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Chronic pain is a common, complex, and challenging condition, where understanding the biological, social, physical and psychological contexts is vital to successful outcomes in primary care. In managing chronic pain the focus is often on promoting rehabilitation and maximizing quality of life rather than achieving cure. Recent screening tools and brief intervention techniques can be effective in helping clinicians identify, stratify and manage both patients already living with chronic pain and those who are at risk of developing chronic pain from acute pain. Frequent assessment and re-assessment are key to ensuring treatment is appropriate and safe, as well as minimizing and addressing side effects. Primary care management should be holistic and evidence-based (where possible) and incorporates both pharmacological and non-pharmacological approaches, including psychology, self-management, physiotherapy, peripheral nervous system stimulation, complementary therapies and comprehensive pain-management programmes. These may either be based wholly in primary care or supported by appropriate specialist referral.

There remains a substantial unmet need for effective and safe treatments for neuropathic pain. The Neuropathic Pain Special Interest Group aimed to update treatment recommendations, published in 2015, on the basis of new evidence from randomised controlled trials, emerging neuromodulation techniques, and advances in evidence synthesis. For this systematic review and meta-analysis, we searched Embase, PubMed, the International Clinical Trials Registry, and ClinicalTrials.gov from data inception for neuromodulation trials and from Jan 1, 2013, for pharmacological interventions until Feb 12, 2024. We included double-blind, randomised, placebo-controlled trials that evaluated pharmacological and neuromodulation treatments administered for at least 3 weeks, or if there was at least 3 weeks of follow-up, and which included at least ten participants per group. Trials included participants of any age with neuropathic pain, defined by the International Association for the Study of Pain. We excluded trials with enriched enrolment randomised withdrawal designs and those with participants with mixed aetiologies (ie, neuropathic and non-neuropathic pain) and conditions such as complex regional pain syndrome, low back pain without radicular pain, fibromyalgia, and idiopathic orofacial pain. We extracted summary data in duplicate from published reports, with discrepancies reconciled by a third independent reviewer on the platform Covidence. The primary efficacy outcome was the proportion of responders (50% or 30% reduction in baseline pain intensity or moderate pain relief). The primary safety outcome was the number of participants who withdrew from the treatment owing to adverse events. We calculated a risk difference for each comparison and did a random-effects meta-analysis. Risk differences were used to calculate the number needed to treat (NNT) and the number needed to harm (NNH) for each treatment. Risk of bias was assessed by use of the Cochrane risk of bias tool 2 and certainty of evidence assessed by use of GRADE. Recommendations were based on evidence of efficacy, adverse events, accessibility, and cost, and feedback from engaged lived experience partners. This study is registered on PROSPERO, CRD42023389375. We identified 313 trials (284 pharmacological and 29 neuromodulation studies) for inclusion in the meta-analysis. Across all studies, 48 789 adult participants were randomly assigned to trial groups (20 611 female and 25 078 male participants, where sex was reported). Estimates for the primary efficacy and safety outcomes were tricyclic antidepressants (TCAs) NNT=4·6 (95% CI 3·2–7·7), NNH=17·1 (11·4–33·6; moderate certainty of evidence), α2δ-ligands NNT=8·9 (7·4–11·10), NNH=26·2 (20·4–36·5; moderate certainty of evidence), serotonin and norepinephrine reuptake inhibitors (SNRIs) NNT=7·4 (5·6–10·9), NNH=13·9 (10·9–19·0; moderate certainty of evidence), botulinum toxin (BTX-A) NNT=2·7 (1·8–9·61), NNH=216·3 (23·5–∞; moderate certainty of evidence), capsaicin 8% patches NNT=13·2 (7·6–50·8), NNH=1129·3 (135·7–∞; moderate certainty of evidence), opioids NNT=5·9 (4·1–10·7), NNH=15·4 (10·8–24·0; low certainty of evidence), repetitive transcranial magnetic stimulation (rTMS) NNT=4·2 (2·3–28·3), NNH=651·6 (34·7–∞; low certainty of evidence), capsaicin cream NNT=6·1 (3·1–∞), NNH=18·6 (10·6–77·1; very low certainty of evidence), lidocaine 5% plasters NNT=14·5 (7·8–108·2), NNH=178·0 (23·9–∞; very low certainty of evidence). The findings provided the basis for a strong recommendation for use of TCAs, α2δ-ligands, and SNRIs as first-line treatments; a weak recommendation for capsaicin 8% patches, capsaicin cream, and lidocaine 5% plasters as second-line recommendation; and a weak recommendation for BTX-A, rTMS, and opioids as third-line treatments for neuropathic pain. Our results support a revision of the Neuropathic Pain Special Interest Group recommendations for the treatment of neuropathic pain. Treatment outcomes are modest and for some treatments uncertainty remains. Further large placebo-controlled or sham-controlled trials done over clinically relevant timeframes are needed. NeuPSIG and ERA-NET Neuron.

Chronic pain is highly prevalent worldwide and imparts a significant socioeconomic and public health burden. Factors influencing susceptibility to, and mechanisms of, chronic pain development, are not fully understood, but sex is thought to play a significant role, and chronic pain is more prevalent in women than in men. To investigate sex differences in chronic pain, we carried out a sex-stratified genome-wide association study of Multisite Chronic Pain (MCP), a derived chronic pain phenotype, in UK Biobank on 178,556 men and 209,093 women, as well as investigating sex-specific genetic correlations with a range of psychiatric, autoimmune and anthropometric phenotypes and the relationship between sex-specific polygenic risk scores for MCP and chronic widespread pain. We also assessed whether MCP-associated genes showed expression pattern enrichment across tissues. A total of 123 SNPs at five independent loci were significantly associated with MCP in men. In women, a total of 286 genome-wide significant SNPs at ten independent loci were discovered. Meta-analysis of sex-stratified GWAS outputs revealed a further 87 independent associated SNPs. Gene-level analyses revealed sex-specific MCP associations, with 31 genes significantly associated in females, 37 genes associated in males, and a single gene, DCC , associated in both sexes. We found evidence for sex-specific pleiotropy and risk for MCP was found to be associated with chronic widespread pain in a sex-differential manner. Male and female MCP were highly genetically correlated, but at an r g of significantly less than 1 (0.92). All 37 male MCP-associated genes and all but one of 31 female MCP-associated genes were found to be expressed in the dorsal root ganglion, and there was a degree of enrichment for expression in sex-specific tissues. Overall, the findings indicate that sex differences in chronic pain exist at the SNP, gene and transcript abundance level, and highlight possible sex-specific pleiotropy for MCP. Results support the proposition of a strong central nervous-system component to chronic pain in both sexes, additionally highlighting a potential role for the DRG and nociception.

Background Adverse childhood experiences (ACEs) have been implicated in the aetiology of a range of health outcomes, including multimorbidity. In this systematic review and meta-analysis, we aimed to identify, synthesise, and quantify the current evidence linking ACEs and multimorbidity. Methods We searched seven databases from inception to 20 July 2023: APA PsycNET, CINAHL Plus, Cochrane CENTRAL, Embase, MEDLINE, Scopus, and Web of Science. We selected studies investigating adverse events occurring during childhood (< 18 years) and an assessment of multimorbidity in adulthood (≥ 18 years). Studies that only assessed adverse events in adulthood or health outcomes in children were excluded. Risk of bias was assessed using the ROBINS-E tool. Meta-analysis of prevalence and dose–response meta-analysis methods were used for quantitative data synthesis. This review was pre-registered with PROSPERO (CRD42023389528). Results From 15,586 records, 25 studies were eligible for inclusion (total participants = 372,162). The prevalence of exposure to ≥ 1 ACEs was 48.1% (95% CI 33.4 to 63.1%). The prevalence of multimorbidity was 34.5% (95% CI 23.4 to 47.5%). Eight studies provided sufficient data for dose–response meta-analysis (total participants = 197,981). There was a significant dose-dependent relationship between ACE exposure and multimorbidity ( p  < 0.001), with every additional ACE exposure contributing to a 12.9% (95% CI 7.9 to 17.9%) increase in the odds for multimorbidity. However, there was heterogeneity among the included studies ( I 2  = 76.9%, Cochran Q  = 102, p  < 0.001). Conclusions This is the first systematic review and meta-analysis to synthesise the literature on ACEs and multimorbidity, showing a dose-dependent relationship across a large number of participants. It consolidates and enhances an extensive body of literature that shows an association between ACEs and individual long-term health conditions, risky health behaviours, and other poor health outcomes.

Epidemiology is an important clinical tool in designing and evaluating management and prevention strategies, and is particularly relevant to neuropathic pain. However, there is a relative lack of accurate information available. In one sense, neuropathic pain describes a symptom or a mechanism, rather than a specific disease; on the other hand, there are sufficient similarities in the effects and response to treatment between different causes to make it worthwhile to consider neuropathic pain as a distinct condition. However, there are important specific disease-based factors that need to be considered separately. Estimates of prevalence that are based on specific causes of neuropathic pain tend to be lower (1–2%) than those that are based on reports of the classic symptoms (6–8%), and further methodological research is needed. All neuropathic pain is associated with poor general health, comparable with other severe chronic diseases. The importance of newly proposed risk factors, including genetic factors, still needs to be assessed at a population level.

Depression and chronic pain are the two most important causes of disability (Global Burden of Disease Study 2013). They occur together more frequently than expected and both conditions have been shown to be co-morbid with cardiovascular disease. Although shared socio-demographic risk factors (e.g. gender, deprivation) might explain the co-morbidity of these three conditions, we hypothesised that these three long-term, highly prevalent conditions co-occur and may be due to shared familial risk, and/or genetic factors. We employed three different study designs in two independent cohorts, namely Generation Scotland and TwinsUK, having standardised, validated questionnaire data on the three traits of interest. First, we estimated the prevalence and co-occurrence of chronic pain, depression and angina among 24,024 participants of a population-based cohort of extended families (Generation Scotland: Scottish Family Health Study), adjusting for age, gender, education, smoking status, and deprivation. Secondly, we compared the odds of co-morbidity in sibling-pairs with the odds in unrelated individuals for the three conditions in the same cohort. Lastly, examination of similar traits in a sample of female twins (TwinsUK, n = 2,902), adjusting for age and BMI, allowed independent replication of the findings and exploration of the influence of additive genetic (A) factors and shared (C) and non-shared (E) environmental factors predisposing to co-occurring chronic widespread pain (CWP) and cardiovascular disease (hypertension, angina, stroke, heart attack, elevated cholesterol, angioplasty or bypass surgery). In the Generation Scotland cohort, individuals with depression were more than twice as likely to have chronic pain as those without depression (adjusted OR 2·64 [95% CI 2·34-2·97]); those with angina were four times more likely to have chronic pain (OR 4·19 [3·64-4·82]); those with depression were twice as likely to have angina (OR 2·20 [1·90-2·54]). Similar odds were obtained when the outcomes and predictors were reversed and similar effects seen among sibling pairs; depression in one sibling predicted chronic pain in the other (OR 1·34 [1·05-1·71]), angina predicted chronic pain in the other (OR 2·19 [1·63-2·95]), and depression, angina (OR 1·98 [1·49-2·65]). Individuals with chronic pain and angina showed almost four-fold greater odds of depression compared with those manifesting neither trait (OR 3·78 [2·99-4·78]); angina showed seven-fold increased odds in the presence of chronic pain and depression (OR 7·76 [6·05-9·95]) and chronic pain nine-fold in the presence of depression and angina (OR 9·43 [6·85-12·98]). In TwinsUK, the relationship between CWP and depression has been published (R = 0.34, p<0.01). Considering the CWP-cardiovascular relationship, the most suitable model to describe the observed data was a combination of A, C and E, with a small but significant genetic predisposition, shared between the two traits (2·2% [95% CI 0·06-0·23]). We found an increased co-occurrence of chronic pain, depression and cardiovascular disease in two independent cohorts (general population-based cohort, twins cohort) suggesting a shared genetic contribution. Adjustment for known environmental influences, particularly those relating to socio-economic status (Generation Scotland: age, gender, deprivation, smoking, education; Twins UK: age,BMI) did not explain the relationship observed between chronic pain, depression and cardiovascular disease. Our findings from two independent cohorts challenge the concept of traditional disease boundaries and warrant further investigation of shared biological mechanisms.

Purpose In order to deliver appropriate and timely care planning and minimise avoidable late diagnoses, clinicians need to be aware of which patients are at higher risk of receiving a late cancer diagnosis. We aimed to determine which demographic and clinical factors are associated with receiving a ‘late’ cancer diagnosis (within the last 12 weeks of life). Method Retrospective cohort study of 2,443 people who died from cancer (‘cancer decedents’) in 2013–2015. Demographic and cancer registry datasets linked using patient-identifying Community Health Index numbers. Analysis used binary logistic regression, with univariate and adjusted odds ratios (SPSS v25). Results One third ( n  = 831,34.0%) received a late diagnosis. Age and cancer type were significantly associated with late cancer diagnosis ( p  < 0.001). Other demographic factors were not associated with receiving a late diagnosis. Cancer decedents with lung cancer (Odds Ratios presented in abstract are the inverse of those presented in the main text, where lung cancer is the reference category. Presented as 1/(OR multivariate)) were more likely to have late diagnosis than those with bowel (95% Confidence Interval [95%CI] Odds Ratio (OR)1.52 (OR1.12 to 2.04)), breast or ovarian (95%CI OR3.33 (OR2.27 to 5.0) or prostate (95%CI OR9.09 (OR4.0 to 20.0)) cancers. Cancer decedents aged > 85 years had higher odds of late diagnosis (95%CI OR3.45 (OR2.63 to 4.55)), compared to those aged < 65 years. Conclusions Cancer decedents who were older and those with lung cancer were significantly more likely to receive late cancer diagnoses than those who were younger or who had other cancer types. Key messages • One third ( n =831,34.0%) of cancer decedents had late diagnoses (within the last 12 weeks of life). • Cancer decedents with lung cancer had higher odds of late diagnosis than those with other cancers. • Cancer decedents >85 years old were 3 times more likely to have late diagnoses than those <65 years old.

The heritability of Major Depressive Disorder (MDD) has been estimated at 37% based largely on twin studies that rely on contested assumptions. More recently, the heritability of MDD has been estimated on large populations from registries such as the Swedish, Finnish, and Chinese cohorts. Family-based designs utilise a number of different relationships and provide an alternative means of estimating heritability. Generation Scotland: Scottish Family Health Study (GS:SFHS) is a large (n = 20,198), family-based population study designed to identify the genetic determinants of common diseases, including Major Depressive Disorder. Two thousand seven hundred and six individuals were SCID diagnosed with MDD, 13.5% of the cohort, from which we inferred a population prevalence of 12.2% (95% credible interval: 11.4% to 13.1%). Increased risk of MDD was associated with being female, unemployed due to a disability, current smokers, former drinkers, and living in areas of greater social deprivation. The heritability of MDD in GS:SFHS was between 28% and 44%, estimated from a pedigree model. The genetic correlation of MDD between sexes, age of onset, and illness course were examined and showed strong genetic correlations. The genetic correlation between males and females with MDD was 0.75 (0.43 to 0.99); between earlier (≤ age 40) and later (> age 40) onset was 0.85 (0.66 to 0.98); and between single and recurrent episodic illness course was 0.87 (0.72 to 0.98). We found that the heritability of recurrent MDD illness course was significantly greater than the heritability of single MDD illness course. The study confirms a moderate genetic contribution to depression, with a small contribution of the common family environment (variance proportion = 0.07, CI: 0.01 to 0.15), and supports the relationship of MDD with previously identified risk factors. This study did not find robust support for genetic differences in MDD due to sex, age of onset, or illness course. However, we found an intriguing difference in heritability between recurrent and single MDD illness course. These findings establish GS:SFHS as a valuable cohort for the genetic investigation of MDD.

Background Physical inactivity is a leading cause of premature mortality and morbidity worldwide. Primary care settings provide an opportunity for effective lifestyle interventions, including physical activity (PA) promotion. This study aims to evaluate the impact of a rural community-based multi-component, 12-week exercise, nutrition, education and peer-support programme on participants health and wellbeing. Methods This retrospective service evaluation included patients referred to the programme between January 2020 and December 2022 from primary care settings. Quantitative data (including body composition measures, mental wellbeing and patient activation) were collected at the entry and exit of the 12-week program. Participants also self-reported healthcare attendance in the 3 months prior to the baseline and post-intervention data-collection. Results Of the 424 people who participated in the programme, 84.7% ( n  = 359) indicated that they had achieved their goals. Significant improvements in BMI, weight, blood pressure, wellbeing, patient activation, muscle mass, body-fat mass and reduced healthcare attendance over a 12-week intervention were identified by repeated measure ANOVA. Post-hoc tests with a Bonferroni correction found that younger participants were significantly more likely to decrease their BMI and increase their mental wellbeing (as measured by WEMWBS) over the course of the programme. Higher attendance at the programme was also associated with greater reductions in BMI and greater improvements in patient activation. Discussion The findings support the effectiveness of multicomponent community-based exercise, nutrition, education and peer support interventions in improving health outcomes and reducing healthcare utilisation. Further research is needed to evaluate the long-term health outcomes of the education-exercise referral programme, across settings, and its potential to contribute to a sustainable healthcare system.

The objective to provide an overview of the literature on the barriers and facilitators to physical activity (PA) promotion in primary care, as experienced by practitioners and patients. Method A search strategy of the English‐language literature was conducted in EMBASE, MEDLINE and the COCHRANE LIBRARY. Search terms were primary care OR general practice OR family medicine OR family practitioner AND physical activity OR exercise AND barriers OR facilitators. Databases were searched from inception until 21 October 2022. Results After screening, 63 articles were included within the summary and content analysis of this review. Analysis of the barriers to the implementation of PA highlighted four main themes perceived by practitioners: time, knowledge/skills, resources/support and financial implications. Analysis of the patient perspective identified themes which were categorised into individual (pre‐existing health conditions, knowledge of benefits of PA, time/capacity), societal (social support and cultural norms) and environmental (availability of facilities and weather). Conclusions As the importance of PA increases through the manifestation of sedentary behaviour‐related disease, a combined primary care and public health approach to increase PA is required. By identifying the main barriers to PA promotion in primary care, resources and funding can be directed to address this. This is particularly relevant in the United Kingdom, with the re‐negotiation of the primary care contract and the changes to healthcare delivery as a consequence of the Covid‐19 pandemic. Throughout this review, we have explored ways of addressing the identified barriers through evidence‐based interventions.