Genetic variation in the hypothalamic–pituitary–adrenal stress axis influences susceptibility to musculoskeletal pain: results from the EPIFUND study

<b>Objectives</b> To determine if genetic variation in genes in the hypothalamic–pituitary–adrenal (HPA) axis, the primary stress response system, influences susceptibility to developing musculoskeletal pain.<p></p> <b>Methods</b> Pain and comorbidity data was collected at three time points in a prospective population-based cohort study. Pairwise tagging single nucleotide polymorphisms (SNPs) were selected and genotyped for seven genes. Genetic association analysis was carried out using zero-inflated negative binomial regression to test for association between SNPs and the maximum number of pain sites across the three time points in participants reporting pain, reported as proportional changes with 95% CIs. SNPs were also tested for association with chronic widespread pain (CWP) using logistic regression reporting odds ratios and 95% CI.<p></p> <b>Results</b> A total of 75 SNPs were successfully genotyped in 994 participants including 164 cases with persistent CWP and 172 pain-free controls. Multiple SNPs in SERPINA6 were associated with the maximum number of pain sites; for example, each copy of the T allele of rs941601 was associated with having 16% (proportional change=1.16, 95% CI 1.04 to 1.28, p=0.006) more pain sites compared to participants with the CC genotype. SERPINA6 gene SNPs were also associated with CWP. Significant associations between the maximum number of pain sites and SNPs in the CRHBP and POMC genes were also observed and a SNP in MC2R was also associated with CWP. Associations between SNPs and comorbidity of poor sleep quality and depression explained some of the associations observed.<p></p> <b>Conclusions</b> Genetic variation in HPA axis genes was associated with musculoskeletal pain; however, some of the associations were explained by comorbidities. Replication of these findings is required in independent cohorts

Do genetic predictors of pain sensitivity associate with persistent widespread pain?

Genetic risk factors for pain sensitivity may also play a role in susceptibility to chronic pain disorders, in which subjects have low pain thresholds. The aim of this study was to determine if proposed functional single nucleotide polymorphisms (SNPs) in the GTP cyclohydrolase (GCH1) and μ opioid receptor (OPRM1) genes previously associated with pain sensitivity affect susceptibility to chronic widespread pain (CWP). Pain data was collected using body manikins via questionnaire at three time-points over a four year period from subjects aged 25-65 in the North-West of England as part of a population based cohort study, EPIFUND. CWP was defined at each time point using standard criteria. Three SNPs forming a proposed "pain-protective" haplotype in GCH1 (rs10483639, rs3783641 and rs8007267) and two SNPs in OPRM1 (rs1777971 (A118G) and rs563649) were genotyped in cases with persistent CWP (CWP present at ≥2 time-points) and controls who were pain-free at all time-points. The expectation-maximisation algorithm was used to estimate haplotype frequencies. The frequency of the "pain-protective" (CAT - C allele of rs10483639, A allele of rs3783641 and T allele of rs8007267) haplotype was compared to the frequency of the other haplotypes between cases and controls using the χ2 test. Allele frequencies and carriage of the minor allele was compared between cases and controls using χ2 tests for the OPRM1 SNPs. The frequency of the proposed GCH1 "pain-protective" haplotype (CAT) did not significantly differ between cases and controls and no significant associations were observed between the OPRM1 SNPs and CWP. In conclusion, there was no evidence of association between proposed functional SNPs, previously reported to influence pain sensitivity, in GCH1 and OPRM1 with CWP. Further evidence of null association in large independent cohorts is required to truly exclude these SNPs as genetic risk factors for CWP

Novel Therapies for Myocardial Irritability following Extreme Hydroxychloroquine Toxicity

Introduction. Hydroxychloroquine (HCQ) overdose is rare and potentially deadly when consumed in large doses. Management of severe HCQ toxicity is limited and infrequently reported. This report presents the case of a massive ingestion of HCQ. Case Report. A 23-year-old female presents following an intentional ingestion of approximately 40 g of HCQ. Within six hours after ingestion, she developed severe hemodynamic instability resulting from myocardial irritability with frequent ventricular ectopic activity leading to runs of polymorphic ventricular tachycardia (PMVT) and ventricular fibrillation (VF) requiring multiple defibrillations. Additional treatments included intravenous diazepam, epinephrine, norepinephrine, sodium bicarbonate, and magnesium sulfate. Despite the ongoing hemodynamic instability, the patient was also treated with Intralipid (ILE) and received hemodialysis. Improvements in her hemodynamics were observed after 18 hours. She survived her massive overdose of HCQ. Conclusion. HCQ poisoning is rare but serious because of its rapid progression to life-threatening symptoms. Hemodynamic support, gastric decontamination, electrolyte monitoring and replacement, and management of arrhythmias are the mainstays of treatment. The combined role of dialysis and ILE in the setting of massive HCQ overdose may improve outcomes

A strong association between non-musculoskeletal symptoms and musculoskeletal pain symptoms: results from a population study

<p>Abstract</p> <p>Background</p> <p>There is a lack of knowledge about the pattern of symptom reporting in the general population as most research focuses on specific diseases or symptoms. The number of musculoskeletal pain sites is a strong predictor for disability pensioning and, hence, is considered to be an important dimension in symptom reporting. The simple method of counting symptoms might also be applicable to non-musculoskeletal symptoms, rendering further dimensions in describing individual and public health. In a general population, we aimed to explore the association between self-reported non-musculoskeletal symptoms and the number of pain sites.</p> <p>Methods</p> <p>With a cross-sectional design, the Standardised Nordic Questionnaire and the Subjective Health Complaints Inventory were used to record pain at ten different body sites and 13 non-musculoskeletal symptoms, respectively, among seven age groups in Ullensaker, Norway (n = 3,227).</p> <p>Results</p> <p>Results showed a strong, almost linear relationship between the number of non-musculoskeletal symptoms and the number of pain sites (r = 0.55). The <it>number </it>and <it>type </it>of non-musculoskeletal symptoms had an almost equal explanatory power in the number of pain sites reported (27.1% vs. 28.2%).</p> <p>Conclusion</p> <p>The linear association between the number of non-musculoskeletal and musculoskeletal symptoms might indicate that the symptoms share common characteristics and even common underlying causal factors. The total burden of symptoms as determined by the number of symptoms reported might be an interesting generic indicator of health and well-being, as well as present and future functioning. Research on symptom reporting might also be an alternative pathway to describe and, possibly, understand the medically unexplained multisymptom conditions.</p

The placebo effect and its determinants in fibromyalgia: meta-analysis of randomized controlled trials

The aims of this study were to determine whether placebo treatment in randomised controlled trials (RCTs) is effective for fibromyalgia and to identify possible determinants of the magnitude of any such placebo effect. A systematic literature search was undertaken for RCTs in people with fibromyalgia that included a placebo and/or a no-treatment (observation only or waiting list) control group. Placebo effect size (ES) for pain and other outcomes was measured as the improvement of each outcome from baseline divided by the standard deviation of the change from baseline. This effect was compared with changes in the no-treatment control groups. Meta-analysis was undertaken to combine data from different studies. Subgroup analysis was conducted to identify possible determinants of the placebo ES. A total of 3912 studies were identified from the literature search. After scrutiny, 229 trials met the inclusion criteria. Participants who received placebo in the RCTs experienced significantly better improvements in pain, fatigue, sleep quality, physical function, and other main outcomes than those receiving no treatment. The ES of placebo for pain relief was clinically moderate (0.53, 95%CI 0.48 to 0.57). The ES increased with increasing strength of the active treatment, increasing participant age and higher baseline pain severity, but decreased in RCTS with more women and with longer duration of fibromyalgia. In addition, placebo treatment in RCTs is effective in fibromyalgia. A number of factors (expected strength of treatment, age, gender, disease duration) appear to influence the magnitude of the placebo effect in this condition

Physical inactivity is associated with chronic musculoskeletal complaints 11 years later: results from the Nord-Trøndelag Health Study

Background Physical inactivity is associated with several diseases, but studies evaluating the association between chronic musculoskeletal complaints (MSCs) and physical exercise have shown conflicting results. The aim of this large-scale prospective population-based study was to investigate the association between self-reported physical exercise at baseline and the prevalence of chronic musculoskeletal complaints (MSCs) 11 years later. Methods The results are based upon two consecutive public health studies conducted within the county of Nord-Trøndelag, Norway (The HUNT studies). A total of 39,520 (83%) out of 47,556 adults who participated in HUNT 1 and HUNT 2 responded to questions about physical exercise at baseline in 1984–86, and to questions about musculoskeletal complaints 11 years later (1995–97). Chronic MSCs was defined as MSCs ≥ 3 months during the past year, and chronic widespread MSCs such as pain ≥ 15 days during the last month from the axial region, above the waist, and below the waist. Associations were assessed using multiple logistic regression, estimating prevalence odds ratio (OR) with 95% confidence intervals (CIs). All the final analyses were adjusted for age, gender, body mass index, smoking and education level. Results At follow-up 20,223 (51%) reported chronic MSCs, and among these 2,318 (5.9%) reported chronic widespread MSCs. Individuals who exercised at baseline were less likely to report chronic MSCs 11 years later (OR 0.91, 95% CI 0.85–0.97) than inactive persons. Among individuals who exercised more than three times per week, chronic widespread MSCs were 28% less common (OR 0.72, 95% CI 0.59–0.88) compared to inactive individuals. Conclusion In this large-scale population-based study, physical exercise was associated with lower prevalence of chronic MSCs, in particular chronic widespread MSCs. Future studies should try to clarify whether chronic MSCs are a cause or a consequence of inactivity

Social capital in relation to depression, musculoskeletal pain, and psychosomatic symptoms: a cross-sectional study of a large population-based cohort of Swedish adolescents

<p>Abstract</p> <p>Background</p> <p>Social capital has lately received much attention in health research. The present study investigated whether two measures of subjective social capital were related to psychosomatic symptoms, musculoskeletal pain, and depression in a large population of Swedish adolescents.</p> <p>Methods</p> <p>A total of 7757 13-18 year old students anonymously completed the Survey of Adolescent Life in Vestmanland 2008 which included questions on sociodemographic background, neighbourhood social capital, general social trust, and ill health.</p> <p>Results</p> <p>Low neighbourhood social capital and low general social trust were associated with higher rates of psychosomatic symptoms, musculoskeletal pain, and depression. Individuals with low general social trust had more than three times increased odds of being depressed, three times increased odds of having many psychosomatic symptoms, and double the odds of having many symptoms of musculoskeletal pain.</p> <p>Conclusions</p> <p>The findings make an important contribution to the social capital - health debate by demonstrating relations between social capital factors and self-reported ill health in a young population.</p

The transition of reported pain in different body regions – a one-year follow-up study

BACKGROUND: The course of pain at a specific region such as the lower back has previously been shown as well as for generalized pain. However we have not found any report on the course of pain from various different specific regions. The aim of this investigation was to study the one-year transition of reported pain in different body locations. METHODS: From a general population 14555 men and women, 46–68 years, responded to an extensive health questionnaire including the standardized Nordic questionnaire. The population represented 27% of the total population within the age group in Malmö, Sweden. At the one year follow-up 12607 responded to the questionnaire, yielding a response rate of 87%. The one year prevalence of long-lasting pain and the pattern of pain reporting from different regions were studied for men and women. RESULTS: The one-year prevalence of long-lasting neck pain was 14% (95% CI 13–15) among men and 25% (95% CI 24–26) among women at baseline and 15% (95% CI 14–16) for the men and 23% (95% CI 22–24) for the women at follow-up. Of those reporting neck pain "all the time" at baseline, 48% of the men and 54% of the women also reported neck pain "all the time" at the one-year follow-up. At the follow-up neck pain was reported as present "often" by 43% of the men and 47% of the women who reported neck pain "often" at baseline. Similar transition pattern were found for neck, shoulders, elbow/wrist/hand and lower back symptoms, as well as consistent prevalence rates. CONCLUSION: The one-year transition pattern of reported pain was similar in different body regions and among men and women. Furthermore the prevalence rates of long-lasting pain in the population were consistent at baseline and the follow-up. The findings of similar transition patterns support the interpretation of long-lasting pain as a generalized phenomenon rather than attributed to specific exposure. This may have implications for future pain research

Factors explaining variance in perceived pain in women with fibromyalgia

BACKGROUND: We hypothesized that a substantial proportion of the subjectively experienced variance in pain in fibromyalgia patients would be explained by psychological factors alone, but that a combined model, including neuroendocrine and autonomic factors, would give the most parsimonious explanation of variance in pain. METHODS: Psychometric assessment included McGill Pain Questionnaire, General Health Questionnaire, Hospital Anxiety and Depression Rating Scale, Eysenck personality Inventory, Neuroticism and Lie subscales, Toronto Alexithymia Scale, and Multidimensional Health Locus of Control Scale and was performed in 42 female patients with fibromyalgia and 48 female age matched random sample population controls. A subgroup of the original sample (22 fibromyalgia patients and 13 controls) underwent a pharmacological challenge test with buspirone to assess autonomic and adrenocortical reactivity to serotonergic challenge. RESULTS: Although fibromyalgia patients scored high on neuroticism, anxiety, depression and general distress, only a minor part of variance in pain was explained by psychological factors alone. High pain score was associated with high neuroticism, low baseline cortisol level and small drop in systolic blood pressure after buspirone challenge test. This model explained 41.5% of total pain in fibromyalgia patients. In population controls, psychological factors alone were significant predictors for variance in pain. CONCLUSION: Fibromyalgia patients may have reduced reactivity in the central sympathetic system or perturbations in the sympathetic-parasympathetic balance. This study shows that a biopsychosocial model, including psychological factors as well as factors related to perturbations of the autonomic nervous system and hypothalamic-pituitary-adrenal axis, is needed to explain perceived pain in fibromyalgia patients