Open Access Research article

Reduced hypothalamic-pituitary-adrenal axis activity in chronic multi-site musculoskeletal pain: partly masked by depressive and anxiety disorders

Ellen Generaal1*, Nicole Vogelzangs1, Gary J Macfarlane2, Rinie Geenen3, Johannes H Smit1, Brenda WJH Penninx1 and Joost Dekker14

Author Affiliations

1 Department of Psychiatry and EMGO Institute for Health and Care Research, VU University Medical Center, PO Box 74077, 1070 BB Amsterdam, The Netherlands

2 Musculoskeletal Research Collaboration (Epidemiology Group), University of Aberdeen, Aberdeen, UK

3 Department of Clinical and Health Psychology, Utrecht University, Utrecht, the Netherlands

4 Department of Rehabilitation Medicine, VU University Medical Center, Amsterdam, The Netherlands

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BMC Musculoskeletal Disorders 2014, 15:227  doi:10.1186/1471-2474-15-227

Published: 9 July 2014



Studies on hypothalamic-pituitary-adrenal axis (HPA-axis) function amongst patients with chronic pain show equivocal results and well-controlled cohort studies are rare in this field. The goal of our study was to examine whether HPA-axis dysfunction is associated with the presence and the severity of chronic multi-site musculoskeletal pain.


Data are from the Netherlands Study of Depression and Anxiety including 1125 subjects with and without lifetime depressive and anxiety disorders. The Chronic Pain Grade questionnaire was used to determine the presence and severity of chronic multi-site musculoskeletal pain. Subjects were categorized into a chronic multi-site musculoskeletal pain group (nā€‰=ā€‰471) and a control group (nā€‰=ā€‰654). Salivary cortisol samples were collected to assess HPA-axis function (awakening level, 1-h awakening response, evening level, diurnal slope and post-dexamethasone level).


In comparison with the control group, subjects with chronic multi-site musculoskeletal pain showed significantly lower cortisol level at awakening, lower evening level and a blunted diurnal slope. Lower cortisol level at awakening and a blunted diurnal slope appeared to be restricted to those without depressive and/or anxiety disorders, who also showed a lower 1-h awakening response.


Our results suggest hypocortisolemia in chronic multi-site musculoskeletal pain. However, if chronic pain is accompanied by a depressive or anxiety disorder, typically related to hypercortisolemia, the association between cortisol levels and chronic multi-site musculoskeletal pain appears to be partly masked. Future studies should take psychopathology into account when examining HPA-axis function in chronic pain.

Hypothalamic-pituitary-adrenal axis; Salivary cortisol; Chronic pain; Central sensitization; Psychopathology