Chronic pain in COPD: prevalence and longitudinal associations with multimorbidity, breathlessness, emotional distress, and adverse clinical outcomes

Chronic pain in COPD: prevalence and longitudinal associations with multimorbidity, breathlessness, emotional distress, and adverse clinical outcomes | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Chronic pain in COPD: prevalence and longitudinal associations with multimorbidity, breathlessness, emotional distress, and adverse clinical outcomes Tor Arnison, Carolina Smith, Gabriella Eliason, Ayako Hiyoshi, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8580535/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 14 You are reading this latest preprint version Abstract Background Chronic pain is common in patients with chronic obstructive pulmonary disease (COPD) and is linked to adverse clinical outcomes, multimorbidity and COPD symptoms, but the exact associations remain unclear. Importantly, chronic pain is underrepresented in most current clinical management guidelines. This study aimed to describe chronic pain prevalence in patients with COPD across 16 years, and its longitudinal association with mortality and respiratory-related hospital visits, multimorbidity, and COPD-related symptoms. Methods This study included patients with COPD, with survey data sweeps in 2005 and 2012, and Swedish national register data from 2005 to 2021. The prevalence of chronic pain and mortality were described in the patients. Repeated dispensed physician-prescribed pain medication defined chronic pain. Survival analyses were used to investigate longitudinal associations among chronic pain, multimorbidity, breathlessness, emotional distress, all-cause mortality, and respiratory-related hospital visits. Results Chronic pain prevalence among 1071 COPD patients was 27% in 2005, 37% in 2012, and 38% in 2021. Initially, chronic pain was associated with all-cause mortality with a 72% higher hazard, compared to patients without pain. Adjustment for sociodemographic factors, breathlessness severity and multimorbidity attenuated this association to 19% (adjusted hazard ratio (adjHR) 1.19, 95% CI 1.01–1.40), although only partially. Chronic pain, breathlessness (adjHR 1.33, 95% CI 1.24–1.43), and multimorbidity (adjHR 1.44, 95% CI 1.36–1.54) were associated with all-cause mortality in fully adjusted models, and emotional distress (adjHR 1.29, 95% CI 1.20–1.38), breathlessness (adjHR 1.41, 95% CI 1.32–1.51), and multimorbidity (adjHR 1.07, 95% CI 1.01–1.13) were associated with recurrence of respiratory-related hospital visits. Conclusions Chronic pain was common and strongly associated with mortality in COPD patients and highlights the importance of considering chronic pain in patients with COPD. Emotional distress was associated with increased respiratory-related hospital visits but not with mortality. This emphasises the relevance of prioritising somatic COPD symptoms, more than subjective distress, in clinical decision-making. Chronic pain should be considered in COPD assessment and management, as it is associated with adverse outcomes and mortality risk in these patients. COPD chronic obstructive pulmonary disease chronic pain breathlessness multimorbidity emotional distress mortality respiratory-related hospital visits. Figures Figure 1 1. Background Chronic obstructive pulmonary disease (COPD) is a progressive lung disease that affects approximately 10% of the globalpopulation 1 and ranks among the leading causes of mortality, particularly in low- and middle-income countries. 2 The disease is associated with substantial reductions in quality of life, functional impairment, 3 and imposes significant healthcare 1 and socioeconomic burden. 4 Patients rarely present with COPD in isolation. The prevalence of COPD and its association with multimorbidity, defined as the coexistence of at least one additional chronic disease, 5 both increase with age. 4 , 6 Common comorbid diseases include cardiovascular disease, metabolic disorders, musculoskeletal conditions and mental illness. 7 , 8 Multimorbidity in patients with COPD is associated with elevated mortality rates, disability, and healthcare utilisation; 9 multimorbidity complicates the clinical course of COPD and management, yet optimal approaches remain inadequately defined. 3 Recent research highlights that chronic pain is common but under-recognised among patients with COPD, reported by 30–70% of individuals, 10–13 predominantly manifesting as musculoskeletal pain in the back and chest. 14 There is a high magnitude association between multimorbidity and chronic pain, with more than half of the people with multimorbidity reporting chronic pain symptoms, 15,16 and the likelihood increases with the number of comorbid conditions. 15 Patients with COPD and multimorbidity are more likely to experience chronic pain, compared to those without multimorbidity, 12,17 and chronic pain is more common in patients with COPD, compared to many other chronic diseases. 18 Potential aetiology includes muscle overuse secondary to respiratory effort, 19 osteoporosis-related complications 20 , and systemic inflammation leading to ischaemic or neuropathic pain. 11 Although chronic pain in patients with COPD might be explained more by multimorbidity than a direct association with breathlessness, 11 chronic pain in patients with COPD has been associated with more severe breathlessness and emotional distress symptoms. 18 , 21 While the bidirectional relationship between breathlessness and emotional distress symptoms in COPD is well established, 22,23 less is known about the additional role of chronic pain. Emerging evidence suggests that breathlessness, pain and emotional distress may interact in a negative spiral of increasing illness severity. 10 , 19 , 24 However, the precise nature of these relationships remains unclear. Clarifying these longitudinal associations is clinically important, as targeting any one of the three through specific treatment approaches may yield improvements across all. Patients with COPD and chronic pain experience functional limitations, 24 10, 11 increased medication use, healthcare consumption, 10,13 poorer adherence to COPD management, 7,10,25 and higher all-cause mortality, 11 compared to those without pain. Despite these implications, chronic pain management remains underrepresented in COPD care guidelines and the topic is insufficiently explored. 7,10,13,26 Given the high prevalence and adverse impact of chronic pain in COPD, there is a need for longitudinal research to elucidate temporal relationships among the aforementioned conditions, and their effects on mortality and healthcare utilisation. The objectives of the present study was to 1) assess the prevalence of chronic pain in patients with COPD, and to characterise longitudinal differences between COPD patients with and without chronic pain, and 2) to investigate the associations of chronic pain, breathlessness, emotional distress, and multimorbidity with all-cause mortality and frequency of COPD-specific hospital admissions. 2. Methods 2. Design and study participants The current research is based on a cohort data from the PRAXIS study, using the first cohort from the total three in the overall project to date. Several studies have been published previously using the PRAXIS study data. These are listed on the PRAXIS study’s web page ( https://praxisstudien.com/publications ). This cohort (PRAXIS 1) included 1071 randomly selected patients aged 18–75 years in 2005 (baseline). Some 759 patients were recruited from primary care and 312 from secondary or tertiary care, from central Sweden with a confirmed physician’s diagnosis of COPD, identified using the 10th edition of International Classification of Diseases (ICD-10) code, J-44. Participation was voluntary. Written informed consent was obtained before data collection using a consent form distributed and returned by postal mail. A separate, optional consent item in the survey asked participants to authorize linkage of their survey responses to medical records. The baseline data collection in 2005 as well as a follow-up survey in 2012 were implemented using a self-completion questionnaire distributed via postal mail. The 2012 survey included the Clinical COPD questionnaire (CCQ) 36 and the Modified Medical Research Council Dyspnea Scale (mMRC), 35 as well as 32 items developed for the study. An English translation of the survey can be found in the Supplementary Materials, and the original Swedish version can be viewed and downloaded at the PRAXIS study’s web page ( https://praxisstudien.com/forms ). Participants’ data are also linked with Swedish national registers, including the Swedish National Patient Register, with inpatient and outpatient diagnoses in secondary care, 27,28 the Cause of Death Register, 29 and the Swedish National Prescription Register, covering the years 2005 to 2021. 30 2.2. Measures 2.2.1. Exposure Chronic pain was defined in this study as dispensed pain medication recorded in the Swedish National Prescription Register. Pain medication that was included had ATC code N02*, although our register data lacked information on prescriptions with ATC codes M*, such as NSAIDs. However, NSAIDs are, due to potential negative interactions, of limited use in older, multimorbid patients.To align with the self-completed questionnaire data, we identified pain medications dispensed between 2005 and 2006 and from 2012 to 2013. In addition, we created a third time point by measuring pain medication from 2019 to 2021. To categorise chronic pain within each time interval, there had to have been at least four dispensed pain medications (N02*) during the interval, to align with definitions in previous research. 31–33 In addition, we performed sensitivity analyses where we defined chronic pain as at least two opioid dispensations during the period (N02A*). 34 2.2.2. COPD-related measures Breathlessness was assessed with the mMRC, 35 which is a five-item self-reported measure aimed at capturing breathlessness severity or functional disability due to breathlessness (range = 0 to 4). The current study includes two measures of breathlessness, one from the first questionnaire survey in 2005 and the other from the 2012 survey. Emotional distress was measured with the mental state subscale of the CCQ. 36 It encompasses two of the total of seven self-reported items that aim to capture emotional distress due to COPD (“Concerned about getting a cold or your breathing getting worse” and “Depressed (down) because of your breathing problems”). Two measurements were included, one from 2005 and one from 2012. 2.2.3. Mutlimorbidity Multimorbidity was assessed using diagnoses recorded in the National Patient Register. We identified comorbid conditions based on ICD-10 codes from hospital outpatient visits and admissions during two time periods aligned with the PRAXIS data collection sweeps in 2005–2006 and 2012–2013. To obtain a comprehensive yet standardised measure of comorbid conditions, we applied the Elixhauser Comorbidity Index as a proxy for multimorbidity. 37,38 The Elixhauser Comorbidity Index captures 31 chronic conditions. In the current study, the COPD category was excluded, as all participants per definition had COPD, resulting in a total of 30 conditions: congestive heart failure, cardiac arrhythmias, valvular disease, pulmonary circulation disorders, peripheral vascular disorders, hypertension (with or without complications), paralysis, neurodegenerative disorders, diabetes (uncomplicated or complicated), hypothyroidism, renal failure, liver disease, peptic ulcer disease excluding perforated ulcers, AIDS/HIV, lymphoma, metastatic cancer, solid tumours without metastasis, rheumatoid arthritis/collagen vascular disease, coagulopathy, obesity, excessive/unexplained weight loss, fluid and electrolyte disorders, blood loss anaemia, deficiency anaemia, alcohol abuse, drug abuse, psychoses, and depression. 39 Because our aim in this component of the analysis was to quantify comorbidity burden rather than predict mortality, we used the unweighted version of the index. 2.2.4. Outcomes All-cause mortality was derived from the Cause of Death Register, where the patient’s date of death is recorded, if the patient died between 2005 and 2021. The Number of respiratory-related hospital visits was measured by the number of hospital visits/admissions in the National Patient Register (inpatient and outpatient), with a respiratory disease (ICD-10 code J*) as the primary diagnosis, across two time intervals: 2005 to 2011 and 2012 to 2021. 2.2.5. Covariates Demographic and patient characteristics at baseline were included as potential confounding factors and reported as descriptive data. These include age, sex, the highest level of completed education (lower, with up to 11 years of schooling, and higher, with 12 or more years of schooling), body mass index (BMI in kg/m 2 ), and smoking status. Information on the frequency of recent emergency contacts due to COPD, in either primary care or hospital care, was included as descriptive baseline results. These variables were collected through self-reported questionnaires in 2005 and 2012. In addition, specific pain diagnoses (headache/migraine: (ICD-10) R51/G43; irritable bowel syndrome: K58; gout: M10; arthropathies: M00-M25; joint pain: M25; back pain: M54; other soft tissue disorders: M70-M79; pain in throat and chest: R07; symptoms and signs involving the digestive system and abdomen: R10-R19; osteoporosis: M80-M81; and other pain: R52) were derived from the Swedish National Patient Register. 2.3. Statistical analysis All data preparation and statistical analysis was performed in R v.4.3.3 using the packages tidyverse, networkD3, psych, survival, and frailtypack. Differences between COPD patients with or without pain were reported descriptively using means and frequencies. Longitudinal transitions between not having comorbid chronic pain, having comorbid chronic pain, and death were reported descriptively and presented using a Sankey diagram. A survival analysis with all-cause mortality from 2005 to 2021 as the outcome was conducted using a Cox proportional hazards regression model while modelling chronic pain, breathlessness, emotional distress, multimorbidity as time-dependent characteristics,measured in 2005 and 2012, as well as sex, age, and education level included as baseline covariates. Some four hierarchical models were fitted sequentially into four blocks: (1) included chronic pain only, (2) additionally adjusted for age, sex, and education, (3) further included breathlessness and emotional distress, and (4) also included multimorbidity. Model fit was assessed using Akaike’s information criterion (AIC) and likelihood ratio tests between successive models. Missing data for baseline covariates were handled using single stochastic imputation with predictive mean matching (mice package in R). Continuous variables were standardised. To assess how chronic pain, breathlessness, emotional distress, and multimorbidity were associated with recurrence of respiratory-related hospital visits, we implemented a joint gamma-frailty model with Weibull baseline hazard. All-cause mortality was modelled as a competing event.. Chronic pain, breathlessness, emotional distress, and multimorbidity were included as time-dependent characteristics in 2005 and 2012. Four hierarchical models were fitted sequentially as in the Cox regression model described previously. Model improvement was evaluated using likelihood ratio tests and AIC. Missing data for baseline covariates were imputed and continuous variables were standardised. 3. Results 3.1. Chronic pain prevalence in patients with COPD from 2005 to 2021 In 2005, 284 of 1071 (26.5%) patients with COPD were treated for chronic pain (≥ 4 dispensed pain medications during the period), as were 282 of 761 (37.1%) patients in 2012, and 137 (38.1%) of 360 in 2021. Among the 280 patients with chronic pain in 2005, 117 (41.2%) had died by 2012, and of the surviving 167, 131 (78.4%) still suffered from chronic pain in 2012. Among 282 patients with chronic pain in 2012, 178 (63.1%) had died by 2021, and of the surviving 104 patients, 82 (78.8%) still suffered from chronic pain in 2021. The transitions between chronic pain and mortality across the time points are depicted in Fig. 1 . 3.2. Descriptive baseline characteristics of patients with COPD, with and without comorbid pain As seen in Table 1, in 2005, COPD patients with chronic pain were, to a higher degree women, those who had had more emergency contacts, had more comorbid diagnoses, but were of similar age, education level, and BMI, compared to those without pain. The chronic pain group had more frequent pain diagnoses registered in the Swedish National Patient Register, particularly for arthropathies, back pain and abdominal pain. Table 1. Descriptive baseline characteristics (2005) of COPD patients, with or without chronic pain. With chronic pain (n=284) Without chronic pain (n=787) Year 2005 n mean or % SD n mean or /% SD Total 284 100 787 100 Age (years) 280 64.8 7.5 787 64.3 7.5 Sex (female) 280 68.7 787 54.3 Highest completed education 280 787 Lower 233 83.2 642 81.6 Higher 43 15.4 131 16.6 Missing 8 2.9 14 1.8 Smoking 280 787 Never 13 4.6 56 7.1 Previous 166 59.3 455 57.8 Sometimes 20 7.1 53 6.7 Daily 85 30.4 221 28.1 Missing 0 0 2 <0.1 Emergency contact with primary care (times/last 6 months) 284 787 None 42 14.8 45 5.7 Once 161 56.7 577 73.3 Twice 49 17.3 106 13.5 More than twice 26 9.2 40 5.1 ;issing 6 2,1 19 2.4 Emergency contact with hospital care (times/last 6 months) 284 787 None 21 7.4 18 2.3 Once 198 69.7 671 85.3 Twice 40 14.1 67 8.5 More than twice 23 8.1 20 2.5 Missing 2 0.7 11 1.4 BMI (kg/m2) 272 26.2 5.9 764 25.8 5.0 Breathlessness (mMRC) 268 2.6 1.4 763 2.0 1.4 Emotional distress (mental state CCQ) 277 2.6 1.9 773 2.2 1.9 Pain-related diagnoses, overall 284 39.1 787 16.0 Headache/Migraine 284 0.7 787 0.9 IBS 284 0.7 787 0.4 Gout 284 0.4 787 0.1 Arthropathies 284 10.2 787 2.8 Joint pain 284 1.8 787 0.6 Back pain 284 6.0 787 1.0 Other soft tissue disorder 284 9.5 787 3.0 Pain in throat and chest 284 6.7 787 4.1 Symptoms and signs involving the digestive system and abdomen 284 14.1 787 4.8 Osteoporosis 284 3.2 787 0.9 Other pain 284 2.5 787 0.3 Multimorbidity 284 0.8 1.1 787 0.4 0.7 Note. Chronic pain status was defined as either having recently used pain medication (≥4 dispensed physician-prescribed pain medications during the period) or not. Multimorbidity, average number of Elixhauser comorbidity index diagnoses beyond COPD. Age, sex, highest completed education, body mass index (BMI), smoking status and emergency contacts with primary and hospital care were derived from PRAXIS self-reported questionnaires. The planned visits could be either to a nurse or a physician. The pain diagnoses were derived from the Swedish National Patient Register. SD, Standard deviation. 3.4. Sequential associations of chronic pain, breathlessness, emotional distress, and multimorbidity with all-cause mortality and frequency of respiratory-related hospital visits. As shown in Table 2, chronic pain was univariately (block I) associated with all-cause mortality, having chronic pain corresponding to a 72% higher hazard of death. Demographic factors did not diminish this association (block II), although older age (HR 1.08 95% CI 1.07-1.09) and lower education level (HR 0.93, 95% CI 0.88-0.98) were also statistically significantly associated with mortality. Including breathlessness (HR 1.33 95% CI 1.24-1.43) and multimorbidity (HR 1.44, 95% CI 1.36-1.54) in blocks III and IV attenuated the association of chronic pain with all-cause mortality to HR 1.19, 95% CI 1.01-1.40), but it remained statistically significant The progressive reduction in the Akaike Information Criterion (AIC) across the four models (from 9177.4 to 8755.0) indicates that the addition of age, breathlessness, and multimorbidity substantially improved model fit. Table 2. Sequential predictors of all-cause mortality among 1071 COPD patients, from 2005 to 2021. HR 95% CI P-value Block I. AIC: 9177.4 Chronic pain 1.72 1.47-2.01 <0.001 Block II. AIC: 9003.3; Δχ² = 180.06, p = <0.001 Chronic pain 1.69 1.44-1.97 <0.001 Age 1.08 1.07-1.09 <0.001 Male sex 0.94 0.81-1.10 0.45 Education level 0.93 0.88-0.98 0.003 Block III. AIC: 8884; Δχ² = 123.35, p = <0.001 Chronic pain 1.43 1.22-1.68 <0.001 Age 1.07 1.06-1.09 <0.001 Male sex 0.95 0.82-1.11 0.53 Education level 0.94 0.90-0.99 0.02 Breathlessness 1.38 1.28-1.48 <0.001 Emotional distress 1.03 0.98-1.09 0.27 Block IV. AIC: 8755; Δχ² = 130.98, p = <0.001 Chronic pain 1.19 1.01-1.40 0.04 Age 1.06 1.05-1.08 <0.001 Male sex 0.93 0.80-1.09 0.36 Education level 0.91 0.86-0.97 0.002 Breathlessness 1.33 1.24-1.43 <0.001 Emotional distress 1.01 0.96-1.07 0.62 Multimorbidity 1.44 1.36-1.54 <0.001 Note. This was a sequential or nested Cox proportional hazards model with chronic pain, breathlessness, emotional distress and multimorbidity as time-dependent exposures at 2005 and 2012, and all-cause mortality as a continuous-time outcome from 2005 to 2021. Multimorbidity, diagnoses from the Elixhauser comorbidity index, excluding chronic respiratory disease. Chronic pain status was defined as having recently used pain medication (≥4 dispensed pain medications during the period). HR, hazard ratio; CI, confidence interval; AIC, Akaike’s information criterion. Significant associations are in bold. Table 3 shows that chronic pain was not associated with more frequent respiratory-related hospital visits in the unadjusted model (block I; HR 1.01, 95% CI 0.96-1.06). However, when accounting only for demographic factors (block II), it was associated with more hospital visits (HR 1.06). When additionally adjusting for breathlessness, emotional distress, and multimorbidity, it was associated with fewer hospital visits (HR 0.89, 95% CI 0.85-0.94). Older age and male sex were associated with fewer hospital visits. Breathlessness (HR 1.41, 95% CI 1.32-1.51), emotional distress (HR 1.29, 95% CI 1.20-1.38), and multimorbidity (HR 1.07, 95% CI 1.01-1.13) were all independently associated with more frequent respiratory-related hospital visits (block IV). The continued decline in AIC values (from 101078.0 to 100721.7) again indicates that successive model adjustments yielded improved explanatory power. Table 3. Sequential associations with recurrent respiratory-related hospital visits in 1071 COPD patients, from 2005 to 2021. HR 95%CI P-value Block I. AIC: 101078 Chronic pain 1.01 0.96-1.06 0.74 Block II. AIC: 101065.8; Δχ² = 24.21, p = <.001 Chronic pain 1.06 1.01-1.12 0.03 Age 0.91 0.86-0.97 0.004 Male sex 0.92 0.86-0.98 0.008 Education level 0.97 0.87-1.07 0.50 Block III. AIC: 100740.2; Δχ² = 333.59, p = <.001 Chronic pain 0.93 0.89-0.98 0.010 Age 0.83 0.78-0.89 <.001 Male sex 0.93 0.87-0.99 0.03 Education level 1.00 0.91-1.10 0.95 Breathlessness 1.42 1.33-1.51 <.001 Emotional distress 1.30 1.19-1.42 <.001 Block IV. AIC: 100721.7; Δχ² = 22.51, p = <.001 Chronic pain 0.89 0.85-0.94 <.001 Age 0.82 0.77-0.88 <.001 Male sex 0.91 0.86-0.97 0.002 Education level 0.99 0.90-1.09 0.86 Breathlessness 1.41 1.32-1.51 <.001 Emotional distress 1.29 1.20-1.38 <.001 Multimorbidity 1.07 1.01-1.13 0.02 Note. This was a sequential or nested joint gamma frailty model with time-dependent exposures at 2005 and 2012, and recurrent respiratory-related hospital visits (Anderson-Gill formulation) and all-cause mortality (terminal event) as continuous-time outcomes from 2005 to 2021. Note that in the table, only the recurrent event part of the model is reported. Multimorbidity, present diagnoses from the Elixhauser comorbidity index, excluding chronic respiratory disease. Chronic pain status was defined as having recently used pain medication (≥4 dispensed physician-prescribed pain medications during the period). Significant associations are in bold. 4. Discussion The current study followed a cohort of 1071 COPD patients between 2005 and 2021 and examined the characteristics of patients with and without chronic pain, described the longitudinal course of chronic pain and mortality, and explored longitudinal associations between chronic pain, breathlessness, emotional distress, and multimorbidity in relation to all-cause mortality and respiratory-related hospital visits. We found that throughout the study period, the prevalence of chronic pain was 26.5% in 2005, 37.1% in 2012 and 38.1% in 2021. The most frequent chronic pain diagnoses were arthropathies, other soft tissue disorders, abdominal pain, and back pain. The prevalence observed by us, lies at the lower end, compared with previous studies which reported prevalence between 30–70% of chronic pain among COPD patients, 10–13 although it is considerably higher than the prevalence in the general population which ranges from between 10 to 19%. 32,40,41 This may be due to our method of identifying chronic pain being conservative, requiring at least 4 dispensations within each time period, as many with chronic pain do not consistently use analgesics. This notion was confirmed by a recent study, which found that persistent analgesic use underestimated the prevalence of chronic pain, compared to a definition using pain diagnoses. 32 The fact that the patterns of associations with outcomes correspond with the alternative definition of recurrent opioid use (Table S2 and Table S3) indicates that our method of using repeated medication dispensations is, however, robust. As can be seen in these supplemental materials, the prevalence of recurrent opioid use was decreasing from 2005 to 2021. In contrast, the prevalence using our main definition of chronic pain defined as ≥ 4 analgesics dispensations were increasing over time, which is in line with current guidelines advising against long-term opioid use as treatment for both chronic pain 42 and for respiratory symptoms in COPD (although low-dose systemic opioids may be indicated for refractory breathlessness in palliative COPD care). 1 Despite this, it is a concern that 23% of patients with COPD were recurrently prescribed opioids as recently as in 2021. In univariate analyses, chronic pain predicted mortality during follow-up with a 72% higher hazard, compared with patients without chronic pain. Of those with chronic pain in 2005, 41% had died by 2012, and among those with chronic pain in 2012, 63% had died by 2021. A previous study also found an association between chronic pain and mortality in COPD patients, also with evidence that the association became of higher magnitude with greater pain interference, 11 and a review article concluded that there is a higher mortality risk among COPD patients receiving opioids for breathlessness. 43 These findings, together with ours, suggest that chronic pain may reflect COPD phenotype of greater overall disease burden and vulnerability. We encourage future research to further elaborate on the association between chronic pain and mortality, by incorporating more detailed pain measures such as pain duration, pain intensity, pain frequency and pain interference, as well as the patterns and extent of analgesics and opioid use, in order to disentangle the likely complex associations between chronic pain characteristics, analgesics and opioid use, and mortality. We believe the finding that chronic pain is common and notably associated with mortality in patients with COPD is especially important given that pain assessment and management are rarely, if at all, mentioned in current COPD management guidelines. 7 , 10 , 13 , 26 We recommend future research to further explore chronic pain in COPD patients, and for COPD management guidelines to re-evaluate their lack of inclusion of pain. Our results indicated that a large proportion of the association between pain with mortality was explained by breathlessness and multimorbidity, which is in line with our prior hypothesis Previous research has indicated that they may reciprocally influence each other in a downward spiral in COPD patients. 10 , 19 , 24 However, the earlier studies have been predominantly retrospective, qualitative or cross-sectional, meaning that no previous research has explored these associations longitudinally as in the current study. Indeed, a cross-sectional symptom cluster of breathlessness, emotional distress and pain has consistently been identified, both in respiratory disease cohorts, 44 as well as, for example, in cancer 45 or palliative care populations. 46 Our results add a piece to this complex puzzle of associations by showing that they appear to hold over time, in a longitudinal context, and they emphasise the need for an integrated, multidisciplinary approach by combining respiratory rehabilitation, psychological support, and controlling analgesic strategies in COPD management. In our study, we also found that breathlessness was associated with both mortality and respiratory-related hospital visits, even when adjusting for other factors such as age, chronic pain, and multimorbidity. The link between breathlessness and mortality is well established in previous research in COPD, 47,48 and our results are consistent with this literature. However, emotional distress over respiratory symptoms showed a significant association with respiratory-related hospital visits, but not with mortality. These results suggest that patients’ emotional responses to their symptoms may influence care seeking behaviour and patterns of care in addition to their somatic illness-specific symptoms. This is a well-known pattern in COPD management – emotional distress over COPD symptoms appears to increase the risk of COPD exacerbations requiring hospital visits, 49 as well as overall increased healthcare utilisation, independent of physical COPD characteristics. 50 We found that, among the examined constructs, multimorbidity had the most notable association with later mortality. This is consistent with previous research, which has found an association between the number of comorbid disease and mortality in COPD patients. 51 – 53 The most recent Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (GOLD) 2025 guidelines highlight the importance of multimorbidity in COPD patients, and how important it is to address this due to its association with mortality. 1 The results of our study confirm and underscore this emphasis in the GOLD 2025 guidelines, by demonstrating the need to address multimorbidity in COPD patients. In this study, chronic pain was associated with all-cause mortality, even when adjusting for other risk factors such as advancing age, education level, breathlessness, or multimorbidity, although breathlessness and multimorbidity attenuated the association of chronic pain with mortality, indicating they are interrelated. Multimorbidity and breathlessness were more common in COPD patients with chronic pain, compared to those without. Our interpretation of these results is that chronic pain may be a common clinical manifestation of multimorbidity and respiratory symptoms in patients with COPD. Although chronic pain was associated with recurrent respiratory-related hospital visits in the deomgraphics-only adjusted model, the association was reversed when adjusting for breathlessness, emotional distress and multimorbidity. One possible explanation to this is that the patients with chronic pain are generally more ill, beyond what we could capture via breathlessness and multimorbidity, and require other care to such an extent that COPD care become de-prioritised. Indeed, as can be seen in Table S3 (Supplementary materials), patients with chronic pain have more hospital visits overall, even when adjusting for breathlessness, emotional distress, and multimorbidity. However, a previous publication by our research group indicated that multimorbidity in general did not lead to de-prioritisation of COPD management. 54 Since appropriate COPD management is important also in patients with other illness than COPD, we recommend future research to further explore these associations. . A strength of the current study is that it is based on a large sample of COPD patients who were followed for 17 years (2005 to 2021), and that it integrates data from several Swedish national registers, which allowed for more extensive measures and outcomes than survey data alone. We combined this with advanced statistical methods for longitudinal data, which allowed us to assess complex longitudinal associations between the examined constructs. Nevertheless, the study also has potential limitations. The study was based on observational data, so although we could establish longitudinal relationships among the constructs, we were not able to make firm causal claims from any of the results. We also included broad and nonspecific measures of pain, multimorbidity and cause of mortality, and they were based only on the data that were recorded in the national registers during each time period. This allowed us to address wide research questions, but at the same time, potentially relevant sensitivity and specificity were lost. This is particularly problematic for the measure of multimorbidity, as each comorbid condition must have been registered in the relatively small time window around each time-point to be recorded as a comorbid condition, possibly leading to an underestimation of multimorbidity. We recommend future studies further explore the associations between different types of pain and pain characteristics, as well as specific comorbid conditions or their combinations, and cause-specific mortality. In addition, the self-reported nature of breathlessness and emotional distress introduced a risk of reporting bias, and potentially valuable information was not available through the register-based measures of chronic pain and multimorbidity. Lastly, several additional constructs that are relevant to the examined relationships, including functional disability, nutrition, and lifestyle factors such as physical activity, which were not available. 5. Conclusions In conclusion, chronic pain is common in COPD patients and is notably associated with all-cause mortality. Much, but not all, of this association appears to be explained by multimorbidity and breathlessness, of which chronic pain appears to be a symptom or indicator. Multimorbidity was the most consistent predictor of all-cause mortality and was also associated with recurrent respiratory-related hospital visits. Breathlessness was indirectly related to all-cause mortality through an increase in multimorbidity and indirectly linked to respiratory-related hospital visits via emotional distress. In contrast, emotional distress was not associated with mortality, but was associated with greater healthcare use. We recommend including chronic pain as an important aspect in COPD management. Not only because chronic pain is common in COPD, but also because it may be that this group is under-treated in their COPD management. Although COPD management is already comprehensive and complex, we believe that simple questions about pain are feasible to routinely include in COPD management, and that addressing pain in COPD has the potential not only to relieve them of considerable suffering, but also to better identify risks for future disability and mortality. Declarations 6.1. Ethics approval and consent to participate The study was approved by the regional ethics vetting board of Uppsala (registration number 2004:M-445) and the Swedish Ethical Review Authority (Dnnr 2010/090 and Dnnr 2020-00270). Participation in the study was voluntary. Written informed consent was obtained before data collection using a consent form distributed and returned by postal mail. A separate, optional consent item in the survey asked participants to authorize linkage of their survey responses to medical records. 6.2. Availability of data and materials The data that support the findings of this study are available from Maaike Giezeman ( [email protected] ) upon reasonable request and with appropriate ethical permission. Register data used in this study cannot be shared publicly due to regulations under Swedish law. Researchers who are interested in Swedish register data can refer to https://www.registerforskning.se/en/. 6.3. Competing interest CJ has received honoraria for educational activities and lectures from ALK, AstraZeneca, Chiesi, GlaxoSmithKline, Orion, Sanofi and Stallergenes, and has served on advisory boards arranged by ALK, AstraZeneca, GlaxoSmithKline, Orion, Sanofi and Stallergenes. BS declare no competing financial or non-financial interests associated with this work. Outside the submitted work, BS has received personal fees for educational activities and lectures from AstraZeneca, Boehringer Ingelheim, Novartis, and GlaxoSmithKline and served on advisory boards arranged by AstraZeneca, Novartis, GlaxoSmithKline, MSD, and Boehringer Ingelheim. The remaining authors report no conflicts with any product mentioned or concept discussed in this article. 6.4. Funding Funding was received from Vetenskapsrådet - the Swedish Research Council (2023–05997), as well as from The Swedish Heart and Lung Association, The Swedish Heart Lung Foundation, the Swedish Asthma and Allergy Association, the Bror Hjerpstedt Foundation, the Regional Research Council Mid Sweden, the Centre for Clinical Research, Region Dalarna, Sweden, and the Centre for Clinical Research, Region Värmland, Sweden. ALF funding Region Örebro County. 6.5. Author contributions T.A., S.M. and B.S. were responsible for initiation and conceptualisation of the study. Data curation and statistical analyses were conducted by T.A. Main interpretation of the results was undertaken by T.A. and S.M. T.A. wrote the original draft. All authors provided intellectual input into the manuscript, reviewed and edited the manuscript and approved its final version. 6.6. 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American Journal of Respiratory and Critical Care Medicine 2012;186(2):155-161. doi:10.1164/rccm.201201-0034OC Smith C, Hasselgren M, Janson C, et al. Does multimorbidity result in de-prioritisation of COPD in primary care? npj Primary Care Respiratory Medicine 2023;33(1)doi:10.1038/s41533-023-00326-x Additional Declarations Competing interest reported. CJ has received honoraria for educational activities and lectures from ALK, AstraZeneca, Chiesi, GlaxoSmithKline, Orion, Sanofi and Stallergenes, and has served on advisory boards arranged by ALK, AstraZeneca, GlaxoSmithKline, Orion, Sanofi and Stallergenes. BS declare no competing financial or non-financial interests associated with this work. Outside the submitted work, BS has received personal fees for educational activities and lectures from AstraZeneca, Boehringer Ingelheim, Novartis, and GlaxoSmithKline and served on advisory boards arranged by AstraZeneca, Novartis, GlaxoSmithKline, MSD, and Boehringer Ingelheim. The remaining authors report no conflicts with any product mentioned or concept discussed in this article. 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chronic pain status and mortality among COPD patients (N=1,071) from 2005-2021. Chronic pain was defined as use of pain medication (≥4 dispensed pain medications during the period). Node width represents the number of patients in each state. Flow width represents the number of patients transitioning between states. Orange nodes - chronic pain present; blue nodes - no chronic pain; grey nodes: deceased.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8580535/v1/6292ef7756f93c12869a580e.png"},{"id":106963400,"identity":"0574d0c2-02e9-4186-8f3c-6299fcab5c5f","added_by":"auto","created_at":"2026-04-15 09:44:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1211396,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8580535/v1/91a564d3-c79a-46f4-bbca-3dc60427ce6a.pdf"},{"id":106945081,"identity":"7fb05933-2eba-4daf-bdd8-ea6b14869f4b","added_by":"auto","created_at":"2026-04-15 06:28:56","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":156025,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementarymaterialsR1clean.docx","url":"https://assets-eu.researchsquare.com/files/rs-8580535/v1/970d9d9f71f57050ae347c23.docx"}],"financialInterests":"Competing interest reported. CJ has received honoraria for educational activities and lectures from ALK, AstraZeneca, Chiesi, GlaxoSmithKline, Orion, Sanofi and Stallergenes, and has served on advisory boards arranged by ALK, AstraZeneca, GlaxoSmithKline, Orion, Sanofi and Stallergenes. BS declare no competing financial or non-financial interests associated with this work. Outside the submitted work, BS has received personal fees for educational activities and lectures from AstraZeneca, Boehringer Ingelheim, Novartis, and GlaxoSmithKline and served on advisory boards arranged by AstraZeneca, Novartis, GlaxoSmithKline, MSD, and Boehringer Ingelheim. The remaining authors report no conflicts with any product mentioned or concept discussed in this article.","formattedTitle":"Chronic pain in COPD: prevalence and longitudinal associations with multimorbidity, breathlessness, emotional distress, and adverse clinical outcomes","fulltext":[{"header":"1. Background","content":"\u003cp\u003eChronic obstructive pulmonary disease (COPD) is a progressive lung disease that affects approximately 10% of the globalpopulation\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e and ranks among the leading causes of mortality, particularly in low- and middle-income countries.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e The disease is associated with substantial reductions in quality of life, functional impairment,\u003csup\u003e3\u003c/sup\u003e and imposes significant healthcare\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e and socioeconomic burden.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003ePatients rarely present with COPD in isolation. The prevalence of COPD and its association with multimorbidity, defined as the coexistence of at least one additional chronic disease, \u003csup\u003e5\u003c/sup\u003e both increase with age.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Common comorbid diseases include cardiovascular disease, metabolic disorders, musculoskeletal conditions and mental illness.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Multimorbidity in patients with COPD is associated with elevated mortality rates, disability, and healthcare utilisation;\u003csup\u003e9\u003c/sup\u003e multimorbidity complicates the clinical course of COPD and management, yet optimal approaches remain inadequately defined.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eRecent research highlights that chronic pain is common but under-recognised among patients with COPD, reported by 30–70% of individuals, \u003csup\u003e10–13\u003c/sup\u003e predominantly manifesting as musculoskeletal pain in the back and chest.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e There is a high magnitude association between multimorbidity and chronic pain, with more than half of the people with multimorbidity reporting chronic pain symptoms,\u003csup\u003e15,16\u003c/sup\u003e and the likelihood increases with the number of comorbid conditions.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Patients with COPD and multimorbidity are more likely to experience chronic pain, compared to those without multimorbidity,\u003csup\u003e12,17\u003c/sup\u003e and chronic pain is more common in patients with COPD, compared to many other chronic diseases.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003ePotential aetiology includes muscle overuse secondary to respiratory effort,\u003csup\u003e19\u003c/sup\u003e osteoporosis-related complications \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, and systemic inflammation leading to ischaemic or neuropathic pain.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Although chronic pain in patients with COPD might be explained more by multimorbidity than a direct association with breathlessness,\u003csup\u003e11\u003c/sup\u003e chronic pain in patients with COPD has been associated with more severe breathlessness and emotional distress symptoms.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e While the bidirectional relationship between breathlessness and emotional distress symptoms in COPD is well established,\u003csup\u003e22,23\u003c/sup\u003e less is known about the additional role of chronic pain. Emerging evidence suggests that breathlessness, pain and emotional distress may interact in a negative spiral of increasing illness severity.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e However, the precise nature of these relationships remains unclear. Clarifying these longitudinal associations is clinically important, as targeting any one of the three through specific treatment approaches may yield improvements across all.\u003c/p\u003e \u003cp\u003ePatients with COPD and chronic pain experience functional limitations,\u003csup\u003e24 10,\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e increased medication use, healthcare consumption,\u003csup\u003e10,13\u003c/sup\u003e poorer adherence to COPD management,\u003csup\u003e7,10,25\u003c/sup\u003e and higher all-cause mortality,\u003csup\u003e11\u003c/sup\u003e compared to those without pain. Despite these implications, chronic pain management remains underrepresented in COPD care guidelines and the topic is insufficiently explored. \u003csup\u003e7,10,13,26\u003c/sup\u003e Given the high prevalence and adverse impact of chronic pain in COPD, there is a need for longitudinal research to elucidate temporal relationships among the aforementioned conditions, and their effects on mortality and healthcare utilisation. The objectives of the present study was to 1) assess the prevalence of chronic pain in patients with COPD, and to characterise longitudinal differences between COPD patients with and without chronic pain, and 2) to investigate the associations of chronic pain, breathlessness, emotional distress, and multimorbidity with all-cause mortality and frequency of COPD-specific hospital admissions. 2. Methods\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e \u003c/div\u003e \u003c/div\u003e "},{"header":"2. Design and study participants","content":"\u003cp\u003eThe current research is based on a cohort data from the PRAXIS study, using the first cohort from the total three in the overall project to date. Several studies have been published previously using the PRAXIS study data. These are listed on the PRAXIS study’s web page (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://praxisstudien.com/publications\u003c/span\u003e\u003cspan class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). This cohort (PRAXIS 1) included 1071 randomly selected patients aged 18–75 years in 2005 (baseline). Some 759 patients were recruited from primary care and 312 from secondary or tertiary care, from central Sweden with a confirmed physician’s diagnosis of COPD, identified using the 10th edition of International Classification of Diseases (ICD-10) code, J-44. Participation was voluntary. Written informed consent was obtained before data collection using a consent form distributed and returned by postal mail. A separate, optional consent item in the survey asked participants to authorize linkage of their survey responses to medical records. The baseline data collection in 2005 as well as a follow-up survey in 2012 were implemented using a self-completion questionnaire distributed via postal mail. The 2012 survey included the Clinical COPD questionnaire (CCQ)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e and the Modified Medical Research Council Dyspnea Scale (mMRC),\u003csup\u003e35\u003c/sup\u003e as well as 32 items developed for the study. An English translation of the survey can be found in the Supplementary Materials, and the original Swedish version can be viewed and downloaded at the PRAXIS study’s web page (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://praxisstudien.com/forms\u003c/span\u003e\u003cspan class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Participants’ data are also linked with Swedish national registers, including the Swedish National Patient Register, with inpatient and outpatient diagnoses in secondary care,\u003csup\u003e27,28\u003c/sup\u003e the Cause of Death Register,\u003csup\u003e29\u003c/sup\u003e and the Swedish National Prescription Register, covering the years 2005 to 2021.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003ch2\u003e2.2. Measures\u003c/h2\u003e\u003ch2\u003e2.2.1. Exposure\u003c/h2\u003e\u003cp\u003e \u003cem\u003eChronic pain\u003c/em\u003e was defined in this study as dispensed pain medication recorded in the Swedish National Prescription Register. Pain medication that was included had ATC code N02*, although our register data lacked information on prescriptions with ATC codes M*, such as NSAIDs. However, NSAIDs are, due to potential negative interactions, of limited use in older, multimorbid patients.To align with the self-completed questionnaire data, we identified pain medications dispensed between 2005 and 2006 and from 2012 to 2013. In addition, we created a third time point by measuring pain medication from 2019 to 2021. To categorise chronic pain within each time interval, there had to have been at least four dispensed pain medications (N02*) during the interval, to align with definitions in previous research. \u003csup\u003e31–33\u003c/sup\u003e In addition, we performed sensitivity analyses where we defined chronic pain as at least two opioid dispensations during the period (N02A*). \u003csup\u003e34\u003c/sup\u003e\u003c/p\u003e\u003ch2\u003e2.2.2. COPD-related measures\u003c/h2\u003e\u003cp\u003e \u003cem\u003eBreathlessness\u003c/em\u003e was assessed with the mMRC,\u003csup\u003e35\u003c/sup\u003e which is a five-item self-reported measure aimed at capturing breathlessness severity or functional disability due to breathlessness (range = 0 to 4). The current study includes two measures of breathlessness, one from the first questionnaire survey in 2005 and the other from the 2012 survey.\u003c/p\u003e\u003cp\u003e \u003cem\u003eEmotional distress\u003c/em\u003e was measured with the mental state subscale of the CCQ.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e It encompasses two of the total of seven self-reported items that aim to capture emotional distress due to COPD (“Concerned about getting a cold or your breathing getting worse” and “Depressed (down) because of your breathing problems”). Two measurements were included, one from 2005 and one from 2012.\u003c/p\u003e\u003ch2\u003e2.2.3. Mutlimorbidity\u003c/h2\u003e\u003cp\u003e \u003cem\u003eMultimorbidity\u003c/em\u003e was assessed using diagnoses recorded in the National Patient Register. We identified comorbid conditions based on ICD-10 codes from hospital outpatient visits and admissions during two time periods aligned with the PRAXIS data collection sweeps in 2005–2006 and 2012–2013. To obtain a comprehensive yet standardised measure of comorbid conditions, we applied the Elixhauser Comorbidity Index as a proxy for multimorbidity. \u003csup\u003e37,38\u003c/sup\u003e The Elixhauser Comorbidity Index captures 31 chronic conditions. In the current study, the COPD category was excluded, as all participants per definition had COPD, resulting in a total of 30 conditions: congestive heart failure, cardiac arrhythmias, valvular disease, pulmonary circulation disorders, peripheral vascular disorders, hypertension (with or without complications), paralysis, neurodegenerative disorders, diabetes (uncomplicated or complicated), hypothyroidism, renal failure, liver disease, peptic ulcer disease excluding perforated ulcers, AIDS/HIV, lymphoma, metastatic cancer, solid tumours without metastasis, rheumatoid arthritis/collagen vascular disease, coagulopathy, obesity, excessive/unexplained weight loss, fluid and electrolyte disorders, blood loss anaemia, deficiency anaemia, alcohol abuse, drug abuse, psychoses, and depression. \u003csup\u003e39\u003c/sup\u003e Because our aim in this component of the analysis was to quantify comorbidity burden rather than predict mortality, we used the unweighted version of the index.\u003c/p\u003e\u003ch2\u003e2.2.4. Outcomes\u003c/h2\u003e\u003cp\u003e \u003cem\u003eAll-cause mortality\u003c/em\u003e was derived from the Cause of Death Register, where the patient’s date of death is recorded, if the patient died between 2005 and 2021.\u003c/p\u003e\u003cp\u003e \u003cem\u003eThe Number of respiratory-related hospital visits\u003c/em\u003e was measured by the number of hospital visits/admissions in the National Patient Register (inpatient and outpatient), with a respiratory disease (ICD-10 code J*) as the primary diagnosis, across two time intervals: 2005 to 2011 and 2012 to 2021.\u003c/p\u003e\u003ch2\u003e2.2.5. Covariates\u003c/h2\u003e\u003cp\u003e \u003cem\u003eDemographic and patient characteristics at baseline\u003c/em\u003e were included as potential confounding factors and reported as descriptive data. These include age, sex, the highest level of completed education (lower, with up to 11 years of schooling, and higher, with 12 or more years of schooling), body mass index (BMI in kg/m\u003csup\u003e2\u003c/sup\u003e), and smoking status. Information on the frequency of recent emergency contacts due to COPD, in either primary care or hospital care, was included as descriptive baseline results. These variables were collected through self-reported questionnaires in 2005 and 2012. In addition, specific pain diagnoses (headache/migraine: (ICD-10) R51/G43; irritable bowel syndrome: K58; gout: M10; arthropathies: M00-M25; joint pain: M25; back pain: M54; other soft tissue disorders: M70-M79; pain in throat and chest: R07; symptoms and signs involving the digestive system and abdomen: R10-R19; osteoporosis: M80-M81; and other pain: R52) were derived from the Swedish National Patient Register.\u003c/p\u003e\u003ch2\u003e2.3. Statistical analysis\u003c/h2\u003e\u003cp\u003eAll data preparation and statistical analysis was performed in R v.4.3.3 using the packages tidyverse, networkD3, psych, survival, and frailtypack. Differences between COPD patients with or without pain were reported descriptively using means and frequencies. Longitudinal transitions between not having comorbid chronic pain, having comorbid chronic pain, and death were reported descriptively and presented using a Sankey diagram.\u003c/p\u003e\u003cp\u003eA survival analysis with all-cause mortality from 2005 to 2021 as the outcome was conducted using a Cox proportional hazards regression model while modelling chronic pain, breathlessness, emotional distress, multimorbidity as time-dependent characteristics,measured in 2005 and 2012, as well as sex, age, and education level included as baseline covariates. Some four hierarchical models were fitted sequentially into four blocks: (1) included chronic pain only, (2) additionally adjusted for age, sex, and education, (3) further included breathlessness and emotional distress, and (4) also included multimorbidity. Model fit was assessed using Akaike’s information criterion (AIC) and likelihood ratio tests between successive models. Missing data for baseline covariates were handled using single stochastic imputation with predictive mean matching (mice package in R). Continuous variables were standardised.\u003c/p\u003e\u003cp\u003eTo assess how chronic pain, breathlessness, emotional distress, and multimorbidity were associated with recurrence of respiratory-related hospital visits, we implemented a joint gamma-frailty model with Weibull baseline hazard. All-cause mortality was modelled as a competing event.. Chronic pain, breathlessness, emotional distress, and multimorbidity were included as time-dependent characteristics in 2005 and 2012. Four hierarchical models were fitted sequentially as in the Cox regression model described previously. Model improvement was evaluated using likelihood ratio tests and AIC. Missing data for baseline covariates were imputed and continuous variables were standardised.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Chronic pain prevalence in patients with COPD from 2005 to 2021\u003c/h2\u003e \u003cp\u003eIn 2005, 284 of 1071 (26.5%) patients with COPD were treated for chronic pain (\u0026ge;\u0026thinsp;4 dispensed pain medications during the period), as were 282 of 761 (37.1%) patients in 2012, and 137 (38.1%) of 360 in 2021. Among the 280 patients with chronic pain in 2005, 117 (41.2%) had died by 2012, and of the surviving 167, 131 (78.4%) still suffered from chronic pain in 2012. Among 282 patients with chronic pain in 2012, 178 (63.1%) had died by 2021, and of the surviving 104 patients, 82 (78.8%) still suffered from chronic pain in 2021. The transitions between chronic pain and mortality across the time points are depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e\u003cp\u003e3.2. Descriptive baseline characteristics of patients with COPD, with and without comorbid pain\u003c/p\u003e\n\u003cp\u003eAs seen in Table 1, in 2005, COPD patients with chronic pain were, to a higher degree women, those who had had more emergency contacts, had more comorbid diagnoses, but were of similar age, education level, and BMI, compared to those without pain. The chronic pain group had more frequent pain diagnoses registered in the Swedish National Patient Register, particularly for arthropathies, back pain and abdominal pain.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eTable 1. Descriptive baseline characteristics (2005) of COPD patients, with or without chronic pain.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e\u0026nbsp;With chronic pain\u003c/p\u003e\n \u003cp\u003e(n=284)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 34px;\"\u003e\n \u003cp\u003e\u0026nbsp;Without chronic pain\u003c/p\u003e\n \u003cp\u003e(n=787)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e\u003cu\u003e\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003e\u003cu\u003eYear 2005\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003e\u003cu\u003e\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cu\u003en\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cu\u003emean or %\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cu\u003eSD\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u003cu\u003en\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u003cu\u003emean or /%\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u003cu\u003eSD\u003c/u\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e284\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e280\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10px;\"\u003e\n \u003cp\u003e64.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e7.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e64.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e7.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003eSex (female)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e280\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10px;\"\u003e\n \u003cp\u003e68.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e54.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 31px;\"\u003e\n \u003cp\u003eHighest completed education\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e280\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 31px;\"\u003e\n \u003cp\u003eLower\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e233\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e83.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e642\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e81.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 31px;\"\u003e\n \u003cp\u003eHigher\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e15.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e131\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e16.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 31px;\"\u003e\n \u003cp\u003eMissing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 31px;\"\u003e\n \u003cp\u003eSmoking\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e280\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 31px;\"\u003e\n \u003cp\u003eNever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e4.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e7.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 31px;\"\u003e\n \u003cp\u003ePrevious\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e166\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e59.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e455\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e57.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 31px;\"\u003e\n \u003cp\u003eSometimes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e7.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e6.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 31px;\"\u003e\n \u003cp\u003eDaily\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e30.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e221\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e28.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 31px;\"\u003e\n \u003cp\u003eMissing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026lt;0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003eEmergency contact with primary care (times/last 6 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e284\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e14.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e5.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003eOnce\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e161\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e56.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e577\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e73.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003eTwice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e17.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e106\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e13.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003eMore than twice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e9.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e5.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003e;issing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e2,1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003eEmergency contact with hospital care (times/last 6 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e284\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e7.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e2.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003eOnce\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e198\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e69.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e671\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e85.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003eTwice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e14.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e8.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003eMore than twice\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e8.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003eMissing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003eBMI (kg/m2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e272\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e26.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e5.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e764\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e25.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e5.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003eBreathlessness (mMRC)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e268\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e763\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e2.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003eEmotional distress (mental state CCQ)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e277\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e773\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e2.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003ePain-related diagnoses, overall\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e284\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e39.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e16.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cul\u003e\n \u003cli\u003eHeadache/Migraine\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e284\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cul\u003e\n \u003cli\u003eIBS\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e284\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cul\u003e\n \u003cli\u003eGout\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e284\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cul\u003e\n \u003cli\u003eArthropathies\u0026nbsp;\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e284\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e10.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e2.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cul\u003e\n \u003cli\u003eJoint pain\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e284\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cul\u003e\n \u003cli\u003eBack pain\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e284\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e6.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cul\u003e\n \u003cli\u003eOther soft tissue disorder\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e284\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e9.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e3.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cul\u003e\n \u003cli\u003ePain in throat and chest\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e284\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e6.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e4.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cul\u003e\n \u003cli\u003eSymptoms and signs involving the digestive system and abdomen\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e284\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e14.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e4.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cul\u003e\n \u003cli\u003eOsteoporosis\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e284\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cul\u003e\n \u003cli\u003eOther pain\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 9px;\"\u003e\n \u003cp\u003e284\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 31px;\"\u003e\n \u003cp\u003eMultimorbidity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e284\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eNote. Chronic pain status was defined as either having\u0026nbsp;recently used pain medication (\u0026ge;4 dispensed physician-prescribed pain medications during the period) or not. Multimorbidity, average number of Elixhauser comorbidity index diagnoses beyond COPD. Age, sex, highest completed education, body mass index (BMI), smoking status and emergency contacts with primary and hospital care were derived from PRAXIS self-reported questionnaires. The planned visits could be either to a nurse or a physician. The pain diagnoses were derived from the Swedish National Patient Register. SD, Standard deviation.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e3.4. Sequential associations of chronic pain, breathlessness, emotional distress, and multimorbidity with all-cause mortality and frequency of respiratory-related hospital visits.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs shown in Table 2, chronic pain was univariately (block I) associated with all-cause mortality, having chronic pain corresponding to a 72% higher hazard of death. Demographic factors did not diminish this association (block II), although older age (HR 1.08 95% CI 1.07-1.09) and lower education level (HR 0.93, 95% CI 0.88-0.98) were also statistically significantly associated with mortality. Including breathlessness (HR 1.33 95% CI 1.24-1.43) and multimorbidity (HR 1.44, 95% CI 1.36-1.54) in blocks III and IV attenuated the association of chronic pain with all-cause mortality to HR 1.19, 95% CI 1.01-1.40), but it remained statistically significant The \u003cstrong\u003eprogressive reduction in the Akaike Information Criterion (AIC)\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eacross the four models (from 9177.4 to 8755.0) indicates that the addition of age, breathlessness, and multimorbidity substantially improved model fit.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"606\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 606px;\"\u003e\n \u003cp\u003eTable 2. Sequential predictors of all-cause mortality among 1071 COPD patients, from 2005 to 2021.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eHR\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 606px;\"\u003e\n \u003cp\u003eBlock I. AIC: 9177.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Chronic pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.72\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.47-2.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 606px;\"\u003e\n \u003cp\u003eBlock II. AIC: 9003.3;\u0026nbsp;\u0026Delta;\u0026chi;\u0026sup2; = 180.06, p = \u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Chronic pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.69\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.44-1.97\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Age\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.08\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.07-1.09\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Male sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e0.81-1.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e0.45\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Education level \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.93\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.88-0.98\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.003\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 606px;\"\u003e\n \u003cp\u003eBlock III. AIC: 8884;\u0026nbsp;\u0026Delta;\u0026chi;\u0026sup2; = 123.35, p = \u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Chronic pain\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.43\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.22-1.68\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.07\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.06-1.09\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Male sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e0.82-1.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e0.53\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Education level\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.94\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.90-0.99\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.02\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Breathlessness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.38\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.28-1.48\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Emotional distress\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e1.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e0.98-1.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e0.27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 606px;\"\u003e\n \u003cp\u003eBlock IV. AIC: 8755; \u0026Delta;\u0026chi;\u0026sup2; = 130.98, p = \u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Chronic pain\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.19\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.01-1.40\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.04\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.06\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.05-1.08\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Male sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e0.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e0.80-1.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Education level\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.91\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.86-0.97\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.002\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Breathlessness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.33\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.24-1.43\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Emotional distress\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e0.96-1.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Multimorbidity\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.44\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.36-1.54\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 606px;\"\u003e\n \u003cp\u003eNote. This was a sequential or nested Cox proportional hazards model with chronic pain, breathlessness, emotional distress and multimorbidity as time-dependent exposures at 2005 and 2012, and all-cause mortality as a continuous-time outcome from 2005 to 2021. Multimorbidity, diagnoses from the Elixhauser comorbidity index, excluding chronic respiratory disease. Chronic pain status was defined as having recently used pain medication (\u0026ge;4 dispensed pain medications during the period). HR, hazard ratio; CI, confidence interval; AIC, Akaike\u0026rsquo;s information criterion. Significant associations are in bold.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 3 shows that chronic pain was not associated with more frequent respiratory-related hospital visits in the unadjusted model (block I; HR 1.01, 95% CI 0.96-1.06). However, when accounting only for demographic factors (block II), it was associated with more hospital visits (HR 1.06). When additionally adjusting for breathlessness, emotional distress, and multimorbidity, it was associated with fewer hospital visits (HR 0.89, 95% CI 0.85-0.94). Older age and male sex were associated with fewer hospital visits. Breathlessness (HR 1.41, 95% CI 1.32-1.51), emotional distress (HR 1.29, 95% CI 1.20-1.38), and multimorbidity (HR 1.07, 95% CI 1.01-1.13) were all independently associated with more frequent respiratory-related hospital visits (block IV). The continued decline in AIC values (from 101078.0 to 100721.7) again indicates that successive model adjustments yielded improved explanatory power.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"606\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 606px;\"\u003e\n \u003cp\u003eTable 3. Sequential associations with recurrent respiratory-related hospital visits in 1071 COPD patients, from 2005 to 2021.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eHR\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 140px;\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 606px;\"\u003e\n \u003cp\u003eBlock I. AIC: 101078\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Chronic pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e0.96-1.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 606px;\"\u003e\n \u003cp\u003eBlock II. AIC: 101065.8;\u0026nbsp;\u0026Delta;\u0026chi;\u0026sup2; = 24.21, p = \u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Chronic pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.06\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.01-1.12\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.03\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Age\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.91\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.86-0.97\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Male sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.92\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.86-0.98\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.008\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Education level \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e0.87-1.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e0.50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 606px;\"\u003e\n \u003cp\u003eBlock III. AIC: 100740.2; \u0026Delta;\u0026chi;\u0026sup2; = 333.59, p = \u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Chronic pain\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.93\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.89-0.98\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.010\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.83\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.78-0.89\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Male sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.93\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.87-0.99\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.03\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Education level\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e0.91-1.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Breathlessness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.42\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.33-1.51\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Emotional distress\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.30\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.19-1.42\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 606px;\"\u003e\n \u003cp\u003eBlock IV. AIC: 100721.7;\u0026nbsp;\u0026Delta;\u0026chi;\u0026sup2; = 22.51, p = \u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Chronic pain\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.89\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.85-0.94\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.82\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.77-0.88\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Male sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.91\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.86-0.97\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.002\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Education level\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e0.90-1.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Breathlessness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.41\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.32-1.51\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Emotional distress\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.29\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.20-1.38\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 212px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Multimorbidity\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.07\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1.01-1.13\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.02\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 606px;\"\u003e\n \u003cp\u003eNote. This was a sequential or nested joint gamma frailty model with time-dependent exposures at 2005 and 2012, and recurrent respiratory-related hospital visits (Anderson-Gill formulation) and all-cause mortality (terminal event) as continuous-time outcomes from 2005 to 2021. Note that in the table, only the recurrent event part of the model is reported. Multimorbidity, present diagnoses from the Elixhauser comorbidity index, excluding chronic respiratory disease. Chronic pain status was defined as having recently used pain medication (\u0026ge;4 dispensed physician-prescribed pain medications during the period). Significant associations are in bold.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThe current study followed a cohort of 1071 COPD patients between 2005 and 2021 and examined the characteristics of patients with and without chronic pain, described the longitudinal course of chronic pain and mortality, and explored longitudinal associations between chronic pain, breathlessness, emotional distress, and multimorbidity in relation to all-cause mortality and respiratory-related hospital visits.\u003c/p\u003e \u003cp\u003eWe found that throughout the study period, the prevalence of chronic pain was 26.5% in 2005, 37.1% in 2012 and 38.1% in 2021. The most frequent chronic pain diagnoses were arthropathies, other soft tissue disorders, abdominal pain, and back pain. The prevalence observed by us, lies at the lower end, compared with previous studies which reported prevalence between 30\u0026ndash;70% of chronic pain among COPD patients,\u003csup\u003e10\u0026ndash;13\u003c/sup\u003e although it is considerably higher than the prevalence in the general population which ranges from between 10 to 19%. \u003csup\u003e32,40,41\u003c/sup\u003e This may be due to our method of identifying chronic pain being conservative, requiring at least 4 dispensations within each time period, as many with chronic pain do not consistently use analgesics. This notion was confirmed by a recent study, which found that persistent analgesic use underestimated the prevalence of chronic pain, compared to a definition using pain diagnoses. \u003csup\u003e32\u003c/sup\u003e The fact that the patterns of associations with outcomes correspond with the alternative definition of recurrent opioid use (Table S2 and Table S3) indicates that our method of using repeated medication dispensations is, however, robust. As can be seen in these supplemental materials, the prevalence of recurrent opioid use was decreasing from 2005 to 2021. In contrast, the prevalence using our main definition of chronic pain defined as \u0026ge;\u0026thinsp;4 analgesics dispensations were increasing over time, which is in line with current guidelines advising against long-term opioid use as treatment for both chronic pain \u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e and for respiratory symptoms in COPD (although low-dose systemic opioids may be indicated for refractory breathlessness in palliative COPD care). \u003csup\u003e1\u003c/sup\u003e Despite this, it is a concern that 23% of patients with COPD were recurrently prescribed opioids as recently as in 2021.\u003c/p\u003e \u003cp\u003eIn univariate analyses, chronic pain predicted mortality during follow-up with a 72% higher hazard, compared with patients without chronic pain. Of those with chronic pain in 2005, 41% had died by 2012, and among those with chronic pain in 2012, 63% had died by 2021. A previous study also found an association between chronic pain and mortality in COPD patients, also with evidence that the association became of higher magnitude with greater pain interference,\u003csup\u003e11\u003c/sup\u003e and a review article concluded that there is a higher mortality risk among COPD patients receiving opioids for breathlessness.\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e These findings, together with ours, suggest that chronic pain may reflect COPD phenotype of greater overall disease burden and vulnerability. We encourage future research to further elaborate on the association between chronic pain and mortality, by incorporating more detailed pain measures such as pain duration, pain intensity, pain frequency and pain interference, as well as the patterns and extent of analgesics and opioid use, in order to disentangle the likely complex associations between chronic pain characteristics, analgesics and opioid use, and mortality. We believe the finding that chronic pain is common and notably associated with mortality in patients with COPD is especially important given that pain assessment and management are rarely, if at all, mentioned in current COPD management guidelines.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e We recommend future research to further explore chronic pain in COPD patients, and for COPD management guidelines to re-evaluate their lack of inclusion of pain.\u003c/p\u003e \u003cp\u003eOur results indicated that a large proportion of the association between pain with mortality was explained by breathlessness and multimorbidity, which is in line with our prior hypothesis Previous research has indicated that they may reciprocally influence each other in a downward spiral in COPD patients.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e However, the earlier studies have been predominantly retrospective, qualitative or cross-sectional, meaning that no previous research has explored these associations longitudinally as in the current study. Indeed, a cross-sectional symptom cluster of breathlessness, emotional distress and pain has consistently been identified, both in respiratory disease cohorts,\u003csup\u003e44\u003c/sup\u003e as well as, for example, in cancer \u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e or palliative care populations.\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e Our results add a piece to this complex puzzle of associations by showing that they appear to hold over time, in a longitudinal context, and they emphasise the need for an integrated, multidisciplinary approach by combining respiratory rehabilitation, psychological support, and controlling analgesic strategies in COPD management. In our study, we also found that breathlessness was associated with both mortality and respiratory-related hospital visits, even when adjusting for other factors such as age, chronic pain, and multimorbidity. The link between breathlessness and mortality is well established in previous research in COPD,\u003csup\u003e47,48\u003c/sup\u003e and our results are consistent with this literature. However, emotional distress over respiratory symptoms showed a significant association with respiratory-related hospital visits, but not with mortality. These results suggest that patients\u0026rsquo; emotional responses to their symptoms may influence care seeking behaviour and patterns of care in addition to their somatic illness-specific symptoms. This is a well-known pattern in COPD management \u0026ndash; emotional distress over COPD symptoms appears to increase the risk of COPD exacerbations requiring hospital visits,\u003csup\u003e49\u003c/sup\u003e as well as overall increased healthcare utilisation, independent of physical COPD characteristics.\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWe found that, among the examined constructs, multimorbidity had the most notable association with later mortality. This is consistent with previous research, which has found an association between the number of comorbid disease and mortality in COPD patients.\u003csup\u003e\u003cspan additionalcitationids=\"CR52\" citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u003c/sup\u003e The most recent Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (GOLD) 2025 guidelines highlight the importance of multimorbidity in COPD patients, and how important it is to address this due to its association with mortality.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e The results of our study confirm and underscore this emphasis in the GOLD 2025 guidelines, by demonstrating the need to address multimorbidity in COPD patients.\u003c/p\u003e \u003cp\u003eIn this study, chronic pain was associated with all-cause mortality, even when adjusting for other risk factors such as advancing age, education level, breathlessness, or multimorbidity, although breathlessness and multimorbidity attenuated the association of chronic pain with mortality, indicating they are interrelated. Multimorbidity and breathlessness were more common in COPD patients with chronic pain, compared to those without. Our interpretation of these results is that chronic pain may be a common clinical manifestation of multimorbidity and respiratory symptoms in patients with COPD. Although chronic pain was associated with recurrent respiratory-related hospital visits in the deomgraphics-only adjusted model, the association was reversed when adjusting for breathlessness, emotional distress and multimorbidity. One possible explanation to this is that the patients with chronic pain are generally more ill, beyond what we could capture via breathlessness and multimorbidity, and require other care to such an extent that COPD care become de-prioritised. Indeed, as can be seen in Table S3 (Supplementary materials), patients with chronic pain have more hospital visits overall, even when adjusting for breathlessness, emotional distress, and multimorbidity. However, a previous publication by our research group indicated that multimorbidity in general did not lead to de-prioritisation of COPD management.\u003csup\u003e\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e Since appropriate COPD management is important also in patients with other illness than COPD, we recommend future research to further explore these associations. .\u003c/p\u003e \u003cp\u003eA strength of the current study is that it is based on a large sample of COPD patients who were followed for 17 years (2005 to 2021), and that it integrates data from several Swedish national registers, which allowed for more extensive measures and outcomes than survey data alone. We combined this with advanced statistical methods for longitudinal data, which allowed us to assess complex longitudinal associations between the examined constructs. Nevertheless, the study also has potential limitations. The study was based on observational data, so although we could establish longitudinal relationships among the constructs, we were not able to make firm causal claims from any of the results. We also included broad and nonspecific measures of pain, multimorbidity and cause of mortality, and they were based only on the data that were recorded in the national registers during each time period. This allowed us to address wide research questions, but at the same time, potentially relevant sensitivity and specificity were lost. This is particularly problematic for the measure of multimorbidity, as each comorbid condition must have been registered in the relatively small time window around each time-point to be recorded as a comorbid condition, possibly leading to an underestimation of multimorbidity. We recommend future studies further explore the associations between different types of pain and pain characteristics, as well as specific comorbid conditions or their combinations, and cause-specific mortality. In addition, the self-reported nature of breathlessness and emotional distress introduced a risk of reporting bias, and potentially valuable information was not available through the register-based measures of chronic pain and multimorbidity. Lastly, several additional constructs that are relevant to the examined relationships, including functional disability, nutrition, and lifestyle factors such as physical activity, which were not available.\u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eIn conclusion, chronic pain is common in COPD patients and is notably associated with all-cause mortality. Much, but not all, of this association appears to be explained by multimorbidity and breathlessness, of which chronic pain appears to be a symptom or indicator. Multimorbidity was the most consistent predictor of all-cause mortality and was also associated with recurrent respiratory-related hospital visits. Breathlessness was indirectly related to all-cause mortality through an increase in multimorbidity and indirectly linked to respiratory-related hospital visits via emotional distress. In contrast, emotional distress was not associated with mortality, but was associated with greater healthcare use.\u003c/p\u003e \u003cp\u003eWe recommend including chronic pain as an important aspect in COPD management. Not only because chronic pain is common in COPD, but also because it may be that this group is under-treated in their COPD management. Although COPD management is already comprehensive and complex, we believe that simple questions about pain are feasible to routinely include in COPD management, and that addressing pain in COPD has the potential not only to relieve them of considerable suffering, but also to better identify risks for future disability and mortality.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e6.1. Ethics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThe study was approved by the regional ethics vetting board of Uppsala (registration number 2004:M-445) and the Swedish Ethical Review Authority (Dnnr 2010/090 and Dnnr 2020-00270). Participation in the study was voluntary. Written informed consent was obtained before data collection using a consent form distributed and returned by postal mail. A separate, optional consent item in the survey asked participants to authorize linkage of their survey responses to medical records.\u003c/p\u003e\n\u003cp\u003e6.2. Availability of data and materials\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from Maaike Giezeman ([email protected]) upon reasonable request and with appropriate ethical permission. Register data used in this study cannot be shared publicly due to regulations under Swedish law. Researchers who are interested in Swedish register data can refer to https://www.registerforskning.se/en/.\u003c/p\u003e\n\u003cp\u003e6.3. Competing interest\u003c/p\u003e\n\u003cp\u003eCJ has received honoraria for educational activities and lectures from ALK, AstraZeneca, Chiesi, GlaxoSmithKline, Orion, Sanofi and Stallergenes, and has served on advisory boards arranged by ALK, AstraZeneca, GlaxoSmithKline, Orion, Sanofi and Stallergenes.\u0026nbsp;BS declare no competing financial or non-financial interests associated with this work. Outside the submitted work, BS has received personal fees for educational activities and lectures from AstraZeneca, Boehringer Ingelheim, Novartis, and GlaxoSmithKline and served on advisory boards arranged by AstraZeneca, Novartis, GlaxoSmithKline, MSD, and Boehringer Ingelheim.\u0026nbsp;The remaining authors report no conflicts with any product mentioned or concept discussed in this article.\u003c/p\u003e\n\u003cp\u003e6.4. Funding\u003c/p\u003e\n\u003cp\u003eFunding was received from \u003cem\u003eVetenskapsrådet\u003c/em\u003e - the Swedish Research Council (2023–05997), as well as from\u0026nbsp;The Swedish Heart and Lung Association, The Swedish Heart Lung Foundation, the Swedish Asthma and Allergy Association, the Bror Hjerpstedt Foundation, the Regional Research Council Mid Sweden, the Centre for Clinical Research, Region Dalarna, Sweden, and the Centre for Clinical Research, Region Värmland, Sweden. ALF funding Region Örebro County.\u003c/p\u003e\n\u003cp\u003e6.5. Author contributions\u003c/p\u003e\n\u003cp\u003eT.A., S.M. and B.S. were responsible for initiation and conceptualisation of the study. Data curation and statistical analyses were conducted by T.A. Main interpretation of the results was undertaken by T.A. and S.M. T.A. wrote the original draft. All authors provided intellectual input into the manuscript, reviewed and edited the manuscript and approved its final version.\u003c/p\u003e\n\u003cp\u003e6.6. Acknowledgements\u003c/p\u003e\n\u003cp\u003eThe authors thank patients and centres who has participated in data collection, the health care staff who provided data to the Swedish national registers, as well as Eva Manell and Ulrike Spetz-Nyström for reviewing the medical records.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003e\u003cem\u003eGlobal strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2024 report)\u003c/em\u003e. 2024. https://goldcopd.org/2024-gold-report\u003c/li\u003e\n\u003cli\u003eMeghji J, Mortimer K, Agusti A, et al. Improving lung health in low-income and middle-income countries: from challenges to solutions. \u003cem\u003eThe Lancet\u003c/em\u003e 2021;397(10277):928-940. doi:10.1016/s0140-6736(21)00458-x\u003c/li\u003e\n\u003cli\u003eBurke H, Wilkinson TMA. 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Predictors of mortality in chronic obstructive pulmonary disease: a systematic review and meta-analysis. \u003cem\u003eBMC Pulmonary Medicine\u003c/em\u003e 2022;22(1)doi:10.1186/s12890-022-01911-5\u003c/li\u003e\n\u003cli\u003eKim Y, Kim Y-J, Cho W-K. Effect of multiple comorbidities on mortality in chronic obstructive pulmonary disease among Korean population: a nationwide cohort study. \u003cem\u003eBMC Pulmonary Medicine\u003c/em\u003e 2021;21(1)doi:10.1186/s12890-021-01424-7\u003c/li\u003e\n\u003cli\u003eDivo M, Cote C, de Torres JP, et al. Comorbidities and Risk of Mortality in Patients with Chronic Obstructive Pulmonary Disease. \u003cem\u003eAmerican Journal of Respiratory and Critical Care Medicine\u003c/em\u003e 2012;186(2):155-161. doi:10.1164/rccm.201201-0034OC\u003c/li\u003e\n\u003cli\u003eSmith C, Hasselgren M, Janson C, et al. Does multimorbidity result in de-prioritisation of COPD in primary care? \u003cem\u003enpj Primary Care Respiratory Medicine\u003c/em\u003e 2023;33(1)doi:10.1038/s41533-023-00326-x\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"COPD, chronic obstructive pulmonary disease, chronic pain, breathlessness, multimorbidity, emotional distress, mortality, respiratory-related hospital visits.","lastPublishedDoi":"10.21203/rs.3.rs-8580535/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8580535/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eChronic pain is common in patients with chronic obstructive pulmonary disease (COPD) and is linked to adverse clinical outcomes, multimorbidity and COPD symptoms, but the exact associations remain unclear. Importantly, chronic pain is underrepresented in most current clinical management guidelines. This study aimed to describe chronic pain prevalence in patients with COPD across 16 years, and its longitudinal association with mortality and respiratory-related hospital visits, multimorbidity, and COPD-related symptoms.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study included patients with COPD, with survey data sweeps in 2005 and 2012, and Swedish national register data from 2005 to 2021. The prevalence of chronic pain and mortality were described in the patients. Repeated dispensed physician-prescribed pain medication defined chronic pain. Survival analyses were used to investigate longitudinal associations among chronic pain, multimorbidity, breathlessness, emotional distress, all-cause mortality, and respiratory-related hospital visits.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eChronic pain prevalence among 1071 COPD patients was 27% in 2005, 37% in 2012, and 38% in 2021. Initially, chronic pain was associated with all-cause mortality with a 72% higher hazard, compared to patients without pain. Adjustment for sociodemographic factors, breathlessness severity and multimorbidity attenuated this association to 19% (adjusted hazard ratio (adjHR) 1.19, 95% CI 1.01\u0026ndash;1.40), although only partially. Chronic pain, breathlessness (adjHR 1.33, 95% CI 1.24\u0026ndash;1.43), and multimorbidity (adjHR 1.44, 95% CI 1.36\u0026ndash;1.54) were associated with all-cause mortality in fully adjusted models, and emotional distress (adjHR 1.29, 95% CI 1.20\u0026ndash;1.38), breathlessness (adjHR 1.41, 95% CI 1.32\u0026ndash;1.51), and multimorbidity (adjHR 1.07, 95% CI 1.01\u0026ndash;1.13) were associated with recurrence of respiratory-related hospital visits.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eChronic pain was common and strongly associated with mortality in COPD patients and highlights the importance of considering chronic pain in patients with COPD. Emotional distress was associated with increased respiratory-related hospital visits but not with mortality. This emphasises the relevance of prioritising somatic COPD symptoms, more than subjective distress, in clinical decision-making. Chronic pain should be considered in COPD assessment and management, as it is associated with adverse outcomes and mortality risk in these patients.\u003c/p\u003e","manuscriptTitle":"Chronic pain in COPD: prevalence and longitudinal associations with multimorbidity, breathlessness, emotional distress, and adverse clinical outcomes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-15 06:28:51","doi":"10.21203/rs.3.rs-8580535/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-15T14:06:53+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-28T22:42:31+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-18T21:42:40+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-13T12:25:36+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-13T09:10:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"191391912482430951072046269164866355302","date":"2026-04-09T14:28:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"79449965953697236150720901351806830561","date":"2026-04-08T01:33:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"286477528482416436200925765960747494024","date":"2026-04-07T12:45:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"59698826422621726507722199216747780924","date":"2026-04-07T11:46:02+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-07T09:17:44+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-15T09:44:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-20T12:04:14+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-20T10:50:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pulmonary Medicine","date":"2026-01-20T10:33:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2a11f0fa-834e-4d9e-ab6d-8ac464daa745","owner":[],"postedDate":"April 15th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-15T14:06:53+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-15T14:10:35+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-15 06:28:51","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8580535","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8580535","identity":"rs-8580535","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}