBJECTIVES: Smoking is a leading cause of death worldwide. Cessation aids include varenicline, bupropion, nicotine replacement therapy (NRT), and e-cigarettes at various doses (low, standard and high) and used alone or in combination with each other. Previous cost-effectiveness analyses have not fully accounted for adverse effects nor compared all cessation aids. The objective was to determine the relative cost-effectiveness of cessation aids in the United Kingdom.METHODS: An established Markov cohort model was adapted to incorporate health outcomes and costs due to depression and self-harm associated with cessation aids, alongside other health events. Relative efficacy in terms of abstinence and major adverse neuropsychiatric events was informed by a systematic review and network meta-analysis. Base case results are reported for UK-licensed interventions only. Two sensitivity analyses are reported, one including unlicensed interventions and another comparing all cessation aids but removing the impact of depression and self-harm. The sensitivity of conclusions to model inputs was assessed by calculating the expected value of partial perfect information.RESULTS: When limited to UK-licensed interventions, varenicline standard-dose and NRT standard-dose were most cost-effective. Including unlicensed interventions, e-cigarette low-dose appeared most cost-effective followed by varenicline standard-dose + bupropion standard-dose combined. When the impact of depression and self-harm was excluded, varenicline standard-dose + NRT standard-dose was most cost-effective, followed by varenicline low-dose + NRT standard-dose.CONCLUSION: Although found to be most cost-effective, combined therapy is currently unlicensed in the United Kingdom and the safety of e-cigarettes remains uncertain. The value-of-information analysis suggested researchers should continue to investigate the long-term effectiveness and safety outcomes of e-cigarettes in studies with active comparators.

Background Antigen testing using lateral flow devices (LFDs) plays an important role in the management of the novel coronavirus pandemic of 2019 (COVID-19) by rapidly identifying individuals who are asymptomatically carrying high levels of the virus. By January 2021, LFD community testing sites were set up across English local authority areas to support the management and containment of regional COVID-19 cases, initially targeting essential workers unable to work from home during the national lockdown. This study aimed to examine the characteristics and motivations of individuals accessing community LFD testing across two local authority areas (LAAs) in the South West of England. Methods Data were collected as part of a service evaluation from December 22nd 2020 until March 15th 2021 for two LAAs. Demographic and postcode data were collected from an online test appointment booking platform and the National Health Service testing service online system, with data accessed from Public Health England. An online survey was sent to individuals who made a testing appointment at an LAA1 site using the online booking platform, consisting of 12 questions to collect data on individual’s motivations for and experiences of testing. Results Data were available for individuals who completed 12,516 tests in LAA1 and 12,327 tests in LAA2. Most individuals who engaged with testing were female, working age, white, and worked as early years or education staff, health and social care staff, and supermarket or food production staff. 1249 individuals completed the survey with 60% of respondents reported getting tested for work-related reasons. Individuals first heard about LFD testing through various channels including work, media, and word of mouth, and decided to get tested based on the ease and convenience of testing, workplace communications, and to identify asymptomatic cases to help stop the spread. Most tests were completed by individuals living in less deprived areas based on national deciles of deprivation. Conclusions While national and local COVID-19 testing strategies have evolved, community and personal LFD testing remains a crucial pillar of the testing strategy. Future studies should collect quantitative and qualitative data from residents to most effectively shape testing offers based on the needs and preferences of their population.

Background Cigarette smoking is one of the leading causes of early death. Varenicline [Champix (UK), Pfizer Europe MA EEIG, Brussels, Belgium; or Chantix (USA), Pfizer Inc., Mission, KS, USA], bupropion (Zyban; GlaxoSmithKline, Brentford, UK) and nicotine replacement therapy are licensed aids for quitting smoking in the UK. Although not licensed, e-cigarettes may also be used in English smoking cessation services. Concerns have been raised about the safety of these medicines and e-cigarettes. Objectives To determine the clinical effectiveness, safety and cost-effectiveness of smoking cessation medicines and e-cigarettes. Design Systematic reviews, network meta-analyses and cost-effectiveness analysis informed by the network meta-analysis results. Setting Primary care practices, hospitals, clinics, universities, workplaces, nursing or residential homes. Participants Smokers aged ≥ 18 years of all ethnicities using UK-licensed smoking cessation therapies and/or e-cigarettes. Interventions Varenicline, bupropion and nicotine replacement therapy as monotherapies and in combination treatments at standard, low or high dose, combination nicotine replacement therapy and e-cigarette monotherapies. Main outcome measures Effectiveness – continuous or sustained abstinence. Safety – serious adverse events, major adverse cardiovascular events and major adverse neuropsychiatric events. Data sources Ten databases, reference lists of relevant research articles and previous reviews. Searches were performed from inception until 16 March 2017 and updated on 19 February 2019. Review methods Three reviewers screened the search results. Data were extracted and risk of bias was assessed by one reviewer and checked by the other reviewers. Network meta-analyses were conducted for effectiveness and safety outcomes. Cost-effectiveness was evaluated using an amended version of the Benefits of Smoking Cessation on Outcomes model. Results Most monotherapies and combination treatments were more effective than placebo at achieving sustained abstinence. Varenicline standard plus nicotine replacement therapy standard (odds ratio 5.75, 95% credible interval 2.27 to 14.90) was ranked first for sustained abstinence, followed by e-cigarette low (odds ratio 3.22, 95% credible interval 0.97 to 12.60), although these estimates have high uncertainty. We found effect modification for counselling and dependence, with a higher proportion of smokers who received counselling achieving sustained abstinence than those who did not receive counselling, and higher odds of sustained abstinence among participants with higher average dependence scores. We found that bupropion standard increased odds of serious adverse events compared with placebo (odds ratio 1.27, 95% credible interval 1.04 to 1.58). There were no differences between interventions in terms of major adverse cardiovascular events. There was evidence of increased odds of major adverse neuropsychiatric events for smokers randomised to varenicline standard compared with those randomised to bupropion standard (odds ratio 1.43, 95% credible interval 1.02 to 2.09). There was a high level of uncertainty about the most cost-effective intervention, although all were cost-effective compared with nicotine replacement therapy low at the £20,000 per quality-adjusted life-year threshold. E-cigarette low appeared to be most cost-effective in the base case, followed by varenicline standard plus nicotine replacement therapy standard. When the impact of major adverse neuropsychiatric events was excluded, varenicline standard plus nicotine replacement therapy standard was most cost-effective, followed by varenicline low plus nicotine replacement therapy standard. When limited to licensed interventions in the UK, nicotine replacement therapy standard was most cost-effective, followed by varenicline standard. Limitations Comparisons between active interventions were informed almost exclusively by indirect evidence. Findings were imprecise because of the small numbers of adverse events identified. Conclusions Combined therapies of medicines are among the most clinically effective, safe and cost-effective treatment options for smokers. Although the combined therapy of nicotine replacement therapy and varenicline at standard doses was the most effective treatment, this is currently unlicensed for use in the UK. Future work Researchers should examine the use of these treatments alongside counselling and continue investigating the long-term effectiveness and safety of e-cigarettes for smoking cessation compared with active interventions such as nicotine replacement therapy. Study registration This study is registered as PROSPERO CRD42016041302. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 59. See the NIHR Journals Library website for further project information.

Background Opioid prescribing to treat chronic non-cancer pain has rapidly increased, despite a lack of evidence for long-term safety and effectiveness. A pain review service was developed to work with patients taking opioids long-term to explore opioid use, encourage non-drug-based alternatives, and, where appropriate, support dose reduction.Aim To evaluate the service and its potential impact on opioid use, health and wellbeing outcomes, and quality of life (QoL).Design and setting Mixed-methods evaluation of a one-to-one service based in two GP practices in South Gloucestershire, England, which took place from September 2016 to December 2017.Method Quantitative data were collected on baseline demographics; data on opioid use, misuse, and dose, health, wellbeing, QoL, and pain and interference with life measures were collected at baseline and follow-up. Twenty-five semi-structured interviews (n = 18 service users, n = 7 service providers) explored experiences of the service including perceived impacts and benefits.Results Of 59 patients who were invited, 34 (57.6%) enrolled in the service. The median prescribed opioid dose reduced from 90 mg (average daily morphine equivalent; interquartile range [IQR] 60 to 240) at baseline to 72 mg (IQR 30 to 160) at follow-up (PConclusion The service was well received, and health and wellbeing outcomes suggest a potential benefit. Following further service development, a randomised controlled trial to test this type of care pathway is warranted.

Highlights • Primary care databases can be used for innovative and relevant addiction research. • Strengths include ready access of real-world longitudinal patient data for research. • Limitations include missing data and lack of accuracy and completeness of data., Primary care databases extract and combine routine data from the electronic patient records of various participating practices on a regular basis. These databases can be used for innovative and relevant addiction research, but such use requires a thorough understanding of how data were originally collected and how they need to be processed and statistically analysed to produce sound scientific evidence. The aims of this paper are therefore to (1) make a case for why primary care databases should be considered more frequently for addiction research; (2) provide an overview of how primary care databases are constructed; (3) highlight important methodological and statistical strengths and weaknesses of using primary care databases for research; and (4) give practical advice about how a researcher can get access to databases. Three major primary care databases from the UK serve as examples: Clinical Practice Research Datalink (CPRD), The Health Improvement Network (THIN), and QResearch.

AIM: To determine how varenicline, bupropion, nicotine replacement therapy (NRT) and electronic cigarettes compare with respect to their clinical effectiveness and safety.METHOD: Systematic reviews and Bayesian network meta-analyses of randomized controlled trials, in any setting, of varenicline, bupropion, NRT and e-cigarettes (in high, standard and low doses, alone or in combination) in adult smokers and smokeless tobacco users with follow-up duration of 24 weeks or greater (effectiveness) or any duration (safety). Nine databases were searched until 19 February 2019. Primary outcomes were sustained tobacco abstinence and serious adverse events (SAEs). We estimated odds ratios (ORs) and treatment rankings and conducted meta-regression to explore covariates.RESULTS: We identified 363 trials for effectiveness and 355 for safety. Most monotherapies and combination therapies were more effective than placebo at helping participants to achieve sustained abstinence; the most effective of these, estimated with some imprecision, were varenicline standard [OR = 2.83, 95% credible interval (CrI) = 2.34-3.39] and varenicline standard + NRT standard (OR = 5.75, 95% CrI = 2.27-14.88). Estimates were higher in smokers receiving counselling than in those without and in studies with higher baseline nicotine dependence scores than in those with lower scores. Varenicline standard + NRT standard showed a high probability of being ranked best or second-best. For safety, only bupropion at standard dose increased the odds of experiencing SAEs compared with placebo (OR = 1.27, 95% CrI = 1.04-1.58), and we found no evidence of effect modification.CONCLUSIONS: Most tobacco cessation monotherapies and combination therapies are more effective than placebo at helping participants to achieve sustained abstinence, with varenicline appearing to be most effective based on current evidence. There does not appear to be strong evidence of associations between most tobacco cessation pharmacotherapies and adverse events; however, the data are limited and there is a need for improved reporting of safety data.

Background and Aims Recovery outcomes for opioid substitution treatment are poorer than those for alcohol and other drugs. In order to understand why this is and to synthesise the findings of a large number of qualitative studies, we conducted a systematic review and thematic synthesis to understand facilitators of and barriers to recovery from opioid dependency. Methods Electronic databases (Pubmed, PsychInfo, CINAHL and Embase) were searched. English language studies exploring the views of adult service user and stakeholders with experiences of opioid substitution treatment were considered for inclusion. Included studies were inductively analysed using thematic synthesis. During analysis, the socioecological model was selected as an analytical framework for organising and making links between themes as it captured the complexity of the topic well. ResultsFrom 3646 screened papers, we included 37 studies reporting the views of 1212 staff and service users. Studies highlighted complex interactions between factors influencing recovery across the five levels of the socioecological model (intrapersonal, inter-personal, organisational, community and policy). Early life experiences of trauma were common; lack of support (both psychological and social) was also a recurring theme resulting in feelings of disconnection and isolation. Stigma played a particularly important role in an individual’s capacity to recover from opioid dependency and cut-across all levels of the socioecological model. Conclusions Interventions targeted at the individual level fail to take account of the complexity of recovery within opioid substitution treatment and may ignore the complex socio-political context that service users and services exist within. Stigma permeates all levels of the opioid substitution treatment system; we suggest that addressing this is likely to improve healthcare encounters, help-seeking, increase access to social support and facilitate community reintegration for individuals receiving opioid substitution treatment.

Background Patients often have very different ideas from clinicians about what they want treatments to achieve. Their views on what outcomes are important are not always reflected in trials. Aims To elicit the views of people who self-harm on the most commonly used outcome measures and to identify the outcomes that matter to them. Method We conducted in-depth interviews with 18 people with histories of self-harm, recruited from hospital and community settings. We conducted thematic analysis using a framework approach and used visual mapping to arrive at our final analysis and interpretation. Results Participants' accounts contained a number of challenges to the validity and meaningfulness of current trial outcome measures. Five broad issues emerged: (a) relationship between frequency and severity of self-harm; (b) behavioural substitution; (b) self-management skills; (d) the role of self-harm as survival tool and affect regulator, and (e) strategic self-presentation. We show how these affect the visibility and measurability of commonly used outcomes. The outcomes that mattered to participants focused on positive achievements in three domains: (a) general functioning and activities of everyday living; (b) social participation, and (c) engagement with services. Participants conceptualised these as both measures and means of sustained improvement. Conclusions Our findings suggest that current self-harm trial science rests on flawed assumptions about the relationship between mental states and behaviours and about our ability to measure both. Greater understanding of the outcomes that matter to people who self-harm is needed to inform both intervention development and trial design.

Aims To investigate whether smokers prescribed varenicline had lower risks of serious ill-health during the 4 years following treatment compared with those prescribed nicotine replacement therapy (NRT). Design Observational cohort study of electronic medical records. Setting A total of 370 UK general practices sampled from the Clinical Practice Research Datalink. Participants A total of 126 718 patients aged 18 and over who were issued smoking cessation prescriptions between 1 September 2006 and 31 March 2014. Measurements Our primary outcome was all-cause mortality within 2 years of first prescription as indicated by linked Office of National Statistics data. Our secondary outcomes were cause-specific mortality, all-cause, cause-specific hospitalization, primary care diagnosis of myocardial infarction or chronic obstructive pulmonary disease (COPD), body mass index and attendance rate to primary care within 2 years of first prescription. Risk differences and 95% confidence intervals were estimated by multivariable adjusted regression and propensity score matched regression. We used instrumental variable analysis to overcome residual confounding. Findings People prescribed varenicline were healthier at baseline than those prescribed NRT in almost all characteristics, highlighting the potential for residual confounding. Our instrumental variable analysis results found that people prescribed varenicline had a similar risk of mortality at 2 years [risk difference per 100 patients treated = 0.67, 95% confidence interval (CI) = -0.11 to 1.46)] to those prescribed NRT, and there were similar rates of all-cause hospitalization, incident primary-care diagnoses of myocardial infarction and COPD. People prescribed varenicline subsequently attended primary care less frequently. Conclusions Smokers prescribed varenicline in primary care in the United Kingdom do not appear to be less likely to die, be hospitalized or experience a myocardial infarction or chronic obstructive pulmonary disease during the following 2 years compared with smokers prescribed nicotine replacement therapy, but they gain more weight and attend primary care less frequently.

Background The co-location of expertise in public health, social care, and place services in local authorities facilitates tackling the wider determinants of health using transdisciplinary approaches. Local authority research systems are needed to enable local authorities to become research active, co-produce research, evaluate their impact, and produce and use evidence to shape practice and policy at pace. We aimed to explore and recommend what is necessary for a South Gloucestershire Council (SGC) research system to sustainably produce impactful research activity. Methods We did qualitative interviews with elected members and senior leadership of SGC and key stakeholders from local National Institute for Health Research (NIHR) infrastructure and organisations identified by expert sampling. Interviews were semi-structured with tailored topic guides exploring several topics, including relationships between SGC and local partners, resource and support, co-production, social care research, and the impact of COVID-19. Data from interviews were electronically transcribed verbatim using Otter.ai and coded using NVivo qualitative data analysis software. Data were analysed using the framework method and recommendations were proposed based on the findings. Ethical approval was granted by the University of Bristol's Faculty of Health Science Research Ethics Committee. Findings We interviewed 27 participants (five from SGC, 22 from local research organisations). Participants identified a need for a SGC research lead to facilitate collaboration and relationship building, and more joint posts across the local authority and external organisations. There was a need for collaborative cross-boundary working, as SGC works with other local authorities in their Sustainability and Transformation Partnership and Clinical Commissioning Group. Challenges included difficulties identifying SGC's priorities and population needs, data, staff training, and collaboration with academic researchers. They also reported resource issues exacerbated by COVID-19. Participants did not express conflicting views on these findings. Interpretation We recommended the creation of a local authority research lead post working across Council directorates, local authority research networks, support for joint posts, increased accessibility and use of local authority data, cross-boundary research systems, and infrastructure to support research to respond to local authority needs. We also suggested increased funding and incentivisation for academics to engage with local authority research. Potential barriers to these recommendations include local authority funding and staff capacity challenges. This study was limited by its recruitment method, sample size, and data collection and analyses completed by a single researcher. Future research should explore what types of evidence local authorities consider most relevant and useful. Funding NIHR Public Health Research (grant number NIHR131952).

Background and aimsVarenicline and nicotine replacement therapy (NRT) are the most commonly used medications to quit smoking. Given their widespread use, monitoring adverse risks remains important. This study aimed to estimate the neuropsychiatric and cardiovascular risks associated with varenicline and NRT as used in routine UK care.DesignCase–cross‐over study.SettingUK‐based electronic primary care records in the Clinical Practice Research Datalink from 2006 to 2015 linked to hospital and mortality data sets.ParticipantsAdult smokers observed during periods when exposed and not exposed to either varenicline or NRT.MeasurementsMain outcomes included suicide, self‐harm, myocardial infarction (MI), all‐cause death and cause‐specific death [MI, chronic obstructive pulmonary disease (COPD)]. In primary analyses, conditional logistic regression was used to compare the chance of varenicline or NRT exposure during the risk period (90 days prior to the event) with the chance of exposure during an earlier single reference period (91–180 days prior to the event) or multiple 90‐day reference periods to increase statistical power.FindingsIn the primary analyses, findings were inconclusive for the associations between varenicline and the main outcomes using a single reference period, while NRT was associated with MI [odds ratio (OR) = 1.40, 95% confidence interval (CI) = 1.18–1.67]. Using multiple reference periods, varenicline was associated with an increased risk of self‐harm (OR = 1.32, 95% CI = 1.12–1.56) and suicide (OR = 3.56, 95% CI = 1.32–9.60) but a reduction in all‐cause death (OR = 0.75, 95% CI = 0.61–0.93). NRT was associated with MI (OR = 1.54, 95% CI = 1.36–1.74), self‐harm (OR = 1.30, 95% CI = 1.18–1.44) and deaths from MI (OR = 1.53, 95% CI = 1.11–2.10), COPD (OR = 1.33, 95% CI = 1.14–1.56) and all causes (OR = 1.28, 95% CI = 1.18–1.40) when using multiple reference periods.ConclusionsThere appear to be positive associations between (1) nicotine replacement therapy (NRT) and myocardial infarction, death and risk of self‐harm and (2) varenicline and increased risk of self‐harm and suicide, as well as a negative association between varenicline and all‐cause death. The associations may not be causal. They may reflect health changes at the time of smoking cessation (nicotine replacement therapy is prescribed for people with cardiac problems) or be associated with quit attempts (exposure to both medicines was associated with self‐harm).

This study aimed to determine the effectiveness and safety of varenicline versus NRT for smoking cessation in people with neurodevelopmental disorders, compared to those without, at up to four years after exposure. We analysed electronic medical records from the Clinical Practice Research Datalink using three different statistical approaches: multivariable logistic regression, propensity score matching (PSM), and instrumental variable analysis. Exposure was prescription of varenicline versus NRT and the primary outcome was smoking cessation at 2-years. We included 235,314 people aged 18 and above with eligible smoking cessation prescriptions in the effectiveness analysis. Smokers with neurodevelopmental disorders were 48% less likely (95% confidence interval: 42%, 54%) to be prescribed varenicline than NRT, compared to smokers without neurodevelopmental disorders. At 2-year follow-up, smokers with neurodevelopmental disorders prescribed varenicline were 38% more likely to quit smoking (95% confidence interval: 6%, 78%). Similar results were obtained using PSM and instrumental variable analyses. There was little evidence showing that varenicline increased the likelihood of mental health related adverse events in people with neurodevelopmental disorders. Varenicline is less likely to be prescribed to people with neurodevelopmental disorders despite results suggesting it is more effective than NRT and little evidence of increased likelihood of mental health related adverse events.

ObjectivesOur primary objective was to estimate smoking prevalence and prescribing rates of varenicline and nicotine replacement therapy (NRT) in people with and without general practitioner (GP)-recorded dementia. Our secondary objective was to assess and compare quit rates of smokers with versus without GP-recorded dementia who were prescribed varenicline or NRT for smoking cessation.DesignA retrospective cohort study based on the analysis of electronic medical records within the Clinical Practice Research Datalink (2007–2015).Setting683 general practices in England.ParticipantsPeople with and without GP-recorded dementia, aged 18 years and have a code indicating that they are a current smoker.InterventionIndex prescription of varenicline or NRT (from 1 September 2006).Outcome measuresThe primary outcomes were smoking prevalence and prescribing rates of varenicline and NRT (2007–2015). The secondary outcome was smoking cessation at 2 years.ResultsAge and sex-standardised prevalence of smoking was slightly higher in people with GP-recorded dementia than in those without. There were 235 314 people aged 18 years and above prescribed NRT or varenicline. Among smokers with GP-recorded dementia (N=447), 409 were prescribed NRT and 38 varenicline. Smokers with GP-recorded dementia were 74% less likely (95% CI 64% to 82%) to be prescribed varenicline than NRT, compared with smokers without GP-recorded dementia. Compared with people without GP-recorded dementia, people with GP-recorded dementia had consistently lower prescribing rates of varenicline from 2007 to 2015. Two years after prescription, there was no clear evidence for a difference in the likelihood of smoking cessation after prescription of these medications between individuals with and without dementia (OR 1.0, 95% CI 0.8 to 1.2).ConclusionsBetween 2007 and 2015, people with GP-recorded dementia were less likely to be prescribed varenicline than those without dementia. Quit rates following prescription of either NRT or varenicline were similar in those with and without dementia.

Objective We conducted a prospective cohort study of the Clinical Practice Research Database to estimate rates of varenicline and nicotine replacement therapy (NRT) prescribing and the relative effects on smoking cessation, and mental health. Methods We used multivariable logistic regression, propensity score matched regression, and instrumental variable analysis. Exposure was varenicline or NRT prescription. Mental disorders were bipolar, depression, neurotic disorder, schizophrenia, or prescriptions of antidepressants, antipsychotics, hypnotics/anxiolytics, mood stabilizers. Outcomes were smoking cessation, and incidence of neurotic disorder, depression, prescription of antidepressants, or hypnotics/anxiolytics. Follow-ups were 3, 6, and 9 months, and at 1, 2, and 4 years. Results In all patients, NRT and varenicline prescribing declined during the study period. Seventy-eight thousand four hundred fifty-seven smokers with mental disorders aged ≥18 years were prescribed NRT (N = 59 340) or varenicline (N = 19 117) from September 1, 2006 to December 31, 2015. Compared with smokers without mental disorders, smokers with mental disorders had 31% (95% CI: 29% to 33%) lower odds of being prescribed varenicline relative to NRT, but had 19% (95% CI: 15% to 24%) greater odds of quitting at 2 years when prescribed varenicline relative to NRT. Overall, varenicline was associated with decreased or similar odds of worse mental health outcomes than NRT in patients both with and without mental disorders, although there was some variation when analyses were stratified by mental disorder subgroup. Conclusions Smoking cessation medication prescribing may be declining in primary care. Varenicline was more effective than NRT for smoking cessation in patients with mental disorders and there is not clear consistent evidence that varenicline is adversely associated with poorer mental health outcomes. Implications Patients with mental disorders were less likely to be prescribed varenicline than NRT. We triangulated results from three analytical techniques. We found that varenicline was more effective than NRT for smoking cessation in patients with mental disorders. Varenicline was generally associated with similar or decreased odds of poorer mental health outcomes (ie, improvements in mental health) when compared with NRT. We report these findings cautiously as our data are observational and are at risk of confounding.

BackgroundIn 2010, the “Tackling Suicide on the Railways” programme was launched as a joint initiative among Network Rail, the Samaritans and other key organisations such as the British Transport Police and train operators to achieve a 20 % reduction in railway suicides from 2010 to 2015 in Great Britain. We report the most recent age and sex specific trends in railway suicide in England and Wales from 2000 to 2013 and examine whether the initiative’s target reduction in railway suicides is likely to be achieved.MethodsPopulation data and suicide mortality data (all methods combined and railway) for England and Wales were obtained from the Office for National Statistics (ONS) and used to calculate age and gender specific rates for deaths registered from 2000 to 2013. Data on railway suicides were also obtained from the Rail Safety and Standards Board (RSSB) and compared with ONS data. We used joinpoint regression to identify changes in suicide trends across the study period.ResultsThe railway was used in 4.1 % of all suicides in England and Wales (RSSB data were similar to ONS data for most years). Suicides in all persons from all causes decreased from 2000 to 2007, with small increases from 2008 until 2013; this rise was entirely due to an increase in male suicides. Railway suicide rates increased over the entire study period; the proportion of railway suicides in all persons increased from 3.5 to 4.9 % during the study period. This trend was also mainly driven by increases in male suicides as female railway suicide rates remained steady over time. The highest age specific railway suicide rates were observed in middle aged men and women. Although there was no conclusive evidence of an increase in ONS railway suicides, RSSB data showed a statistically significant increase in railway suicides in males from 2009 onwards.ConclusionThe continued rise in male railway suicide in England and Wales is concerning, particularly due to the high economic costs and psychological trauma associated with these deaths. The initiative’s target of a 20 % reduction in railway suicide is unlikely to be achieved.

Background Primary care can be an appropriate setting to address opioid analgesic dependence among patients with chronic non-cancer pain. This study evaluated the South Gloucestershire Opioid Pain Review Pilot which aims to help patients understand their relationship with opioids and to develop alternative, non-drug-based, pain management strategies. Methods Patients from two general practices in South Gloucestershire, UK, were invited to take part in the pilot (September 2016-October 2018). They were given an individually tailored intervention, based on the shared care model, and social prescribing including pain management, and referred to external services. Experiences of the pilot were explored with semi-structured interviews. Routine quantitative data were collected on demographics; opioid use and dose; wellbeing and quality of life; and pain intensity, pain relief, and interference with life. A mixed-methods approach supported a comprehensive evaluation of the pilot. Interviews were analysed thematically. Quantitative and qualitative data were integrated using “following a thread” and triangulation. The study was given ethics approval by West Midlands – Coventry and Warwickshire Research Ethics Committee, and participants gave written or verbal informed consent. Findings Of 59 invited patients, 34 (58%) enrolled into the service and contributed quantitative data. 18 of the 34 service-users and seven service providers were interviewed. On average, service-users showed improvement in all outcomes except pain relief from medication. Baseline opioid dose (median 90, IQR 60-240)]reduced at follow-up (median 90 mg, IQR 60–240 vs 72 mg, 30–160, Wilcoxon signed-rank test p=0·00013). Service-users received the pilot positively, valuing their relationship with the project worker, time to discuss pain management, and individually tailored support. Individual needs and readiness to change shaped responses to the intervention. Perceived benefits related to understanding of pain, wellbeing, and quality of life; pain management strategies; and medication changes. Interpretation This novel pilot has shown promise. We recommend that future initiatives within primary care are individually tailored. Project worker and service-user relationships are important. A randomised controlled trial is needed to test the impact of this care-pathway. Funding This research was funded by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) West. The pain review pilot was funded by the Public Health and Wellbeing Division at South Gloucestershire Council.

Background: There is limited evidence about the effectiveness of varenicline and nicotine replacement therapy (NRT) for long-term smoking cessation in primary care, or whether the treatment effectiveness differs by socioeconomic position (SEP). Therefore, we estimated the long-term effectiveness of varenicline versus NRT ( > 2 years) on smoking cessation, and investigated whether effectiveness differs by SEP. Methods: This is a prospective cohort study of electronic medical records from 654 general practices in England, within the Clinical Practice Research Datalink, using three different analytical methods: multivariable logistic regression, propensity score matching and instrumental variable analyses. Exposure was prescription of varenicline versus NRT, and the primary outcome was smoking cessation at 2 years' follow-up; outcome was also assessed at 3, 6, and 9 months, and at 1 and 4 years after exposure. SEP was defined using the Index of Multiple Deprivation. Results: At 2 years, 28.8% (N=20 362/70 610) of participants prescribed varenicline and 24.3% (N=36 268/149 526) of those prescribed NRT quit; adjusted odds ratio was 1.26 [95% confidence interval (CI): 1.23 to 1.29], P < 0.0001. The association persisted for up to 4 years and was consistent across all analyses. We found little evidence that the effectiveness of varenicline differed greatly by SEP. However, patients from areas of higher deprivation were less likely to be prescribed varenicline; adjusted odds ratio was 0.91 (95% CI: 0.90 to 0.92), P < 0.0001. Conclusions: Patients prescribed varenicline were more likely to be abstinent up to 4 years after first prescription than those prescribed NRT. In combination with other evidence, the results from this study may be used to update clinical guidelines on the use of varenicline for smoking cessation.

Aims To investigate whether smokers prescribed varenicline had lower risks of serious ill‐health during the 4 years following treatment compared with those prescribed nicotine replacement therapy (NRT). Design Observational cohort study of electronic medical records. Setting A total of 370 UK general practices sampled from the Clinical Practice Research Datalink. Participants A total of 126 718 patients aged 18 and over who were issued smoking cessation prescriptions between 1 September 2006 and 31 March 2014. Measurements Our primary outcome was all‐cause mortality within 2 years of first prescription as indicated by linked Office of National Statistics data. Our secondary outcomes were cause‐specific mortality, all‐cause, cause‐specific hospitalization, primary care diagnosis of myocardial infarction or chronic obstructive pulmonary disease (COPD), body mass index and attendance rate to primary care within 2 years of first prescription. Risk differences and 95% confidence intervals were estimated by multivariable adjusted regression and propensity score matched regression. We used instrumental variable analysis to overcome residual confounding. Findings People prescribed varenicline were healthier at baseline than those prescribed NRT in almost all characteristics, highlighting the potential for residual confounding. Our instrumental variable analysis results found that people prescribed varenicline had a similar risk of mortality at 2 years [risk difference per 100 patients treated = 0.67, 95% confidence interval (CI) = ‐0.11 to 1.46)] to those prescribed NRT, and there were similar rates of all‐cause hospitalization, incident primary‐care diagnoses of myocardial infarction and COPD. People prescribed varenicline subsequently attended primary care less frequently. Conclusions Smokers prescribed varenicline in primary care in the United Kingdom do not appear to be less likely to die, be hospitalized or experience a myocardial infarction or chronic obstructive pulmonary disease during the following 2 years compared with smokers prescribed nicotine replacement therapy, but they gain more weight and attend primary care less frequently.

INTRODUCTION: Cigarette smoking is one of the leading causes of early death in the UK and worldwide. Public health guidance recommends the use of varenicline, bupropion and nicotine replacement therapy (NRT) as smoking cessation aids in the UK. Additionally, the first electronic cigarette has been licensed for use as a smoking cessation medicine. However, there are ongoing concerns about the safety of these medicines. We present a protocol for a systematic review and network meta-analysis (NMA) to determine how these smoking cessation medicines compare to each other with respect to their neuropsychiatric safety in adult smokers. Secondary aims include updating the evidence regarding the effectiveness and cardiovascular safety of these medicines for use in a cost-effectiveness analysis.METHODS AND ANALYSIS: We will include randomised controlled trials and observational studies with control groups comparing monotherapy with varenicline, bupropion, NRT or electronic cigarette and combination therapies to each other, placebo or usual care. The primary composite safety outcome will be serious adverse events, defined as events that resulted in death, were life threatening, required hospitalisation or resulted in significant disability or congenital/birth defect. The preferred effectiveness outcome will be sustained smoking cessation defined as abstinence for a minimum of 6 months as determined by biochemical validation. We will include trials identified by previous reviews and search relevant databases for newly published trials as well as contacting study authors to identify unpublished information. We will conduct fixed-effect and random-effect meta-analyses for each pairwise comparison of treatments and outcome; where these estimates differ, we will consider reasons for heterogeneity, quantified using the between-study variance (τ(2)). For each outcome, we will construct a NMA in a Bayesian framework which will be compared with the pair-wise results, allowing us to rank treatments. The effectiveness estimates from the NMA will be entered into a probabilistic economic model.ETHICS AND DISSEMINATION: Ethics approval is not required for this evidence synthesis study as it involves analysis of secondary data from randomised controlled trials and observational studies. The review will make an important contribution to the knowledge base around the effectiveness, safety and cost-effectiveness of smoking cessation medicines. Results will be disseminated to the general public, healthcare practitioners and clinicians, academics, industry and policy makers.PROSPERO REGISTRATION NUMBER: CRD42016041302.

Objective: Non-response to antidepressant treatment is a substantial problem in primary care, and many patients with depression require additional second-line treatments. This study aimed to examine the prevalence and patterns of antidepressant switching in the UK, and identify associated demographic and clinical factors. Method: Cohort analysis of antidepressant prescribing data from the Clinical Practice Research Datalink, a large, anonymised UK primary care database. The sample included 262,844 patients who initiated antidepressant therapy between 1 January 2005 and 31 June 2011. Results: 9.3% of patients switched to a different antidepressant product, with most switches (60%) occurring within 8 weeks of the index date. The proportion switching was similar for selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants and other antidepressants (9.3%, 9.8% and 9.2%, respectively). Most switches were to an SSRI (64.5%), and this was the preferred option regardless of initial antidepressant class. Factors predictive of switching included male gender, age, and history of self-harm and psychiatric illness. Conclusion: Over one in every 11 patients who initiates antidepressant therapy will switch medication, suggesting that initial antidepressant treatment has been unsatisfactory. Evidence to guide choice of second-line treatment for individual patients is currently limited. Additional research comparing different pharmacological and psychological second-line treatment strategies is required in order to inform guidelines and improve patient outcomes.

BackgroundThe South Gloucestershire Pain Review pilot is an individually-tailored service to help primary care patients on long-term (>3 months) treatment with opioid painkillers for chronic non-cancer pain understand their relationship with opioids and support alternative non-drug-based pain management strategies. The pilot was based in two GP practices in South Gloucestershire.AimTo evaluate the health and well-being outcomes and perceived impact of the pilot service to inform future service development.MethodQuantitative data were collected for all enrolled patients on demographics; opioid use, misuse and dose; and pre-post intervention changes in health, well-being, quality of life (QoL), pain intensity/relief, and interference with life measures. Twenty-five semi-structured interviews (18 service users, seven service providers) explored experiences of the pilot including perceived impacts.ResultsFifty-nine patients were invited to use the service and 34 (58%) enrolled. The median prescribed opioid dose reduced from 90 mg (interquartile range [IQR] 60–240) at baseline to 72 mg (IQR 30–160) at follow-up (PConclusionThe pilot has shown promising results. The service was viewed as acceptable and health and well-being outcomes suggest a benefit. Following further development of the service, a randomised controlled trial is needed to formally test the effects of this type of care pathway on pain management and reducing long-term opioid use.

ObjectivesTo investigate whether physicians' prescribing preferences were valid instrumental variables for the antidepressant prescriptions they issued to their patients.Study Design and SettingWe investigated whether physicians' previous prescriptions of (1) tricyclic antidepressants (TCAs) vs. selective serotonin reuptake inhibitors (SSRIs) and (2) paroxetine vs. other SSRIs were valid instruments. We investigated whether the instrumental variable assumptions are likely to hold and whether TCAs (vs. SSRIs) were associated with hospital admission for self-harm or death by suicide using both conventional and instrumental variable regressions. The setting for the study was general practices in the United Kingdom.ResultsPrior prescriptions were strongly associated with actual prescriptions: physicians who previously prescribed TCAs were 14.9 percentage points (95% confidence interval [CI], 14.4, 15.4) more likely to prescribe TCAs, and those who previously prescribed paroxetine were 27.7 percentage points (95% CI, 26.7, 28.8) more likely to prescribe paroxetine, to their next patient. Physicians' previous prescriptions were less strongly associated with patients' baseline characteristics than actual prescriptions. We found no evidence that the estimated association of TCAs with self-harm/suicide using instrumental variable regression differed from conventional regression estimates (P-value = 0.45).ConclusionThe main instrumental variable assumptions held, suggesting that physicians' prescribing preferences are valid instruments for evaluating the short-term effects of antidepressants.

Aims The UK Clinical Practice Research Datalink (CPRD) is increasingly being used to investigate suicide-related adverse drug reactions. No studies have comprehensively validated the recording of suicide and nonfatal self-harm in the CPRD. We validated general practitioners' recording of these outcomes using linked Office for National Statistics (ONS) mortality and Hospital Episode Statistics (HES) admission data. Methods We identified cases of suicide and self-harm recorded using appropriate Read codes in the CPRD between 1998 and 2010 in patients aged ≥15 years. Suicides were defined as patients with Read codes for suicide recorded within 95 days of their death. International Classification of Diseases codes were used to identify suicides/hospital admissions for self-harm in the linked ONS and HES data sets. We compared CPRD-derived cases/incidence of suicide and self-harm with those identified from linked ONS mortality and HES data, national suicide incidence rates and published self-harm incidence data. Results Only 26.1% (n = 590) of the ‘true’ (ONS-confirmed) suicides were identified using Read codes. Furthermore, only 55.5% of Read code-identified suicides were confirmed as suicide by the ONS data. Of the HES-identified cases of self-harm, 68.4% were identified in the CPRD using Read codes. The CPRD self-harm rates based on Read codes had similar age and sex distributions to rates observed in self-harm hospital registers, although rates were underestimated in all age groups. Conclusions The CPRD recording of suicide using Read codes is unreliable, with significant inaccuracy (over- and under-reporting). Future CPRD suicide studies should use linked ONS mortality data. The under-reporting of self-harm appears to be less marked.

There is increasing interest in the use of instrumental variable analysis to overcome unmeasured confounding in observational pharmacoepidemiological studies. This is partly because instrumental variable analyses are potentially less biased than conventional regression analyses. However, instrumental variable analyses are less precise, and regulators and clinicians find it difficult to interpret conflicting evidence from instrumental variable compared with conventional regression analyses. In this paper, we describe three techniques to assess which approach (instrumental variable versus conventional regression analyses) is least biased. These techniques are negative control outcomes, negative control populations and tests of covariate balance. We illustrate these methods using an analysis of the effects of smoking cessation therapies (varenicline) prescribed in primary care.

BACKGROUND: This is the first update of the original Cochrane Review published in 2013. The conclusions of this review have not changed from the 2013 publication. People with chronic non-cancer pain who are prescribed and are taking opioids can have a history of long-term, high-dose opioid use without effective pain relief. In those without good pain relief, reduction of prescribed opioid dose may be the desired and shared goal of both patient and clinician. Simple, unsupervised reduction of opioid use is clinically challenging, and very difficult to achieve and maintain.OBJECTIVES: To investigate the effectiveness of different methods designed to achieve reduction or cessation of prescribed opioid use for the management of chronic non-cancer pain in adults compared to controls.SEARCH METHODS: For this update we searched CENTRAL, MEDLINE, and Embase in January 2017, as well as bibliographies and citation searches of included studies. We also searched one trial registry for ongoing trials.SELECTION CRITERIA: Included studies had to be randomised controlled trials comparing opioid users receiving an intervention with a control group receiving treatment as usual, active control, or placebo. The aim of the study had to include a treatment goal of dose reduction or cessation of opioid medication.DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias. We sought data relating to prescribed opioid use, adverse events of opioid reduction, pain, and psychological and physical function. We planned to assess the certainty of the evidence using the GRADE approach, however, due to the heterogeneity of studies, we were unable to combine outcomes in a meta-analysis and therefore we did not assess the evidence with GRADE.MAIN RESULTS: Three studies are new to this update, resulting in five included studies in total (278 participants). Participants were primarily women (mean age 49.63 years, SD = 11.74) with different chronic pain conditions. We judged the studies too heterogeneous to pool data in a meta-analysis, so we have summarised the results from each study qualitatively. The studies included acupuncture, mindfulness, and cognitive behavioral therapy interventions aimed at reducing opioid consumption, misuse of opioids, or maintenance of chronic pain management treatments. We found mixed results from the studies. Three of the five studies reported opioid consumption at post-treatment and follow-up. Two studies that delivered 'Mindfulness-Oriented Recovery Enhancement' or 'Therapeutic Interactive Voice Response' found a significant difference between groups at post-treatment and follow-up in opioid consumption. The remaining study found reduction in opioid consumption in both treatment and control groups, and between-group differences were not significant. Three studies reported adverse events related to the study and two studies did not have study-related adverse events. We also found mixed findings for pain intensity and physical functioning. The interventions did not show between-group differences for psychological functioning across all studies. Overall, the risk of bias was mixed across studies. All studies included sample sizes of fewer than 100 and so we judged all studies as high risk of bias for that category.AUTHORS' CONCLUSIONS: There is no evidence for the efficacy or safety of methods for reducing prescribed opioid use in chronic pain. There is a small number of randomised controlled trials investigating opioid reduction, which means our conclusions are limited regarding the benefit of psychological, pharmacological, or other types of interventions for people with chronic pain trying to reduce their opioid consumption. The findings to date are mixed: there were reductions in opioid consumption after intervention, and often in control groups too.

BACKGROUND: Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist).OBJECTIVES: To review the efficacy of nicotine receptor partial agonists, including varenicline and cytisine, for smoking cessation.SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('cytisine' or 'Tabex' or 'dianicline' or 'varenicline' or 'nicotine receptor partial agonist') in the title or abstract, or as keywords. The register is compiled from searches of MEDLINE, EMBASE, and PsycINFO using MeSH terms and free text to identify controlled trials of interventions for smoking cessation and prevention. We contacted authors of trial reports for additional information where necessary. The latest update of the specialised register was in May 2015, although we have included a few key trials published after this date. We also searched online clinical trials registers.SELECTION CRITERIA: We included randomised controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion and nicotine patches where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment.DATA COLLECTION AND ANALYSIS: We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomisation procedure, concealment of allocation, and completeness of follow-up.The main outcome measured was abstinence from smoking at longest follow-up. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we pooled risk ratios (RRs), using the Mantel-Haenszel fixed-effect model.MAIN RESULTS: Two trials of cytisine (937 people) found that more participants taking cytisine stopped smoking compared with placebo at longest follow-up, with a pooled risk ratio (RR) of 3.98 (95% confidence interval (CI) 2.01 to 7.87; low-quality evidence). One recent trial comparing cytisine with NRT in 1310 people found a benefit for cytisine at six months (RR 1.43, 95% CI 1.13 to 1.80).One trial of dianicline (602 people) failed to find evidence that it was effective (RR 1.20, 95% CI 0.82 to 1.75). This drug is no longer in development.We identified 39 trials that tested varenicline, 27 of which contributed to the primary analysis (varenicline versus placebo). Five of these trials also included a bupropion treatment arm. Eight trials compared varenicline with nicotine replacement therapy (NRT). Nine studies tested variations in varenicline dosage, and 13 tested usage in disease-specific subgroups of patients. The included studies covered 25,290 participants, 11,801 of whom used varenicline.The pooled RR for continuous or sustained abstinence at six months or longer for varenicline at standard dosage versus placebo was 2.24 (95% CI 2.06 to 2.43; 27 trials, 12,625 people; high-quality evidence). Varenicline at lower or variable doses was also shown to be effective, with an RR of 2.08 (95% CI 1.56 to 2.78; 4 trials, 1266 people). The pooled RR for varenicline versus bupropion at six months was 1.39 (95% CI 1.25 to 1.54; 5 trials, 5877 people; high-quality evidence). The RR for varenicline versus NRT for abstinence at 24 weeks was 1.25 (95% CI 1.14 to 1.37; 8 trials, 6264 people; moderate-quality evidence). Four trials which tested the use of varenicline beyond the 12-week standard regimen found the drug to be well-tolerated during long-term use. The number needed to treat with varenicline for an additional beneficial outcome, based on the weighted mean control rate, is 11 (95% CI 9 to 13). The most commonly reported adverse effect of varenicline was nausea, which was mostly at mild to moderate levels and usually subsided over time. Our analysis of reported serious adverse events occurring during or after active treatment suggests there may be a 25% increase in the chance of SAEs among people using varenicline (RR 1.25; 95% CI 1.04 to 1.49; 29 trials, 15,370 people; high-quality evidence). These events include comorbidities such as infections, cancers and injuries, and most were considered by the trialists to be unrelated to the treatments. There is also evidence of higher losses to follow-up in the control groups compared with the intervention groups, leading to a likely underascertainment of the true rate of SAEs among the controls. Early concerns about a possible association between varenicline and depressed mood, agitation, and suicidal behaviour or ideation led to the addition of a boxed warning to the labelling in 2008. However, subsequent observational cohort studies and meta-analyses have not confirmed these fears, and the findings of the EAGLES trial do not support a causal link between varenicline and neuropsychiatric disorders, including suicidal ideation and suicidal behaviour. The evidence is not conclusive, however, in people with past or current psychiatric disorders. Concerns have also been raised that varenicline may slightly increase cardiovascular events in people already at increased risk of those illnesses. Current evidence neither supports nor refutes such an association, but we await the findings of the CATS trial, which should establish whether or not this is a valid concern.AUTHORS' CONCLUSIONS: Cytisine increases the chances of quitting, although absolute quit rates were modest in two recent trials. Varenicline at standard dose increased the chances of successful long-term smoking cessation between two- and three-fold compared with pharmacologically unassisted quit attempts. Lower dose regimens also conferred benefits for cessation, while reducing the incidence of adverse events. More participants quit successfully with varenicline than with bupropion or with NRT. Limited evidence suggests that varenicline may have a role to play in relapse prevention. The most frequently recorded adverse effect of varenicline is nausea, but mostly at mild to moderate levels and tending to subside over time. Early reports of possible links to suicidal ideation and behaviour have not been confirmed by current research.Future trials of cytisine may test extended regimens and more intensive behavioural support.

Introduction Smoking is a major avoidable cause of ill-health and premature death. Treatments that help patients successfully quit smoking have an important effect on health and life expectancy. Varenicline is a medication that can help smokers successfully quit smoking. However, there are concerns that it may cause adverse effects, such as increase in the occurrence of depression, self-harm and suicide and cardiovascular disease. In this study we aim to examine the effects of varenicline versus other smoking cessation pharmacotherapies on smoking cessation, health service use, all-cause and cause-specific mortality and physical and mental health conditions. Methods In this project we will investigate the effects of varenicline compared to nicotine replacement therapies on: (1) long-term smoking cessation and whether these effects differ by area level deprivation; and (2) the following clinically-important outcomes: rate of general practice and hospital attendance; all-cause mortality and death due to diseases of the respiratory system and cardiovascular disease; and a primary care diagnosis of respiratory illness, myocardial infarction or depression and anxiety. The study is based on a cohort of patients prescribed these smoking cessation medications from the Clinical Practice Research Datalink (CPRD). We will use three methods to overcome confounding: multivariable adjusted Cox regression, propensity score matched Cox regression, and instrumental variable regression. The total expected sample size for analysis will be at least 180 000. Follow-up will end with the earliest of either an ‘event’ or censoring due to the end of registration or death. Ethics and dissemination Ethics approval was not required for this study. This project has been approved by the CPRD's Independent Scientific Advisory Committee (ISAC). We will disseminate our findings via publications in international peer-reviewed journals and presentations at international conferences.

Some studies suggest that people who self-cut have a higher risk of suicide than those who self-poison. Self-cutting ranges from superficial wrist cutting to severe self-injury involving areas such as the chest, abdomen and neck which can be life threatening. This study aimed to investigate whether the site of self-cutting was associated with risk of subsequent suicide.We followed-up 3928 people who presented to hospital following self-harm between September 2010 and December 2013 in a prospective cohort study based on the Bristol Self-harm Surveillance Register. Demographic information from these presentations was linked with coroner's data to identify subsequent suicides.People who presented with self-cutting to areas other than the arm/wrist were at increased risk of suicide compared to those who self-poisoned (HR 4.31, 95% CI 1.27-14.63, p=0.029) and this increased risk remained after controlling for age, sex, history of previous self-harm and psychiatric diagnosis (HR 4.46, 95% CI 1.50-13.25, p0.001). We observed no such increased risk in people presenting with cutting to the arm/wrist.These data represent the experience of one city in the UK and may not be generalisable outside of this context. Furthermore, as suicide is a rare outcome the precision of our estimates is limited.Site of self-injury may be an important indicator of subsequent suicide risk.

Estimating gestational age in resource-limited settings is prone to considerable inaccuracy because crown-rump length measured by ultrasound before 14 weeks gestation, the recommended method for estimating gestational age, is often unavailable. Judgements regarding provision of appropriate obstetric and neonatal care are dependent on accurate estimation of gestational age. We determined the accuracy of the Dubowitz Gestational Age Assessment, a population-specific symphysis-fundal height formula, and ultrasound biometry performed between 16 and 40 weeks gestation in estimating gestational age using pre-existing data from antenatal clinics of the Shoklo Malaria Research Unit on the Thai-Myanmar border, where malaria is endemic. Two cohorts of women who gave birth to live singletons were analysed: 1) 250 women who attended antenatal care between July 2001 and May 2006 and had both ultrasound crown-rump length (reference) and a Dubowitz Gestational Age Assessment; 2) 975 women attending antenatal care between April 2007 and October 2010 who had ultrasound crown-rump length, symphysis-fundal measurements, and an additional study ultrasound (biparietal diameter and head circumference) randomly scheduled between 16 and 40 weeks gestation. Mean difference in estimated newborn gestational age between methods and 95% limits of agreement (LOA) were determined from linear mixed-effects models. The Dubowitz method and the symphysis-fundal height formula performed well in term newborns, but overestimated gestational age of preterms by 2.57 weeks (95% LOA: 0.49, 4.65) and 3.94 weeks (95% LOA: 2.50, 5.38), respectively. Biparietal diameter overestimated gestational age by 0.83 weeks (95% LOA: -0.93, 2.58). Head circumference underestimated gestational age by 0.39 weeks (95% LOA: -2.60, 1.82), especially if measured after 24 weeks gestation. The results of this study can be used to quantify biases associated with alternative methods for estimating gestational age in the absence of ultrasound crown-rump length to inform critical clinical judgements in this population, and as a point of reference elsewhere.

OBJECTIVE: To determine the risk of neuropsychiatric adverse events associated with use of varenicline compared with placebo in randomised controlled trials.DESIGN: Systematic review and meta-analysis comparing study effects using two summary estimates in fixed effects models, risk differences, and Peto odds ratios.DATA SOURCES: Medline, Embase, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov.ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials with a placebo comparison group that reported on neuropsychiatric adverse events (depression, suicidal ideation, suicide attempt, suicide, insomnia, sleep disorders, abnormal dreams, somnolence, fatigue, anxiety) and death. Studies that did not involve human participants, did not use the maximum recommended dose of varenicline (1 mg twice daily), and were cross over trials were excluded.RESULTS: In the 39 randomised controlled trials (10 761 participants), there was no evidence of an increased risk of suicide or attempted suicide (odds ratio 1.67, 95% confidence interval 0.33 to 8.57), suicidal ideation (0.58, 0.28 to 1.20), depression (0.96, 0.75 to 1.22), irritability (0.98, 0.81 to 1.17), aggression (0.91, 0.52 to 1.59), or death (1.05, 0.47 to 2.38) in the varenicline users compared with placebo users. Varenicline was associated with an increased risk of sleep disorders (1.63, 1.29 to 2.07), insomnia (1.56, 1.36 to 1.78), abnormal dreams (2.38, 2.05 to 2.77), and fatigue (1.28, 1.06 to 1.55) but a reduced risk of anxiety (0.75, 0.61 to 0.93). Similar findings were observed when risk differences were reported. There was no evidence for a variation in depression and suicidal ideation by age group, sex, ethnicity, smoking status, presence or absence of psychiatric illness, and type of study sponsor (that is, pharmaceutical industry or other).CONCLUSIONS: This meta-analysis found no evidence of an increased risk of suicide or attempted suicide, suicidal ideation, depression, or death with varenicline. These findings provide some reassurance for users and prescribers regarding the neuropsychiatric safety of varenicline. There was evidence that varenicline was associated with a higher risk of sleep problems such as insomnia and abnormal dreams. These side effects, however, : are already well recognised.SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2014:CRD42014009224.

Background Psychiatric adverse drug reactions (ADRs) are distressing for patients and have important public health implications. We identified the drugs with the most frequent spontaneous reports of depression, and fatal and non-fatal suicidal behaviour to the UK’s Yellow Card Scheme from 1998 to 2011. Methods We obtained Yellow Card data from the Medicines and Healthcare products Regulatory Agency for the drugs with the most frequent spontaneous reports of depression and suicidal behaviour from 1964 onwards. Prescribing data were obtained from the NHS Information Centre and the Department of Health. We examined the frequency of reports for drugs and estimated rates of reporting of psychiatric ADRs using prescribing data as proxy denominators from 1998 to 2011, as prescribing data were not available prior to 1998. Results There were 110 different drugs with ≥ 20 reports of depression, 58 with ≥10 reports of non-fatal suicidal behaviour and 33 with ≥5 reports of fatal suicidal behaviour in the time period. The top five drugs with the most frequent reports of depression were the smoking cessation medicines varenicline and bupropion, followed by paroxetine (a selective serotonin reuptake inhibitor), isotretinoin (used in acne treatment) and rimonabant (a weight loss drug). Selective serotonin reuptake inhibitors, varenicline and the antipsychotic medicine clozapine were included in the top five medicines with the most frequent reports of fatal and non-fatal suicidal behaviour. Medicines with the highest reliably measured reporting rates of psychiatric ADRs per million prescriptions dispensed in the community included rimonabant, isotretinoin, mefloquine (an antimalarial), varenicline and bupropion. Robust denominators for community prescribing were not available for two drugs with five or more suicide reports, efavirenz (an antiretroviral medicine) and clozapine. Conclusions Depression and suicide-related ADRs are reported for many nervous system and non-nervous system drugs. As spontaneous reports cannot be used to determine causality between the drug and the ADR, psychiatric ADRs which can cause significant public alarm should be specifically assessed and reported in all randomised controlled trials.

Objective To compare the risk of suicide, self harm, and depression in patients prescribed varenicline or bupropion with those prescribed nicotine replacement therapy. Design Prospective cohort study within the Clinical Practice Research Datalink. Setting 349 general practices in England. Participants 119 546 men and women aged 18 years and over who used a smoking cessation product between 1 September 2006 and 31 October 2011. There were 81 545 users of nicotine replacement products (68.2% of all users of smoking cessation medicines), 6741 bupropion (5.6%), and 31 260 varenicline (26.2%) users. Main outcome measures Outcomes were treated depression and fatal and non-fatal self harm within three months of the first smoking cessation prescription, determined from linkage with mortality data from the Office for National Statistics (for suicide) and Hospital Episode Statistics data (for hospital admissions relating to non-fatal self harm). Hazard ratios or risk differences were estimated using Cox multivariable regression models, propensity score matching, and instrumental variable analysis using physicians’ prescribing preferences as an instrument. Sensitivity analyses were performed for outcomes at six and nine months. Results We detected 92 cases of fatal and non-fatal self harm (326.5 events per 100 000 person years) and 1094 primary care records of treated depression (6963.3 per 100 000 person years). Cox regression analyses showed no evidence that patients prescribed varenicline had higher risks of fatal or non-fatal self harm (hazard ratio 0.88, 95% confidence interval 0.52 to 1.49) or treated depression (0.75, 0.65 to 0.87) compared with those prescribed nicotine replacement therapy. There was no evidence that patients prescribed bupropion had a higher risk of fatal or non-fatal self harm (0.83, 0.30 to 2.31) or of treated depression (0.63, 0.46 to 0.87) compared with patients prescribed nicotine replacement therapy. Similar findings were obtained using propensity score methods and instrumental variable analyses. Conclusions There is no evidence of an increased risk of suicidal behaviour in patients prescribed varenicline or bupropion compared with those prescribed nicotine replacement therapy. These findings should be reassuring for users and prescribers of smoking cessation medicines.

Background Regulators have issued warnings about the potential adverse effects of the smoking cessation medication varenicline. However, there is little evidence of the long-term effects of varenicline when prescribed in everyday clinical practice. We aimed to investigate the association of varenicline and nicotine replacement therapy (NRT) with adverse outcomes when prescribed in primary care. Methods Using the Clinical Practice Research Datalink (CPRD), we conducted an observational cohort study of electronic medical records and linked mortality and hospital admission data of 126 718 primary care patients in the UK prescribed varenicline (41 742) and NRT (84 976). We used three approaches to overcome potential residual confounding: multivariable adjusted regression, propensity score matching, and instrumental variable regression. The exposure was first prescription of varenicline or nicotine replacement therapy. The primary outcome was all-cause mortality 2 years after first prescription. Secondary outcomes were mortality from cardiovascular and respiratory disease, all-cause hospital admission and for cardiovascular and respiratory disease, incident primary care diagnosis of myocardial infarction or chronic obstructive pulmonary disease, and frequency of primary care attendance. Findings In multivariable adjusted analysis, mortality was lower among patients prescribed varenicline than in those prescribed NRT (OR 0·78, 95% CI 0·69 to 0·87; p Interpretation There was little evidence of a substantial increase in risk of adverse outcomes in patients prescribed varenicline as part of their standard clinical care. The regulatory warnings associated with varenicline do not accurately reflect the scientific evidence and should be reconsidered by policy makers and regulators. Funding The research described in this paper was funded by the Medical Research Council (MR/N01006X/1), the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (project number 14/49/94). KHT is funded by a clinical lectureship award from the NIHR. RMM is supported by Cancer Research UK (programme grant C18281/A19169) (the Integrative Cancer Epidemiology Programme). TJ is supported by the NIHR Collaboration for Leadership in Applied Health Research and Care West, University Hospitals Bristol NHS Foundation Trust. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the abstract for submission.

Background Smoking is the leading preventable cause of death. A network meta-analysis of randomised trials has demonstrated that varenicline is the most efficacious treatment for short-term smoking cessation. However, there is no evidence of the relative effectiveness of varenicline versus nicotine replacement therapy (NRT) in general practice on long-term smoking cessation; or whether its effectiveness is modified by socioeconomic position (SEP). In this study we estimated the effectiveness of varenicline on smoking cessation using clinical data from primary care electronic medical records; and investigated if the effectiveness differed by SEP. Methods Data were obtained from the Clinical Practice Research Datalink of electronic medical records (Trial Registration: NCT02681848). We conducted a prospective cohort study using electronic medical records of patients aged 18 years and over who were prescribed NRT (N = 149,526) or varenicline (N = 70,610) after September 1st 2006. We compared the abstinence rates of patients prescribed varenicline to those prescribed NRT. We used three different analytic methods: Cox proportional hazards models, propensity score matched Cox models and instrumental variable analyses. Results The Cox proportional hazards model indicated that patients prescribed varenicline were less likely to relapse to smoking for up to four years compared to those prescribed NRT, the fully adjusted hazard ratio and 95% confidence interval were: 0.95 (0.94 to 0.96). Estimates from the propensity score matched and instrumental variable analyses supported estimates derived from the Cox hazards model. We found little evidence that the effectiveness of varenicline differed by SEP. However, people from areas of lower deprivation were less likely to be prescribed varenicline. Discussion Our results were consistent with the results from a network meta-analysis of RCTs. We add important evidence about the effectiveness of varenicline for long-term smoking cessation in primary care. Conclusion Our results suggest that varenicline is more effective than nicotine replacement therapy for smoking cessation in primary care, and that its effectiveness does not vary by socioeconomic position.

Background Varenicline is a medication which has been shown to be more efficacious for smoking cessation than nicotine replacement products in large randomised controlled trials. Concerns have been raised about possible adverse effects of varenicline which has led the FDA to issue a black box warning. However, there is limited real-world evidence about the effects of varenicline on clinical outcomes, such as mortality, incidence of cardiovascular and respiratory disease, and primary and secondary care attendance. Methods We investigated this hypothesis using a prospective cohort study of all patients issued a first smoking cessation prescription in the Clinical Practice Research Datalink (CPRD) between the 1st of September 2006 and the 31st of March 2014. We used linked Office of National Statistics mortality data and secondary care attendance through the Hospital Episodes Statistics dataset. Our primary outcome was all-cause mortality within two years of first prescription. We used multivariable adjusted and propensity score matched Cox regression, and included a range of baseline confounders. However, we were concerned that our results could suffer from residual confounding, as patients prescribed varenicline were substantially less likely to be older or have comorbidities. To overcome this we applied an instrumental variable analysis using physicians prescribing preferences. We tested for heterogeneity between our instrumental variable and conventional results using Hausman tests. Our study protocol is registered: NCT02681848. Results There were 126,718 patients who met our inclusion criteria. The multivariable adjusted results suggested that patients prescribed varenicline had lower mortality (adjusted hazard ratio (HR) = 0.72, 95% confidence interval (CI): 0.64, 0.80), lower hospital admission rates (HR = 0.84, 95% CI: 0.92, 0.86) and less frequent attendance to primary care (mean difference in attendance over two years per patient treated = 0.29 95% CI: 0.11, 0.47). The instrumental variable analysis found little evidence that varenicline affected mortality (risk difference per 100 patients treated = 0.13, 95% CI: −0.65, 0.90). This suggests that the reduction in mortality found in the conventional multivariable adjusted and propensity score matched regressions may be due to residual confounding (pHausman = 0.002). Conclusion We found little evidence that patients prescribed varenicline were at increased the risk of adverse outcomes. We found some evidence that they were less likely to attend primary care in the two years following their first prescription. However, apparent protective effects on mortality found in conventional analysis are likely to be due to residual confounding. These results provide reassurance to patients and clinicians about the safety of varenicline.

Background This study explains how to compare the relative bias of instrumental variable and conventional regression using negative controls and bias plots. Conventional observational analyses such as multivariable adjusted regression depend on the assumption of no unmeasured confounding. This assumption is rarely plausible, and results from observational studies have frequently been inconsistent with results from randomised controlled trials. Instrumental variable analyses can provide consistent estimates of causal effects in the presence of unmeasured confounding. Instrumental variables are defined by three assumptions, they must: 1) be associated with the exposure of interest, 2) share no common cause with the outcome, and 3) have no direct effects on the outcome except through the exposure of interest. However, regulators and clinicians find it difficult to interpret conflicting evidence from instrumental variable compared with conventional regression analyses and need to assess which approach is likely to be less biassed. Methods In this paper we describe three techniques that can help answer this question: negative control outcomes, negative control populations and covariate balance tests. We illustrate these methods using an analysis of the effects of varenicline versus nicotine replacement products in primary care using data from 175,140 patients in the Clinical Practice Research Datalink. These patients were prescribed between 1 September 2006 and 31 October 2011. Results Patients prescribed varenicline were more healthy in terms of almost all baseline characteristics. For example, they were younger (mean age differences in years = 1.66: 95% confidence interval (95% CI): 1.49, 1.84), visited the GP less often (mean difference in attendance per year = 5.82: 95% CI: 5.65, 5.99) and were less likely to have neuropsychiatric co-morbidities such as depression (risk difference per 100 patients treated = 2.57: 95% CI: 2.31, 2.83). The proposed instrumental variable, physicians’ previous prescription, was less associated with each of these baseline covariates (p heterogeneity = 0.004, 5.84E-04, and 0.07 respectively). This suggests instrumental variable estimates of the effects of varenicline are likely to be less biassed than conventional methods. Discussion Clinicians and regulators struggle to interpret conflicting evidence from instrumental variable compared with conventional regression analysis. The relative bias of these methods can and should be assessed using negative control populations and outcomes. The relative bias of instrumental variable and conventional analysis should be assessed using observed covariates. Researchers should report covariate balance plots with confidence intervals to robustly assess the relative bias for each covariate.

Objective To investigate changes in the range of suicide methods used in two time periods a century apart (1901–1907 and 2001–2007) in England and Wales. Method Suicide mortality and population data were obtained for England and Wales from the ONS and used to calculate gender and method-specific mortality rates. Results There have been striking changes in the methods of suicide used since the 1900s. Hanging was the most commonly used method during both time periods. However suicides involving drowning (22.5% of suicides in 1901–1907) and weapons (e.g. firearms and razors, 24.2% of suicides in 1901–1907) were rarely used in 2001–2007 (2.6% and 5.8% respectively). Although the use of poisons was popular in both time periods, the types of poisons used differed substantially over time. Household cleaning products and disinfectants accounted for almost half of poisoning suicides in the early 1900s whereas self-poisoning with medicines accounted for most poisoning suicides in 2001–2007. Limitations There were changes in the coding of suicides over time. Additionally, deaths by drowning and poisoning are more difficult to confirm as suicides than those that occur due to hanging or the use of weapons. Conclusions The changes in popularity of some suicide methods can be mainly attributed to changes in the physical availability (access) of these methods over time. Other methods which remain readily available have fallen out of fashion in recent times, suggesting a contributory role of other factors such as cognitive availability and personal preference/acceptability in influencing the choice of suicide method.

BACKGROUND: Suicide is one of the leading causes of premature mortality worldwide. Few studies have assessed long-term trends or sex differences in its incidence over time. We have investigated the age-, sex- and method-specific trends in suicide in England and Wales from 1861 to 2007. METHODS: Overall age-standardized suicide rates using the European Standard Population and age-, sex- and method-specific rates were calculated for ages >/=15 years from 1861 to 2007. RESULTS: Rates in males were consistently higher than females throughout the 19th and 20th centuries, although the male-to-female sex ratio fluctuated from 4 : 1 in the 1880s to 1.5 : 1 in the 1960s. Suicide rates increased in all age groups in the 1930s, coinciding with the Great Depression. The highest male rates (30.3 per 100 000) were recorded in 1905 and 1934 and have since been declining. Female rates peaked in the 1960s (11.8 per 100 000), declining afterwards. In both sexes the lowest recorded rates were in the 21st century. There was a rapid rise in the use of domestic gas as a method of suicide in both sexes following its introduction at the end of the 19th century. There was no evidence that this rise was accompanied by a decline in the use of other methods. Self-poisoning also increased in popularity from the 1860s (5% of suicides) to the 1990s (22% of suicides). CONCLUSIONS: The epidemiology of suicide in England and Wales has changed markedly over the past 146 years. The rapid rise in gas suicide deaths in the 1920s highlights how quickly a new method of suicide can be established in a population when it is easily available. The increase in suicides during the Great Depression has implications in relation to the current economic crisis. Changes in the acceptability and lethality of various suicide methods may account for the large variations in sex ratios over time. Language: en

A cross-sectional study was conducted to determine the microbial quality of domestic and imported brands of bottled water available in Trinidad, purchased from six geographical regions in Trinidad, and representing the whole island. A sample size of 344 bottles of water was determined by using a precision rate of 2% and a Type 1 error of 5%. The membrane filter technique was used with cultures grown on m-Endo agar and m-FC agar for total coliforms and thermotolerant coliforms, respectively. Aerobic plate count (APC) was determined on nutrient agar; Pseudomonas aeruginosa was detected on MacConkey agar, Escherichia coli was isolated on eosin methylene blue (EMB) and Salmonella spp. was assayed by using standard methods. Of the 344 water samples tested, 262 (76.2%) and 82 (23.8%) were domestic and imported brands, respectively. Eighteen (5.2%) of the 344 samples contained coliforms with a mean count of 0.88F6.38 coliforms per 100 ml, while 5 (1.5%) samples contained E. coli. The prevalence of total coliforms in domestic brands of bottled water was 6.9% (18 of 262) as compared with 0.0% (0 of 82) detected in imported brands. The difference was statistically significant (p=0.004). Similarly, the prevalence of aerobic bacteria in domestic brands of bottled water (33.6%) was significantly higher (p=0.001) than was found in imported brands (14.8%). Twenty-six (7.6%) of the total samples of water contained Pseudomonas species, but all were negative for thermotolerant coliforms and Salmonella spp. It was concluded that based on the recommended zero tolerance for coliforms in potable water, 5% of bottled water sold in Trinidad could be considered unfit for human consumption. D 2002 Elsevier Science B.V. All rights reserved.

Purpose The number of antidepressants prescribed in the UK has been increasing over the last 25 years; however, the reasons for this are not clear. This study examined trends in antidepressant prescribing in the UK between 1995 and 2011 according to age, sex, and drug class, and investigated reasons for the increase in prescribing over this period. Methods This is a retrospective analysis of antidepressant prescribing data from the Clinical Practice Research Datalink: a large, anonymised, primary care database in the UK. The dataset used in this study included 138 practices, at which a total of 1,524,201 eligible patients were registered across the 17-year period. The proportion of patients who received at least one antidepressant prescription and the number of patients who started a course of antidepressants were calculated for each year of the study. We used person years (PY) at risk as the denominator. The duration of treatment for those starting antidepressants was also examined. Results 23% of patients were prescribed an antidepressant on at least one occasion over the 17-year study period. Antidepressant prescriptions rose from 61.9 per 1000 PY in 1995 to 129.9 per 1000 PY in 2011. This was largely driven by an increase in prescribing of selective serotonin reuptake inhibitors and ‘other’ antidepressants. In contrast, incidence rates of those starting antidepressants remained relatively stable (1995: 21.3 per 1000 PY; 2011: 17.9 per 1000 PY). The duration of treatment increased with later starting years, with an increasing proportion of long-term use, and decrease in short-term use. Conclusion The increase in antidepressant prescribing over the study period appears to be driven by an increase in long-term use of these medications. Electronic supplementary material The online version of this article (doi:10.1007/s00127-016-1306-4) contains supplementary material, which is available to authorized users.

Background: The impact of newly emerging, popular suicide methods on overall rates of suicide has not previously been investigated systematically. Understanding these effects may have important implications for public health surveillance. We examine the emergence of three novel methods of suicide by gassing in the 20 th and 21 st centuries and determine the impact of emerging methods on overall suicide rates. Methods. We studied the epidemic rises in domestic coal gas (1919-1935, England and Wales), motor vehicle exhaust gas (1975-1992, England and Wales) and barbecue charcoal gas (1999-2006, Taiwan) suicide using Poisson and joinpoint regression models. Joinpoint regression uses contiguous linear segments and join points (points at which trends change) to describe trends in incidence. Results: Epidemic increases in the use of new methods of suicide were generally associated with rises in overall suicide rates of between 23% and 71%. The recent epidemic of barbecue charcoal suicides in Taiwan was associated with the largest rise in overall rates (40-50% annual rise), whereas the smallest rise was seen for car exhaust gassing in England and Wales (7% annual rise). Joinpoint analyses were only feasible for car exhaust and charcoal burning suicides; these suggested an impact of the emergence of car exhaust suicides on overall suicide rates in both sexes in England and Wales. However there was no statistical evidence of a change in the already increasing overall suicide trends when charcoal burning suicides emerged in Taiwan, possibly due to the concurrent economic recession. Conclusions: Rapid rises in the use of new sources of gas for suicide were generally associated with increases in overall suicide rates. Suicide prevention strategies should include strengthening local and national surveillance for early detection of novel suicide methods and implementation of effective media guidelines and other appropriate interventions to limit the spread of new methods. © 2011 Thomas et al; licensee BioMed Central Ltd., published_or_final_version