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Publicly Available Published by De Gruyter September 6, 2018

Cause-specific mortality of patients with severe chronic pain referred to a multidisciplinary pain clinic: a cohort register-linkage study

  • Henrik Bjarke Vaegter ORCID logo EMAIL logo , Martine Støten , Siv Laine Silseth , Annette Erlangsen , Gitte Handberg , Stine Sondergaard and Elsebeth Stenager

Abstract

Background and aims

Almost 20% of the adult population suffers from chronic pain. Chronic pain may be linked to an elevated mortality; however, results from previous studies are inconsistent. Some studies find similar mortality levels in chronic pain patients and pain-free controls while other studies show elevated mortality levels among chronic pain patients, primarily with respect to cancer, diseases of the circulatory and respiratory systems, and suicide. These conflicting results are potentially due to different population samples and different operational definitions of chronic pain. Further research on overall and cause-specific mortality in patients with severe chronic pain is needed to inform clinical practice. The objective of this register-linkage study was to investigate whether patients with severe chronic pain referred to multidisciplinary pain treatment have higher cause-specific mortality rates than the general population.

Methods

In this register-linkage cohort study, data from 6,142 chronic pain patients (female: n=3,941, male: n=2,201, mean age: 48.2±14.2; range: 16–97 years) attending an interdisciplinary Pain Center in Odense, Denmark from 2005 to 2014 were linked to the Danish Register of Causes of Death. Age and gender standardized mortality ratios (SMRs) with their 95% confidence intervals (CI) were calculated and compared with those of the general population. Data from the general population was extracted from the Danish Register of Causes of Death, and Causes of death were classified according to national Classification of Disease (ICD-10).

Results

In all, 276 deaths (women: n=152, men: n=124) were observed among the chronic pain patients, and a six-fold higher overall mortality rate was found [SMR: 6.2 (95% CI: 5.5–7.0)] compared with the general population. Elevated cause-specific mortality rates were noted for chronic patients with respect to cancer and neoplasms [4.7 (95% CI: 3.7–5.9)], diseases of the circulatory system [5.7 (95% CI: 4.3–7.3)], diseases of the respiratory system [8.7 (95% CI: 6.2–11.9)], and suicide [7.3 (95% CI: 2.7–15.9)].

Conclusions

The overall mortality rate of patients with severe chronic pain in this study was six-fold higher than the rate of the general population in this region. This was reflected in select specific causes of death (cancer and neoplasms, diseases of the circulatory system, diseases of the respiratory system, and suicide). The results are in agreement with previous studies and emphasize the need to understand which factors causally affect this increased mortality allowing for targeted interventions in similar chronic pain populations.

Implications

Potential reasons for the excess mortality should be adequately addressed by future studies in order to better target this in the management of these patients. The chronic pain population included in this study may have several comorbidities contributing to the increased mortality. To better address these aspects, complete medical profiles are needed in future studies. In addition, implementation of management strategies towards potential risk factors such as poor diet, low levels of physical activity, smoking, and high BMI as well as sleep deprivation and morphine use previously shown associated with having pain may reduce the excess mortality ratio.

1 Introduction

Chronic pain is a common complaint in adults with an estimated prevalence of 19% [1]. It is often associated with adversities in terms of quality of life, general health, and social functioning as well as increased psychological distress, irrespective of the cause of pain or the pain localization [2]. Although the relationship between chronic pain and poor general health is well established, inconsistencies in findings pertaining to the association between chronic pain and mortality are noted. While some studies find similar mortality levels in chronic pain patients and pain-free controls [2], [3], [4], other studies show elevated mortality levels among chronic pain patients, primarily with respect to cancer, diseases of the circulatory and respiratory systems, and suicide [5], [6], [7], [8], [9], [10], [11]. The conflicting evidence is further highlighted by two large population-based cohort studies, i.e. the HUNT Study [12] and the UK Biobank [13]. When adjusted for age and sex, the HUNT study of 65,026 participants did not provide support for a relevant higher mortality rate in patients with chronic musculoskeletal pain [hazard ratio: 1.06 (95% CI: 1.02–1.10)] or chronic widespread pain (CWP) [hazard ratio: 1.07 (95% CI: 1.03–1.12)] when compared to pain-free subjects [12]. However, increased mortality risk ratios [2.23 (95% CI: 1.90–2.62)] were noted among the 7,130 subjects with CWP in the UK Biobank study who were also compared to pain-free subjects [13]. These conflicting results may relate to different operational definitions of chronic pain in the studied samples. Although both studies were based on survey data, one study defined chronic pain as ‘continuously pain and/or stiffness in muscles and joints for more than 3 months’ [12], and the other as ‘pain all over the body for more than 3 months’ [13]; suggesting that severity of chronic pain might be linked to level of mortality.

Further evidence on overall and cause-specific mortality in patients with severe chronic pain is needed to inform clinical practice. The aim of this study was to examine whether the overall mortality as well as cause-specific mortality rates in a large sample of patients with severe chronic pain referred to an interdisciplinary University Pain Center in Denmark differed from those of the general population. It was hypothesized that patients with chronic pain had excess mortality rates when compared with the general population.

2 Methods

2.1 Design and method summary

A register-linkage cohort study design was applied. All patients who due to chronic (≥6 months) non-malignant pain were referred to and consulted at the interdisciplinary University Pain Center at Odense University Hospital, Denmark, from the period of January 2005 to December 2014 were included. Because all citizens in Denmark have a unique identification number [14], it was possible to link the study population with the Danish Register of Causes of Death (RCD) [15], [16]. Using the participants’ identification number, data on causes of death were obtained from the RCD. Data on overall and cause-specific mortality for the general population of Southern Denmark were obtained from The Health Data Administration of Denmark.

2.2 Study populations

2.2.1 Patients with chronic pain

The Pain Center receives patients ≥18 years of age with non-malignant chronic pain who are referred by their general practitioner, primarily from the Region of Southern Denmark (n=1.2 mill inhabitants). As previously reported, patients referred have a mean age of 48.5±12.5 years, their reported mean pain duration is 8–9 years, and 66% of patients are women. A large share of patients report a high degree of pain-related disability as well as psychological distress, and approximately 50% of patients use opioids when referred [17], [18]. Patients were identified in the patient booking and registration system (F-PAS: “Fyns patient administrative system”) used at Odense University Hospital during the study period.

2.2.2 General population

To generate a comparison group, data on the general population was extracted from the RCD [15]. To adjust for demographical differences, a sub-sample of the general population consisting of the entire population in the Region of Southern Denmark was used for the analysis. Data on specific causes-specific mortality rates per 100.000 persons were obtained by gender and age group for the period 2005–2014 [15]. The censor date was December 31st 2014, as newer data were not available at the time of data extraction from RCD. Causes of death were classified according to national Classification of Disease (ICD-10) in the follow-up period.

2.3 Outcomes

The outcomes of primary interests were any cause of death as well as the following specific causes of death: cancer and neoplasms (ICD-10: C00-D48), diseases of the circulatory system (ICD-10: I00-I99), diseases of the respiratory system (ICD-10: J00-J99), and suicides (ICD-10: X60-X84 and Y870) as these causes of death have previously been associated with chronic pain. Moreover, data on the following cause-specific causes of deaths were also collected: diseases of the nervous system (ICD-10: G00-G99), diseases of digestive system (ICD-10: K00-K93), accidents (ICD-10: V01-X59, Y40-69, Y70-86, Y88), mental and behavioral disorders (ICD-10: F03-F99), endocrine, nutritional and metabolic diseases (ICD-10: E00-E99), diseases of the musculoskeletal system and connective tissue (ICD-10: M00-M99), symptoms, signs and abnormal findings (ICD-10: R00-99), and all other causes (ICD-10: A00-B99, D50-D89, L00-L99, N00-N99, O00-O99, P00-P96, Q00-Q99, X85-99, Y00-36, Y871-Y872, Y890-Y891, Y899). Causes of death were classified according to the 10th revision of the International Classification of Diseases (ICD-10) with main- and supplementary diagnoses.

2.4 Statistical analysis

Standardized mortality ratios (SMRs) of observed-to-expected number of death were calculated with their 95% confidence intervals, using the population in the Region of Southern Denmark as a standard. Using indirect standardization, we calculated the ratio between the observed of number deaths among patients with chronic pain and the expected of number deaths, i.e. the number of deaths that the group would have had if their mortality rates were similar to those of the general population while accounting for age and gender differences [19].

An anonymized version of the data was analyzed using the STATA software package. The Danish Data Protection Agency and the Danish Patient Safety Authority approved the study. According to Danish law, no ethical committee was applied, as the study was purely based on data extraction from registers.

3 Results

A total of 6,150 patients attended the Pain Center between January 1st 2005 and December 31st 2014. Of these, eight patients were excluded (four were <18 years at first consultation, two changed identification number, and two migrated). Hence, 6,142 patients were included in the study (female: n=3,941, male: n=2,201, mean age: 48.2±14.2; range: 16–97 years), accounting for 21,073 person-years (mean follow-up period from attending Pain Center to data extraction: 3.4 person-years, range: 1 day – 10 years).

3.1 Overall and cause-specific mortality in women and men with chronic pain

In all, 276 deaths (women: n=152, men: n=124) were observed among the chronic pain patients. The overall SMR was 6.2 [95% CI: 5.5–7.0]; implying a six-fold higher mortality rate among chronic pain patients when compared to the general population. For women, the overall SMR was 6.2 [95% CI: 5.3–7.3] while men had a ratio of 6.1 [95% CI: 5.1–7.3]. As illustrated in Table 1, an excess mortality was noted for all investigated causes of death among chronic pain patients compared with the general population including cancer and neoplasms: 4.7 [95% Cl: 3.7–5.9], diseases in the circulatory system: 5.7 [95% Cl 4.3–7.3], diseases in the respiratory system: 8.7 [95% CI: 6.2–11.9], and suicide: 7.3 [95% CI: 2.7–15.9].

Table 1:

Cause-specific mortality rates per 1,000 person-years in women and men with chronic pain attending the University Hospital Pain Center from 2005 to 2014.

Cause-specific mortality Total (n=6,142)
Women (n=3,941)
Men (n=2,201)
n (% of cases) Rate per 1,000 person-years SMR (95% CI) n (% of cases) Rate per 1,000 person-years SMR (95% CI) n (% of cases) Rate per 1,000 person-years SMR (95% CI)
All causes 276 (100) 44.9 6.2 (5.5–7.0) 152 (100) 38.6 6.2 (5.3–7.3) 124 (100) 56.3 6.1 (5.1–7.3)
Cancer and neoplasms (C00-D48) 73 (26.4) 11.9 4.7 (3.7–5.9) 44 (15.9) 11.2 4.9 (3.6–6.6) 29 (10.5) 13.2 4.4 (2.9–6.3)
Diseases of the nervous system (G00-G99) 12 (4.3) 2.0 7.6 (3.9–13.3) 6 (2.2) 1.5 6.2 (2.3–13.4) 6 (2.2) 2.7 9.9 (3.6–21.4)
Diseases of circulatory system (I00-I99) 62 (22.5) 10.1 5.7 (4.3–7.3) 30 (10.9) 7.6 5.2 (3.5–7.4) 32 (11.6) 14.5 6.6 (4.3–8.8)
Diseases of respiratory system (J00-J99) 38 (13.8) 6.2 8.7 (6.2–11.9) 23 (8.3) 5.8 9.0 (5.7–13.5) 15 (5.4) 6.8 8.3 (4.6–13.6)
Diseases of digestive system (K00-K93) 21 (7.6) 3.4 8.1 (5.0–12.4) 13 (4.7) 3.3 9.7 (5.2–16.6) 8 (2.9) 3.6 6.4 (2.8–12.7)
Suicides (X60-X84 and Y870) 6 (2.2) 1.0 7.3 (2.7–15.9) 2 (0.7) 0.5 6.4 (0.8–23.0) 4 (1.5) 1.8 7.9 (2.2–20.3)
Accidents (V01-X59, Y40-69, Y70-86, Y88) 9 (3.3) 1.5 6.3 (2.9–11.9) 3 (1.1) 0.8 4.8 (1.0–14.1) 6 (2.2) 2.7 7.4 (2.7–16.1)
Mental and behavioral disorders (F03-F99) 12 4.3) 2.0 4.8 (2.5–8.5) 8 (2.9) 2.0 6.0 (2.6–11.7) 4 (1.5) 1.8 3.5 (1.0–9.0)
Endocrine, nutritional and metabolic diseases (E00-E99) 11 (4.0) 1.8 7.4 (3.7–13.2) 6 (2.2) 1.5 7.5 (2.8–16.4) 5 (1.8) 2.3 7.1 (2.3–16.7)
Diseases of the musculoskeletal system and connective tissue (M00-M99) 6 (2.2) 1.0 16.4 (6.0–35.7) 4 (1.5) 1.0 16.4 (4.5–42.0) 2 (0.7) 0.9 16.3 (2.0–59.0)
Symptoms, signs and abnormal findings (R00-99), 13 defined as “Ill-defined and unknown causes of mortality (R95-99)” 14 (5.1) 2.3 11.0 (6.0–18.5) 7 (2.5) 1.8 9.7 (3.9–20.0) 7 (2.5) 3.2 12.7 (5.1–26.2)
All other causes (A00-B99, D50-D89, L00-L99, N00-N99, O00-O99, P00-P96, Q00-Q99, X85-99, Y00-36, Y871-Y872, Y890-Y891, Y899) 12 (4.3) 2.0 3.7 (1.9–6.5) 6 (2.2) 1.5 3.2 (1.2–7.0) 6 (2.2) 2.7 4.4 (1.6–9.5)
  1. Standardized mortality ratios (SRM) are the observed numbers of death in the chronic pain population compared to an “expected” numbers of deaths, if the study population had similar age and gender distribution as the general population.

4 Discussion

4.1 Summary of findings

This study investigated mortality levels of patients suffering from severe chronic pain and referred to a multidisciplinary pain center compared with the general population. In a large sample of patients with severe chronic pain, an excess overall mortality was noted in comparison with the general population, i.e. a six-fold higher SMR. In addition, elevated cause-specific mortality was found for all investigated causes of death among chronic patients, particularly with respect to cancer and neoplasms, diseases of the circulatory system, diseases of the respiratory system, and suicide.

4.2 Mortality in patients with chronic pain

Patients with severe chronic pain had elevated overall mortality rates compared to the general population. This is in agreement with previous studies investigating mortality in patients with chronic pain [5], [6], [7], [8], [9], [10], [11] including a large study of chronic widespread pain [13]. However, the findings are in contrast with another large study of chronic musculoskeletal pain or chronic widespread pain compared with pain-free subjects [12].

The patients included in this study were complex chronic pain patients, which have suffered with their condition for several years, living with high degree of pain-related disability and psychological distress [17], [18]. The patients included in this study seem to be more comparable to the patients included in the Macfarlane et al. study [13], as per definition. They investigated patients with “widespread pain” and thereby excluding chronic pain patients, if the pain were not widespread. It is possible that these patients with complex- and widespread location of the pain represent a more severe and disabled patient group, than the patients suffering from localized, simplex pain – as the study group included in the Asberg et al. [12] study. The sample included in this study and in the study by Macfarlane et al. [13] may also be similar in terms of the prevalence of potential risk factors (e.g. poor diet, low levels of physical activity, smoking, and high BMI as well as other comorbidities, depression, sleep deprivation and morphine use) possibly mediating this excess mortality. The most frequent causes of death in patients with chronic pain were cancer and neoplasms, diseases of the circulatory- and respiratory systems, and suicide.

4.3 Potential explanations for excess mortality in patients with chronic pain

Patients included in the current study have reported to be suffering from chronic pain on average for 8–9 years prior to referral as well as having had high levels of pain-related disability and psychological distress [17], [18]. Lifestyle related risk factor is a well-known catalyst to develop disease, and it has been shown that the excess mortality in chronic pain patients is unlikely to be due to the experience of pain per se but rather is substantially linked to lifestyle factors associated with having pain, such as poor diet, low levels of physical activity, functional limitations, smoking, and high BMI [13], [20].

Other potential causes could be related to sleep deprivation, morphine use, and opioid addiction [21], [22]. The prevalence of smoking among patients referred to a similar Pain Center in Denmark is twice as high as in the general population [21]. Smokers, former smokers or patients using nicotine substitution tend to use opioids more frequently and at higher doses, probably because smoking interferes negatively with the opioid system. Concerning cancer development, opioids have been reported to induce tumor growth, inhibit apoptosis, and promote angiogenesis and migration of tumor cells. Opioids are also shown to have pro-apoptotic and anti-angiogenic properties [23]. Furthermore, smoking is directly correlated with lung cancer [24], progression of disease of the circulatory system [25], and disease of the respiratory system [26]. The high prevalence of smoking may explain why a common cause of death is cancer, diseases of the circulatory- and respiratory systems among the population. Implementation of management strategies towards reduced sedentary time, promotion of physical activity, healthier diets and cessation of smoking and opioids in the management of patients with chronic pain may reduce the excess mortality ratio.

Compared to the general population overall standardized mortality ratio for suicide were increased in the chronic pain population, with an eight-fold increase of suicide in the male population. However, it should be noted that the number of suicide cases were very low (n=2 women and 4 men). The suicide deaths were due to intoxications, exclusively. Chronic pain conditions are associated with an elevated risk of suicide, probably due to pain combined with depression and/or substance use disorders [6], [8], [27]. A previous study investigating prevalence of mental disorders in the same population as in this study found in comparison with the general population significantly higher rates of anxiety and depression, and only the males had a higher rate of substance abuse disorders [28]. The latter finding might indicate that men tend to cope with somatic symptoms with self- medication through alcohol [29], which may contribute to the increased suicide risk in males. Dreyer and colleagues examined the suicide risk of Danish females with fibromyalgia and noted an increased risk of death by suicide with a SMR of 10.5 [95% Cl; 5.5–20.7] but no increased risk by all-cause mortality [3]. Previous research and the results of this study underline the importance of suicide assessment in the management of chronic pain patients.

4.4 Strengths and limitations

This study has a number of strengths. First of all, the study included a rather large sample of patients with non-malignant chronic pain who due to the pain center’s admission criteria makes the group more homogenous than populations included in previous studies. Second, by using register-based data it is possible to include a large sample size with a definite outcome, and no data loss at follow-up. The quality of the Danish Cause of Death Register is known to be high [16]. Third, all Danish citizens have free access to general practitioners and referral to specialized treatment, which limits potential selection bias to a minimum.

The study also has several limitations that should be considered when interpreting the results. Patients with chronic pain included in this study were all referred to specialist pain treatment, which could reduce the mortality rate due to e.g. cessation of opioids, thus reducing the mortality rate [30]. Although the results may be generalizable to similar chronic pain patients referred to multidisciplinary pain treatment, other chronic pain patient with less risk factors and comorbidities likely driving the association identified may not have similar increased mortality ratio. Moreover, the comparison group consisted of all persons living in the Region of Southern Denmark, thus also subjects living with chronic pain. Hence, the reported SMR could be underestimated. Although a large sample was studied, death is a rare event and as a consequence the estimates had wide confidence intervals, implying some uncertainly. It is beyond the scope of this study to investigate why the mortality is increased and why some causes of death are more prevalent than others. In addition, the chronic pain population may have several comorbidities contributing to the increased mortality. Unfortunately relevant details (e.g. other diagnoses, diet, levels of physical activity, smoking, BMI, sleep, depression and morphine use) for the chronic pain sample was not available. To better address these aspects, complete medical profiles of the studied sample would be needed, which was not feasible with the available data for this study.

4.5 Conclusion

We found an increased overall mortality in patients with severe chronic pain compared with the general population. An excess cause-specific mortality among patients with chronic pain was noted with respect to cancer and neoplasms, diseases of the circulatory- and respiratory systems, and suicides. As the relationship between chronic pain and mortality are certainly not causal, potential reasons (e.g. poor diet, low levels of physical activity, smoking, and high BMI as well as sleep deprivation and morphine use) for the excess mortality should be addressed by future studies in order to better target these factors in the management of similar patients.


Corresponding author: Henrik Bjarke Vaegter, PhD, Pain Research Group, Pain Center, Odense University Hospital, Odense, Denmark; and Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Heden 7-9, Indgang 200, DK – 5000 Odense C, Denmark, Phone: +45 65413869; Fax: +45 65415064

  1. Authors’ statements

  2. Research funding: This study was funded by the The Psychiatry’s Research Fund in The Region of Southern Denmark.

  3. Conflict of interest: There are no actual or potential conflicts of interest for any of the authors.

  4. Informed consent: Not applicable.

  5. Ethical approval: The Danish Health and Medicines Authority’s, The Health Data Authority, and the Danish Data Protection Agency approved data extraction from the registries. As treatment was not affected in this registry study, under Danish law, no ethics approval was needed (Act on Research Ethics Review of Health Research Projects, October 2013, Section 14.2).

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Received: 2018-05-29
Revised: 2018-08-15
Accepted: 2018-08-17
Published Online: 2018-09-06
Published in Print: 2019-01-28

©2018 Scandinavian Association for the Study of Pain. Published by Walter de Gruyter GmbH, Berlin/Boston. All rights reserved.

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