Ecological Momentary Assessment of the Relationships between Sleep Disturbance, Hypothalamic-Pituitary-Adrenal Axis Function, and Pain in Fibromyalgia Patients: The Impact of Daily Yoga-Based Exercise

Awardee Recipient

  • Kristin Schreiber, MD, PhD

    Kristin Schreiber, MD, PhD

    Clinical Anesthesiologist and Instructor

    Brigham and Women's Hospital and Harvard Medical School

    Kristin L. Schreiber, MD, PhD is a translational pain researcher with a background in Neuroscience. Her research focuses on the development of chronic pain after surgical injury and inflammation, with a goal to translate knowledge of the...


Award

  • 2015 - Pilot Grant

Specific Aims

Pain and sleep problems represent hallmark symptoms of fibromyalgia (FM), markedly decreasing quality of life and psychosocial functioning. In previous research, poor sleep is associated with Hypothalamic- Pituitary-Adrenal (HPA) axis abnormalities (e.g., reduced diurnal cortisol variation), and the importance of the HPA axis in pain perception is well-documented; however, the potential mediating role of HPA axis function in the association between poor sleep and pain among FM patients has not been systematically investigated.

Among the non-pharmacologic treatments for FM, exercise shows great potential, and few side effects. Exercise activates endogenous analgesia, improves sleep, and enhances quality of life in patients with chronic pain, with exercise interventions showing some promise in decreasing pain and other symptoms in FM patients. Despite some interesting findings relating to the release of endogenous analgesic substances, relatively little is known about the mechanisms underlying the beneficial effects of exercise in FM patients, and whether this may be mediated by improved sleep and normalization of HPA axis function. One of the challenges of implementing a regular exercise program in this patient group is that intense exercise programs may increase muscle inflammation and pain. Yoga-based exercise, however, seems well adapted to meet this challenge, being more gentle, while retaining an aerobic component. Importantly, it is adaptable to individual practice, and includes the benefit of breathing, awareness, and stress reduction, effects which have been previously demonstrated in this patient population,45,10 and which may be sustainable in the longer term.11

In the proposed project, we will investigate how the interaction between endocrine function and sleep might underlie FM symptomatology, and how it is impacted by exercise treatment. In previous studies, HPA function has been assessed cross-sectionally (e.g., during a single laboratory session). However, we propose here that by using a multiple day intensive ecological momentary assessment (EMA), the dynamic nature and temporal relationships between stress, sleep and pain could be better understood. Findings from this study would likely give insight to clinicians about the dynamic daily interrelationships between sleep, HPA function, and pain in FM patients. Moreover, the proposed study would illuminate the biological basis of the impact of exercise on FM pain and sleep disturbance, potentially promoting a treatment with minimal side effects and a broad array of benefits for the physical and mental health of these patients. Specifically, we will address the following aims:

Aim 1: Examine the role of HPA axis abnormalities in the association between poor sleep and pain in FM patients.

Hypothesis 1. The association between poor sleep and next-day pain intensity is mediated by HPA axis abnormalities (i.e. poor sleep leads to blunted cortisol, which then leads to more intense FM pain).

Aim 2: To examine the role of HPA axis normalization as a mechanism underlying yoga-associated changes in sleep, pain, and psychosocial function in FM patients.

Hypothesis 2.1: Daily yoga exercise will improve sleep architecture and quality, as well as reduce daily fibromyalgia pain ratings and sensitivity, compared to baseline.
Hypothesis 2.2: Daily yoga exercise will improve psychosocial functioning, compared to baseline. Hypothesis 2.3: Yoga-associated changes in sleep, pain, and psychosocial function are mediated by normalization in HPA axis functioning.

Background & Significance

The challenge of fibromyalgia: impact on physical and mental function

Chronic pain is an international health problem that imposes costs of over 600 billion dollars per year in the U.S. alone.21 This proposal focuses on fibromyalgia (FM), a chronic, common pain disorder and a primary cause of disability.35 Characterized by persistent, widespread pain, myofascial tenderness, high levels of distress, and dysregulated sleep, FM is considered the quintessential “functional” pain disorder. The diversity of symptoms reported by FM patients is consistent with the view that FM is a pervasive nervous system disorder involving a complex interaction of biopsychosocial mechanisms. Some of the hallmarks of FM include:

1) Alterations in central pain-modulatory processes in the spinal cord and brain, 2) A prominent role of negative affective factors in maintaining pain and disability, 3) Extremely disrupted sleep and circadian rhythms and related fatigue and 4) A relative lack of efficacy of many pharmacologic treatments.

Psychosocial functioning, and negative affect in particular (anxiety, depressive symptoms), play a key role in shaping individual differences in pain reports and pain outcomes, particularly in the context of functional pain disorders such as FM. Previous diary studies indicate that psychosocial variables such as depression impact the extent and day-to day variability of pain. 36 Our own work suggests that negative affect and catastrophizing can amplify pain sensitivity and influence pain modulation in patients with a variety of chronic pain conditions, including low back pain, osteoarthritis, rheumatoid arthritis, and others.17,37 Similarly, increased nociceptive sensitivity and decreased endogenous pain modulation (measured by psychophysical, quantitative sensory testing (QST)) are part of the phenotype of and contribute to the experience of pain in FM patients.37,38 Measurement of these psychosocial and psychophysical factors is therefore crucial to adequately characterizing pain and its relief in FM patients.

The relationship between sleep disturbance and pain in FM

A confluence of laboratory, clinical, and epidemiologic studies have suggested that individual differences in sleep length and quality influence subsequent pain report, that sleep deprivation in healthy subjects results in enhanced pain, and that poor sleep is correlated with elevated pain severity and disability in chronic pain conditions. 15,18 Individuals with sleep disturbance are at elevated risk for the future development of pain complaints over time frames from as short as 1 year to as long as 28 years, and poor sleep quality is one of the most robust prospective risk factors for the development of FM. 1,19 Epidemiologic surveys consistently report that the vast majority of patients with FM suffer from significant disturbances initiating or maintaining sleep, 13 and robust relationships are observed between pain severity and sleep disturbance in FM patients.16 One study examining the reciprocal relationship between pain and sleep suggests that sleep quality impacts pain levels upon waking and during the earlier part of the next day. 42 Taken together, these findings suggest that disrupted sleep forms part of the core pathophysiology of FM, is fundamentally associated with the manifestation of pain in FM, and as such represents an important target of any successful treatment strategy.

Evidence for the importance of disruption of HPA function in patients with FM

Fibromyalgia is a multifactorial disorder characterized by dysfunction of multiple physiological systems, including the endocrine system. In recent years, studies have documented reduced cortisol secretion both at baseline and in response to stimulation tests, with a potential role for disrupted cortisol secretion in the pathogenesis of FM. 34 Studies comparing FM patients with controls have reported reduced salivary, plasma, and free 24-h urinary cortisol levels in patients. Hyposecretion of cortisol has also been demonstrated in groups with severe chronic stress exposure, like occupationally stressed patients and veterans with posttraumatic stress disorder. 4,26 FM patients generally show lower cortisol values than healthy controls at all time points of the day, including a reduced cortisol reactivity (cortisol awakening response), and these deficits have been linked to poorer quality and shorter sleep. 2,32,33 Indeed, FM patients even show reduced HPA axis activation in comparison to patients with other persistent pain syndromes, not just healthy controls, suggesting that hypocortisolism plays a prominent role in the pathophysiologic signature of FM. 33

The potential for yoga-based exercise as a therapy in FM patients; evidence from previous studies

Exercise has strong empirical support as a treatment for FM symptoms. 23 Collective evidence suggests that: 1. Aerobic exercise reduces pain, fatigue and depressed mood, and improves quality of life and physical fitness, 2. Moderate intensity of exercise is effective, while there is less evidence for low-intensity exercise (<50% maxHR), 3. Exercise frequency of 2-3 times/week for at least 4-6 weeks is necessary for a reduction of symptoms, and 4. Simple resistance training is not as effective as training that included an aerobic component.8 Regardless of the therapy studied, it is apparent that continuing exercise into the long term (after the study is over) is necessary to maintain positive effects of exercise on pain.

Yoga, chronic pain and psychoneuroimmunology

Yoga-based exercise interventions produce clinically relevant improvements in pain and functional outcomes associated with a range of musculoskeletal conditions, including low back pain and FM. 45 In one study, a yoga program that included home practice for 20 minutes/day decreased FM symptoms.10 Importantly, a follow-up study of these patients revealed that much of the pain reduction was retained even after the end of the trial.11 Moreover, participation in yoga classes is associated not only with reductions in pain, but also reductions in catastrophizing, stress, and increases in acceptance and mindfulness, as well as alterations in total cortisol, proinflammatory cytokine and beta endorphin levels in women with FM.15,29,48 Although these previous studies suggest that yoga-based exercise is associated with both objective and subjective measures of stress and pain, there is a dearth of studies investigating the relationship between these variables.20 The questions that will be addressed by this study are: 1) how sleep, stress and pain are related over time in FM, 2) whether this relationship is mediated by abnormal cortisol response, 3) how these variables change over time with institution of a moderate daily yoga exercise program, and 4) how psychosocial and psychophysical functioning relate to these changes.

References

  1. Ablin JN, Buskila D. Predicting fibromyalgia, a narrative review: are we better than fools and children? Eur J Pain. 18(8):1060-6 (2014).
  2. Balbo M, Leproult R, Van Cauter E. Impact of sleep and its disturbances on hypothalamo-pituitary-adrenal axis activity. Int J Endocrinol. 2010:759234 (2010).
  3. Bennett MI, Smith BH, Torrance N, Potter J: The S-LANSS score for identifying pain of predominantly neuropathic origin: validation for use in clinical and postal research. J Pain. 6:149-58 (2005).
  4. Boscarino JA. Posttraumatic stress disorder, exposure to combat, and lower plasma cortisol among Vietnam veterans: findings and clinical implications. J Consult Clin Psychol. 64:191–201(1996).
  5. Bosch JA. The use of saliva markers in psychobiology: mechanisms and methods. Monogr Oral Sci.;24:99-108 (2014).
  6. Bote ME, Garcia JJ, Hinchado MD, Ortega E, Fibromyalgia: anti-inflammatory and stress responses after acute moderate exercise.PLoS One. 8(9):e74524 (2013).
  7. Bote ME, García JJ, Hinchado MD, Ortega E An exploratory study of the effect of regular aquatic exercise on the function of neutrophils from women with fibromyalgia: role of IL-8 and noradrenaline. Brain Behav Immun. 39:107-12(2014).
  8. Busch AJ, Webber SC, Richards RS, Bidonde J, Schachter CL, Schafer LA, Danyliw A, Sawant A, Dal Bello-Haas V, Rader T, Overend TJ. Resistance exercise training for fibromyalgia. Cochrane Database Syst Rev.( 2013).
  9. Buysse, D.J. Reynolds, C.F., Monk, T.H.. Berman, S.R. Kupfer D.J. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res, 28, pp. 193–213 (1989).
  10. Carson JW, Carson KM, Jones KD, Bennett RM, Wright CL, Mist SD.A pilot randomized controlled trial of the Yoga of Awareness program in the management of fibromyalgia. Pain; 151(2):530-9(2010).
  11. Carson JW, Carson KM, Jones KD, Mist SD, Bennett RM.Follow-up of yoga of awareness for fibromyalgia: results at 3 months and replication in the wait-list group. Clin J Pain. 28(9):804-13 (2012).
  12. Cella D, Riley W, Stone A, Rothrock N, Reeve B, Yount S, Amtmann D, Bode R, Buysse D, Choi S, Cook K, Devellis R, DeWalt D, Fries JF, Gershon R, Hahn EA, Lai JS, Pilkonis P, Revicki D, Rose M, Weinfurt K, Hays R: The Patient-Reported Outcomes Measurement Information System (PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005-2008. J Clin Epidemiol 63:1179-1194 (2010).
  13. Clauw DJ. Fibromyalgia: a clinical review JAMA. 2014 Apr 16;311(15):1547
  14. Cohen S, Kamarck T, Mermelstein R:A global measure of perceived stress. J Health Soc Behav.24: 385–396 (1983).
  15. Curtis K, Osadchuk A, Katz J. An eight-week yoga intervention is associated with improvements in pain, psychological functioning and mindfulness, and changes in cortisol levels in women with fibromyalgia. J Pain Res.;4:189–201(2011).
  16. Diaz-Piedra C, Di Stasi LL, Baldwin CM, Buela-Casal G, Catena A.Sleep disturbances of adult women suffering from fibromyalgia: A systematic review of observational studies. Sleep Med Rev. pii: S1087-0792(14)00097-5 (2014)
  17. Edwards RR, Calahan C, Mensing G, Smith M, Haythornthwaite JA. Pain, catastrophizing, and depression in the rheumatic diseases. Nat Rev Rheumatol 7(4):216-24 (2011).
  18. Fabian LA, McGuire L, Page GG, Goodin BR, Edwards RR, Haythornthwaite J. The association of the cortisol awakening response with experimental pain ratings. Psychoneuroendocrinology. 34(8):1247-51 (2009).
  19. Finan PH, Goodin BR, Smith MT. The association of sleep and pain: an update and a path forward. J Pain.14(12):1539-52 (2013).
  20. Fuentes CJ, Armijo-Olivo S, Magee DJ, et al.. Effects of exercise therapy on endogenous pain-relieving peptides in musculoskeletal pain: a systematic review. Clin J Pain.27:365–374 (2011).
  21. Gaskin DJ, Richard P. The economic costs of pain in the United States. J Pain 13(8):715-724 (2012).
  22. Goodin BR, Quinn NB, King CD, Page GG, Haythornthwaite JA, Edwards RR, Stapleton L, McGuire L. Salivary cortisol and soluble tumor necrosis factor-α receptor II responses to multiple experimental modalities of acute pain. Psychophysiology. 49(1):118-27 (2012).
  23. Häuser  W, Klose  P, Langhorst  J,  et al.  Efficacy of different types of aerobic exercise in fibromyalgia syndrome: a systematic review and meta-analysis of randomised controlled trials. Arthritis Res Ther. 12(3):R79 (2010).
  24. Hellhammer DH, Wüst S, Kudielka BM. Salivary cortisol as a biomarker in stress research. Psychoneuroendocrinology.34(2):163-71 (2009).
  25. Keller S, Bann CM, Dodd SL, Schein J, Mendoza TR, Cleeland CS. Validity of the brief pain inventory for use in documenting the outcomes of patients with noncancer pain. Clin J Pain. 20(5):309-18 (2004).
  26. Kudielka BM, Bellingrath S, Hellhammer DH. Cortisol in burnout and vital exhaustion: an overview. Appl Psychol Work Rehabil Med. 28:34–42(2006).
  27. Kudielka BM, Wüst S.Human models in acute and chronic stress: assessing determinants of individual hypothalamus-pituitary-adrenal axis activity and reactivity. Stress.13(1):1-14(2010).
  28. Martin L, Nutting A, Macintosh BR et al. An exercise program in the treatment of fibromyalgia. J Rheumatol 23:1050– 1053)(1996).
  29. Michalsen, A., Grossman, P., Acil, A., Langhorst, J., Ludtke, R., Esch, T., Stefano, G. B., & Dobos, G. J. Rapid stress reduction and anxiolysis among distressed women as a consequence of a three-month intensive yoga program. Medical Science Monitor, 11, 555-5(2005).
  30. O’Brien EM1, Waxenberg LB, Atchison JW, Gremillion HA, Staud RM, McCrae CS, Robinson ME. Intraindividual variability in daily sleep and pain ratings among chronic pain patients: bidirectional association and the role of negative mood.) and FM patients Clin J Pain.27(5):425-33(2011).
  31. Pruessner JC, Kirschbaum C, Meinlschmid G, Hellhammer DH.Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change. Psychoneuroendocrinology.28(7):916-31(2003).
  32. Riva R, Mork PJ, Westgaard RH, Rø M, Lundberg U. Fibromyalgia syndrome is associated with hypocortisolism. Int J Behav Med.17(3):223-33 (2010).
  33. Riva R, Mork PJ, Westgaard RH, Lundberg U. Comparison of the cortisol awakening response in women with shoulder and neck pain and women with fibromyalgia. Psychoneuroendocrinology. 37(2):299-306 (2012).
  34. Romano GF, Tomassi S, Russell A, Mondelli V, Pariante CM. Adv Psychosom Med. Fibromyalgia and chronic fatigue: the underlying biology and related theoretical issues. 34:61-77 (2015).
  35. Schmidt-Wilcke T, Clauw DJ. Fibromyalgia: from pathophysiology to therapy. Nat Rev Rheumatol 7(9):518-527 (2011).
  36. Schneider S, Junghaenel DU, Keefe FJ, Schwartz JE, Stone AA, Broderick JE. Individual differences in the day-to-day variability of pain, fatigue, and well-being in patients with rheumatic disease: associations with psychological variables. Pain.153(4):813-22 (2012).
  37. Schreiber KL, Campbell C, Martel MO, Greenbaum S, Wasan AD, Borsook D, Jamison RN, Edwards RR. Distraction analgesia in chronic pain patients: the impact of catastrophizing. Anesthesiology 121(6):1292-301 (2014).
  38. Schreiber KL, Loggia M, Calahan C, Kim J, Napadow V, and Edwards RR. Modulation of experimental and clinical pain by Distraction in Fibromyalgia Patients and Controls, American Pain Society 2015 Abstr.
  39. Staud R, Koo E, Robinson ME, Price DD. Spatial summation of mechanically evoked muscle pain and painful aftersensations in normal subjects and fibromyalgia patients. Pain.130(1-2):177-87 (2007).
  40. Stuifbergen AK, Phillips L, Carter P, Morrison J, Todd A., Subjective and objective sleep difficulties in women with fibromyalgia syndrome. J Am Acad Nurse Pract. 22(10):548-56 (2010).
  41. Sullivan MJ, Bishop SR, Pivik J: The Pain Catastrophizing Scale: Development and Validation. Psychol Assess 7:524-32 (1995).
  42. Tang NK, Goodchild CE, Sanborn AN, Howard J, Salkovskis PM. Deciphering the temporal link between pain and sleep in a heterogeneous chronic pain patient sample: a multilevel daily process study. Sleep. 35(5):675-87A (2012).
  43. Torgrimson-Ojerio B, Ross RL, Dieckmann NF, Avery S, Bennett RM, Jones KD, Guarino AJ, Wood LJ. Preliminary evidence of a blunted anti-inflammatory response to exhaustive exercise in fibromyalgia.J Neuroimmunol. 277(1-2):160-7 (2014).
  44. Turpeinen U, Hämäläinen E. Determination of cortisol in serum, saliva and urine. Best Pract Res Clin Endocrinol Metab. 27(6):795-801 (2013).
  45. Ward L, Stebbings S, Cherkin D, Baxter GD.Yoga for functional ability, pain and psychosocial outcomes in musculoskeletal conditions: a systematic review and meta-analysis. Musculoskeletal Care.11(4):203-17 (2013).
  46. Wigers SH, Stiles TC, Vogel PA. Effects of aerobic exercise versus stress management treatment in fibromyalgia. A 4.5 year prospective study. Scand J Rheumatol 25:77–86 (1996).
  47. Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, Russell AS, Russell IJ, Winfield JB, Yunus MB: The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken) 62:600-610 (2010).
  48. Yadav, R. K., Magan, D., Mehta, N., Sharma, R., & Mhapatra, S. C. Efficacy of a short term yoga-based lifestyle intervention in reducing stress and inflammation: Preliminary results. The Journal of Alternative and Complementary Medicine, 2012, 662-667(2012).

Outcomes

Kristin Schreiber received an R35 grant from NIH/NIGMS, which will fund her program of research, including further investigations into alternative non-opioid therapies for pain:

Maximizing Investigators’ Research Award (MIRA – R35) grant, 1 R35 GM128691-01: Personalized Perioperative Medicine: Translational Studies in the Prevention of Postoperative Pain and Opioid Misuse