Background & Aims

Chronic pain and pain-related diseases are the main causes of years lived with disability (YLD) globally (1,2). Yet, the mortality of people with chronic non-cancer pain (CNCP) is difficult to determine as it has only recently been classified in the ICD-11 (3,4) and is unlikely to be listed as a cause of death. Two systematic reviews have been conducted to assess the mortality associated with chronic pain. The first review published in 2014 included all types of chronic pain and found a modest but non-significant association between mortality and chronic pain (5). The second review published in 2017 focused on chronic widespread pain and found an association with mortality (6). These reviews included mortalities from cancer pain. Therefore, this review aimed to determine the prevalence in people with all types of CNCP and assess the causes and risk factors associated with these deaths.

Methods

A systematic review of observational studies was designed and pre-registered (https://doi.org/10.17605/OSF.IO/7E48V). MEDLINE (Ovid) and EMBASE (Ovid) were searched on 23 March 2023 using keywords relating to “chronic pain” and “mortality”. Studies were dual-screened using Rayyan software and discrepancies were resolved by a third reviewer. The quality of studies was critically appraised by one researcher using the National Institute of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI) Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies (7). Data was extracted by one researcher and cross-checked by a second researcher. The extracted data were synthesised quantitively where possible (e.g. mortality rates, mean, median, and percentages). An exploratory meta-analysis and sensitivity analysis were conducted using RevMan (8) to compare the number of deaths in those with and without CNCP. Studies were included if they reported a control non-pain group.

Results

Nineteen prospective cohort studies were included in this systematic review (6,9–26). In 16 studies that included raw data, there were 438,593 people with CNCP of whom 28,740 deaths occurred, giving a mortality rate of 6.6 deaths per 100 people. Eleven studies included a reference group that reported no pain. In this subgroup of studies, there were 419,088 people with CNCP of which 26,931 deaths were reported, equating to a mortality rate of 6.4 deaths per 100 people. In the exploratory meta-analysis, there was a significant mortality risk ratio of 1.47 (95% CI: 1.22-1.77; I2=99%; n=11 studies) for those with CNCP compared to the no-pain groups. Ten studies (53%) reported the number of deaths by specific causes, totalling 15,108 deaths. Of these deaths, cardiovascular disease and subsequent malignancy were the most reported. The top three risk factors reported for mortality in those with CNCP were smoking (n=5), lower physical activity levels (n=4), and opioid use (n=4).

Conclusions

People with CNCP are at a higher risk of mortality than the general population. This risk is likely driven by lifestyle and social factors such as smoking and inactivity, as well as the inappropriate use of opioids. The relationship between these factors, CNCP, and mortality is an important area of research that should be further explored. Future research should use standardised definitions of chronic pain from ICD-11 and agree on standardised outcome measures for mortality studies, including reporting the raw number of deaths in all cohorts, mean ages at death for pain and non-pain groups, and use mortality risk ratios, to reduce the heterogeneity between studies and allow for evidence synthesis of such studies. To reduce mortality, adequate access to multidisciplinary pain management programmes is needed to improve lifestyle and reduce the misuse of opioids.

References

1. ???GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020 Oct 17;396(10258):1204–22.
2. ???GBD 2021 Low Back Pain Collaborators. Global, regional, and national burden of low back pain, 1990-2020, its attributable risk factors, and projections to 2050: a systematic analysis of the Global Burden of Disease Study 2021. Lancet Rheumatol. 2023 Jun;5(6):e316–29.
3. ???World Health Organization. ICD-11: International classification of diseases (11th revision). [Internet]. 2019 [cited 2023 Apr 4]. Available from: https://icd.who.int/
4. ???Treede R-D, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, et al. A classification of chronic pain for ICD-11. Pain. 2015 Jun;156(6):1003–7.
5. ???Smith D, Wilkie R, Uthman O, Jordan JL, McBeth J. Chronic pain and mortality: a systematic review. PLoS ONE. 2014 Jun 5;9(6):e99048.
6. ???Macfarlane GJ, Barnish MS, Jones GT. Persons with chronic widespread pain experience excess mortality: longitudinal results from UK Biobank and meta-analysis. Ann Rheum Dis. 2017 Nov;76(11):1815–22.
7. ???NIH: National Heart, Lung, and Blood Institute. Quality assessment tool for observational cohort and cross-sectional studies. [Internet]. 2014 [cited 2023 Mar 28]. Available from: https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools
8. ???The Cochrane Collaboration. Review Manager Web (RevMan Web). [Internet]. 2020 [cited 2023 May 11]. Available from: https://The Cochrane Collaboration
9. ???Wang M, Ropponen A, Narusyte J, Helgadóttir B, Bergström G, Blom V, et al. Adverse outcomes of chronic widespread pain and common mental disorders in individuals with sickness absence – a prospective study of Swedish twins. BMC Public Health. 2020 Aug 27;20(1):1301.
10. ??Sjøgren P, Grønbæk M, Peuckmann V, Ekholm O. A population-based cohort study on chronic pain: the role of opioids. Clin J Pain. 2010;26(9):763–9.
11. ??Chen L, Ferreira ML, Nassar N, Preen DB, Hopper JL, Li S, et al. Association of chronic musculoskeletal pain with mortality among UK adults: A population-based cohort study with mediation analysis. EClinicalMedicine. 2021 Dec;42:101202.
12. ??Inoue K, Ritz B, Arah OA. Causal Effect of Chronic Pain on Mortality Through Opioid Prescriptions: Application of the Front-Door Formula. Epidemiology. 2022 Jul 1;33(4):572–80.
13. ??Vaegter HB, Støten M, Silseth SL, Erlangsen A, Handberg G, Sondergaard S, et al. Cause-specific mortality of patients with severe chronic pain referred to a multidisciplinary pain clinic: a cohort register-linkage study. Scand J Pain. 2019 Jan 28;19(1):93–9.
14. ??Kim Y, Umeda M. Chronic Pain, Physical Activity, and All-Cause Mortality in the US Adults: The NHANES 1999-2004 Follow-Up Study. Am J Health Promot. 2019 Nov;33(8):1182–6.
15. ??Andersson HI. Increased mortality among individuals with chronic widespread pain relates to lifestyle factors: a prospective population-based study. Disabil Rehabil. 2009;31(24):1980–7.
16. ??Dreyer L, Kendall S, Danneskiold-Samsøe B, Bartels EM, Bliddal H. Mortality in a cohort of Danish patients with fibromyalgia: increased frequency of suicide. Arthritis Rheum. 2010 Oct;62(10):3101–8.
17. ??Wolfe F, Hassett AL, Walitt BT, Michaud KD. Mortality in fibromyalgia: An 8,186 patient study over 35 years. Arthritis and Rheumatism. 2010;62(SUPPL. 10):651–651.
18. ??Nitter AK, Forseth KØ. Mortality rate and causes of death in women with self-reported musculoskeletal pain: Results from a 17-year follow-up study. Scand J Pain. 2013 Apr 1;4(2):86–92.
19. ??Andorsen OF, Ahmed LA, Emaus N, Klouman E. Musculoskeletal Complaints (Pain and/or Stiffness) and Their Impact on Mortality in the General Population. The Tromsø Study. PLoS ONE. 2016 Oct 13;11(10):e0164341.
20. ??McBeth J, Symmons DP, Silman AJ, Allison T, Webb R, Brammah T, et al. Musculoskeletal pain is associated with a long-term increased risk of cancer and cardiovascular-related mortality. Rheumatology (Oxford). 2009 Jan;48(1):74–7.
21. ??Smith BH, Elliott AM, Hannaford PC. Pain and subsequent mortality and cancer among women in the Royal College of General Practitioners Oral Contraception Study. The British journal of general practice?: the journal of the Royal College of General Practitioners. 2003;53(486):45–6.
22. ??Elliott AM, Burton CD, Hannaford PC. Resilience does matter: evidence from a 10-year cohort record linkage study. BMJ Open. 2014 Jan 14;4(1):e003917.
23. ??Maruta T, Malinchoc M, Offord KP, Colligan RC. Status of patients with chronic pain 13 years after treatment in a pain management center. Pain. 1998 Feb;74(2–3):199–204.
24. ??Macfarlane GJ, Beasley M, Jones GT, Stannard C. The epidemiology of regular opioid use and its association with mortality: Prospective cohort study of 466 486 UK biobank participants. EClinicalMedicine. 2020 Apr 18;21:100321.
25. ??Macfarlane GJ, McBeth J, Silman AJ. Widespread body pain and mortality: prospective population based study. BMJ. 2001 Sep 22;323(7314):662–5.
26. ??Ekholm O, Kurita GP, Hjsted J, Juel K, Sjogren P. Chronic pain, opioid prescriptions, and mortality in Denmark: A population-based cohort study. Pain. 2014 Dec;155(12):2486–90.

Presenting Author

Stephanie Webb

Poster Authors

Stephanie Webb

PhD

University of Oxford

Lead Author

Antonia-Olivia Roberts

University of Oxford

Lead Author

Lauren Scullion

University of Oxford

Lead Author

Georgia Richards

DPhil (Oxon)

Nuffield Department of Primary Care Health Sciences, University of Oxford

Lead Author

Topics

  • Epidemiology