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Licensed Unlicensed Requires Authentication Published online by De Gruyter April 14, 2022

A bidirectional study of the association between insomnia, high-sensitivity C-reactive protein, and comorbid low back pain and lower limb pain

Kevin K. N. Ho, Eivind S. Skarpsno, Kristian B. Nilsen, Paulo H. Ferreira, Marina B. Pinheiro, Laila A. Hopstock, Marianne Bakke Johnsen, Ólöf A. Steingrímsdóttir, Christopher S. Nielsen, Audun Stubhaug and Milena Simic



To examine the possible bidirectional association between insomnia and comorbid chronic low back pain (LBP) and lower limb pain and to explore whether high-sensitivity C-reactive protein (hsCRP) amplifies these associations.


We calculated adjusted risk ratios (RR) with 95% confidence intervals (CI) for the development of insomnia and mild-to-severe chronic LBP and lower limb pain at 11 years follow-up in participants aged ≥32 years and with hsCRP ≤10 mg/L at baseline in 2007–2008: 3,714 without chronic LBP or lower limb pain (sample 1) and 7,892 without insomnia (sample 2).


Compared to participants without chronic pain, participants with comorbid chronic LBP and lower limb pain had a RR of insomnia of 1.37 (95% CI 1.12–1.66). Compared with participants without insomnia, participants with insomnia did not have an increased risk of comorbid chronic LBP and lower limb pain (RR: 1.06, 95% CI 0.76–1.46); however, participants with insomnia had a RR of chronic LBP of 1.20 (95% CI 1.02–1.42). There was no strong amplifying effect of elevated hsCRP (3.00–10.0 mg/L) on these associations.


These findings suggest that elevated hsCRP does not amplify the associations between insomnia and mild-to-severe chronic LBP and lower limb pain. Further research using data on the temporal relation between insomnia, chronic pain, and inflammatory responses are required to fully understand the causal pathways.

Corresponding author: Kevin K. N. Ho, Faculty of Medicine and Health, Sydney School of Health Sciences, The University of Sydney, Level 7 East, Susan Wakil Health Building, Western Ave, Camperdown, Sydney, 2050, NSW, Australia, Phone: +61 2 9351 9010, E-mail:
Dr Ho and Dr Skarpsno share first authorship.


We acknowledge the participants and staff of the Tromsø Study.

  1. Research funding: The authors state there was no specific funding involved for this project. PHF is funded by an Australian National and Health Medical Research Council (NHMRC) fellowship. MS is funded by a Sydney University Research Accelerator Fellowship. MBP is funded by an Australian National and Health Medical Research Council (NHMRC) early career fellowship. ESS is funded by a grant from the Liaison Committee between the Central Norway Regional Health Authority (RHA) and the Norwegian University of Science and Technology (NTNU) (grant number: 90502200).

  2. Author Contribution: Author contributions in reference to (1) the conception and design of the study, or acquisition of data, or analysis and interpretation of data, (2) drafting the article or revising it critically for important intellectual content, (3) final approval of the version to be submitted, are: Dr Kevin Kwan Ngai HO: 1, 2 and 3; Dr Eivind S SKARPSNO: 1, 2 and 3; Dr Kristian Bernhard NILSEN: 1, 2 and 3; Professor Paulo FERREIRA: 1, 2 and 3; Dr Marina De Barros PINHEIRO: 1, 2 and 3; Dr Laila Arnesdatter HOPSTOCK: 1, 2 and 3; Dr Marianne Bakke JOHNSEN: 1, 2 and 3; Dr Olöf Anna STEINGRIMSDOTTIR: 1, 2 and 3; Dr Christopher Sivert NIELSEN: 1, 2 and 3; Professor Audun STUBHAUG: 1, 2 and 3; Associate Professor Milena SIMIC: 1, 2 and 3

  3. Conflict of interest: Authors state no conflict of interest.

  4. Informed consent: Informed consent has been obtained from all individuals included in this study.

  5. Ethical approval: The research related to human use complies with all the relevant national regulations, institutional policies and was performed in accordance with the tenets of the Helsinki Declaration, and has been approved by the authors’ institutional review board or equivalent committee.


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Received: 2021-10-29
Accepted: 2022-03-08
Published Online: 2022-04-14

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