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Rheumatology Advance Access published online on June 11, 2008
Rheumatology, doi:10.1093/rheumatology/ken220
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Glucose regulation and chronic pain at multiple sites

P. Mäntyselkä1, J. Miettola1, L. Niskanen2 and E. Kumpusalo1

1Family Practice Unit, University of Kuopio and Kuopio University Hospital and 2Department of Medicine, Kuopio University Hospital, Kuopio, Finland.

Correspondence to: P. Mäntyselkä, Family Practice Unit, University of Kuopio and Kuopio University Hospital, PO Box 1777, Kuopio, FIN-70211, Finland. E-mail: pekka.mantyselka{at}uku.fi


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Objective. To analyse how glucose regulation status is associated with chronic regional pain and chronic widespread pain (CWP) in the adult population.

Methods. A structured interview and health examination study with 480 participants aged 30–65 yrs was carried out in Lapinlahti municipality in eastern Finland. The number of painful sites in the right or left upper and lower extremities, shoulders and hips, and in neck and back was summated. Those subjects with chronic pain in at least four sites were defined as having CWP. Diabetes and glucose tolerance status diagnosis were based on self-reported diagnoses, reimbursed medication and laboratory tests. Subjects with impaired fasting plasma glucose and/or elevated 2-h glucose level were combined into a group of impaired glucose regulation (IGR).

Results. Of the total sample, 55 subjects (11%) had diabetes. The prevalence of CWP was 13% (n = 62) in all subjects. The corresponding percentages for subjects with normal glucose regulation, IGR and diabetes were 9, 18 and 28%. In the multivariate analysis, diabetes was associated with CWP (odds ratio = 2.99; 95% CI 1.19, 7.53; P = 0.020).

Conclusions. These results point to a significant association between diabetes and CWP in the adult population.

KEY WORDS: Pain, Diabetes mellitus, Glucose intolerance


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
Chronic widespread pain (CWP) is a common symptom in adults. The prevalence of CWP has been found to range from 10.6% to13.5%. CWP occurs more often in females, and it is rather common among 60- to 69-yr-old people. It has been found to associate with unemployment and a low level of education [1].

According to ACR [2], CWP is pain that has persisted for longer than 3 months and has been experienced in the axial skeleton and in upper and lower segments and in left and right sides. There have also been other definitions of CWP published in the scientific literature [3–4]. The pathophysiology and aetiology of CWP and fibromyalgia are still unclear in spite of extensive research. Several hypotheses have been proposed e.g. muscle dysfunction or misuse, sleep disorders, as well as biochemical abnormalities such as altered hypothalamic–pituitary–adrenal stress axis function [1], which interestingly have been considered as risk factors for disturbed glucose regulation [5–7].

A recent report indicated that chronic pain is very common among patients with diabetes; it represents an important limiting factor in their ability to perform self-care [8]. In addition to experiencing painful diabetic peripheral neuropathy, non-neuropathic pain is common among diabetic patients [9]. In a clinical setting, fibromyalgia has been found to be more common among subjects with diabetes than among subjects without diabetes, and furthermore fibromyalgia-related findings are most common in those diabetic patients with poor control of their disease [10].

In the present community-based study, our aim was to study whether the glucose regulation status would be associated with chronic pain at multiple sites.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
The Lapinlahti 2005 study conducted by the University of Kuopio in Finland involved all 760 adults born in the years 1939, 1944, 1949, 1954, 1959, 1964, 1969 and 1974 living in Lapinlahti municipality in eastern Finland. The total population of the municipality is 7500 people. In all, 594 (78%) of the sample responded satisfactorily to a postal questionnaire in 2004. A total of 480 subjects (63%) underwent a complete health survey that consisted of a structured questionnaire-based interview and a health examination conducted by a qualified research nurse. The proportion of men was smaller in the study sample than in the original population sample (48% vs 51%). The mean age of respondents was slightly higher in the study sample (49 yrs for both men and women) than in the original population sample (47 yrs for men, 48 yrs for women) [11]. Three subjects were omitted due to their failure to fill in the responses to the items regarding pain, which meant that there were 477 respondents in the final analyses.

Basic sociodemographic information was obtained from the structured questionnaire. Consequently, we recoded education into two groups: primary school or at least basic vocational education, and higher vocational education or university. Working status was recoded into two groups: not working, including unemployed and retired, and working. We reclassified the subjects into two age groups: 30–45 yrs and 50–65 yrs.

The presence of any pain symptom during the preceding week was recorded. The duration and frequency of pain was assessed with structured questions. Chronic pain was defined as pain lasting for at least 3 months. We applied the definition of chronic regional pain and CWP from a previous population-based study from Finland [4]. The subjects were asked to localize pain to any of the depicted 17 sites. In this study, we took into account painful sites in the upper and lower extremities, shoulders and hips, and in neck and back, and the number of painful sites was summated. Subjects with chronic pain were grouped according to the number of painful sites: (i) for subjects without painful sites; (ii) for subjects with 1–3 painful sites (chronic regional pain) and (iii) for subjects with at least four painful sites (CWP).

The subjects were defined as subjects with diabetes if they reported diabetes or if they used long-term reimbursed medication for diabetes or if their fasting plasma glucose was ≥7.0 mmol/l or if the level was ≥11.1 mmol/l after a 2-h glucose tolerance test [12]. In addition, we defined impaired glucose tolerance (IGT, fasting plasma glucose level <7.0 mmol/l and after a 2-h glucose tolerance test with a value in the range 7.8–11.0 mmol/l) and impaired fasting glycaemia (IFG, range of fasting plasma glucose levels 6.1–6.9 mmol/l and after a 2-h glucose tolerance test <7.8 mmol/l). IGT and IFG were grouped together as impaired glucose regulation (IGR). As a consequence we created three glucose tolerance categories: normal glucose regulation (NGR), IGR and diabetes.

Diagnosis of ischaemic heart disease and hypertension were based on self-reports and on long-term use of reimbursed medication. Information about reimbursed medication was obtained from the subject's personal Health Insurance Card. Depression was assessed with a 21-item Beck's depression inventory (BDI-21) [13]. Subjects with a total score of 0–14 were regarded as normal and subjects with a total score of >14 were regarded as having a depressive trait.

The health examination included the measurement of height and body weight to allow the calculation of the BMI. In this study, subjects with a BMI >30 kg/m2 were regarded as obese. The study subjects were asked to fast for 12 h before blood sampling. The standardized procedure of Kuopio University Hospital medical laboratory was used to measure the plasma glucose level.

The prevalence of chronic regional pain and chronic pain with multiple painful sites was studied by sociodemographic factors, anthropometric measures and the presence of chronic diseases (ischaemic heart disease, hypertension) and the BDI-21 score. Univariate multinomial logistic regression analysis was used to assess the non-adjusted association of each variable with regional chronic pain and with CWP.

A multinomial logistic regression analysis (with ‘no chronic pain’ as the reference group) was used to control for the potentially confounding effects of age, gender, educational level, working status, BDI-21 score, BMI, hypertension and ischaemic heart disease. A P-value of <0.05 was regarded as statistically significant. Data analysis was performed with SPSS, Statistical Software for Windows, version 14.0.

The Ethics Committee of Kuopio University Hospital and the University of Kuopio approved the study. All the subjects provided written informed consent before entering the study.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
IGR was identified in 20% and diabetes in 11% of the subjects. With respect to the subjects categorized as diabetics, 36 subjects reported diabetes or reimbursed medication, 12 subjects exhibited an abnormal 2-h glucose tolerance test and 7 subjects had elevated fasting glucose level. The numbers within groups defined by the covariates are presented in Table 1 (variable total).


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  		TABLE 1. Prevalence of subjects without chronic pain, those with chronic regional pain and those with CWP

 
Chronic regional pain was reported by 33% of the respondents. The prevalence of CWP was 13%. CWP was more common among females than males (Table 1). Chronic regional pain and CWP were more prevalent among older subjects. According to the univariate analysis, age and hypertension were associated with chronic regional pain. All the studied background variables except for marital status and ischaemic heart disease were associated with CWP. Both IGR and diabetes were associated with CWP. The strongest associations were found for diabetes and high BDI-21 score.

In the multivariate multinomial logistic regression analysis with the glucose regulation status included in the analysis, none of the covariates were associated with chronic regional pain. Age group 50–65 yrs [odds ratio (OR) 2.43; 95% CI 1.11, 5.30] and female gender were positively associated with CWP. Working status was inversely associated with CWP (OR 0.51; 95% CI 0.27, 0.97) but educational level displayed no association with it. High depression score exhibited a strong association with CWP (OR 3.57; 95% CI 1.48, 8.61). Obesity, hypertension and ischaemic heart disease were not associated with CWP. Diabetes was associated with CWP (OR 2.99; 95% CI 1.19, 7.53), while the impact of IGR was reduced to being non-significant (OR 1.89; 95% CI 0.89, 4.03) (Fig. 1).


Figure 1
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  		FIG. 1. Adjusted OR with 95% CI of glucose regulation status for chronic regional pain and CWP (the reference group is the no chronic pain group). The associations are adjusted with age, gender and marital status, educational level, working status, ischaemic heart disease, hypertension, BMI and depression score.

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
This study indicates that diabetes is associated with the presence of chronic musculoskeletal pain at multiple painful sites in adults living in mid-eastern Finland. In accordance with current knowledge, CWP was associated with female gender, older age, low education and depressive trait.

We obtained a comprehensive sample of the adult population of this defined area in eastern Finland, with at least moderate participation. The proportions of females and older subjects were slightly larger than in the whole population. Therefore, it is possible that people with diabetes and chronic pain were more willing to participate in this study and that could have resulted in detection of increased prevalence of chronic pain and diabetes in the study population. Though the results represent the population of this study area, they may not be generalized to the whole Finnish population.

The prevalence of CWP in the present study (10% for men, 16% for women) was slightly less than that reported in a large population-based study from Finland (12% for men, 20% for women) [4]. However, the referred study did not take duration of pain into account. If the duration of the pain had been omitted from the present study, then the prevalence of widespread pain would have been somewhat elevated, i.e. 19% for women and 13% for men and these percentages are rather close to those obtained in the study by MacFarlane et al. [4]. Although we did not use the ACR criteria, the prevalence of CWP in the present study was comparable with findings of previous studies from other countries using the ACR definition [1].

We could not detect subjects with fibromyalgia or set any other diagnoses because information related to pain was obtained from the self-reports of the participants. This study was conducted as a part of a survey focusing on cardiovascular risk factors. BMI, ischaemic heart disease and hypertension were included in the analysis as potential confounders in the assessment of the association between CWP and glucose regulation status. Although we could not assess the impact of several chronic diseases we did control for other common CWP-related factors, such as depressive trait and education.

The duration of diabetes markedly increases the frequency of neuropathic pain: in a controlled, 10-yr prospective population-based study the prevalence of neuropathic pain increased from 8% to 21% [14]. The pathological processes that initiate neuropathic pain may appear before the clinical evidence of neuropathy [9]. A recent study found that subjects with neuropathic pain more often have pain in multiple sites than subjects with non-neuropathic pain [15]. Many cases of diabetes were newly diagnosed in our survey and the pattern of pain was atypical for neuropathy. Diabetic neuropathy may not be the explanation for our findings though it is possible that neuropathic pain is more prevalent among diabetic subjects with CWP. Previous clinical studies have identified an association between diabetes and palmar flexor tenosynovitis [16] or periarthritis [17, 18]. In a population-based study, insulin-dependent diabetes was associated with chronic shoulder tendinitis but not with non-specific shoulder pain [19]. These syndromes are not as common in population as in clinical samples but we cannot definitely exclude the possibility of increased prevalence of shoulder syndromes among diabetic subjects with CWP.

One could speculate that some specific factor may be responsible for the origin of CWP in diabetes. One intriguing hypothesis is that hyperglycaemia evokes tissue degeneration by promoting the formation of advanced glycation end-products (AGEs) that are proteins or lipids that become glycated after exposure to sugars. The presence and accumulation of AGEs in many cell types affect extracellular and intracellular structure and function [20]. AGEs contribute to complications through the cross-links between molecules in the basement membrane of the extracellular matrix and by activating the receptor for AGEs. They block nitric oxide activity, evoke the production of reactive oxygen species [20] and accumulate in cartilage [21]. Therefore, AGEs may be involved in the elevated prevalence of CWP among subjects with diabetes and IGR. Thus, it is conceivable that some circulating cytokines have been associated with chronic pain [22] and diabetes [23]. Furthermore, exercise has been found to be effective in the treatment of CWP [24] and in decreasing the risk of diabetes in individuals with IGT [25].

Our results indicate that chronic pain at multiple painful sites is more prevalent among diabetics than among non-diabetics. The hypothesis that CWP is independently associated with IGR will need to be studied further with larger populations. Due to the cross-sectional nature of this study, we cannot conclude whether CWP is a consequence of IGR or diabetes or vice versa, and therefore prospective studies are needed. Furthermore, it is possible that CWP or fibromyalgia share some common pathophysiological features with diabetes. This could reveal new insights into prevention of these conditions.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
We express our gratitude to the participating Lapinlahti residents, our research staff and the staff members of the Lapinlahti Primary Health Care Centre and the Kuopio University Hospital Laboratory.

Funding: This study was financially supported by Lapinlahti Municipality and the Development Programme for the Prevention and Care of Diabetes in Finland (DEHKO/D2D) through the Northern Savo Hospital District.

Disclosure statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 20 December 2007; revised version accepted 14 May 2008.
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I. Andersson and I. Leden
Comment on: Glucose regulation and chronic pain at multiple sites
Rheumatology, March 1, 2009; 48(3): 324 - 324.
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P. Mantyselka, J. Miettola, L. Niskanen, and E. Kumpusalo
Comment on: Glucose regulation and chronic pain at multiple sites: reply
Rheumatology, March 1, 2009; 48(3): 325 - 325.
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