Reliability and measurement error of exercise-induced hypoalgesia in pain-free adults and adults with musculoskeletal pain: A systematic review.

OBJECTIVES: We systematically reviewed the reliability and measurement error of exercise-induced hypoalgesia (EIH) in pain-free adults and in adults with musculoskeletal (MSK) pain. METHODS: We searched EMBASE, PUBMED, SCOPUS, CINAHL, and PSYCINFO from inception to November 2021 (updated in February 2024). In addition, manual searches of the grey literature were conducted in March 2022, September 2023, and February 2024. The inclusion criteria were as follows: adults - pain-free and with MSK pain - a single bout of exercise (any type) combined with experimental pre-post pain tests, and assessment of the reliability and/or measurement error of EIH. Two independent reviewers selected the studies, assessed their Risk of Bias (RoB) with the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) RoB tool, and graded the individual results (COSMIN modified Grading of Recommendations Assessment, Development, and Evaluation). RESULTS: We included five studies involving pain-free individuals (n = 168), which were deemed to have an overall "doubtful" RoB. No study including adults with MSK pain was found. The following ranges of parameters of reliability and measurement error of EIH were reported: intraclass correlation coefficients: 0-0.61; kappa: 0.01-0.46; standard error of measurement: 30.1-105 kPa and 10.4-21%; smallest detectable changes: 83.54-291.1 kPa and 28.83-58.21%. CONCLUSIONS: We concluded, with a very low level of certainty, that the reliability and measurement error of EIH is, in pain-free adults, respectively, "insufficient" and "indeterminate." Future studies should focus on people with MSK pain and could consider using tailored exercises, other test modalities than pressure pain threshold, rater/assessor blinding, and strict control of the sources of variations (e.g., participants' expectations).

Naltrexone 6 mg once daily versus placebo in women with fibromyalgia: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Low-dose naltrexone is used to treat fibromyalgia despite minimal evidence for its efficacy. This trial aimed to investigate whether 12-week treatment with 6 mg low-dose naltrexone was superior to placebo for reducing pain in women with fibromyalgia. METHODS: We did a single-centre, randomised, double-blind, placebo-controlled trial in Denmark. We enrolled women aged 18-64 years who were diagnosed with fibromyalgia. Participants were randomly assigned 1:1 to receive low-dose naltrexone (6 mg) or an identical-appearing placebo, using a computerised algorithm with no stratifications applied. Participants, investigators, outcome assessors, and statistical analysts were all masked to treatment allocation. The primary outcome was change in pain intensity on an 11-point numeric rating scale from baseline to week 12, in the intention-to-treat population. Safety was assessed in participants in the intention-to-treat population who received at least one dose of their allocated intervention. This trial was registered with ClincalTrials.gov (NCT04270877) and EudraCT (2019-000702-30). FINDINGS: We screened 158 participants for eligibility from Jan 6, 2021, to Dec 27, 2022, and 99 patients were randomly assigned to low-dose naltrexone (n=49) or placebo (n=50). The mean age was 50·6 years (SD 8·8), one (1%) of 99 participants was Arctic Asian and 98 (99%) were White. No participants were lost to follow-up. The mean change in pain intensity was -1·3 points (95% CI -1·7 to -0·8) in the low-dose naltrexone group and -0·9 (-1·4 to -0·5) in the placebo group, corresponding to a between-group difference of -0·34 (-0·95 to 0·27; p=0·27, Cohen's d 0·23). Discontinuations due to adverse events were four (8%) of 49 in the low-dose naltrexone group and three (6%) of 50 in the placebo group. 41 (84%) of 49 patients in the low-dose naltrexone group had an adverse event versus 43 (86%) of 50 in the placebo group. One serious adverse event occurred in the placebo group and no deaths occurred. INTERPRETATION: This study did not show that treatment with low-dose naltrexone was superior to placebo in relieving pain. Our results indicate that low-dose naltrexone might improve memory problems associated with fibromyalgia, and we suggest that future trials investigate this further. FUNDING: The Danish Rheumatism Association, Odense University Hospital, Danielsen's Foundation, and the Oak Foundation.

Changes in pain, daily occupations, lifestyle, and health following an occupational therapy lifestyle intervention: a secondary analysis from a feasibility study in patients with chronic high-impact pain.

OBJECTIVES: This study explored changes in pain-related parameters, occupational function, occupational balance, lifestyle factors, and self-perceived health status in adults with chronic high-impact pain participating in an occupational therapy lifestyle intervention. METHODS: This one-group longitudinal feasibility study was performed in three continuous feasibility rounds. The occupational therapists-led intervention targeted meaningful occupations, regular physical activity, and a healthy diet. The intervention contained individual and group sessions and was added to the standard multidisciplinary chronic pain treatment. Outpatients (n=40, 85 % females, 46.6 ± 10.9 years old) participated in the study between April 2019 and December 2021. The analysis includes data for 31 participants. Analysis of pre-post changes assessed after each feasibility round were performed for the outcomes: pain intensity, pain sensitivity and pain modulation (pressure pain threshold and tolerance, temporal summation of pain and conditioned pain modulation), pain self-efficacy, pain catastrophizing, motor and process skills, occupational balance, daily wake-time movement, daily walking steps, body mass index, waist circumference, blood pressure, and self-perceived health status. RESULTS: Improvements in motor skills (assessment of motor and process skills score=0.20 (1.37; 1.57), 95 % CI 0.01; 0.38) and temporal summation of pain (-1.19 (2.86; -1.67), 95 % CI -2.16; -0.22), but a decrease in pain tolerance (-7.110 (54.42; 47.32), 95 % CI -13.99; -0.22) were observed. Correlation analysis suggested moderate-to-very strong statistically significant relationships in several outcomes related to pain, health, pain coping, occupational balance, occupational functioning, body anthropometrics, and pain sensitivity. CONCLUSIONS: This study suggested that the lifestyle intervention would benefit motor skills while effects on other outcomes were unclear in adults with chronic pain. To confirm the findings, a randomized trial evaluating effectiveness is needed. Ethical committee number: SJ-307 Reg. Clinicaltrials.gov: NCT03903900.

The Danish Pain Research Biobank (DANPAIN-Biobank): a collection of blood, cerebrospinal fluid, and clinical data for the study of neuroimmune and glia-related biomarkers of chronic pain.

Background: Chronic pain is a major health problem worldwide but the limited knowledge of its underlying pathophysiology impairs the opportunities for diagnostics and treatment. Biomarkers of chronic pain are greatly needed to understand the disease and develop new targets for interventions and drug treatments, and potentially introduce more precise diagnostic procedures. Much evidence points to a neuroimmune pathology for many chronic pain conditions and that important neuroimmune biomarkers exist in the cerebrospinal fluid (CSF) of patients with chronic pain. Systematic collection of CSF in large cohorts of chronic pain patients and healthy volunteers has proven difficult, however. We established the Danish Pain Research Biobank (DANPAIN-Biobank) with the aim of studying potential neuroimmune and glia-related biomarkers of chronic pain. In this paper, we describe the methods and the study population of the DANPAIN-Biobank. Methods: In this cross-sectional study, we included (I) participants with high-impact (HI) chronic pain from a tertiary, interdisciplinary pain center; (II) participants with osteoarthritic pain scheduled for arthroplasty surgery of the hip or knee at a regional hospital; and (III) pain-free volunteers. All participants completed a questionnaire assessing pain, functional impairment, anxiety, depression, and insomnia before samples of blood and CSF were extracted. Quantitative sensory tests were performed on participants with HI chronic pain and pain-free volunteers, and postoperative outcome scores were available on participants with osteoarthritic pain. Results: Of the 352 participants included, 201 had HI chronic pain (of which 71% had chronic widespread pain), 81 had chronic osteoarthritic pain, and 70 were pain-free volunteers. Samples were handled uniformly, and CSF samples were frozen within 30 minutes. Conclusions: We describe the content of the DANPAIN-Biobank, which is unique in terms of the number of participants (including pain-free volunteers), extensive clinical data, and uniformity in sample handling. We believe it presents a promising new platform for the study of neuroimmune and glia-related biomarkers of chronic pain.

Experience and usability of a website containing research-based knowledge and tools for pain self-management: a mixed-method study in people with high-impact chronic pain.

OBJECTIVES: Smerteinfo.dk is a freely accessible Danish website containing research-based, up-to-date knowledge on chronic pain, written in lay language, with a focus on information, guidance and self-management tools, developed in collaboration between health professionals and persons with high-impact chronic pain. This mixed-method study explored experiences, perceived usability, and challenges of Smerteinfo among patients with high-impact chronic pain. METHODS: Semi-structured interviews enabling thinking-aloud and participant observation while using Smerteinfo were performed in 11 patients with high-impact chronic pain. Survey data were collected three months after being invited to use Smerteinfo among 200 patients on waiting-list at a Pain Center in Denmark. RESULTS: Three themes captured the depth and variation in patterns of experiences, usability and challenges using Smerteinfo during interviews: 1) Appreciated easy access to new knowledge yet strived for more personalized information, 2) Experienced incentives as well as challenges when navigating the website, and 3) Suggested earlier introduction to the website. Challenges concerned the unknown update frequency of the website, information consisting of mostly text and many links, lack of material to improve self-management and too general information. Survey data revealed that 87 % found the language in the articles easy to understand and 73 % could recognize themselves and their challenges in the articles. A proportion of the respondents reported improved understanding of their pain condition (56 %), improved coping (33 %), and that they had made changes in their everyday life after reading on the website (33 %). CONCLUSIONS: Patients with high-impact chronic pain found Smerteinfo valuable. The results suggest attention towards spreading knowledge of the website to general practitioners, who could introduce the site at an earlier stage of illness. Continuously improving the site and expand the applicable tools based on scientific evidence and in collaboration with end-users are crucial to ensure the usability of the website in the future.

Interpretation of the Patient Health Questionnaire 9 in High-Impact Chronic Pain: Do We Measure Depressive Symptoms the Way We Think?

OBJECTIVES: Depression is prevalent among patients with chronic pain and may impact pain management. An accurate assessment is, however, complicated by overlapping symptoms. This study investigated how patients with high-impact chronic pain interpreted and responded to the Patient Health Questionnaire 9 (PHQ-9) to identify problematic items and causes hereof. MATERIALS AND METHODS: Cognitive interviews using the Three-Step Test-Interview procedure were conducted during the completion of the PHQ-9 in 33 patients with high-impact chronic pain referred to interdisciplinary treatment. Responses were analyzed using 4 coding categories: (1) "congruent" (response consistent with intention); (2) "incongruent" (response not consistent intention); (3) "ambiguous" (response both congruent and incongruent or insufficient to evaluate congruency); and (4) "confused" (response with confused or misunderstood statements). Next, the content of responses to problematic items was analyzed to identify causes for noncongruency, and encountered response difficulties were identified across all items. RESULTS: Three items (items 2, 6, and 9) performed as intended (>97% congruent responses), while 7 items (items 1, 3, 4, 5, 7, 8, and 10) were identified as problematic (<50% congruent responses). Problematic items had 1 or more issues: Responses were based on (1) pain-related issues or (2) other (non-pain) factors unrelated to depression, or item structure caused response difficulties due to wordings, reversion, or having 2 questions in 1. DISCUSSION: Problematic items limit the construct validity of the PHQ-9, leaving an increased risk of inflated depression scores in high-impact chronic pain. Identified problems should guide future revisions to enhance validity and screening accuracy for the benefit of both research and clinical practice.

The role of spontaneous vs. experimentally induced attentional strategies for the pain response to a single bout of exercise in healthy individuals.

OBJECTIVES: Exercise-induced pain and exercise-induced hypoalgesia (EIH) are well described phenomena involving physiological and cognitive mechanisms. Two experiments explored whether spontaneous and instructed mindful monitoring (MM) were associated with reduced exercise-induced pain and unpleasantness, and increased EIH compared with spontaneous and instructed thought suppression (TS) in pain-free individuals. METHODS: Eighty pain-free individuals participated in one of two randomized crossover experiments. Pressure pain thresholds (PPTs) were assessed at the leg, back and hand before and after 15 min of moderate-to-high intensity bicycling and a non-exercise control condition. Exercise-induced pain and unpleasantness were rated after bicycling. In experiment 1 (n=40), spontaneous attentional strategies were assessed with questionnaires. In experiment 2, participants (n=40) were randomly allocated to use either a TS or MM strategy during bicycling. RESULTS: In experiment 1, the change in PPTs was significantly larger after exercise compared with quiet rest (p<0.05). Higher spontaneous MM was associated with less exercise-induced unpleasantness (r=-0.41, p<0.001), whereas higher spontaneous TS was associated with higher ratings of exercise-induced unpleasantness (r=0.35, p<0.05), but not with pain intensity or EIH. In experiment 2, EIH at the back was increased in participants using instructed TS compared with participants using instructed MM (p<0.05). CONCLUSIONS: These findings suggest that spontaneous and presumably habitual (or dispositional) attentional strategies may primarily affect cognitive-evaluative aspects of exercise, such as feelings of exercise-induced unpleasantness. MM was related to less unpleasantness, whereas TS was related to higher unpleasantness. In terms of brief experimentally-induced instructions, TS seems to have an impact on physiological aspects of EIH; however, these preliminary findings need further research.

Acute exercise of painful muscles does not reduce the hypoalgesic response in young healthy women - a randomized crossover study.

OBJECTIVES: Exercise-induced hypoalgesia (EIH) is characterized by an increase in pain threshold following acute exercise. EIH is reduced in some individuals with chronic musculoskeletal pain, although the mechanisms are unknown. It has been hypothesized that this may relate to whether exercises are performed in painful or non-painful body regions. The primary aim of this randomized experimental crossover study was to investigate whether the presence of pain per se in the exercising muscles reduced the local EIH response. The secondary aim was to investigate if EIH responses were also reduced in non-exercising remote muscles. METHODS: Pain-free women (n=34) participated in three separate sessions. In session 1, the maximal voluntary contraction (MVC) for a single legged isometric knee extension exercise was determined. In sessions 2 and 3, pressure pain thresholds (PPT) were assessed at the thigh and shoulder muscles before and after a 3-min exercise at 30 % of MVC. Exercises were performed with or without thigh muscle pain, which was induced by either a painful injection (hypertonic saline, 5.8 %) or a non-painful injection (isotonic saline, 0.9 %) into the thigh muscle. Muscle pain intensity was assessed with an 11-point numerical rating scale (NRS) at baseline, after injections, during and after exercises. RESULTS: PPTs increased at thigh and shoulder muscles after exercise with painful (14.0-24.9 %) and non-painful (14.3-19.5 %) injections and no significant between-injection EIH differences were observed (p>0.30). Muscle pain intensity was significantly higher following the painful injection compared to the non-painful injection (p<0.001). CONCLUSIONS: Exercising painful muscles did not reduce the local or remote hypoalgesic responses, suggesting that the pain-relieving effects of isometric exercises are not reduced by exercising painful body regions. ETHICAL COMMITTEE NUMBER: S-20210184. TRIAL REGISTRATION NUMBER: NCT05299268.

Validation of the Danish PTSD Checklist for DSM-5 in trauma-exposed chronic pain patients using the Clinician-Administered PTSD Scale for DSM-5.

Background: Validation of post-traumatic stress disorder (PTSD) screening tools across various populations to ensure accurate PTSD estimates is important. Because of the high symptom overlap between PTSD and pain, it is particularly important to validate PTSD screening tools in trauma-exposed chronic pain patients.Objective: The present study is the first seeking to validate the PTSD Checklist for DSM-5 (PCL-5) in a sample of trauma-exposed, treatment-seeking chronic pain patients.Method: The validation and optimal scoring of the PCL-5 were investigated using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) in chronic pain patients exposed to traffic or work-related traumas (n = 84). Construct validity was investigated using confirmatory factor analyses testing six competing DSM-5 models in a sample of mixed trauma-exposed chronic pain patients (n = 566), and a subsample of chronic pain patients exposed to traffic or work-related trauma only (n = 202). Furthermore, concurrent validity and discriminant validity were investigated using correlation analysis.Results: The results showed moderate (κ = .46) diagnostic consistency between the PCL-5 and the CAPS-5 using the DSM-5 symptom cluster criteria, and the overall accuracy of the scale (area under the curve = .79) was highly acceptable. Furthermore, the Danish PCL-5 showed excellent construct validity both in the full sample and in the subsample of traffic and work-related accidents, with superior fit of the seven-factor hybrid model. Excellent concurrent validity and discriminant validity were also established in the full sample.Conclusion: The PCL-5 appears to have satisfactory psychometric properties in trauma-exposed, treatment-seeking chronic pain patients.

The present study is the first seeking to validate the PCL-5 using the CAPS-5 in chronic pain patients following traffic and work-related injury.The results showed moderate diagnostic consistency and acceptable overall accuracy using the DSM-5 criteria.Excellent construct, concurrent, and discriminant validity was established in chronic pain patients following mixed traumatic exposure and traffic and work-related trauma only.

Less is more: reliability and measurement error for three versions of the Tampa Scale of Kinesiophobia (TSK-11, TSK-13, and TSK-17) in patients with high-impact chronic pain.

OBJECTIVES: The Tampa Scale of Kinesiophobia (TSK) is a valid and reliable tool to assess somatic focus and activity avoidance in patients. Currently, the test-retest reliability and measurement error for the Danish version is unknown. The aim of the study was to determine standard error of measurement (SEM) and smallest detectable change (SDC) for three Danish lengths of the TSK in patients with chronic pain. METHODS: Waiting-list patients (n = 77) completed the TSK-17 twice from home with a test interval between 7 and 14 days. Based on COSMIN recommendations, the test-retest reliability was estimated using intraclass correlation coefficient (ICC2,1), and measurement error in terms of standard error of measurement (SEMagreement) and SDC95% were calculated. RESULTS: All three versions showed good test-retest reliability with ICC2,1-values (CI95%) of 0.86(0.79-0.91), 0.88(0.82-0.92) and 0.87(0.81-0.92) for the TSK-17, TSK-13, and TSK-11. The SEM-values were 3.08, 2.42 and 2.10 respectively and SDC95%-values were 8.53, 6.71 and 5.82. CONCLUSIONS: The Danish versions of TSK-11, TSK-13 and TSK-17 showed good to excellent test-retest reliability. SEM and SDC95% values in patients with chronic pain are reported. The TSK-11 did not show systematic bias between test and retest and may be preferred to minimize responder burden.

The Effect of Virtual Reality on Cold Pain Sensitivity in Patients with Fibromyalgia and Pain-Free Individuals: A Randomized Crossover Study.

Introduction: Fibromyalgia is a complex pain syndrome with high personal and societal costs, with only few effective tools for treatment. Virtual reality (VR) may be an efficient pain management tool although the effectiveness in fibromyalgia patients is unclear. Objective: This randomized crossover study set out to 1) investigate the effect of VR on cold pain threshold, -tolerance, and -intensity in fibromyalgia patients and in pain-free individuals and 2) explore the potential relationships between the effect of VR and pain catastrophizing. Materials and Methods: Twenty-two female fibromyalgia patients and 22 sex- and age-matched pain-free individuals participated in two conditions (one with VR and one without VR) with foot immersion in 1°C-2°C cold water. The order of conditions was randomized and counterbalanced for each group. Conditions were separated by 20 minutes. Cold pain threshold, -tolerance, and -intensity were assessed during the conditions. Pain catastrophizing was assessed using the Pain Catastrophizing Scale. Results: VR induced moderate to large increases in cold pain threshold and pain tolerance compared with the control condition for both the fibromyalgia group and pain-free individuals (P < 0.03). Pain intensity was reduced after VR only in pain-free individuals (P < 0.003). Pain catastrophizing was not related to VR effect on pain threshold, -tolerance, or -intensity for any group. Conclusion: VR had a significant effect on pain threshold and tolerance in fibromyalgia patients and pain-free individuals, which supports its ability to distract from pain. Future studies exploring the VR's potential as part of clinical pain management alone or in combination with other treatments are warranted. ClinicalTrials.gov (NCT04294914).

Occupational therapy lifestyle intervention added to multidisciplinary treatment for adults living with chronic pain: a feasibility study.

OBJECTIVES: To evaluate the feasibility and outcomes of an occupational therapy lifestyle intervention for adults living with chronic pain. DESIGN: This one-group pre-post interventional study investigated the feasibility and outcomes of the Redesign Your Everyday Activities and Lifestyle with Occupational Therapy (REVEAL(OT)) intervention targeting meaningful activities and lifestyle. SETTINGS: The occupational therapist-led intervention was added to standard multidisciplinary chronic pain treatment at a Danish pain centre. PARTICIPANTS: Of the 40 adult participants aged 18-64 (mean 46.6±10.9 years old, 85% females, chronic pain duration ≥3 months), there were 31 completers. INTERVENTION: Three feasibility rounds were carried out in 2019-2021. The intervention focused on meaningful activities, healthy eating habits and daily physical activity. Methods of didactical presentations, group discussions, personal reflection and experiential learning were used in the intervention composed both of individual and group sessions. OUTCOMES: Primary outcomes were predefined research progression criteria evaluated by the red-amber-green method. Secondary outcomes measured pre-post changes in health-related quality of life and occupational performance and satisfaction. RESULTS: The study demonstrated satisfactory programme adherence (77.5%), patients' self-perceived relevance (97%), timing and mode of delivery (97%) and assessment procedure acceptance (95%). No adverse events causing discontinuation occurred. Recruitment rate (n=5.7 monthly), retention (77.5%) and the fidelity of delivery (83.3%) needed improvement. We observed no improvement in health-related quality of life (mean=0.04, 95% CI -0.03 to 0.12) but positive change in occupational performance (mean=1.80, 95% CI 1.25 to 2.35) and satisfaction (mean=1.95, 95% CI 1.06 to 2.84). The participants reached the minimal clinically important difference for occupational performance (≥3.0 points in 13.8%) and satisfaction (≥3.2 points in 24.0%). CONCLUSIONS: The REVEAL(OT) intervention was feasible to deliver and beneficial for the participants' occupational performance and satisfaction. The interventions' recruitment, retention and delivery strategies need optimisation in a future definitive trial. TRIAL REGISTRATION NUMBER: NCT03903900.

Hypoalgesia after exercises with painful vs. non-painful muscles in healthy subjects - a randomized cross-over study.

OBJECTIVES: Exercise-induced hypoalgesia (EIH) is a decrease in the pain sensitivity after exercise. Individuals with chronic pain show less EIH after one exercise session compared with pain-free individuals possibly due to pain in exercising muscles. The primary aim of this randomized controlled cross-over study was to compare the EIH response at the exercising thigh muscle following exercises performed with painful vs. non-painful muscles. Secondary aims were to explore if a reduced EIH response was confined to the painful muscle, and whether the muscle pain intensity and the EIH responses were negatively associated. METHODS: In two sessions, 34 pain-free participants received a painful (hypertonic saline, 5.8%) injection and a control (isotonic saline, 0.9%) injection in the right thigh muscle before performing a 3 min isometric wall squat exercise. Pressure pain thresholds (PPTs) were assessed at both thighs and the left neck/shoulder at baseline, after injections and after exercise. Pain intensities in the thighs were rated on numerical rating scales (NRS: 0-10). RESULTS: Hypertonic saline induced moderate thigh pain at rest (NRS: 4.6 ± 2.1) compared to the control injection (NRS: 0.3 ± 0.4; p<0.001). EIH at the thighs and neck/shoulder were not different between sessions (Injected thigh: 0 kPa; 95% CI: -51 to 52; Contralateral thigh: -6 kPa; 95% CI: -42 to 30; neck/shoulder: 19 kPa; 95% CI: -6 to 44). No significant associations between pain intensity ratings immediately after the Painful injection and EIH responses at any assessment sites were found (right thigh: ß=0.08, 95% CI: -12.95 to 20.64, p=0.64, left thigh: ß=-0.33, 95% CI: -27.86 to 0.44, p=0.06; neck/shoulder: ß=-0.18, 95% CI: -15.11 to 4.96, p=0.31). CONCLUSIONS: Pain in the area of an exercising muscle did not reduce local or systemic EIH responses. TRIAL REGISTRATION NUMBER: NCT04354948.

Performance of the 2016 diagnostic criteria for fibromyalgia in a tertiary care pain rehabilitation setting: a diagnostic accuracy study

OBJECTIVES: With the International Classification of Diseases 11th revision (classifying fibromyalgia as a primary pain disorder) soon to be implemented, the importance of pain physicians being able to identify patients with fibromyalgia is emphasized. The diagnostic criteria proposed in 2016 are based on self-reported pain distribution and symptom severity. The study aimed to evaluate the diagnostic accuracy of the 2016 diagnostic criteria for fibromyalgia applied in a population of patients with high impact chronic pain referred for pain rehabilitation. METHODS: The study was performed as a diagnostic accuracy study at two Danish interdisciplinary pain rehabilitation centers, including 215 participants. All participants were evaluated clinically to identify patients with fibromyalgia. The diagnosis was based on expert opinion, but the minimum requirements were: (1) pain in all four body quadrants and axially for at least three months and (2) minimum 8 of 18 positive tender points. Participants filled in the fibromyalgia survey questionnaire, the patient version of the 2016 diagnostic criteria. Sensitivity, specificity, likelihood ratios, and positive and negative post-test probabilities were calculated using a clinical diagnosis of fibromyalgia as the reference standard. RESULTS: Based on clinical diagnosis 45% of the participants were diagnosed with fibromyalgia; of these, only 19% had been diagnosed previously. The 2016 diagnostic criteria demonstrated a sensitivity of 88.5%, a specificity of 81.5%, a positive likelihood ratio of 4.79, a negative likelihood ratio of 0.14, a positive post-test probability of 79.4%, and a negative post-test probability of 10.2%. CONCLUSIONS: Fibromyalgia was severely under-diagnosed among patients with high impact chronic pain referred to tertiary care in two pain rehabilitation centers in Denmark. The 2016 diagnostic criteria showed sufficient discriminatory properties suggesting that the fibromyalgia survey questionnaire can be used as a screening tool assisting the identification of fibromyalgia in this patient population.

Obstructive sleep apnea is common in patients with high-impact chronic pain - an exploratory study from an interdisciplinary pain center.

OBJECTIVES: Sleep disturbances are increasingly recognized as a major part of chronic pain pathology. Obstructive sleep apnea (OSA) is a common occurrence in patients with chronic pain attending specialized pain clinics, yet its prevalence remains unclear. Using screening tools such as the Berlin and STOP-BANG questionnaires may aid in early identification of OSA and improve clinical care. This study i) examined the frequency of OSA based on objective sleep monitoring in patients with high-impact chronic pain, ii) explored potential differences in self-reported pain and sleep characteristics between patients with and without OSA, and iii) tested the agreement between OSA classification based on objective assessment and two OSA screening questionnaires. METHODS: A consecutive cohort of 90 patients (71 women and 19 men; mean age: 47.1 ± 11.0 years) referred for interdisciplinary pain treatment, underwent one night of sleep monitoring using portable respiratory polygraphy (RP), and suspected OSA was confirmed with polysomnography (PSG). Self-reported data on clinical pain (severity, pain drawings and health-related quality of life), sleep characteristics (sleep quality insomnia, sleepiness), and risk of OSA (Berlin and STOP-BANG questionnaires) were collected the day before RP assessment. RESULTS: Forty-six (51.1%) patients were classified with OSA according to RP and verified with PSG. Twenty-eight patients (31.1%) had moderate or severe OSA (apnea-hypopnea index [AHI] >15). Patients with OSA reported lower sleep quality compared with patients without OSA. Scores on pain severity, disability, quality of life, insomnia and sleepiness were comparable between patients with and without OSA. Sensitivity and specificity were 78.6 and 45.2% respectively for the Berlin questionnaire, and 71.4 and 58.1% respectively for the STOP-BANG questionnaire. The agreement for both questionnaires with objective assessment was poor-to-fair. Both questionnaires had acceptable negative predictive values but low positive predictive values reducing the clinical utility to identify patients with low OSA-risk in this sample. CONCLUSIONS: The current study demonstrates a high prevalence of OSA in patients with high-impact chronic pain referred to specialized pain treatment, however the clinical pain profiles were similar in patients with and without OSA. The Berlin and STOP-BANG questionnaires have poor specificity and low-to-fair agreement with RP/PSG questioning their clinical utility in identifying OSA in this sample.

Low-dose naltrexone for the treatment of fibromyalgia: protocol for a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Low-dose naltrexone (LDN) is used widely as an off-label treatment for pain despite limited evidence for its effectiveness. A few small trials with a high risk of bias have investigated the effect of LDN on pain associated with fibromyalgia in women, but larger and more methodologically robust studies are needed. The primary aim of this randomized controlled trial is to investigate if 12 weeks of LDN treatment is superior to placebo in reducing the average pain intensity during the last 7 days in women with fibromyalgia. METHODS: A single-center, permuted block randomized, double-blind, placebo-controlled, parallel-group trial will be performed in Denmark. Randomization comprises 100 women aged 18-64 years diagnosed with fibromyalgia who will be treated with either LDN or placebo for 12 weeks including a 4-week titration phase. The primary outcome is change in average pain intensity (during the last 7 days) from baseline to 12 weeks. Secondary outcomes are other fibromyalgia-related symptoms, i.e., tenderness, fatigue, sleep disturbance, stiffness, memory problems, depression, anxiety and measures of global assessment, physical function, impact of fibromyalgia, pain distribution, and health-related quality of life. Intention-to-treat analysis will be performed, and the number of responders with a more than 15%, 30%, and 50% improvement of pain after 12 weeks will be calculated for the LDN and placebo groups. Exploratory outcomes include measures of pain sensitivity, muscle performance, and biomarkers. DISCUSSION: This study will contribute with high-level evidence on the efficacy of low-dose naltrexone for the treatment of pain in women with fibromyalgia. Secondary outcomes include both disease-specific and generic components investigating whether LDN influences other symptoms than pain. Explorative outcomes are included to provide greater insight into the mechanism of action of LDN and possibly a better understanding of the underlying pathology in fibromyalgia. TRIAL REGISTRATION: EudraCT 2019-000702-30. Registered on 12 July 2019. ClinicalTrials.gov NCT04270877. Registered on 17 February 2020.

A Cognitive Functional Therapy+ Pathway Versus an Interdisciplinary Pain Management Pathway for Patients With Severe Chronic Low Back Pain (CONFeTTI Trial): Protocol for a Pragmatic Randomized Controlled Trial.

OBJECTIVE: Chronic low back pain (cLBP) is the leading cause of disability. Interdisciplinary pain management is recommended for patients with severe/high-impact cLBP. Such programs are expensive, not easily accessible, and have limited effect; therefore, new cost-effective strategies are warranted. Cognitive functional therapy (CFT) has shown promising results but has not been compared with an interdisciplinary pain management approach. The primary aim of this randomized controlled trial is to investigate if a pathway starting with CFT including psychologist support (CFT+) with the option of additional usual care (if needed) is superior in improving disability and more cost-effective at 12 months compared with an interdisciplinary pain management pathway (usual care). METHODS: This pragmatic, 2-arm, parallel-group randomized controlled trial will randomly allocate patients (n = 176) aged 18 to 75 years referred to an interdisciplinary pain center due to severe cLBP to 1 of 2 groups (1:1 ratio). Participants randomized to CFT+ will participate in a 3-month functional rehabilitation pathway with the option of additional usual care (if needed), and participants randomized to the interdisciplinary pain management pathway will participate in an individualized program of longer duration designed to best suit the individual's situation, needs, and resources. The primary outcome is the proportion of participants with an 8-point improvement in the Oswestry Disability Index score at 12 months. Exploratory outcomes are change in Oswestry Disability Index scores over time and an economic analysis of quality-adjusted life years using the 3-level version of the EuroQol EQ-5D. IMPACT: The study evaluates the cost-effectiveness of CFT+ with the option of additional usual care (if needed) for individuals with severe cLBP. Findings can potentially improve future care pathways and reduce cost for the health care system.

Socio-Demographics, Pain Characteristics, Quality of Life and Treatment Values Before and After Specialized Interdisciplinary Pain Treatment: Results from the Danish Clinical Pain Registry (PainData).

BACKGROUND AND AIMS: PainData is an electronic internet-based clinical pain registry established to improve the understanding and treatment of high-impact chronic pain. The primary aim of this paper is to describe socio-demographics, pain characteristics, quality of life, and treatment values at baseline and follow-up in individuals referred to public and private interdisciplinary pain centers in Denmark between 2018 and 2020. METHODS: Self-reported patient-reported outcomes collected through PainData before (n=12,257) and after (n=4,111) treatment across 13 public and private interdisciplinary specialized pain centers in Denmark (87% of all pain centers in Denmark) are described. RESULTS: Mean duration of pain was 10 years, and one in three patients reported chronic widespread pain. More than 40% reported opioid use, and 50% had tried four or more different treatment modalities prior to referral. More than 60% reported poor sleep, severe fatigue, and memory and/or concentration deficits. Mean scores on pain catastrophizing, fear of movement, and pain-related disability were high, whereas scores on pain acceptance and self-efficacy were low. Physical and mental health were rated as poor and fair, respectively. One in four patients reported being very much improved or much improved after treatment. Items commonly reported after treatment were increased knowledge about pain, emotions and mood (66.5%), being better at accepting life with chronic pain (63.1%), and improved activity pacing (60.6%). CONCLUSION: The PainData registry, containing data from a large cohort of individuals, can help to improve the understanding and treatment of high-impact chronic pain, and collaborations with other researchers are welcome.

Validation of the Danish International Trauma Questionnaire for posttraumatic stress disorder in chronic pain patients using clinician-rated diagnostic interviews.

Background: The estimated prevalence rate of comorbid posttraumatic stress disorder (PTSD) is high in trauma-exposed chronic pain patients. At the same time, self-report measures of PTSD tend to be over-inclusive within this specific population due to the high symptom overlap resulting in potential false positives. There is a need for an updated PTSD screening tools with a proper validation against clinical interviews according to the recently published 11th revision of the World Health Organization's International Classification of Diseases (ICD-11). Objective: The present study aimed to validate the Danish International Trauma Questionnaire (ITQ) PTSD part in a sample of trauma-exposed chronic pain patients. Method: The ITQ was validated using a clinician-rated diagnostic interview of ICD-11 PTSD among chronic pain patients exposed to accident or work-related trauma (N = 40). Construct validity, concurrent and discriminant validity was investigated using confirmatory factor analyses (CFA) and correlation analysis, respectively. Three CFA models of ITQ PTSD part were tested in a sample of trauma-exposed chronic pain patients (N = 1,017) and a subsample of chronic pain patients exposed to accident or work-related trauma only (n = 367). Results: Diagnostic consistency between the six ICD-11 PTSD symptoms derived from the ITQ and the clinical interview (κ = .59) and the overall accuracy of the scale (AUC = .90) were good. The Danish ITQ showed excellent construct, concurrent and discriminant validity. The ICD-11 three factor PTSD model had excellent fit in both the full sample and the subsample of traffic and work-related accidents. Conclusions: The results indicate that the ITQ also has good psychometric properties in patients with chronic pain.

Antecedentes: La prevalencia estimada del trastorno de estrés postraumático (TEPT) como comorbilidad es alta en los pacientes con dolor crónico expuestos a trauma. Asimismo, las mediciones por autorreporte del TEPT suelen ser en exceso incluyentes para este tipo de población debido a que existe una alta superposición de los síntomas, lo que resulta en potenciales resultados falsos positivos. Existe la necesidad de actualizar las herramientas de tamizaje del TEPT con una validación adecuada y acorde con las entrevistas clínicas basadas en la recientemente publicada 11° revisión de la Clasificación Internacional de Enfermedades de la Organización Mundial de la Salud (CIE-11).Objetivo: El objetivo de este estudio fue el de validar la sección del TEPT del Cuestionario Internacional de Trauma danés (ITQ, por sus siglas en inglés) en una muestra de personas con dolor crónico expuestas a trauma.Método: Se validó el ITQ empleando una entrevista diagnóstica para el TEPT según la CIE-11 calificada por un clínico en pacientes con dolor crónico expuestos a accidentes o a traumas relacionados con el trabajo (N = 40). Se investigaron la validez del constructo y la validez concurrente y discriminativa mediante el empleo de análisis confirmatorios de factor (ACF) y análisis de correlación, respectivamente. Los tres modelos realizados mediante ACF de la sección del TEPT del ITQ fueron luego evaluados en una muestra de pacientes con dolor crónico expuestos a trauma (N = 1.017) y en un grupo de esta muestra de pacientes con dolor crónico expuestos únicamente a accidentes o a traumas relacionados con el trabajo (N = 367).Resultados: Tanto la consistencia diagnóstica entre seis síntomas del TEPT basados en la CIE-11 obtenidos mediante el ITQ y la entrevista diagnóstica (k = .59) como la precisión general de la escala (AUC = .90) fueron buenas. El ITQ danés mostró tanto una validez del constructo como una validez concurrente y discriminativa excelentes. El modelo de tres factores para el TEPT según la CIE-11 tiene una excelente adaptación tanto en la muestra completa como en el grupo tomado de la muestra para accidentes o traumas relacionados con el trabajo.Conclusiones: Los resultados indican que el ITQ también posee propiedades psicométricas buenas en pacientes con dolor crónico.

The effect of pre-analytical handling on the stability of fractalkine, monocyte chemoattractant protein 1 (MCP1), interleukin 6 and interleukin 8 in samples of human cerebrospinal fluid.

Cytokine networks in cerebrospinal fluid (CSF) are important to our understanding of several neuroinflammatory diseases. Knowledge about optimal handling of samples is limited but important to minimize bias and reduce costs in CSF biomarker studies. The aim of this study was to examine the effect of storage temperature and time delay from CSF sample collection until freezing on the concentration of 11 different cytokines thought to be associated with chronic pain. CSF samples from 21 individuals undergoing hip or knee arthroplasty under spinal anesthesia were divided between two tubes. One tube was stored and centrifuged (within 30 min) at room temperature, and one tube was stored in ice water and centrifuged (within 30 min) at 4 °C. Each tube was split into six vials that were frozen at -80 °C, 0.5, 1, 2, 3, 4, or 5 h after collection. Cytokines were analyzed using a multiplex panel. A random effect panel data regression was conducted for each biomarker including the variables of storage temperature until freezing and time delay. Four cytokines had detectable levels: Fractalkine, monocyte chemoattractant protein 1(MCP-1), interleukine 6 (IL-6), and interleukine 8 (IL-8). There was no significant effect of storage temperature and time delay on MCP-1, IL-6, or IL-8 concentrations. Fractalkine concentration showed no clear trend. No concentration differences were observed between samples kept in ice water and those at room temperature except at the 3-h time point, and there was no overall significant effect of time delay on fractalkine concentration. We found no clear effect of storage temperature and time delay up to five hours from sample collection until freezing on the CSF concentrations of fractalkine, MCP-1, IL-6, or IL-8.