Moderation of psychosocial risk factors through dysfunction of the hypothalamic–pituitary–adrenal stress axis in the onset of chronic widespread musculoskeletal pain : Findings of a population-based prospective cohort study




To test the hypothesis that abnormalities in the hypothalamic–pituitary–adrenal (HPA) stress-response system would act as an effect moderator between HPA function and the onset of chronic widespread pain (CWP).


We conducted a population-based prospective cohort study. Current pain and psychosocial status were ascertained in 11,000 subjects. Of the 768 eligible subjects free of CWP but at future risk based on their psychosocial profile, 463 were randomly selected, and 267 (57.7%) consented to assessment of their HPA axis function. Diurnal function was measured by assessing levels of salivary cortisol in the morning (9:00 AM) and evening (10:00 PM). Serum cortisol levels were measured after an overnight low-dose (0.25 mg) dexamethasone suppression test and a potentially stressful clinical examination. All subjects were followed up 15 months later to identify cases of new-onset CWP.


A total of 241 subjects (94.9%) completed the followup study, and 28 (11.6%) reported the new onset of CWP. High levels of cortisol post-dexamethasone (odds ratio [OR] 3.53, 95% confidence interval [95% CI] 1.17–10.65), low levels in morning saliva (OR 1.43, 95% CI 0.52–3.94), and high levels in evening saliva (OR 2.32, 95% CI 0.64–8.42) were all associated with CWP. These 3 factors were found to be independent and additive predictors of CWP (OR for all 3 factors 8.5, 95% CI 1.5–47.9) in analyses controlling for age, sex, depression, sleep disturbance, recent traumatic life events, and pain status. One or more of these 3 HPA factors identified 26 (92.9%) cases of new-onset CWP.


Among a group of psychologically at-risk subjects, dysfunction of the HPA axis helps to distinguish those who will and will not develop new-onset CWP.