Kelly A. Davies

Restorative sleep predicts the resolution of chronic widespread pain: results from the EPIFUND study

Objectives. Poor sleep is associated with chronic widespread pain (CWP). Conversely, good-quality sleep may play a role in the resolution of pain symptoms. Sleep is a multidimensional construct, comprising a number of diverse components. The aims of the current study were to examine the hypotheses that: (i) good sleep quality would predict the resolution of CWP, (ii) restorative sleep would predict the resolution of CWP and (iii) that these relationships would be independent of confounding psychological factors. Methods. Subjects in a population-based prospective study completed a pain questionnaire at baseline from which subjects with CWP were identified. Baseline sleep was measured using the Estimation of Sleep Problems Scale which measures sleep onset, maintenance, early wakening and restorative sleep. The questionnaire also contained scales examining psychosocial status. Subjects were followed up 15 months later and pain status was assessed. Results. A total of 1061 subjects reported CWP at baseline of whom 679 (75% of eligible subjects) responded at follow-up. Of those, a total of 300 (44%) no longer satisfied criteria for CWP. Univariate analysis revealed that three of the four sleep components were associated with the resolution of CWP: rapid sleep onset, odds ratio (OR) = 1.7, 95% CI 1.2, 2.5; absence of early wakening, OR = 1.6, 95% CI 1.1, 2.4; and restorative sleep, OR = 2.7, 95% CI 1.5, 4.8. After adjusting for the effect of psychosocial factors, which may have confounded the relationship, only restorative sleep (OR = 2.0, 95% CI 1.02, 3.8) was associated. Conclusions. Self-reported restorative sleep was independently associated with the resolution of CWP and return to musculoskeletal health.

Insecure attachment style is associated with chronic widespread pain

ABSTRACT Individuals with “insecure” adult attachment styles have been shown to experience more pain than people with secure attachment, though results of previous studies have been inconsistent. We performed a cross‐sectional study on a large population‐based sample to investigate whether, compared to pain free individuals, subjects with chronic widespread pain were more likely to report insecure adult attachment style. Subjects in a population‐based cross‐sectional study completed a self‐rated assessment of adult attachment style. Attachment style was categorised as secure (i.e., normal attachment style); or preoccupied, dismissing or fearful (insecure attachment styles). Subjects completed a pain questionnaire from which three groups were identified: pain free; chronic widespread pain; and other pain. Subjects rated their pain intensity and pain‐related disability on an 11 point Likert scale. Subjects (2509) returned a completed questionnaire (median age 49.9 years (IQR 41.2–50.0); 59.2% female). Subjects with CWP were more likely to report a preoccupied (RRR 2.6; 95%CI 1.8–3.7), dismissing (RRR 1.9; 95%CI 1.2–3.1) or fearful attachment style (RRR 1.4; 95%CI 1.1–1.8) than those free of pain. Among CWP subjects, insecure attachment style was associated with number of pain sites (Dismissing: RRR 2.8; 95%CI 1.2–2.3, Preoccupied: RRR = 1.8, 95%CI 0.98–3.5) and degree of pain‐related disability (Preoccupied: RRR = 2.1, 95%CI 1.0–4.1), but not pain intensity. These findings suggest that treatment strategies based on knowledge of attachment style, possibly using support and education, may alleviate distress and disability in people at risk of, or affected by, chronic widespread pain.

Premorbid psychosocial factors are associated with poor health- related quality of life in subjects with new onset of chronic widespread pain - Results from the EPIFUND study

Abstract Chronic widespread pain (CWP) is associated with poor health‐related quality of life (HRQoL). It is unclear whether pain itself is the cause of poor HRQoL or other factors play a role. We hypothesised that new onset of CWP was associated with poor physical and mental HRQoL but that psychosocial risk markers for CWP onset would explain this relationship. A prospective population‐based survey measured pain and psychosocial status at baseline. Subjects free of CWP at baseline were followed up 15 months later, when pain status, threatening life events and HRQoL (SF‐12) were assessed. The risk associated with the new onset of CWP and reporting poor SF12‐MCS and SF12‐PCS was quantified using multinomial logistic regression (relative risk ratios (RRRs) with 95% confidence intervals (95% CI)), adjusted for age and gender. 3000 subjects (77%) free of CWP at baseline participated at follow‐up. 2650 subjects (88%) provided full SF‐12 and pain data and formed the cohort for this analysis. 9.4% of subjects (n = 248) reported new CWP. New CWP was associated with an increased risk of having the poorest SF12‐MCS (RRR = 2.3; 95% CI 1.6–3.2) and SF12‐PCS (RRR = 8.0; 95% CI 5.4–11.8) scores. After adjusting for baseline psychosocial status, the relationship between CWP onset and SF12‐MCS was attenuated (RRR = 1.2; 95% CI 0.8–1.8), although the association with SF12‐PCS remained (RRR = 4.8% CI 3.1–7.47). New onset of CWP is associated with poor mental and physical HRQoL. However, the relationship with mental HRQoL is explained by psychosocial risk markers.

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

Objectives 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. Methods 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. Results 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. Conclusions 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.

Chronic widespread pain predicts physical inactivity: results from the prospective EPIFUND study.

This study tested the hypothesis that chronic widespread pain (CWP) would predict low levels of physical activity (PA). Pain status and PA levels were ascertained at baseline and 32 months in community subjects. Three PA questions were used: “in comparison with others your own age, is your PA “the same” (referent), “more‐much more” or “less‐much less””, and “during the past month on average how many days/week have you taken exercise that has (i) lasted at least 20 min? and (ii) made you sweat?: “4–7” (referent), “1–3” or “none””. Multinomial logistic regression models quantified the relationship between baseline CWP and PA at follow‐up (relative risk ratios (RRR) (95% confidence intervals)). Two thousands one hundred and eighty‐two subjects participated and provided complete pain and PA information at both timepoints. CWP was reported by 18% (n = 429) of participants at baseline. Compared to subjects who were free of CWP at baseline, those with CWP had an increased odds of reporting “less‐much less” PA at follow‐up (RRR = 4.5 (3.2–6.2)). This relationship remained after adjustment for confounders (RRR = 1.9 (1.3–2.9)). A similar association was observed with exercise that lasted at least 20 min (RRR = 1.9 (1.3–2.8)). The current study suggests that low self‐reported levels of physical activity are a consequence of having CWP.

Association of HTR2A polymorphisms with chronic widespread pain and the extent of musculoskeletal pain: Results from two population-based cohorts

OBJECTIVE The aim of the current study was to investigate whether genetic variation in genes across the serotoninergic system is associated with chronic widespread pain (CWP) and the number of pain sites reported. METHODS A discovery cohort, with pain data at 3 time points, was used to investigate genetic associations with 2 phenotypes: 1) CWP (at ≥ 2 time points; n = 164) compared with pain-free controls (at 3 time points; n = 172), and 2) the maximum number of pain sites reported at any 1 of the 3 time points (range of sites 0-29; n = 989). A cohort of 2,285 men for whom a DNA sample and pain data were available (including 203 CWP cases and 929 controls) was used for validation. Pairwise tagging (r(2) > 0.8) single-nucleotide polymorphisms (SNPs) were genotyped. Logistic and zero-inflated negative binomial regression analyses were used to test for SNP associations with CWP and the number of pain sites, respectively. RESULTS SNPs in HTR2A were associated with both pain phenotypes in the discovery cohort, and a number of these SNP associations were replicated in the validation cohort, some of which were attenuated after adjustment for depression. There was an increased likelihood of having CWP in subjects with 1 or 2 copies of the T allele of rs12584920 (odds ratio [OR] 1.64, 95% confidence interval [95% CI] 1.01-2.60 [P = 0.03] in the discovery cohort, and OR 1.46, 95% CI 1.07-2.00 [P = 0.018] in the validation cohort). A similar association was observed between rs17289394 and the maximum number of pain sites reported in both cohorts. Results from a meta-analysis of the data from the 2 cohorts further strengthened these findings. CONCLUSION The findings of this study support the role of HTR2A in the genetic predisposition to musculoskeletal pain.

Role of road traffic accidents and other traumatic events in the onset of chronic widespread pain: Results from a population-based prospective study

To determine the relationship between physically traumatic events and the onset of chronic widespread pain (CWP).

The association between neighbourhood socio-economic status and the onset of chronic widespread pain: Results from the EPIFUND study

Background: Cross‐sectional studies have reported an inverse relationship between socio‐economic status and the prevalence of chronic widespread pain (CWP). However, the extent to which this relationship is explained by psychological factors is unknown. The aim of this study was to examine the hypothesis that socio‐economic status predicts the onset of CWP but that this relationship would be explained by psychological factors.

No evidence for a role of the catechol-O-methyltransferase pain sensitivity haplotypes in chronic widespread pain

Objectives The aim of this study was to investigate the association between the catechol-O-methyltransferase (COMT) ‘pain sensitivity’ haplotypes and chronic widespread pain (CWP) in two distinct cohorts. Methods Cases of CWP and controls free of pain were selected from two population-based studies: the Epidemiology of Functional Disorders study (EPIFUND) (UK) and the European Male Ageing Study (European). The number of cases and controls were 164 and 172, and 204 and 935, respectively. Identical American College of Rheumatology criteria were used in both studies to ascertain CWP status. The EPIFUND study had three time points and cases were classified as subjects with CWP at two or three time points and controls as those free of pain at all three time points. Four single nucleotide polymorphisms (SNP): rs6269, rs4633, rs4818 and rs4680 (V158M) were genotyped using Sequenom technology. Allele and genotype frequencies were compared and haplotype analysis was conducted using PLINK software. Results No differences in allele or genotype frequencies for any of the four SNP were observed between cases and controls for either cohort. Haplotype analysis also showed no difference in the frequency of haplotypes between cases and controls. Conclusions There was no evidence of association between the COMT ‘pain sensitivity’ haplotypes and CWP in two population-based cohorts.

HTR2A polymorphisms are associated with chronic widespread pain and the extent of musculoskeletal pain: Results from two population based cohorts.

OBJECTIVE The aim of the current study was to investigate whether genetic variation in genes across the serotoninergic system is associated with chronic widespread pain (CWP) and the number of pain sites reported. METHODS A discovery cohort, with pain data at 3 time points, was used to investigate genetic associations with 2 phenotypes: 1) CWP (at ≥ 2 time points; n = 164) compared with pain-free controls (at 3 time points; n = 172), and 2) the maximum number of pain sites reported at any 1 of the 3 time points (range of sites 0-29; n = 989). A cohort of 2,285 men for whom a DNA sample and pain data were available (including 203 CWP cases and 929 controls) was used for validation. Pairwise tagging (r(2) > 0.8) single-nucleotide polymorphisms (SNPs) were genotyped. Logistic and zero-inflated negative binomial regression analyses were used to test for SNP associations with CWP and the number of pain sites, respectively. RESULTS SNPs in HTR2A were associated with both pain phenotypes in the discovery cohort, and a number of these SNP associations were replicated in the validation cohort, some of which were attenuated after adjustment for depression. There was an increased likelihood of having CWP in subjects with 1 or 2 copies of the T allele of rs12584920 (odds ratio [OR] 1.64, 95% confidence interval [95% CI] 1.01-2.60 [P = 0.03] in the discovery cohort, and OR 1.46, 95% CI 1.07-2.00 [P = 0.018] in the validation cohort). A similar association was observed between rs17289394 and the maximum number of pain sites reported in both cohorts. Results from a meta-analysis of the data from the 2 cohorts further strengthened these findings. CONCLUSION The findings of this study support the role of HTR2A in the genetic predisposition to musculoskeletal pain.