Endogenous pain modulation after sleep restriction in migraine: a blinded crossover study.

BACKGROUND: Patients with migraine are vulnerable to insufficient sleep, but the impact of sleep restriction is largely unknown. In addition, the importance of sleep may be different in patients with migraine who mostly have attack onsets during sleep, so called sleep-related migraine, compared to patients with non-sleep-related migraine. In this study we investigate the effect of sleep restriction on endogenous pain modulation in patients with migraine and healthy controls. We also compared the effect of sleep restriction in sleep-related and in non-sleep-related migraine. METHODS: Measurements were conducted in 39 patients with migraine between attacks and 31 controls, once after habitual sleep and once after two consecutive nights of partial sleep restriction. There were 29 and 10 patients with non-sleep-related and sleep-related migraine respectively. Test stimulus was 2-min tonic noxious heat to the left volar forearm. Temporal summation was calculated as the regression coefficient for rated pain in the late part of this 2-min stimulation. Conditioning stimulus was right hand-immersion in 7 °C water. Conditioned pain modulation was defined as the difference in rated pain with and without the conditioning stimulus and was calculated for temporal summation and mean rated pain for the test stimulus. The effect of sleep restriction on temporal summation and conditioned pain modulation was compared in migraine subjects and controls using two-level models with recordings nested in subjects. RESULTS: Conditioned pain modulation for temporal summation of heat pain tended to be reduced after sleep restriction in patients with migraine compared to controls (p = 0.060) and, in an exploratory analysis, was reduced more after sleep restriction in sleep-related than in non-sleep-related migraine (p = 0.017). No other differences between groups after sleep restriction were found for temporal summation or conditioned pain modulation. CONCLUSION: Patients with migraine may have a subtly altered endogenous pain modulation system. Sleep restriction may have an increased pronociceptive effect on this system, suggesting a mechanism for vulnerability to insufficient sleep in migraine. This effect seems to be larger in sleep-related migraine than in non-sleep-related migraine.

Overweight and obesity as risk factors for chronic low back pain: a new follow-up in the HUNT Study.

BACKGROUND: Numerous studies have examined associations between overweight and obesity and risk of low back pain (LBP), but the exact magnitude of these associations is not yet clear. The purpose of this work was to assess such sex-specific associations in a community-based setting in Norway, taking into account potential relationships with other risk factors. METHODS: A cohort study was conducted combining data from two waves of the Trøndelag Health Study, HUNT3 (2006-2008) and HUNT4 (2017-2019). Separate analyses were performed of risk of chronic LBP in HUNT4 among 14,775 individuals without chronic LBP in HUNT3, and of recurrence or persistence in HUNT4 among 5034 individuals with chronic LBP in HUNT3. Relative risks were estimated in generalised linear models for overweight and obesity compared to normal weight. Body size classification was based on values of BMI computed from measurements of height and weight. Chronic LBP was defined as LBP persisting at least 3 months during last year. RESULTS: After adjustment for age, smoking, physical activity in leisure time and work activity, analysis of risk among women produced relative risks 1.11 (95% CI 1.00-1.23) for overweight, 1.36 (95% CI 1.20-1.54) for obesity class I and 1.68 (95% CI 1.42-2.00) for obesity classes II-III. Relative risks among men were 1.10 (95% CI 0.94-1.28) for overweight, 1.36 (95% CI 1.13-1.63) for obesity class I and 1.02 (95% CI 0.70-1.50) for obesity classes II-III, the last estimate being based on relatively few individuals. Analyses of recurrence or persistence indicated similar relationships but with smaller magnitude of relative risks and no drop in risk among obesity classes II-III in men. The change in BMI from HUNT3 to HUNT4 hardly differed between individuals with and without chronic LBP in HUNT3. CONCLUSIONS: Risk of chronic LBP increases with higher values of BMI in both sexes, although it is uncertain whether this applies to very obese men. Very obese women carry a particularly large risk. Probabilities of recurrence or persistence of chronic LBP among those already afflicted also increase with higher values of BMI. Adjustment for other factors does not influence relationships with overweight and obesity to any major extent.

Relationship between migraine and epilepsy in a large population-based cohort: The HUNT Study.

BACKGROUND AND PURPOSE: Several studies have reported substantial comorbidity between epilepsy and migraine. Most of these were based on clinical cohorts or used unvalidated diagnostic instruments. Our study re-examined this association in a large general population cohort using validated diagnoses for both disorders. METHODS: A total of 65,407 participants (≥20 years old) from HUNT (the Trøndelag Health Study) were classified for migraine and nonmigraine headache using a validated questionnaire. Medical record review was used to validate and classify epilepsy in 364 participants (cases), who were compared with 63,298 participants without epilepsy (controls). The association between epilepsy and migraine was analysed using logistic regression adjusted for sex and age. RESULTS: Patients with epilepsy had no increased prevalence of migraine (odds ratio [OR] = 0.95, 95% confidence interval [CI] = 0.68-1.33) or nonmigraine headache (OR = 1.18, 95% CI = 0.93-1.50) compared to controls. When stratified by headache frequency, epilepsy was associated with a higher prevalence of migraine with highly frequent headache (≥7 days/month; OR = 1.73, 95% CI = 1.08-2.78). CONCLUSIONS: Migraine was equally common in people with and without epilepsy. Patients with epilepsy who suffered from migraine were more prone to having highly frequent migraine.

Validation of Trøndelag Apnoea Score Proxy for Obstructive Sleep Apnoea in the General Population of Norway: The HUNT Study.

The aim was to validate a new seven-item "TASC" (Trøndelag Apnoea Score) proxy for obstructive sleep apnoea (OSA) against polysomnography in the general population. Objectives included validation against different polysomnographic criteria, stratification by age and gender, and estimation of OSA prevalence. From the fourth wave of the Trøndelag Health Study (HUNT4), 1,201 participants were randomly invited to a substudy focusing on sleep and headaches, of whom 232 accepted and 84 (64% women, mean age 55.0 years, and standard deviation 11.5 years) underwent polysomnography. The TASC proxy sums seven binary items for snoring, observed breathing pauses, restricted daytime activities, hypertension, body mass index (≥30 kg/m2), age (≥50 years), and gender (male). A single night of ambulatory (home) polysomnography was analysed using both the recommended and optional hypopnoea criteria of the American Academy of Sleep Medicine (AASM). We found 65% sensitivity and 87% specificity (Cohen's κ = 0.53, 95% confidence interval 0.34-0.72) for TASC ≥ 3 against AHI ≥ 15 (recommended AASM criteria). Validity was similar against AHI ≥ 30 but lower against AHI ≥ 5 and against the optional AASM criteria. Sensitivity and overall validity were higher among men and those above 50 years of age. The prevalence of an apnoea-hypopnoea index (AHI) of at least 5, 15, or 30 using the recommended (and optional) AASM criteria was 73% (46%), 37% (18%), or 15% (5%). A seven-item TASC proxy for OSA showed good validity and may be useful in screening and epidemiological settings. Sensitivity, specificity, and validity vary considerably by cut-off, by polysomnographic scoring criteria, and by gender and age strata.

Migraine and risk of atrial fibrillation: A 9-year follow-up based on the Trøndelag Health Study.

BACKGROUND: Data from some population-based studies have indicated an increased risk of atrial fibrillation (AF) among patients with migraine, particularly among individuals with migraine with aura. The present study aimed to assess the association between primary headache disorders and AF. METHODS: In a population-based 9-year follow-up design, we evaluated the questionnaire-based headache diagnosis, migraine and tension-type headache (TTH) included, collected in the Trøndelag Health Study (HUNT3) conducted in 2006-2008, and the subsequent risk of AF in the period until December 2015. The population at risk consisted of 39,340 individuals ≥20 years without AF at HUNT3 baseline who answered headache questionnaire during HUNT3. The prospective association was evaluated by multivariable Cox proportional hazard models with 95% confidence intervals (CIs). RESULTS: Among the 39,340 participants, 1524 (3.8%) developed AF during the 9-year follow up, whereof 91% of these were ≥55 years. In the multivariable analyses, adjusting for known confounders, we did not find any association between migraine or TTH and risk of AF. The adjusted hazard ratios (HRs) were respectively 0.84 (95% CI = 0.64-1.11) for migraine, 1.16 (95% CI = 0.86-1.27) for TTH and 1.04 (95% CI = 0.86-1.27) for unclassified headache. However, in sensitivity analyses of individuals aged ≥55 years, a lower risk of AF was found for migraine (HR = 0.53; 95% CI = 0.39-0.73). CONCLUSIONS: In this large population-based study, no increased risk of AF was found among individuals with migraine or TTH at baseline. Indeed, among individuals aged ≥55 years, migraine was associated with a lower risk for AF.

One-year prevalence of cluster headache, hemicrania continua, paroxysmal hemicrania and SUNCT in Norway: a population-based nationwide registry study.

BACKGROUND: There is lack of population-based studies evaluating the prevalence of paroxysmal hemicrania, hemicrania continua and short-lasting unilateral neuralgiform headache attacks. OBJECTIVES: The aim of this study was to investigate the gender-specific 1-year prevalence of cluster headache, paroxysmal hemicrania, hemicrania continua, and short-lasting unilateral neuralgiform headache attacks. METHODS: A nationwide study was conducted from January 1 2022 and December 31 2022 by linking diagnostic codes from Norwegian Patient Registry and prescription of relevant drugs from Norwegian Prescription Database on an individual basis. The 1-year prevalence with 95% confidence intervals (CI) of cluster headache, paroxysmal hemicrania, hemicrania continua and short-lasting unilateral neuralgiform headache attacks are estimated based on the combination of diagnostic codes, prescription of drugs and corresponding reimbursement codes. RESULTS: Among 4,316,747 individuals aged ≥ 18 years, the 1-year prevalence per 100,000 was 14.6 (95% CI 13.5-15.8) for cluster headache, 2.2 (95% CI 1.8-2.7) for hemicrania continua, 1.4 (95% CI 1.0-1.8) for paroxysmal hemicrania, and 1.2 (95% CI 0.8-1.4) for short-lasting unilateral neuralgiform headache attacks. For all the trigeminal autonomic cephalalgies, cluster headache included, the prevalence was higher for women than men. CONCLUSIONS: In this nationwide register-based study, we found a 1-year prevalence per 100,100 of 14.6 for cluster headache, 2.2 for hemicranias continua, 1.4 for paroxysmal hemicranias, and 1.2 for short-lasting unilateral neuralgiform headache attacks. This is the first study reporting higher prevalence of cluster headache for women than men.

Randomized controlled studies evaluating Topiramate, Botulinum toxin type A, and mABs targeting CGRP in patients with chronic migraine and medication overuse headache: A systematic review and meta-analysis.

BACKGROUND: This systematic review focuses on chronic migraine patients with medication overuse headache using, respectively, topiramate, botulinum toxin type A, and human monoclonal antibodies targeting calcitonin gene-related peptide or its receptor. METHODS: A systematic search was conducted in the databases CENTRAL, MEDLINE, Embase and Web of Science until May 2022. We included randomized controlled trials reporting the outcomes of change in monthly headache/migraine days, ≥50% response rates and change in medication overuse status. Studies were excluded if response rates were not reported. Risk of bias assessment was performed using the Cochrane RoB2 tool. The quality of evidence for outcomes across included studies was evaluated according to the five factors outlined in Cochrane GRADE approach. FINDINGS: The initial search resulted in 1599 records. Following screening, 10 studies met our inclusion criteria, while seven studies with sufficient data were included in the meta-analysis. Studies assessing Botulinum toxin type A included 1139 patients and showed a mean reduction in headache frequency by 1.92 days per month compared to placebo (-1.92; 95% CI -2.68 to -1.16). Studies assessing human monoclonal antibodies included 1982 patients, and showed significant positive effect compared to placebo for all measured outcomes. The overall odds ratio for the ≥50% response rate was 2.90 (95% CI, 2.23 to 3.78). No significant difference was observed in the frequency of adverse effect for both Botulinum toxin type A and low dose of human monoclonal antibodies compared to placebo. There is currently insufficient evidence to determine the impact of topiramate in chronic migraine patients with medication overuse headache. INTERPRETATION: Botulinum toxin type A and human monoclonal antibodies targeting calcitonin gene-related peptide receptor were beneficial in reducing monthly migraine days and ≥50% response rate, but uncertainties remained for Botulinum toxin type A regarding response rate. The effect size for human monoclonal antibodies was greater with relatively lower drop-out rate. High-quality randomized trials are required to evaluate the effect of topiramate in chronic migraine patients with medication overuse headache.

Menopausal hormone therapy, oral contraceptives and risk of chronic low back pain: the HUNT Study.

BACKGROUND: There are indications that use of menopausal hormone therapy (MHT) and oral contraceptives (OC) increases the risk of low back pain (LBP), with higher oestrogen levels involved in the underlying mechanisms. The purpose of the present study was to investigate associations between use of systemic MHT or OC and risk of chronic LBP in a large population-based data set. METHODS: Data were obtained from two surveys in the Trøndelag Health Study in Norway, HUNT2 (1995-1997) and HUNT3 (2006-2008). A cross-sectional study of association between use of systemic MHT and prevalence of chronic LBP comprised 12,974 women aged 40-69 years in HUNT2, with 4007 women reporting chronic LBP. A cohort study involving MHT comprised 6007 women without chronic LBP at baseline in HUNT2, and after 11 years 1245 women reported chronic LBP at follow-up in HUNT3. The cross-sectional study of association with use of OC included 23,593 women aged 20-69 years in HUNT2, with 6085 women reporting chronic LBP. The corresponding cohort study included 10,586 women without chronic LBP at baseline in HUNT2, of whom 2084 women reported chronic LBP in HUNT3. Risk of chronic LBP was examined in both study designs in generalised linear models with adjustment for potential confounders. RESULTS: In the cohort study, current users of systemic MHT at baseline showed a greater risk of chronic LBP (relative risk (RR) 1.30; 95% CI: 1.14-1.49; compared with never users). The risk increased according to duration of MHT use (P for linear trend = 0.003). Known users of systemic MHT based exclusively on oestrogen experienced the highest risk (RR 1.49; 95% CI: 1.16-1.91), but an increased risk was also seen among known users of oestrogen-progestin combination MHT (RR 1.35; 95% CI: 1.16-1.57). A slight increase in risk of chronic LBP was found in the cohort study among former users of OC (RR 1.17; 95% CI: 1.06-1.30; compared with never users). CONCLUSIONS: Long-lasting use of systemic MHT, in particular therapy based on oestrogen only, is associated with greater risk of chronic LBP. Having been a user of OC most likely entails a minor increase in risk.

The global prevalence of headache: an update, with analysis of the influences of methodological factors on prevalence estimates.

BACKGROUND: According to the Global Burden of Disease (GBD) study, headache disorders are among the most prevalent and disabling conditions worldwide. GBD builds on epidemiological studies (published and unpublished) which are notable for wide variations in both their methodologies and their prevalence estimates. Our first aim was to update the documentation of headache epidemiological studies, summarizing global prevalence estimates for all headache, migraine, tension-type headache (TTH) and headache on ≥15 days/month (H15+), comparing these with GBD estimates and exploring time trends and geographical variations. Our second aim was to analyse how methodological factors influenced prevalence estimates. METHODS: In a narrative review, all prevalence studies published until 2020, excluding those of clinic populations, were identified through a literature search. Prevalence data were extracted, along with those related to methodology, world region and publication year. Bivariate analyses (correlations or comparisons of means) and multiple linear regression (MLR) analyses were performed. RESULTS: From 357 publications, the vast majority from high-income countries, the estimated global prevalence of active headache disorder was 52.0% (95%CI 48.9-55.4), of migraine 14.0% (12.9-15.2), of TTH 26.0% (22.7-29.5) and of H15+ 4.6% (3.9-5.5). These estimates were comparable with those of migraine and TTH in GBD2019, the most recent iteration, but higher for headache overall. Each day, 15.8% of the world's population had headache. MLR analyses explained less than 30% of the variation. Methodological factors contributing to variation, were publication year, sample size, inclusion of probable diagnoses, sub-population sampling (e.g., of health-care personnel), sampling method (random or not), screening question (neutral, or qualified in severity or presumed cause) and scope of enquiry (headache disorders only or multiple other conditions). With these taken into account, migraine prevalence estimates increased over the years, while estimates for all headache types varied between world regions. CONCLUSION: The review confirms GBD in finding that headache disorders remain highly prevalent worldwide, and it identifies methodological factors explaining some of the large variation between study findings. These variations render uncertain both the increase in migraine prevalence estimates over time, and the geographical differences. More and better studies are needed in low- and middle-income countries.

Validation of questionnaires for restless legs syndrome in the general population: the Trøndelag Health Study (HUNT).

Questionnaires for restless legs syndrome have rarely been validated against face-to-face interviews in the general population. We aimed to validate the modified Norwegian, seven-item Cambridge-Hopkins restless legs syndrome questionnaire and a single diagnostic question for restless legs syndrome. We also aimed to stratify validity at 65 years of age. Among a random sample of 1,201 participants from the fourth wave of the Trøndelag Health Study, 232 (19%) agreed to participate, out of whom 221 had complete data for analyses. Participants completed the questionnaires for restless legs syndrome immediately before attending a face-to-face interview using the latest diagnostic criteria. We calculated sensitivity, specificity, and Cohen's kappa statistic (κ) of questionnaire- versus interview-based diagnoses. We found acceptable validity of the seven-item modified Cambridge-Hopkins diagnostic questionnaire for restless legs syndrome (κ = 0.37, 95% confidence interval [CI] 0.23-0.51) and good validity of the single diagnostic question (κ = 0.47, 95% CI 0.35-0.58). We also found good validity through the combination of modified Cambridge-Hopkins diagnostic questionnaire for restless legs syndrome items 2 and 5, while item 1 or 2 alone showed only acceptable validity. The single diagnostic question was significantly more valid among those aged <65 years (κ = 0.60 versus κ = 0.26). Both single- and two-item questionnaire-based diagnoses overestimated interview-based restless legs syndrome prevalence. The seven-item modified Cambridge-Hopkins diagnostic questionnaire for restless legs syndrome will be useful for epidemiological studies although low sensitivity may cause underestimation of true restless legs syndrome prevalence in the general population, especially among elderly. Brief questionnaire-based diagnoses of up to three items seem best utilised as an initial screen. Future studies should identify brief and even more valid questionnaire-based diagnoses for restless legs syndrome in order to estimate prevalence accurately in large epidemiological studies.

Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles.

Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.

Does the risk of chronic low back pain depend on age at menarche or menopause? A population-based cross-sectional and cohort study: the Trøndelag Health Study.

OBJECTIVE: In most population-based studies of low back pain (LBP), women have a higher risk than men, possibly reflecting hormonal influences. The aim of this study was to explore associations between age at menarche and menopause and risk of chronic LBP. DESIGN: Population-based cross-sectional and cohort study designs. SETTING: The HUNT2 and HUNT3 medical surveys of the entire population of Nord-Trøndelag County in Norway. MAIN OUTCOME MEASURE: Prevalence or risk of chronic LBP, defined as LBP persisting at least 3 months continuously during last year. PARTICIPANTS: Associations between age at menarche and prevalence of chronic LBP were examined in cross-sectional data from HUNT2, comprising 27 697 women aged 20-69 years, with 7300 women reporting LBP. The corresponding cohort data included 11 659 women without LBP at baseline in HUNT2, with 2353 women reporting LBP at follow-up 11 years later in HUNT3. Cross-sectional data on age at menopause or premenopausal status included 11 332 women aged 40-69 years, with 3439 women reporting chronic LBP. Corresponding cohort data included 7893 women without LBP at baseline, of whom 1100 developed LBP. METHODS: Associations between age at menarche or menopause and risk of chronic LBP were examined by generalised linear modelling. RESULTS: A U-shaped association was indicated between age at menarche and risk of chronic LBP, both in the cross-sectional and cohort studies. Age at menarche ≤11 years was associated with an increased risk of chronic LBP, with a relative risk of 1.32 (95% CI 1.15 to 1.52), compared with age 14 years at menarche, after relevant adjustments. Corresponding cross-sectional crude absolute risks were 32% and 25%, respectively. No association was established between age at menopause and risk of LBP. Being premenopausal had no influence on risk. CONCLUSIONS: In contrast to results for age at menopause, the association with age at menarche suggests that hormonal factors affect the risk of LBP.

FollowTheSutures: Piloting a new way to administer onabotulinumtoxinA for chronic migraine.

BACKGROUND: Anatomical and experimental data indicate that onabotulinimtoxin A could be more efficient and cost-effective for treating chronic migraine with injections targeting the cranial sutures, where collaterals from the meninges penetrate the skull. METHODS: A new injection paradigm (FollowTheSutures) was tested for safety, tolerability and feasibility in a Phase II, open-label, non-controlled, single-center pilot study. Ninety units of onabotulinimtoxin A (Botox®), were injected in 18 sites over the area of the cranial sutures. Adverse events and potential beneficial effects were recorded in a headache diary at least 4 weeks before, and for 12 weeks after the injections. A higher dilution than normal of onabotulinimtoxin A was used to get better diffusion. RESULTS: Nineteen (of 20 included) women with chronic migraine received the injections and were evaluable. There was only one treatment-related adverse event (reduced power of chewing for some weeks). Otherwise, the procedure was overall well tolerated. Patients improved on most efficacy parameters after the injections. There was little or no effect on glabellar or forehead lines. CONCLUSIONS: The protocol was safe and well tolerated. Lower risk of unblinding due to the absence of cosmetic effects should make the injection procedure well suited for a large, randomized, placebo-controlled study. If efficacy is confirmed, it will be markedly less costly than the standard procedure.Trial registration: EUDRACT (2017-002516-13), ClinicalTrials.gov (NCT03543254).

The bidirectional temporal relationship between headache and affective disorders: longitudinal data from the HUNT studies.

BACKGROUND: Few prospective population-based studies have evaluated the bidirectional relationship between headache and affective disorder. The aim of this large-scale population-based follow-up study was to investigate whether tension-type headache (TTH) and migraine had increased risk of developing anxiety and depression after 11 years, and vice-versa. METHODS: Data from the Trøndelag Health Study (HUNT) conducted in 2006-2008 (baseline) and 2017-2019 (follow-up) were used to evaluate the bidirectional relationship between migraine and TTH and anxiety and depression measured by Hospital Anxiety and depression Scale (HADS). The population at risk at baseline consisted of respectively 18,380 persons with HADS score ≤ 7 and 13,893 without headache, and the prospective data was analyzed by Poisson regression. RESULTS: In the multi-adjusted model, individuals with HADS anxiety (HADS-A) and depression scores (HADS-D) of ≥8 at baseline nearly doubled the risk of migraine (Risk rations (RR) between 1.8 and 2.2) at follow-up whereas a 40% increased risk (RR 1.4) was found for TTH. Vice versa, the risk of having HADS-A and HADS-D scores of ≥8 at follow-up were increased for TTH (RR 1.3) and migraine (RR 1.3-1.6) at baseline. Migraine with aura was associated with 81% (RR 1.81, 95% 1.52-2.14) increased risk of HADS-A score of ≥8. CONCLUSIONS: In this large-scale population-based follow-up study we found a bidirectional relationship between anxiety and depression and migraine and TTH. For anxiety, this bidirectional association was slightly more evident for migraine than TTH.

Reliability of a self-administrated musculoskeletal questionnaire: The fourth Trøndelag health study.

BACKGROUND: The reliability of the Nordic Musculoskeletal Questionnaire (NMQ) has not been evaluated in an unselected general population. The aim of this population-based follow-up study was to estimate the reliability between a self-administered NMQ-based questionnaire and a face-to-face interview performed approximately two months later. To interpret the results, we assessed the 1-year prevalence of various pain musculoskeletal pain locations. METHODS: A random sample of 1201 participants in the fourth wave of the Trøndelag Health Survey were invited to a follow-up interview focusing on sleep and pain. A total of 232 (19%) participated a semi-structured interview, and the agreement with the corresponding answers in the musculoskeletal questionnaire in HUNT4 were evaluated by Cohen's kappa statistics with 95% confidence interval (CI). The 1-year prevalence of the various pain sites was stratified by age and gender. RESULTS: The reliability was good for chronic musculoskeletal pain (CMSP), chronic widespread musculoskeletal pain (CWMSP) and pain in hip and knee (kappa values between 0.63 and 0.68). Moderate kappa values between 0.51 and 0.60 were found for pain in the neck, shoulder, elbow, wrist/hand, upper back, lower back, calf, ankle/feet, and ≥7 pain sites. The 1-year prevalence was 54.3% for CMSP and 17.2 for CWMSP, substantially higher for women and among those aged 50 years or more. CONCLUSION: In this population-based study the reliability between interview and questionnaire was good to moderate for most pain locations. In particular, the self-administered musculoskeletal questionnaire seems to be a useful tool in identifying individuals with CMSP, CWMSP, and pain in hip and knee.

Pragmatic trials - what are they? / Pragmatiske studier ­ hva er det?

Pragmatic clinical trials are based on data from unselected patients recruited from common clinical practice. These trials therefore bridge the gap between evidence-based medicine and clinical practice.

Long-term changes in self-reported sleep quality and risk of chronic musculoskeletal pain: The HUNT Study.

We examined the association between long-term (~10 years) changes in self-reported sleep quality and risk of any chronic musculoskeletal pain and chronic widespread pain. The study comprised data on 6,033 people who participated in three consecutive surveys in the Norwegian HUNT Study (1995-1997, 2006-2008 and 2017-2019) and who were without chronic musculoskeletal pain at the first two surveys. We used a modified Poisson regression model to calculate adjusted risk ratios for chronic pain at follow-up (2017-2019) associated with categories of poor and good sleep quality reported in 1995-1997 and 2006-2008. Compared with people who reported good sleep at both surveys (crude absolute risk: 32.4%), the risk ratios of any chronic pain were 1.20 (95% confidence interval: 1.02-1.41) for those who changed from poor to good sleep; 1.25 (95% confidence interval: 1.12-1.39) for those who changed from good to poor sleep; and 1.41 (95% confidence interval: 1.21-1.63) for those who reported long-term poor sleep. The corresponding risk ratios for chronic widespread pain were 1.35 (95% confidence interval: 0.82-2.23), 1.55 (95% confidence interval: 1.14-2.12) and 2.09 (95% confidence interval: 1.38-3.17), respectively. In conclusion, these findings indicate that people with long-term poor sleep quality have a markedly higher risk of chronic musculoskeletal pain and chronic widespread pain, compared with people who remain good sleep quality.

Genome-wide association study identifies RNF123 locus as associated with chronic widespread musculoskeletal pain.

BACKGROUND AND OBJECTIVES: Chronic widespread musculoskeletal pain (CWP) is a symptom of fibromyalgia and a complex trait with poorly understood pathogenesis. CWP is heritable (48%-54%), but its genetic architecture is unknown and candidate gene studies have produced inconsistent results. We conducted a genome-wide association study to get insight into the genetic background of CWP. METHODS: Northern Europeans from UK Biobank comprising 6914 cases reporting pain all over the body lasting >3 months and 242 929 controls were studied. Replication of three independent genome-wide significant single nucleotide polymorphisms was attempted in six independent European cohorts (n=43 080; cases=14 177). Genetic correlations with risk factors, tissue specificity and colocalisation were examined. RESULTS: Three genome-wide significant loci were identified (rs1491985, rs10490825, rs165599) residing within the genes Ring Finger Protein 123 (RNF123), ATPase secretory pathway Ca2+transporting 1 (ATP2C1) and catechol-O-methyltransferase (COMT). The RNF123 locus was replicated (meta-analysis p=0.0002), the ATP2C1 locus showed suggestive association (p=0.0227) and the COMT locus was not replicated. Partial genetic correlation between CWP and depressive symptoms, body mass index, age of first birth and years of schooling were identified. Tissue specificity and colocalisation analysis highlight the relevance of skeletal muscle in CWP. CONCLUSIONS: We report a novel association of RNF123 locus and a suggestive association of ATP2C1 locus with CWP. Both loci are consistent with a role of calcium regulation in CWP. The association with COMT, one of the most studied genes in chronic pain field, was not confirmed in the replication analysis.

Validation of insomnia questionnaires in the general population: The Nord-Trøndelag Health Study (HUNT).

The primary aim was to validate questionnaire-based insomnia diagnoses from a modified Karolinska Sleep Questionnaire (KSQ) and the Insomnia Severity Index (ISI), by age category (< or >65 years), against a semi-structured face-to-face interview. Secondary aims were to split validity by diagnostic certainty of the interview and to compare prevalence estimates of questionnaire- and interview-based diagnoses. A total of 232 out of 1,200 invited (19.3%) from the fourth Nord-Trøndelag Health Study (HUNT4) completed questionnaires, including the KSQ and ISI, shortly before attending a face-to-face diagnostic interview for insomnia based on the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Both a tentative (DSM-5 criteria A-E) and a definite (criteria A-H) interview diagnosis was evaluated. Cohen's kappa statistic quantified questionnaire validity. In all, 33% (95% confidence interval 27-39%) of participants had definite insomnia: 40% of women and 21% of men. The ISI (cut-off 12) and several KSQ-based diagnoses showed very good validity (κ ≤0.74) against the tentative, versus good validity (κ ≤0.61) against the definite interview diagnosis. Short questionnaires, requiring a daytime symptom at least three times a week, may underestimate insomnia prevalence. Validity was consistently higher for persons aged below versus above 65 years (definite insomnia: κ ≤0.64 vs. κ ≤0.56). Our results have implications for epidemiological population-based studies utilising insomnia questionnaires.