By Michael Broder, PhD
Reviewed by Christopher Gharibo, MD, Medical Director of Pain Medicine, NYU Langone Medical Center Hospital for Joint Diseases, New York, NY
- Pain, fatigue, and poor sleep in the setting of anxiety and depression is often intertwined in the complex pain state called fibromyalgia. While fatigue is a debilitating feature of fibromyalgia, the mechanism of fibromyalgia-related fatigue remains poorly understood.
- The hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system (ANS) are the body’s main regulators of stress. Chronic stress is known to be a factor in fatigue.
- Changes in HPA axis activity and physical activity appear to contribute to fatigue in people with fibromyalgia, a finding that highlights the need for treatment approaches that integrate biological, behavioral, and psychological modalities.
Fibromyalgia is a condition affecting an estimated 5 million adults in the United States. Women with fibromyalgia outnumber men by a ratio of 7 to 1. Fibromyalgia is characterized by widespread pain (including painful menstrual symptoms in women) accompanied by fatigue, poor sleep and a range of other emotional and somatic symptoms.1
While fatigue is among the most debilitating features of fibromyalgia, most research in the area focuses on pain, and experts have not determined the mechanisms by which fatigue occurs. “From all we know so far, high stress levels contribute to the worsening of fatigue in the everyday life of fibromyalgia patients, which might be due to changes stress causes at all levels within the organism (eg, psychological, biological, behavioral),” said Johanna M. Doerr, PhD, a clinical biopsychologist in the Department of Psychology at the University of Marburg in Marburg, Germany.
Seeking to learn more about the basis for fatigue in people with fibromyalgia, a recent study by Doerr and colleagues measured the physical activity of patients while evaluating markers of activity in the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) that indicate stress.2
Chronic stress has been shown to be a factor in fatigue. The HPA axis and the ANS are the main biological systems associated with regulating the body’s response to stress. Therefore, one might expect to see changes in markers of HPA axis activity and ANS activity in people with fibromyalgia when they report fatigue.2
When the body is under stress, changes in HPA activity alter peripheral cytokine levels which in turn cause fatigue as a way of signaling that the body needs to rest and conserve energy.2 The hormone cortisol is the most important marker for measuring HPA axis activity,2 and in particular for linking chronic psychosocial stress to adverse health effects.3Normally, cortisol levels increase sharply in the first 30 to 45 minutes after a person wakes up, a phenomenon known as the cortisol awakening response (CAR).3 At least one previous study has observed decreased CAR in people with fibromyalgia.4
Experts have suggested that hyperactivity of the ANS may play a role in symptoms of fibromyalgia such as fatigue and morning stiffness.5 Doerr and colleagues evaluated the role of the enzyme salivary alpha-amylase (sAA), a relatively newly identified marker of ANS activity.2Quite the opposite of cortisol, sAA normally displays a sudden decrease in the morning—the alpha-amylase awakening response (AAR). While evidence suggests that AAR is a good marker of ANS hyperactivity in stress-related conditions, no previous studies have examined AAR in fibromyalgia.2
To test the hypothesis that reduced CAR and increased ANS activity contribute to fatigue in women with fibromyalgia, Doerr and coauthors evaluated data from 26 women who reported their levels of general, mental, and physical fatigue at 6 time points daily for 14 days.2 The study analyzed cortisol and alpha-amylase levels from saliva samples to assess HPA-axis and ANS function. Participants wore actigraphs on their wrists to monitor physical activity.
The study found that lower increases in CAR were associated with greater levels of general and physical fatigue. In addition, there was a positive association between levels of daily physical activity and levels of next-day general fatigue. There was also a positive correlation between momentary cortisol levels and the level of physical fatigue at a specific time point. ANS activity, however, did not appear to be related to fatigue among this study population.2
“It is normal to reduce activity levels when feeling fatigued, but exercise programs have been found to reduce fibromyalgia burden (and also to buffer effects of stress) in other studies,” said Dr. Doerr. “In our study, we found higher levels of fatigue on the days after physically very active days. This shows that it might be very hard for women with fibromyalgia to adhere to programs that aim at enhancing activity. My clinical experience is in line with this: It is very hard for women who suffer from this condition to find a good balance between resting and being physically active. Specialists should be sensitive in helping persons with fibromyalgia to find that balance,” Dr. Doerr noted.
Other experts agree. “The proportion of people with fibromyalgia meeting the current minimum physical activity recommendations of the American College of Sports Medicine is very low,” said Víctor Segura-Jiménez, PhD, assistant professor in the Department of Physical Education, Faculty of Education Sciences, at the University of Cádiz, citing patients’ fears that physical activity will increase their pain. “Multidisciplinary interventions combining exercise and cognitive behavioral therapies could be highly beneficial in reducing fatigue in this population,” Dr. Jiménez added.
- Centers for Disease Control and Prevention National Center for Chronic Disease Prevention and Health Promotion Division of Population Health. Fibromyalgia.
- Doerr JM, Fischer S, Nater UM, et al. Influence of stress systems and physical activity on different dimensions of fatigue in female fibromyalgia patients. J Psychosom Res. 2017;93:55-61. doi: 10.1016/j.jpsychores.2016.12.005. Epub 2016 Dec 11.
- Stalder T, Kirschbaum C, Kudielka BM, et al. Assessment of the cortisol awakening response: expert consensus guidelines. Psychoneuroendocrinology. 2016 ;63:414-432. doi: 10.1016/j.psyneuen.2015.10.010. Epub 2015 Oct 20.
- Riva R, Mork PJ, Westgaard RH, et al. Fibromyalgia syndrome is associated with hypocortisolism. Int J Behav Med. 2010;17(3):223-233. doi: 10.1007/s12529-010-9097-6.
- Martinez-Lavin M. Biology and therapy of fibromyalgia. Stress, the stress response system, and fibromyalgia. Arthritis Res Ther. 2007;9(4):216.