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

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 EMAIL logo , 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
Published/Copyright: April 14, 2022
Download Article (PDF)
Become an author with De Gruyter Brill
Author Information Explore this Subject
Scandinavian Journal of Pain
From the journal Scandinavian Journal of Pain Volume 23 Issue 1

Abstract

Objectives

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.

Methods

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).

Results

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.

Conclusions

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.

Keywords: C-reactive protein; inflammation; insomnia; low back pain; lower limb pain; sleep

Introduction

Chronic low back pain (LBP) and chronic lower limb pain are common conditions, with prevalence estimates of 6–25% for people having chronic LBP [1] and 25% for chronic lower limb pain [2]. In people aged 55 years and older, osteoarthritis is supposed to be the most common reason for chronic lower limb pain [2], [3], [4]. Chronic LBP and lower limb osteoarthritis frequently occur together, with 58% of people with lower limb osteoarthritis reporting chronic LBP [5, 6]. Gaining further insight into risk factors for comorbid chronic LBP and lower limb pain, along with the consequences of these pain conditions will be useful to underpin the development and design of targeted interventions aimed at reducing the incidence of chronic pain.

There is evidence suggesting that chronic insomnia and chronic pain are bidirectional [7], [8], [9], but there is uncertainty in the directionality of these associations specifically for comorbid chronic LBP and lower limb pain. It has been shown that insomnia is associated with the development of hip, knee and foot pain/stiffness [10], but the reverse direction has not been explored. Moreover, some evidence has demonstrated that regional and widespread chronic musculoskeletal pain are associated with an increased risk of insomnia [11, 12], although conflicting results have been reported [13]. However, chronic LBP and lower limb pain, including osteoarthritis, share many similarities. Both conditions include common signs of central sensitization and altered pain modulation, a symptom-based diagnosis, guideline recommended management strategies, and a high prevalence of insomnia [14], [15], [16]. Chronic LBP may also be the reason for (referred) chronic lower limb pain [17]. Research suggests that there is an overlap in neurobiological and psychological correlates of insomnia with the pain mechanisms of these musculoskeletal conditions, such as central sensitization, low grade systemic inflammation, mood and physical function [18, 19]. Conceptual models of the insomnia-pain relationship have proposed that low-grade inflammation might contribute [19]. Insomnia may induce an inflammatory response [20, 21], which may contribute to increased pain sensitivity [22] and thereby increase the risk of chronic pain [21]. It is therefore conceivable that there exists a complex interplay between low-grade inflammation and insomnia on the risk of chronic LBP and chronic lower limb pain and vice versa. Although this latter view is supported by a recent cross-sectional study [23], it is not clear if low-grade systemic inflammation, measured by high-sensitivity C-reactive protein (hsCRP) contributes to the possible bidirectional association between insomnia and site-specific chronic pain [12]. Exploring the influence of hsCRP on the possible bidirectional association between insomnia and comorbid chronic LBP and lower limb pain may improve our understanding of the insomnia-pain relation, and lead to more effective management options in the future.

The aim of the current study was to examine the possible bidirectional association of insomnia and chronic LBP and/or lower limb pain, and also to explore whether elevated hsCRP influences these associations.

Methods

Study sample and data collection

The present study is a longitudinal analysis of the Tromsø Study, a population-based study of people living in the municipality of Tromsø, Norway. This study analyzed questionnaire and blood sample data from the sixth wave (Tromsø 6, 2007–2008) and the seventh wave (Tromsø 7, 2015–2016) with 12,984 and 21,083 participants respectively. Participants were aged 30–87 years in Tromsø 6 and 40–99 years in Tromsø 7. In the present study, we included self-reported questionnaire data on insomnia and musculoskeletal health (chronic LBP and chronic lower limb pain), and hsCRP values from blood serum samples. A comprehensive description of Tromsø 6 study procedures has been published elsewhere [24]. The present study has been written in accordance with the 2007 STROBE Guidelines Version 4 [25].

Participants with valid data on the variables of interest at baseline and follow-up were included. Participants with hsCRP >10 mg/L at baseline were excluded, as this was considered the threshold of acute inflammation [26], and this did not exclude a large portion of participants with chronic pain conditions. For each analysis, we excluded participants with the outcome (insomnia or chronic pain) studied present at baseline (e.g., participants with chronic LBP at baseline were excluded from the analysis when investigating the association between insomnia and risk of chronic LBP).

The present study was approved by the Regional Committee for Ethics in Medical Research (2016/1997/REK Sør-Øst and 2014/940/REK Nord) and the Norwegian Data Protection Authority. All participants gave informed consent, and the study was conducted in accordance with the Helsinki Declaration.

Insomnia

Baseline insomnia was defined in accordance with a previous study [27], where participants were classified as having insomnia if they reported “Pretty Much” or “Very Much” sleep problems during the last week (sufficient severity) and “more than once a week” for how often they suffered from sleeplessness during the last 12 months (sufficient frequency) (Table 1). The follow-up insomnia definition was based on the DSM-V criteria for insomnia [28] by adapting five items from Bergen Insomnia Scale [29] (Table 1).

Table 1:

Survey questions and study variables categorization.

Measure Questions Answer options Categorization
Poor sleep
Insomnia (baseline) “How often have you suffered from sleeplessness during the last 12 months?” Question A: Insomnia (yes):
(1) “Never, or just a few times a year” – Option 4 for question A and either option 3 or 4 for question B.
(2) “1–3 times a month”
(3) “Approximately once a week”
(4) “More than once a week”
“Have you had sleep problems during the last week?” Question B: Insomnia (no):
(1) “No complaint” – All other non-missing responses.
(2) “Little complaint”
(3) “Pretty much”
(4) “Very much”
Insomnia (follow-up) How many nights per week do you usually: Questions A-E: Insomnia (yes):
(A) Use more than 30 min to fall asleep? (0) “No days” – At least 3 days/nights to at least one of questions A-C, and both questions D and E,
(B) Wake up for more than 30 min in the middle of the night? (1) “1 day” – At least 3 months for question F.
(C) Wake up 30 min earlier than you wished, without being able to sleep again? (2) “2 days” Insomnia (no):
(D) “Felt so tired that it has affected your work, school or private life?” (3) “3 days” – All other non-missing responses.
(E) “Been dissatisfied with your sleep?” (4) “4 days”
(F) “If sleep-problems – how long time?” (5) “5 days”
(6) “6 days”
(7) “7 days”
Question F:
(0) “Do not have sleeping problems”
(1) “Less than one week”
(2) “1–3 weeks”
(3) “1 month”
(4) “2 months”
(5) “3 months”
(6) “4–6 months”
(7) “7–12 months”
(8) “1–5 years”
(9) “6–10 years”
(10) “More than 10 years”
Musculoskeletal pain
Chronic low back pain “Have you during the last year suffered from pain and/or stiffness in muscles or joints in the lumbar regions lasting for at least three consecutive months?” (0) “No complaint” Chronic low back pain (yes):
(1) “Little complaint” – Either Option 1 or 2.
(2) “Severe complaint” Chronic low back pain (no):
– All other non-missing responses.
Chronic lower limb pain “Have you during the last year suffered from pain and/or stiffness in muscles or joints in the hip, leg or feet lasting for at least three consecutive months?” (0) “No complaint” Chronic lower limb pain (yes):
(1) “Little complaint” – Either Option 1 or 2.
(2) “Severe complaint” Chronic lower limb pain (no):
– All other non-missing responses.
Combined chronic low back pain and chronic lower limb pain N/A N/A Combined chronic low back pain and chronic lower limb pain (yes):
– Those categorized to have chronic low back pain (yes) and chronic lower limb pain (yes)
Combined chronic low back pain and chronic lower limb pain (none/either):
– All other non-missing responses.
Possible confounders
Education “What is the highest levels of education you have completed?” (1) “Primary/secondary school, modern secondary school” “Primary/secondary school”:
(2) “Technical school, vocation school, 1–2 years senior high school” Option 1
(3) “High school diploma” “Technical/vocational/high school”:
(4) “College/university less than 4 years” Option 2 or 3
(5) “College/university 4 years or more” “College < 4 years”:
Option 4
“College ≥4 years”:
Option 5
Cigarette smoking “Do you/did you smoke daily?” (1) “Yes, now” “Never”:
(2) “Yes, previously” Option 1
(3) “Never” “Former”:
Option 2
“Current”:
Option 3
Alcohol consumption “How often do you usually drink alcohol?” (1) “Never” “Never/Rarely”:
(2) “Monthly or less frequently” Option 1 or 2
(3) “2–4 times a month” “Sometimes”:
(4) “2–3 times a week” Option 3
(5) “4 or more times a week” “Often”
Option 4 or 5
Physical activity (A) “How often do you exercise? (i.e. walking, skiing, swimming or training/sports)” [Scoring shown in italics] Duration of exercise was calculated via multiplication of the responses to question A and C
(B) “If you exercise, how hard do you exercise?” (1) “Never” [=0] Intensity of exercise was calculated from question B
(C) “for how long time do you exercise (give an average)” (2) “Less than once a week” [=0] – Moderate: Options 1 or 2
(3) “Once a week” [=1] – Vigorous: Option 3
(4) “2–3 times a week” [=2.5] “Inactive”:
(5) “Approximately every day” [=5] – Duration of exercise = 0 min
(1) “Easy – you do not become shortwinded or sweaty” “Low” activity:
(2) “You become shortwinded and sweaty” – <150 min of moderate activity, or
(3) “Hard – you become exhausted” – <75 min of vigorous activity
(1) Less than 15 min [=10min] “Medium”:
(2) 15–29 min [=25min] – 150–300 min of moderate activity, or
– 75–150 min of vigorous activity
(3) 30–60 min [=45min] “High”:
(4) more than 1 h [=75min] – >300 min of moderate activity, or
– >150 min of vigorous activity
Mental health During the last week: [Scoring shown in italics] Poor mental Health (yes):
(1) “Have you experienced sudden fear without apparent reason?” (1) “No complaint” [=1] – Score average ≥ 1.85
(2) “Have you felt afraid or anxious?” (2) “Little complaint” [=2] Poor mental Health (No):
(3) “Have you experienced faintness or dizziness?” (3) “pretty much” [=3] – Score average < 1.85
(4) “Have you felt tense or upset?” (4) “very much” [=4]
(5) “Have you easily blamed yourself?”
(6) “Have you had sleeping problems?”
(7) “Have you felt depressed or sad?”
(8) “Have you felt useless, worthless?”
(9) “Have you felt that everything is a struggle?”
(10) “Have you felt hopelessness with regard to the future?”
Shiftwork “Have you worked in a shift work schedule during the past three months?” (0) “No” Shiftwork (yes):
(1) “Yes” – Option 1
Shiftwork (no):
– Option 0
Chronic somatic diseases Have you ever had, or do you have: (0) “No” Hypertension (yes):
(1) Hypertension? (1) “Yes” – Question 1: Option 1
(2) Chronic bronchitis/emphysema/COPD? Chronic obstructive pulmonary disease (yes):
(3) Diabetes? – Question 2: Option 1
(4) Heart attack? Diabetes:
(5) Angina pectoris (heart cramp)? – Question 3: Option 1
(6) Cerebral stroke/brain hemorrhage? Cardiovascular:
(7) Atrial fibrillation? – Question 4, 5, 6 or 7: Option 1
(8) Asthma? Asthma:
(9) Low metabolism? – Question 8: Option 1
(10) Kidney disease? Hypothyroidism:
If they had any pain for more than three months: – Question 9: Option 1
What do you believe is the cause of this pain: Kidney diseases:
(A) Rheumatoid arthritis? – Question 10: Option 1
(B) Bechterews syndrome? Rheumatological:
– Question A or B: Option 1

Chronic low back pain

Chronic LBP was constructed from the following available survey question “Have you during the last year suffered from pain and/or stiffness in muscles or joints in the lumbar regions lasting for at least three consecutive months?”. Participants were dichotomized as having chronic LBP if they answered either “Little Complaint” or “Severe Complaint” (Table 1). This question was identical at baseline and follow-up.

Chronic lower limb pain

The definition of chronic lower limb pain was constructed from the following available survey question “Have you during the last year suffered from pain and/or stiffness in muscles or joints in the hip, leg or feet lasting for at least three consecutive months?”. Participants were classified as having chronic lower limb pain if they answered either “Little Complaint” or “Severe Complaint” (Table 1). This question was identical at baseline and follow-up.

Comorbid chronic low back and chronic lower limb pain

Participants were classified having comorbid chronic LBP/lower limb pain if they met the definition criteria of both conditions (Table 1).

High-sensitivity C-reactive protein (inflammatory marker)

Non-fasting blood samples were collected, coagulated and centrifuged to serum, and stored at −20 °C (Department of Laboratory Medicine, University Hospital North Norway, Tromsø; ISO-standard 17025) [24]. Thawed samples were analyzed by particle-enhanced immunoturbidimetric assay (Modular P autoanalyzer, Roche Diagnostics, Mannheim, Germany) [24]. This method is highly sensitive as the limit of quantification was 0.3 mg/L (analytical coefficients of variation is <10%). hsCRP was categorized as “Low” (<1.0 mg/L) “Normal” (<3.0 mg/L) or “Elevated” (3.0–10.0 mg/L), in accordance to the American Heart Association [26] and the World Health Organization [30].

Possible confounders

We selected possible confounders based on previously confirmed associations with the primary outcomes. These possible confounders were age, sex [31], education, leisure time physical activity [32], body mass index (BMI) [33, 34], shiftwork, alcohol consumption [35], and smoking [36]. Due to uncertainties about the direction of association between insomnia, chronic pain and possible confounders, some variables were considered for sensitivity analyses to evaluate the robustness of the findings: (1) mental health due to its association with insomnia [37], and that one of the 10 questions in this variable was about sleep; (2) other pain sites (e.g. chronic LBP was considered as a possible confounder when investigating insomnia as a risk for the development of chronic lower limb pain, and vice versa) [6]; and (3) chronic somatic conditions which had been shown to be associated with inflammatory markers [7, 13].

The questions, response options and categorization for the possible confounders are detailed in Table 1. Age in years was treated as a continuous variable. BMI was derived from height and weight measurements and categorized as “Normal” (<25 kg/m2), “Overweight” (25–29.9 kg/m2) and “Obese” (≥30 kg/m2) for clinical relevance. Physical activity level was classified following The American College of Sports Medicine Guidelines (inactive, low, medium, high) [38], similar to previous populational survey studies [39]. Mental Health was assessed by the Hopkins symptom check list (HSCL-10) [40, 41], dichotomized into “yes” and “no” at the cut-off value of 1.85 for the descriptive statistics [40]. The following self-reported chronic somatic conditions were available in the data and considered: hypertension [42], chronic obstructive pulmonary disease (COPD) [43], diabetes [44], cardiovascular disease [45], rheumatological conditions [46, 47], asthma [48], hypothyroidism [49], and kidney disease [50]. Missing values for each of these possible confounders were classified as the “unknown” category, to preserve a large sample size which otherwise would have been reduced by complete case analysis.

Statistical analyses

A modified Poisson regression model was used to estimate risk ratios (RR) for insomnia, chronic LBP and chronic lower limb pain at follow-up. The precision of the RRs was assessed by 95% confidence intervals (CI) using robust variance estimation [51]. When investigating the association of insomnia and hsCRP at baseline on risk of developing chronic LBP (n=4,801) and lower limb pain (n=4,827) at follow-up, only participants without the respective chronic pain conditions at baseline were included in the analyses. Participants with insomnia were compared with the reference group without insomnia. Participants with hsCRP 1.00–2.99 mg/L and 3.0–10.0 mg/L were compared with the reference group of people with hsCRP < 1.0 for each chronic pain condition analyzed. All associations were adjusted for age (continuous), sex (women, men), education (primary/secondary school, high school, university), leisure time physical activity (inactive, low activity, medium-to-high activity, unknown), BMI (normal weight, overweight, obese, unknown), shift work (no, yes, unknown), alcohol consumption (never/rarely, sometimes, often, unknown), smoking (never, former, current smoker, unknown), and the chronic pain condition which was not the outcome (e.g. for the association between insomnia and risk of chronic LBP, the multi-adjusted analyses included the adjustment for chronic lower limb pain).

When investigating the association between chronic LBP or chronic lower limb pain at baseline on risk of insomnia at follow-up, only participants without insomnia at baseline were included in the analyses (n=7,892). Participants with chronic LBP, chronic lower limb pain, or comorbid chronic LBP and lower limb pain were compared with the reference group of individuals without chronic LBP and chronic lower limb pain. In these analyses, participants with hsCRP 1.00–2.99 mg/L and 3.0–10.0 mg/L were also compared with the reference group with hsCRP <1.0 mg/L. All associations were adjusted for the covariates specified above. Crude absolute risk ratios were also calculated by dividing the “No. of cases” (participants who developed the dependent variable condition) by “No. of persons” (participants who had the independent variable condition at baseline).

Potential effect modification between the variables at baseline was assessed as departure from additive effects calculating the relative excess risk due to interaction (RERI). RERI estimates with 95% CIs were calculated from the following equation: RERI=RRinsomnia(yes) and hsCRP(elevated) − RRinsomnia(yes) and hsCRP(normal) − RRinsomnia(no) and hsCRP(elevated) + 1, where a RERI>0 indicates a synergistic effect beyond an additive effect [52]. Similar equation was used for the potential synergistic effects between chronic LBP or chronic lower limb pain with hsCRP, e.g., RERI=RRchronic LBP(yes) and hsCRP(elevated) − RRchronic LBP(yes) and hsCRP(normal) − RRchronic LBP(no) and hsCRP(elevated) + 1. For these analyses, hsCRP could only be categorized as <3.0 mg/L and 3.0–10.0 mg/L due to sample size limitations.

We conducted three sensitivity analyses to evaluate the robustness of the results. These were separately performed by repeating the main analysis. First, while poor mental health has been shown to be associated with insomnia, our mental health variable (HSCL-10) was not appropriate for the main analyses as it included a question on sleep “Have you had sleeping problems” [37]. Therefore we repeated the analyses adjusting for mental health as a continuous variable. Second, since several chronic somatic conditions have been shown to be associated with inflammatory markers [7, 13], we adjusted for hypertension, bronchitis/COPD, diabetes, cardiovascular disease, asthma, kidney disease, and arthritis. Third, since it is conceivable that other pain sites distort the association between insomnia, hsCRP and risk of chronic pain, we adjusted for comorbid LBP or lower limb pain when examining the association between insomnia and risk of chronic LBP or lower limb pain.

All analyses were performed with STATA statistical software, version 15.1. (StataCorp LP, College Station, Texas).

Results

Sample characteristics

Baseline characteristics of the main subsamples are detailed in Table 2. Due to exclusion of participants with the studied outcome present at baseline, the population sample varied from 4,801 to 7,892 (Figure 1).

Table 2:

Baseline Characteristics of the study populations.

Variables Free from chronic low back pain at baseline n=4,801 Free from chronic lower limb pain at baseline n=4,827 Free from insomnia at baseline n=7,892
Insomnia Insomnia LBP and lower limb pain
No Yes No Yes No Yes
Participants 4,618 183 4,827 186 5,780 2,112
Age, mean, SD 54.3 (11.9) 56.4 (11.4) 53.6 (11.7) 56.0 (12.1) 54.4 (11.9) 59.1 (11.8)
Women, no., % 2,201 (47.7) 117 (63.9) 2,091 (45.1) 100 (53.8) 2,686 (46.5) 1,295 (61.3)
Body mass index, mean, SD 26.5 (4.0) 26.9 (4.0) 26.3 (3.9) 26.6 (3.9) 26.5 (4.0) 27.7 (4.3)
Obese (≥30 kg/m2), no. (%) 778 (16.9) 37 (20.2) 719 (15.5) 28 (15.1) 962 (16.6) 549 (26.0)
Higher education, no., %a 2,282 (49.4) 72 (39.3) 2,306 (49.7) 71 (38.2) 2,779 (48.1) 609 (28.8)
Current smoker, no., % 754 (16.3) 34 (18.6) 791 (17.0) 34 (18.3) 965 (16.7) 463 (21.9)
High physical activity, no., % 687 (14.9) 29 (15.9) 691 (14.9) 35 (18.8) 837 (14.5) 218 (10.3)
Elevated hsCRP (≥3 mg/L), no. (%) 678 (14.7) 29 (15.9) 644 (13.9) 31 (16.7) 834 (14.4) 435 (20.6)
Poor mental health, no., % 121 (2.6) 53 (29.0) 123 (2.7) 57 (30.7) 184 (3.2) 171 (8.1)
Shift work, no., % 432 (9.4) 13 (7.1) 457 (9.9) 16 (8.6) 543 (9.4) 169 (8.0)
High alcohol consumption, no., %b 1,196 (25.9) 54 (29.5) 1,198 (25.8) 52 (28.0) 1,483 (25.7) 385 (18.2)
Hypertension, no., % 979 (21.2) 52 (28.4) 906 (19.5) 57 (30.7) 1,223 (21.2) 629 (29.8)
COPD, no., % 105 (2.3) 7 (3.8) 97 (2.1) 13 (7.0) 133 (2.3) 102 (4.8)
Diabetes, no., % 171 (3.7) 10 (5.5) 151 (3.3) 9 (4.8) 204 (3.5) 110 (5.2)
Cardiovascular disease, no., % 187 (4.1) 13 (7.1) 191 (4.1) 12 (6.5) 258 (4.5) 157 (7.4)
Rheumatological disease, no., % 39 (0.8) 3 (1.6) 15 (0.3) 2 (1.1) 49 (0.9) 141 (6.7)
Asthma, no., % 337 (7.3) 23 (12.6) 320 (6.9) 16 (8.6) 432 (7.5) 253 (12.0)
Hypothyroidism, no., % 269 (5.8) 18 (9.8) 245 (5.3) 19 (10.2) 346 (6.0) 226 (10.7)
Kidney disease, no., % 137 (3.0) 10 (5.5) 123 (2.7) 9 (4.8) 169 (2.9) 99 (4.7)

  1. SD, standard deviation; hsCRP, high-sensitivity C-reactive protein; COPD, chronic obstructive pulmonary disease. aCollege or higher. b≥4 times/week.

Figure 1: Flowchart of participants
Figure 1:

Flowchart of participants

Compared to participants without insomnia, participants with insomnia had an increased risk of developing chronic LBP (RR=1.20, 95% CI 1.02–1.42) at eight years follow-up, but not chronic lower limb pain (0.97, 0.80–1.16) or comorbid chronic LBP and lower limb pain (1.06, 0.76–1.46) (Table 3). Normal (1.00–2.99 mg/L) and elevated (3.0–10.0 mg/L) hsCRP were not associated with an increased risk of developing chronic LBP, chronic lower limb pain or both, compared to participants with hsCRP < 1.0 mg/L. The RERI estimates in the joint effect analyses were −0.01 (95% CI 0.85–1.12) and 0.21 (95% CI −0.41–0.82), indicating no significant synergistic effect of insomnia and hsCRP 3.0–10.0 mg/L at baseline on the risk of developing chronic LBP or chronic lower limb pain (Table 4).

Table 3:

Risk of chronic low back pain, chronic lower limb pain and comorbid low back pain/lower limb pain at follow-up (2015–2016) associated with insomnia and high-sensitivity C-reactive protein at baseline (2007–2008).

Variables No. of persons No. of cases Crude absolute risk, % Age-adjusted, RRa Multi-adjusted, RR (95% CI)b
Chronic low back pain
Insomnia
 No insomnia 4,618 1,681 36.4 1.00 1.00 (reference)
 Insomnia 183 82 44.8 1.22 1.20 (1.02–1.42)
C-reactive protein
 <1.00 mg/L 2,193 781 35.6 1.00 1.00 (reference)
 1.00–2.99 mg/L 1,901 719 37.8 1.04 1.03 (0.94–1.12)
 3.00–10.00 mg/L 707 263 37.2 1.03 0.99 (0.88–1.12)
Chronic lower limb pain
Insomnia
 No Insomnia 4,641 1,831 39.5 1.00 1.00 (reference)
 Insomnia 186 73 39.2 0.98 0.97 (0.80–1.16)
C-reactive protein
 <1.00 mg/L 2,264 851 37.6 1.00 1.00 (reference)
 1.00–2.99 mg/L 1,888 767 40.6 1.08 1.05 (0.97–1.13)
 3.00–10.00 mg/L 675 286 42.4 1.12 1.08 (0.97–1.21)
Comorbid chronic LBP/lower limb pain †
Insomnia
 No Insomnia 3,603 837 23.2 1.00 1.00 (reference)
 Insomnia 111 28 25.2 1.06 1.06 (0.76–1.46)
C-reactive protein
 <1.00 mg/L 1,773 403 22.7 1.00 1.00 (reference)
 1.00–2.99 mg/L 1,427 345 24.2 1.03 1.00 (0.87–1.14)
 3.00–10.00 mg/L 514 117 22.8 0.97 0.92 (0.76–1.11)

  1. CI, confidence interval; RR, risk ratio †Mutually for chronic low back pain or chronic lower limb pain. aAdjusted for age (continuous). bMulti-adjusted for age (continuous), sex (women, men), education (primary/secondary school, high school, college), leisure time physical activity (inactive, low activity, medium-to-high activity, unknown), body mass index (normal weight, overweight, obese, unknown), shift work (no, yes, unknown), alcohol consumption (never/rarely, sometimes, often, unknown), smoking (never, former, current smoker, unknown).

Table 4:

Risk of chronic low back pain and chronic lower limb pain at follow-up (2015–2016) associated with the joint effect of insomnia and high-sensitivity C-reactive protein at baseline (2007–2008).

Normal hsCRP (<3.00 mg/L) Elevated hsCRP (3.00–10.00 mg/L)
Variables No. of persons No. of cases Multi-adjusted, RR (95% CI)a No. of persons No. of cases Multi-adjusted, RR (95% CI)a
Chronic low back pain
No insomnia 3,940 1,431 1.00 (reference) 678 250 0.98 (0.87–1.09)
Insomnia 154 69 1.20 (1.00–1.44) 29 13 1.17 (0.77–1.77)
RERI: −0.01 (95% CI 0.85–1.12)
Chronic lower limb pain
No Insomnia 3,997 1,560 1.00 (reference) 644 271 1.04 (0.94–1.15)
Insomnia 155 58 0.93 (0.75–1.15) 31 15 1.18 (0.82–1.70)
RERI: 0.21 (95% CI −0.41–0.82)

  1. CI, confidence interval; hsCRP, high-sensitivity C-reactive protein; RERI, Relative Excess Risk due to Interaction; RR, risk ratio. aMulti-adjusted for age (continuous), sex (women, men), education (primary/secondary school, high school, college), body mass index (normal weight, overweight, obese, unknown), shift work (no, yes, unknown), alcohol consumption (never/rarely, sometimes, often, unknown), smoking (never, former, current smoker, unknown).

Compared to participants without chronic LBP and lower limb pain, those with both these pain conditions had a RR for insomnia of 1.37 (95% CI 1.12–1.66) (Table 5). Normal hsCRP (1.00–2.99 mg/L) and elevated hsCRP (3.0–10.0 mg/L) were not clearly associated with an increased risk of insomnia, compared to participants with low hsCRP < 1.0 mg/L, but participants with elevated hsCRP had a RR of 1.23 (95% Cl 0.97–1.56). We found no synergistic effect of comorbid chronic LBP and lower limb pain and hsCRP 3.0–10.0 mg/L at baseline on the risk of developing insomnia (RERI=−0.25 95% CI −0.95–0.45). However, compared to participants without chronic musculoskeletal pain and with normal hsCRP (1.00–2.99 mg/L), participants with no chronic pain and elevated hsCRP had a RR of 1.43 (95% CI 1.04–1.96) (Table 6).

Table 5:

Risk of insomnia at follow-up (2015–2016) associated with chronic low back pain, chronic lower limb pain, and high-sensitivity C-reactive protein at baseline (2007–2008).

Variables No. of persons No. of cases Crude absolute risk, % Age-adjusted, RRa Multi-adjusted, RR (95% CI)b
Chronic musculoskeletal pain
No pain 3,855 249 6.5 1.00 1.00 (reference)
Low back pain 948 62 6.5 1.03 1.03 (0.79–1.34)
Lower limb pain 977 76 7.8 1.28 1.26 (0.98–1.61)
Comorbid low back pain/lower limb pain 2,112 173 8.2 1.37 1.37 (1.12–1.66)
C-reactive protein
<1.00 mg/L 3,439 238 6.9 1.00 1.00 (reference)
1.00–2.99 mg/L 3,184 222 7.0 1.05 1.06 (0.88–1.28)
3.00–10.00 mg/L 1,269 100 7.9 1.21 1.23 (0.97–1.56)

  1. CI, confidence interval; RR, risk ratio †Mutually for chronic low back pain or chronic lower limb pain. aAdjusted for age (continuous). bMulti-adjusted for age (continuous), sex (women, men), education (primary/secondary school, high school, college), body mass index (normal weight, overweight, obese, unknown), shift work (no, yes, unknown), alcohol consumption (never/rarely, sometimes, often, unknown), smoking (never, former, current smoker, unknown).

Table 6:

Risk of insomnia at follow-up (2015–2016) associated with the joint effect of chronic low back pain, chronic lower limb pain, and high-sensitivity C-reactive protein at baseline (2007–2008).

Normal hsCRP (<3.00 mg/L) Elevated hsCRP (3.00–10.00 mg/L)
Variables No. of persons No. of cases Multi-adjusted, RR (95% CI)a No. of persons No. of cases Multi-adjusted, RR (95% CI)a
Chronic musculoskeletal pain
No pain 3,321 205 1.00 (reference) 534 44 1.43 (1.04–1.96)
Low back pain 823 55 1.11 (0.83–1.48) 125 7 0.95 (0.45–1.99)
Lower limb pain 802 64 1.35 (1.03–1.76) 175 12 1.29 (0.73–2.26)
Comorbid low back pain/lower limb pain 1,677 136 1.42 (1.15–1.76) 398 37 1.60 (1.13–2.25)
RERI: −0.25 (95% CI -0.95-0.45)

  1. CI, confidence interval; hsCRP, high-sensitivity C-reactive protein; RERI, Relative Excess Risk due to Interaction; RR, risk ratio. †Mutually for chronic low back pain or chronic lower limb pain. aMulti-adjusted for age (continuous), sex (women, men), education (primary/secondary school, high school, college), body mass index (normal weight, overweight, obese, unknown), shift work (no, yes, unknown), alcohol consumption (never/rarely, sometimes, often, unknown), smoking (never, former, current smoker, unknown).

Sensitivity analyses

The sensitivity analyses demonstrated that our results were robust. However, when adjusting for mental health on the association between insomnia and risk of chronic LBP, the RR became somewhat attenuated (1.23, 95% CI 0.97–1.38).

Discussion

The results from this prospective study show no strong bidirectional association between insomnia and mild-to-severe comorbid chronic LBP and lower limb pain. However, participants with comorbid chronic LBP and lower limb pain had an increased risk of insomnia, and participants with insomnia had an increased risk of chronic LBP. There was no clear independent association between elevated hsCRP and insomnia or chronic pain, nor did elevated hsCRP amplify the association between these conditions.

Interpretation and comparison of the findings with previous literature

Is insomnia an independent risk factor for comorbid chronic LBP and chronic lower limb pain, and does hsCRP influence this association?

We found no strong association between insomnia and risk of mild-to-severe comorbid chronic LBP and lower limb pain. However, participants with insomnia at baseline had 20% higher risk of developing chronic LBP eight years later. Despite a slightly higher relative risk, the absolute risk difference was 8.4%, indicating a substantially higher risk of LBP among those with insomnia than those without insomnia. This finding was consistent after additional adjustment for mental health and chronic somatic conditions. Our finding is in agreement with an Israeli study that examined 2,131 healthy medical center employees over four years [13], and a Norwegian study that examined insomnia sub-types in 16,401 participants [53]. Despite differences in population characteristics and follow-up length, these findings suggest that insomnia is an independent risk factor for chronic LBP. Conversely, the lack of association between insomnia and the development of chronic lower limb pain was contrary to a five-year follow-up study examining the association between non-restorative sleep and unspecified arthritis [54].

There are some potential explanations for why insomnia was associated with chronic LBP and not chronic lower limb pain. While chronic LBP and chronic lower limb pain have shared pain mechanisms of central sensitization and altered pain modulation [14], chronic lower limb pain potentially has a more mechanical nature of pathogenesis as people often develop lower limb pain after mechanical injury or overload related problems [34].

CRP and hsCRP has been found to be cross-sectionally associated with the presence or intensity of chronic LBP [55] and longitudinally associated with the pain intensity [56] and radiographic OA sign progression [57] of knee OA. In the current study, we did not find an association between elevated hsCRP and increased risk of developing chronic LBP or chronic lower limb pain. This finding is similar to previous studies that found a lack of association between baseline hsCRP levels and the development of chronic LBP [13] and chronic widespread pain [12]. Moreover, we found no clear synergistic effect of insomnia and elevated hsCRP on the risk of chronic LBP and chronic lower limb pain. This finding is somewhat surprising considering a recent study based on the same Tromsø surveys [12], showing an interplay between sleeplessness and elevated hsCRP on the risk of chronic widespread pain. Although these findings indicate that elevated hsCRP could be a mechanism linking insomnia to CWP, but not LBP or lower limb pain, there are some important methodological differences between these studies. First, due to the sample size in the current study, we could not categorize hsCRP into <1.00 mg/L, 1.00–2.99 mg/L, and 3.00–10.00 mg/L in our analyses of joint effect. Second, the latter study focused on severe chronic pain and severity of sleeplessness. Thus, it is possible that low-grade systemic inflammation provides a pathway between poor sleep and chronic pain conditions, but that this pathway depends on the severity of insomnia, chronic pain, and inflammatory markers. However, a proper exploration of this inflammatory pathway requires data on the longitudinal relation between insomnia and inflammation [7, 9, 58].

Is comorbid chronic LBP and lower limb pain an independent risk factor for insomnia, and does hsCRP influence this association?

Our findings showing that comorbid LBP and lower limb pain was associated with greater risk of insomnia is consistent with previous studies showing that widespread pain and the number of pain sites are strongly associated with the risk of insomnia [12, 59]. The finding that participants with chronic LBP had no increased risk of insomnia was also consistent with Agmon et al. [13] However, since co-occurring musculoskeletal pain is common in chronic LBP [60], it is likely that people reporting only LBP had less disabling pain, which in turn could have underestimated the association between LBP and insomnia. In the present study, participants with chronic lower limb pain at baseline had a weakly increased risk of insomnia compared to participants without chronic lower limb pain. The only previous study that has investigated this association is a two-year American study of 4,467 elderly adults which found no association between arthritis (unspecified type) and the development of trouble falling asleep [61].

Although our data showed a weak increased risk of insomnia among those with elevated hsCRP the CI was wide, and this result should therefore be interpreted with caution. A Taiwanese six-year follow-up study [62] showed that participants with elevated hsCRP levels did not have an increased risk of developing short or long sleep duration. The latter study, together with our results question the independent contribution of elevated hsCRP on the risk of insomnia. However, it should be noted that we found that participants without chronic musculoskeletal pain and hsCRP 3.0–10.0 mg/L had a 44% increased risk of developing insomnia compared to people with no chronic musculoskeletal pain and hsCRP <3.0 mg/L. Although speculative, one possible explanation is that low-grade inflammation (from any cause) may alter central nervous system processes that regulate sleep [63] and in turn increase the risk for insomnia. Nevertheless, we found no clear synergistic effect of elevated hsCRP and either chronic musculoskeletal pain condition on the association between the chronic musculoskeletal pain and the risk of developing insomnia. It should be noted that people with comorbid low back pain and lower limb pain who also had elevated hsCRP had 60% greater risk of insomnia, indicating that people with comorbid low back pain and lower limb pain who also experience low-grade systemic inflammation are more susceptible to develop insomnia.

Strengths and limitations

The key strengths of this study were its longitudinal design, population-based sample, and robustness of the main analyses throughout sensitivity analyses. We only selected participants who were free of the outcome condition of interest at baseline to evaluate the risk of the respective outcome. The Tromsø Study population is also considered similar to the general Norwegian population in regards to age, gender, and level of education [64, 65].

There are several limitations in this study that need to be addressed. Firstly, the sleep questions available in the two surveys differed. Only the follow-up definition is consistent with the DSM-V criteria for insomnia [28]. However, our baseline definition was quite strict, as participants needed to report “pretty much” or “very much” sleep problems for at least once a week during the past year. Since we excluded people with chronic pain at baseline, the insomnia prevalence rates at both time-points cannot be compared with other studies [66, 67]. Secondly, there are some caveats regarding the chronic LBP and chronic lower limb pain definitions. Since our definition of chronic low back pain and chronic lower limb pain included both pain and/or stiffness in muscles and joint, differences in the pathophysiology of stiffness and pain should be considered when interpreting the results. Though, it is likely that participants who reported stiffness in these regions experienced pain, but this categorization may include participants with only stiffness, causing an overestimate of people with chronic LBP or chronic lower limb pain. Moreover, this categorization may also have led to inclusion of fibromyalgia or other rheumatic conditions at follow-up, but additional adjustment for arthritis had only negligible influence on the estimates. In the exploration of the data, it was found that 40% of the participants who reported no chronic pain still reported “little” site-specific pain/stiffness. However, we used a case definition including both “little complaint” and “severe complaint”, as using only “severe complaint” resulted in underpowered sample sizes. Another consideration is that participants answered whether they had chronic pain in the last 12 months, rather than whether it was present at the time of blood sampling. Furthermore, the chronic lower limb pain definition may have limited generalizability to lower limb osteoarthritis as data such as activity related pain and morning stiffness were not provided to satisfy NICE OA guidelines [2–4] and data such as radiographical findings were not available. Thus, we cannot exclude the possibility that our findings underestimate the true association between insomnia, chronic LBP and chronic lower limb pain. Thirdly, although hsCRP is a good clinical marker for acute inflammation, inflammatory processes are complex and heterogeneous, and it is uncertain whether sub-clinically elevated hsCRP is representative of the putative inflammatory mechanisms mediating the association between pain and insomnia. It is likely that other inflammatory markers (e.g., IL-6 and TNF-a) may be better candidates due to their slightly stronger associations with insomnia, chronic LBP and lower limb OA [55, 68, 69].

Conclusions

We found no strong bidirectional association between insomnia and mild-to-severe comorbid chronic low back pain and lower limb pain; however, participants with insomnia had an increased risk of chronic low back pain, and participants with comorbid chronic LBP and lower limb pain had an increased risk of insomnia. These associations were not amplified by elevated hsCRP.

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.

Acknowledgements

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.

References

1. Meucci, RD, Fassa, AG, Faria, NM. Prevalence of chronic low back pain: systematic review. Rev Saude Publica 2015;49:1. https://doi.org/10.1590/S0034-8910.2015049005874.Search in Google Scholar PubMed PubMed Central

2. Peat, G, McCarney, R, Croft, P. Knee pain and osteoarthritis in older adults: a review of community burden and current use of primary health care. Ann Rheum Dis 2001;60:91–7. https://doi.org/10.1136/ard.60.2.91.Search in Google Scholar PubMed PubMed Central

3. Damen, J, van Rijn, RM, Emans, PJ, Hilberdink, W, Wesseling, J, Oei, EHG, et al.. Prevalence and development of hip and knee osteoarthritis according to American College of Rheumatology criteria in the CHECK cohort. Arthritis Res Ther 2019;21:4. https://doi.org/10.1186/s13075-018-1785-7.Search in Google Scholar PubMed PubMed Central

4. Skou, ST, Koes, BW, Gronne, DT, Young, J, Roos, EM. Comparison of three sets of clinical classification criteria for knee osteoarthritis: a cross-sectional study of 13,459 patients treated in primary care. Osteoarthritis Cartilage 2020;28:167–72. https://doi.org/10.1016/j.joca.2019.09.003.Search in Google Scholar PubMed

5. Suri, P, Morgenroth, DC, Kwoh, CK, Bean, JF, Kalichman, L, Hunter, DJ. Low back pain and other musculoskeletal pain comorbidities in individuals with symptomatic osteoarthritis of the knee: data from the osteoarthritis initiative. Arthritis Care Res 2010;62:1715–23. https://doi.org/10.1002/acr.20324.Search in Google Scholar PubMed PubMed Central

6. Stupar, M, Cote, P, French, MR, Hawker, GA. The association between low back pain and osteoarthritis of the hip and knee: a population-based cohort study. J Manipulative Physiol Therapeut 2010;33:349–54. https://doi.org/10.1016/j.jmpt.2010.05.008.Search in Google Scholar PubMed

7. Afolalu, EF, Ramlee, F, Tang, NKY. Effects of sleep changes on pain-related health outcomes in the general population: a systematic review of longitudinal studies with exploratory meta-analysis. Sleep Med Rev 2018;39:82–97. https://doi.org/10.1016/j.smrv.2017.08.001.Search in Google Scholar PubMed PubMed Central

8. Finan, PH, Goodin, BR, Smith, MT. The association of sleep and pain: an update and a path forward. J Pain 2013;14:1539–52. https://doi.org/10.1016/j.jpain.2013.08.007.Search in Google Scholar PubMed PubMed Central

9. Whibley, D, AlKandari, N, Kristensen, K, Barnish, M, Rzewuska, M, Druce, KL, et al.. Sleep and pain: a systematic review of studies of mediation. Clin J Pain 2019;35:544–58. https://doi.org/10.1097/ajp.0000000000000697.Search in Google Scholar

10. Uhlig, BL, Sand, T, Nilsen, TI, Mork, PJ, Hagen, K. Insomnia and risk of chronic musculoskeletal complaints: longitudinal data from the HUNT study, Norway. BMC Muscoskel Disord 2018;19:128. https://doi.org/10.1186/s12891-018-2035-5.Search in Google Scholar PubMed PubMed Central

11. Tang, NK, McBeth, J, Jordan, KP, Blagojevic-Bucknall, M, Croft, P, Wilkie, R. Impact of musculoskeletal pain on insomnia onset: a prospective cohort study. Rheumatology 2015;54:248–56. https://doi.org/10.1093/rheumatology/keu283.Search in Google Scholar PubMed PubMed Central

12. Skarpsno, ES, Mork, PJ, Nilsen, TIL, Steingrimsdottir, OA, Zwart, JA, Nilsen, KB. The interplay between sleeplessness and high-sensitivity C-reactive protein on risk of chronic musculoskeletal pain: longitudinal data from the Tromso Study. Sleep 2019;42. https://doi.org/10.1093/sleep/zsz127.Search in Google Scholar PubMed

13. Agmon, M, Armon, G. Increased insomnia symptoms predict the onset of back pain among employed adults. PLoS One 2014;9: e103591. https://doi.org/10.1371/journal.pone.0103591.Search in Google Scholar PubMed PubMed Central

14. Staud, R. Evidence for shared pain mechanisms in osteoarthritis, low back pain, and fibromyalgia. Curr Rheumatol Rep 2011;13:513–20. https://doi.org/10.1007/s11926-011-0206-6.Search in Google Scholar PubMed

15. Bernstein, IA, Malik, Q, Carville, S, Ward, S. Low back pain and sciatica: summary of NICE guidance. BMJ 2017;356. https://doi.org/10.1136/bmj.i6748.Search in Google Scholar PubMed

16. National Clinical Guideline C. National Institute for Health and Clinical Excellence: Guidance. Osteoarthritis: Care and Management in Adults. London: UK. National Clinical Guideline Centre; 2014.Search in Google Scholar

17. Koes, BW, van Tulder, MW, Peul, WC. Diagnosis and treatment of sciatica. Br Med J 2007;334:1313–7. https://doi.org/10.1136/bmj.39223.428495.be.Search in Google Scholar

18. Nijs, J, Mairesse, O, Neu, D, Leysen, L, Danneels, L, Cagnie, B, et al.. Sleep disturbances in chronic pain: neurobiology, assessment, and treatment in physical therapist practice. Phys Ther 2018;98:325–35. https://doi.org/10.1093/ptj/pzy020.Search in Google Scholar PubMed

19. Smith, MT, Quartana, PJ, Okonkwo, RM, Nasir, A. Mechanisms by which sleep disturbance contributes to osteoarthritis pain: a conceptual model. Curr Pain Headache Rep 2009;13:447–54. https://doi.org/10.1007/s11916-009-0073-2.Search in Google Scholar PubMed

20. Haack, M, Sanchez, E, Mullington, JM. Elevated inflammatory markers in response to prolonged sleep restriction are associated with increased pain experience in healthy volunteers. Sleep 2007;30:1145–52. https://doi.org/10.1093/sleep/30.9.1145.Search in Google Scholar PubMed PubMed Central

21. Haack, M, Simpson, N, Sethna, N, Kaur, S, Mullington, J. Sleep deficiency and chronic pain: potential underlying mechanisms and clinical implications. Neuropsychopharmacology 2020;45:205–16. https://doi.org/10.1038/s41386-019-0439-z.Search in Google Scholar PubMed PubMed Central

22. Schistad, EI, Stubhaug, A, Furberg, AS, Engdahl, BL, Nielsen, CS. C-reactive protein and cold-pressor tolerance in the general population: the Tromso Study. Pain 2017;158:1280–8. https://doi.org/10.1097/j.pain.0000000000000912.Search in Google Scholar PubMed

23. Ho Kevin Kwan, N, Simic, M, Cvancarova Småstuen, M, de Barros Pinheiro, M, Ferreira Paulo, H, Bakke Johnsen, M, et al.. The association between insomnia, C-reactive protein, and chronic low back pain: cross-sectional analysis of the HUNT study, Norway. Scand J Pain 2019;19:765–77. https://doi.org/10.1515/sjpain-2019-0033.Search in Google Scholar PubMed

24. Eggen, AE, Mathiesen, EB, Wilsgaard, T, Jacobsen, BK, Njolstad, I. The sixth survey of the Tromso Study (Tromso 6) in 2007-08: collaborative research in the interface between clinical medicine and epidemiology: study objectives, design, data collection procedures, and attendance in a multipurpose population-based health survey. Scand J Publ Health 2013;41:65–80. https://doi.org/10.1177/1403494812469851.Search in Google Scholar PubMed

25. von Elm, E, Altman, DG, Egger, M, Pocock, SJ, Gotzsche, PC, Vandenbroucke, JP, et al.. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol 2008;61:344–9. https://doi.org/10.1016/j.jclinepi.2007.11.008.Search in Google Scholar PubMed

26. Pearson, TA, Mensah, GA, Alexander, RW, Anderson, JL, Cannon, RO3rd, Criqui, M, et al.. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499–511. https://doi.org/10.1161/01.cir.0000052939.59093.45.Search in Google Scholar PubMed

27. Sivertsen, B, Lallukka, T, Petrie, KJ, Steingrimsdottir, OA, Stubhaug, A, Nielsen, CS. Sleep and pain sensitivity in adults. Pain 2015;156:1433–9. https://doi.org/10.1097/j.pain.0000000000000131.Search in Google Scholar PubMed

28. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA, USA: American Psychiatric Publishing; 2013.10.1176/appi.books.9780890425596Search in Google Scholar

29. Pallesen, S, Bjorvatn, B, Nordhus, IH, Sivertsen, B, Hjornevik, M, Morin, CM. A new scale for measuring insomnia: the Bergen Insomnia Scale. Percept Mot Skills 2008;107:691–706. https://doi.org/10.2466/pms.107.3.691-706.Search in Google Scholar PubMed

30. Geneva: World Health Organization. C-reactive protein concentrations as a marker of inflammation or infection for interpreting biomarkers of micronutrient status. Vitamin and Mineral Nutrition Information System. (WHO/NMH/NHD/EPG/14.7); 2014.Search in Google Scholar

31. Prieto-Alhambra, D, Judge, A, Javaid, MK, Cooper, C, Diez-Perez, A, Arden, NK. Incidence and risk factors for clinically diagnosed knee, hip and hand osteoarthritis: influences of age, gender and osteoarthritis affecting other joints. Ann Rheum Dis 2014;73:1659–64. https://doi.org/10.1136/annrheumdis-2013-203355.Search in Google Scholar PubMed PubMed Central

32. Shiri, R, Falah-Hassani, K. Does leisure time physical activity protect against low back pain? Systematic review and meta-analysis of 36 prospective cohort studies. Br J Sports Med 2017;51:1410–8. https://doi.org/10.1136/bjsports-2016-097352.Search in Google Scholar PubMed

33. Zhang, TT, Liu, Z, Liu, YL, Zhao, JJ, Liu, DW, Tian, QB. Obesity as a risk factor for low back pain: a meta-analysis. Clin Spine Surg 2018;31:22–7. https://doi.org/10.1097/bsd.0000000000000468.Search in Google Scholar

34. Silverwood, V, Blagojevic-Bucknall, M, Jinks, C, Jordan, JL, Protheroe, J, Jordan, KP. Current evidence on risk factors for knee osteoarthritis in older adults: a systematic review and meta-analysis. Osteoarthritis Cartilage 2015;23:507–15. https://doi.org/10.1016/j.joca.2014.11.019.Search in Google Scholar PubMed

35. Ferreira, PH, Pinheiro, MB, Machado, GC, Ferreira, ML. Is alcohol intake associated with low back pain? a systematic review of observational studies. Man Ther 2013;18:183–90. https://doi.org/10.1016/j.math.2012.10.007.Search in Google Scholar PubMed

36. Shiri, R, Karppinen, J, Leino-Arjas, P, Solovieva, S, Viikari-Juntura, E. The association between smoking and low back pain: a meta-analysis. Am J Med 2010;123:87–35. https://doi.org/10.1016/j.amjmed.2009.05.028.Search in Google Scholar PubMed

37. Pinheiro, MB, Ferreira, ML, Refshauge, K, Ordonana, JR, Machado, GC, Prado, LR, et al.. Symptoms of depression and risk of new episodes of low back pain: a systematic review and meta-analysis. Arthritis Care Res 2015;67:1591–603. https://doi.org/10.1002/acr.22619.Search in Google Scholar PubMed

38. Haskell, WL, Lee, IM, Pate, RR, Powell, KE, Blair, SN, Franklin, BA, et al.. Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. Med Sci Sports Exerc 2007;39:1423–34. https://doi.org/10.1249/mss.0b013e3180616b27.Search in Google Scholar PubMed

39. Mork, PJ, Vik, KL, Moe, B, Lier, R, Bardal, EM, Nilsen, TI. Sleep problems, exercise and obesity and risk of chronic musculoskeletal pain: the Norwegian HUNT study. Eur J Publ Health 2014;24:924–9. https://doi.org/10.1093/eurpub/ckt198.Search in Google Scholar PubMed

40. Strand, BH, Dalgard, OS, Tambs, K, Rognerud, M. Measuring the mental health status of the Norwegian population: a comparison of the instruments SCL-25, SCL-10, SCL-5 and MHI-5 (SF-36). Nord J Psychiatr 2003;57:113–8. https://doi.org/10.1080/08039480310000932.Search in Google Scholar PubMed

41. Derogatis, LR, Lipman, RS, Rickels, K, Uhlenhuth, EH, Covi, L. The Hopkins Symptom Checklist (HSCL): a self-report symptom inventory. Behav Sci 1974;19:1–15. https://doi.org/10.1002/bs.3830190102.Search in Google Scholar PubMed

42. Heuch, I, Heuch, I, Hagen, K, Zwart, JA. Does high blood pressure reduce the risk of chronic low back pain? The Nord-Trondelag Health Study. Eur J Pain 2014;18:590–8. https://doi.org/10.1002/j.1532-2149.2013.00398.x.Search in Google Scholar PubMed

43. Budhiraja, R, Parthasarathy, S, Budhiraja, P, Habib, MP, Wendel, C, Quan, SF. Insomnia in patients with COPD. Sleep 2012;35:369–75. https://doi.org/10.5665/sleep.1698.Search in Google Scholar PubMed PubMed Central

44. Dario, A, Ferreira, M, Refshauge, K, Harmer, A, Sanchez-Romera, J, Perez-Riquelme, F, et al.. Mapping the association between back pain and type 2 diabetes: a cross-sectional and longitudinal study of adult Spanish twins. PLoS One 2017;12:e0174757. https://doi.org/10.1371/journal.pone.0174757.Search in Google Scholar PubMed PubMed Central

45. Sofi, F, Cesari, F, Casini, A, Macchi, C, Abbate, R, Gensini, GF. Insomnia and risk of cardiovascular disease: a meta-analysis. Eur J Prev Cardiol 2014;21:57–64. https://doi.org/10.1177/2047487312460020.Search in Google Scholar PubMed

46. Baykara, RA, Bozgeyik, Z, Akgul, O, Ozgocmen, S. Low back pain in patients with rheumatoid arthritis: clinical characteristics and impact of low back pain on functional ability and health related quality of life. J Back Musculoskelet Rehabil 2013;26:367–74. https://doi.org/10.3233/bmr-130393.Search in Google Scholar PubMed

47. Luyster, FS, Chasens, ER, Wasko, MC, Dunbar-Jacob, J. Sleep quality and functional disability in patients with rheumatoid arthritis. J Clin Sleep Med 2011;7:49–55. https://doi.org/10.5664/jcsm.28041.Search in Google Scholar

48. Luyster, FS, Strollo, PJJr., Holguin, F, Castro, M, Dunican, EM, Fahy, J, et al.. Association between insomnia and asthma burden in the severe asthma research program (SARP) III. Chest 2016;150:1242–50. https://doi.org/10.1016/j.chest.2016.09.020.Search in Google Scholar PubMed PubMed Central

49. Luo, J, Sands, M, Wactawski-Wende, J, Song, Y, Margolis, KL. Sleep disturbance and incidence of thyroid cancer in postmenopausal women the Women’s Health Initiative. Am J Epidemiol 2013;177:42–9. https://doi.org/10.1093/aje/kws193.Search in Google Scholar PubMed PubMed Central

50. Lu, JL, Freire, AX, Molnar, MZ, Kalantar-Zadeh, K, Kovesdy, CP. Association of chronic insomnia with mortality and adverse renal outcomes. Mayo Clin Proc 2018;93:1563–70. https://doi.org/10.1016/j.mayocp.2018.05.032.Search in Google Scholar PubMed

51. Zou, G. A modified Poisson regression approach to prospective studies with binary data. Am J Epidemiol 2004;159:702–6. https://doi.org/10.1093/aje/kwh090.Search in Google Scholar PubMed

52. Andersson, T, Alfredsson, L, Kallberg, H, Zdravkovic, S, Ahlbom, A. Calculating measures of biological interaction. Eur J Epidemiol 2005;20:575–9. https://doi.org/10.1007/s10654-005-7835-x.Search in Google Scholar PubMed

53. Skarpsno, ES, Mork, PJ, Marcuzzi, A, Lund Nilsen, TI, Meisingset, I. Subtypes of insomnia and the risk of chronic spinal pain: the HUNT study. Sleep Med 2021;85:15–20. https://doi.org/10.1016/j.sleep.2021.06.029.Search in Google Scholar PubMed

54. Zhang, J, Lam, SP, Li, SX, Li, AM, Wing, YK. The longitudinal course and impact of non-restorative sleep: a five-year community-based follow-up study. Sleep Med 2012;13:570–6. https://doi.org/10.1016/j.sleep.2011.12.012.Search in Google Scholar PubMed

55. van den Berg, R, Jongbloed, EM, de Schepper, EIT, Bierma-Zeinstra, SMA, Koes, BW, Luijsterburg, PAJ. The association between pro-inflammatory biomarkers and nonspecific low back pain: a systematic review. Spine J 2018;18:2140–51. https://doi.org/10.1016/j.spinee.2018.06.349.Search in Google Scholar PubMed

56. Stannus, OP, Jones, G, Blizzard, L, Cicuttini, FM, Ding, C. Associations between serum levels of inflammatory markers and change in knee pain over 5 years in older adults: a prospective cohort study. Ann Rheum Dis 2013;72:535–40. https://doi.org/10.1136/annrheumdis-2011-201047.Search in Google Scholar PubMed

57. Spector, TD, Hart, DJ, Nandra, D, Doyle, DV, Mackillop, N, Gallimore, JR, et al.. Low-level increases in serum C-reactive protein are present in early osteoarthritis of the knee and predict progressive disease. Arthritis Rheum 1997;40:723–7. https://doi.org/10.1002/art.1780400419.Search in Google Scholar PubMed

58. Lee, H, Herbert, RD, McAuley, JH. Mediation analysis. JAMA 2019;321:697–8. https://doi.org/10.1001/jama.2018.21973.Search in Google Scholar PubMed

59. Skarpsno, ES, Nilsen, TIL, Sand, T, Hagen, K, Mork, PJ. Do physical activity and body mass index modify the association between chronic musculoskeletal pain and insomnia? Longitudinal data from the HUNT study, Norway. J Sleep Res 2017;27:32–9. https://doi.org/10.1111/jsr.12580.Search in Google Scholar PubMed

60. Skarpsno, ES, Mork, PJ, Nilsen, TIL, Nordstoga, AL. Influence of sleep problems and co-occurring musculoskeletal pain on long-term prognosis of chronic low back pain: the HUNT Study. J Epidemiol Community Health 2020;74:283–9. https://doi.org/10.1136/jech-2019-212734.Search in Google Scholar PubMed

61. Quan, SF, Katz, R, Olson, J, Bonekat, W, Enright, PL, Young, T, et al.. Factors associated with incidence and persistence of symptoms of disturbed sleep in an elderly cohort: the Cardiovascular Health Study. Am J Med Sci 2005;329:163–72. https://doi.org/10.1097/00000441-200504000-00001.Search in Google Scholar PubMed

62. Dowd, JB, Goldman, N, Weinstein, M. Sleep duration, sleep quality, and biomarkers of inflammation in a Taiwanese population. Ann Epidemiol 2011;21:799–806. https://doi.org/10.1016/j.annepidem.2011.07.004.Search in Google Scholar PubMed PubMed Central

63. Irwin, MR. Sleep and inflammation: partners in sickness and in health. Nat Rev Immunol 2019;19:702–15. https://doi.org/10.1038/s41577-019-0190-z.Search in Google Scholar PubMed

64. Statistics Norway. Population. Available from: https://www.ssb.no/en/befolkning/statistikker/folkemengde/aar-per-1-januar.Search in Google Scholar

65. Statistics Norway. Educational attainment of the population. Available from: https://www.ssb.no/en/utdanning/statistikker/utniv/aar.Search in Google Scholar

66. Uhlig, BL, Sand, T, Odegard, SS, Hagen, K. Prevalence and associated factors of DSM-V insomnia in Norway: the Nord-trondelag health study (HUNT 3). Sleep Med 2014;15:708–13. https://doi.org/10.1016/j.sleep.2014.01.018.Search in Google Scholar PubMed

67. Riemann, D, Spiegelhalder, K, Feige, B, Voderholzer, U, Berger, M, Perlis, M, et al.. The hyperarousal model of insomnia: a review of the concept and its evidence. Sleep Med Rev 2010;14:19–31. https://doi.org/10.1016/j.smrv.2009.04.002.Search in Google Scholar PubMed

68. Irwin, MR, Olmstead, R, Carroll, JE. Sleep disturbance, sleep duration, and inflammation: a systematic review and meta-analysis of cohort studies and experimental sleep deprivation. Biol Psychiatr 2016;80:40–52. https://doi.org/10.1016/j.biopsych.2015.05.014.Search in Google Scholar PubMed PubMed Central

69. Quartana, PJ, Finan, PH, Page, GG, Smith, MT. Effects of insomnia disorder and knee osteoarthritis on resting and pain-evoked inflammatory markers. Brain Behav Immun 2015;47:228–37. https://doi.org/10.1016/j.bbi.2014.12.010.Search in Google Scholar PubMed PubMed Central

Received: 2021-10-29
Accepted: 2022-03-08
Published Online: 2022-04-14
Published in Print: 2023-01-27

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Editorial Comment
  3. What do we mean by “mechanism” in pain medicine?
  4. Topical Reviews
  5. Topical review – salivary biomarkers in chronic muscle pain
  6. Tendon pain – what are the mechanisms behind it?
  7. Systematic Review
  8. Psychological management of patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS): a systematic review
  9. Topical Review
  10. Predicting pain after standard pain therapy for knee osteoarthritis – the first steps towards personalized mechanistic-based pain medicine in osteoarthritis
  11. Clinical Pain Researches
  12. Neuropathy and pain after breast cancer treatment: a prospective observational study
  13. Neuropeptide Y and measures of stress in a longitudinal study of women with the fibromyalgia syndrome
  14. Nociceptive two-point discrimination acuity and body representation failure in polyneuropathy
  15. Pain sensitivity in relation to frequency of migraine and tension-type headache with or without coexistent neck pain: an exploratory secondary analysis of the population study
  16. Clinician experience of metaphor in chronic pain communication
  17. Observational studies
  18. Chronic vulvar pain in gynecological outpatients
  19. Male pelvic pain: the role of psychological factors and sexual dysfunction in a young sample
  20. A bidirectional study of the association between insomnia, high-sensitivity C-reactive protein, and comorbid low back pain and lower limb pain
  21. Burden of disease and management of osteoarthritis and chronic low back pain: healthcare utilization and sick leave in Sweden, Norway, Finland and Denmark (BISCUITS): study design and patient characteristics of a real world data study
  22. Factors influencing quality of life in patients with osteoarthritis: analyses from the BISCUITS study
  23. Prescription patterns and predictors of unmet pain relief in patients with difficult-to-treat osteoarthritis in the Nordics: analyses from the BISCUITS study
  24. Lifestyle factors, mental health, and incident and persistent intrusive pain among ageing adults in South Africa
  25. Inequalities and inequities in the types of chronic pain services available in areas of differing deprivation across England
  26. Original Experimentals
  27. Conditioned pain modulation is not associated with thermal pain illusion
  28. Association between systemic inflammation and experimental pain sensitivity in subjects with pain and painless neuropathy after traumatic nerve injuries
  29. Endometriosis diagnosis buffers reciprocal effects of emotional distress on pain experience
  30. Educational Case Reports
  31. Intermediate cervical plexus block in the management of treatment resistant chronic cluster headache following whiplash trauma in three patients: a case series
  32. Trigeminal neuralgia in patients with cerebellopontine angle tumors: should we always blame the tumor? A case report and review of literature
  33. Short Communication
  34. Less is more: reliability and measurement error for three versions of the Tampa Scale of Kinesiophobia (TSK-11, TSK-13, and TSK-17) in patients with high-impact chronic pain
https://doi.org/10.1515/sjpain-2021-0197
Keywords for this article
C-reactive protein; inflammation; insomnia; low back pain; lower limb pain; sleep

Articles in the same Issue

  1. Frontmatter
  2. Editorial Comment
  3. What do we mean by “mechanism” in pain medicine?
  4. Topical Reviews
  5. Topical review – salivary biomarkers in chronic muscle pain
  6. Tendon pain – what are the mechanisms behind it?
  7. Systematic Review
  8. Psychological management of patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS): a systematic review
  9. Topical Review
  10. Predicting pain after standard pain therapy for knee osteoarthritis – the first steps towards personalized mechanistic-based pain medicine in osteoarthritis
  11. Clinical Pain Researches
  12. Neuropathy and pain after breast cancer treatment: a prospective observational study
  13. Neuropeptide Y and measures of stress in a longitudinal study of women with the fibromyalgia syndrome
  14. Nociceptive two-point discrimination acuity and body representation failure in polyneuropathy
  15. Pain sensitivity in relation to frequency of migraine and tension-type headache with or without coexistent neck pain: an exploratory secondary analysis of the population study
  16. Clinician experience of metaphor in chronic pain communication
  17. Observational studies
  18. Chronic vulvar pain in gynecological outpatients
  19. Male pelvic pain: the role of psychological factors and sexual dysfunction in a young sample
  20. A bidirectional study of the association between insomnia, high-sensitivity C-reactive protein, and comorbid low back pain and lower limb pain
  21. Burden of disease and management of osteoarthritis and chronic low back pain: healthcare utilization and sick leave in Sweden, Norway, Finland and Denmark (BISCUITS): study design and patient characteristics of a real world data study
  22. Factors influencing quality of life in patients with osteoarthritis: analyses from the BISCUITS study
  23. Prescription patterns and predictors of unmet pain relief in patients with difficult-to-treat osteoarthritis in the Nordics: analyses from the BISCUITS study
  24. Lifestyle factors, mental health, and incident and persistent intrusive pain among ageing adults in South Africa
  25. Inequalities and inequities in the types of chronic pain services available in areas of differing deprivation across England
  26. Original Experimentals
  27. Conditioned pain modulation is not associated with thermal pain illusion
  28. Association between systemic inflammation and experimental pain sensitivity in subjects with pain and painless neuropathy after traumatic nerve injuries
  29. Endometriosis diagnosis buffers reciprocal effects of emotional distress on pain experience
  30. Educational Case Reports
  31. Intermediate cervical plexus block in the management of treatment resistant chronic cluster headache following whiplash trauma in three patients: a case series
  32. Trigeminal neuralgia in patients with cerebellopontine angle tumors: should we always blame the tumor? A case report and review of literature
  33. Short Communication
  34. Less is more: reliability and measurement error for three versions of the Tampa Scale of Kinesiophobia (TSK-11, TSK-13, and TSK-17) in patients with high-impact chronic pain
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 9.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/sjpain-2021-0197/html
Scroll to top button