Hypothalamic-Pituitary-Adrenal Axis Response to Mental Stress Predicts Chronic Widespread Pain Onset: Results from the SPICE Study

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The role of the Hypothalamic-Pituitary-Adrenal (HPA) axis stress response, as assessed by salivary cortisol, has been investigated in modifying risk of chronic widespread pain (CWP). It has been shown that, amongst those at high risk of CWP (high levels of adverse psychosocial factors), those with diminished diurnal variation and those who fail to suppress HPA axis function after a dexamethasone suppression test, are at particularly high risk of developing CWP.

The aims of the current study are (1) to determine the importance of HPA axis dysfunction in a general population sample; and (2) to examine the response of the HPA axis to mental, as opposed to pharmacological, stress.

Baseline: potential participants aged 25–70yrs, randomly selected from 4 primary care practices in Aberdeen, UK, were sent a postal questionnaire. They were asked: "Thinking back over the past month, have you had any pain that has lasted for one day or longer?" Those answering positively were asked to identify the location(s) of this pain on a body manikin. CWP was then determined as per the ACR-1990 classification for fibromyalgia.

Participants were then sent a saliva sampling kit, for 2 samples: approximatly 1hr after waking (AM) and 1hr before going to bed (PM). In addition, a sub-group of respondents were invited into the laboratory and undertook a computerised version of the Stroop "Word-and-Colour" Test – a test known to induce mental stress among study participants. Salivary cortisol was assessed at baseline, and immediately post-Stroop.

new onset CWP was identified, by questionnaire, at 12 months.

Poisson regression was used to examine the relationship between HPA axis function (salivary cortisol concentration, divided into tertiles for analysis) and new onset CWP. Thus, associations are expressed as risk ratios (RR) with 95% confidence intervals.

Of 758 participants free of CWP, 461 (61%) participated at follow-up: 41 (9%) reported CWP. While, there was some evidence to suggest that higher AM cortisol was associated with a lower risk of CWP (RR3rd vs 1st tertile: 0.6; 95%CI: 0.2–1.7), there was no association between between PM cortisol levels and the risk of CWP (RR3rd vs 1st tertile: 1.2; 0.5–2.9); nor with AM-PM cortisol variation (RR3rd vs 1st tertile of difference: 0.8: 0.3–2.1).

56 participants completed the Stroop Test, of whom 50 (89%) participated at follow-up. Those with the lowest stress response were more likely to report CWP than other individuals (RR1st vs 3rd tertile of difference: 4.9; 0.6–39.5) and (RR2nd vs 3rd tertile of difference: 3.6; 0.4–29.6).

This is the first study to examine HPA axis function and CWP onset in the general population. The study is small, and the findings should therefore be interpreted with care. However, the results replicate findings from previous studies in high-risk samples and provide new evidence that persons with the lowest stress response to mental stress are at highest risk of CWP onset. Future work should examine this relationship in the context of —and possibly as a modifier of—environmental (psychosocial) stressors and, in particular, should determine the mechanisms underpinning this relationship.
Original languageEnglish
Pages (from-to)649
Number of pages1
JournalArthritis & Rheumatism
Issue numberS10
Publication statusPublished - Oct 2010


  • hpa axis
  • stress
  • chronic widespread pain


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