Effect of Pregabalin on Cardiovascular Responses to Exercise and Postexercise Pain and Fatigue in Fibromyalgia: A Randomized, Double-Blind, Crossover Pilot Study

Andrea T White, Kathleen C Light, Lucinda Bateman, Ronald W Hughen, Timothy A Vanhaitsma, Alan R Light, Andrea T White, Kathleen C Light, Lucinda Bateman, Ronald W Hughen, Timothy A Vanhaitsma, Alan R Light

Abstract

Pregabalin, an approved treatment for fibromyalgia (FM), has been shown to decrease sympathetic nervous system (SNS) activity and inhibit sympathetically maintained pain, but its effects on exercise responses have not been reported. Methods. Using a randomized double-blind crossover design, we assessed the effect of 5 weeks of pregabalin (versus placebo) on acute cardiovascular and subjective responses to moderate exercise in 19 FM patients. Blood pressure (BP), heart rate (HR), and ratings of perceived exertion (RPE) during exercise and ratings of pain, physical fatigue, and mental fatigue before, during, and for 48 hours after exercise were compared in patients on pregabalin versus placebo and also versus 18 healthy controls. Results. On placebo, exercise RPE and BP were significantly higher in FM patients than controls (p < 0.04). Pregabalin responders (n = 12, defined by patient satisfaction and symptom changes) had significantly lower exercise BP, HR, and RPE on pregabalin versus placebo (p < 0.03) and no longer differed from controls (p > 0.26). Cardiovascular responses of nonresponders (n = 7) were not altered by pregabalin. In responders, pregabalin improved ratings of fatigue and pain (p < 0.04), but negative effects on pain and fatigue were seen in nonresponders. Conclusions. These preliminary findings suggest that pregabalin may normalize cardiovascular and subjective responses to exercise in many FM patients.

Figures

Figure 1
Figure 1
Rating of perceived exertion (RPE) in pregabalin responders, nonresponders, and controls. ∗∗ indicates significant difference, p < 0.01.
Figure 2
Figure 2
Individual ratings of perceived exertion (RPE) in pregabalin responders and nonresponders during pregabalin and placebo conditions.
Figure 3
Figure 3
Subjective ratings of physical fatigue (a), pain (b), and mental fatigue (c) in responders and nonresponders during pregabalin and placebo treatments. Values are mean ± SE at baseline (preexercise) and at 0.5, 8, 24, and 48 hours after exercise. † indicates significant treatment effect across all time points, p < 0.05.
Figure 4
Figure 4
Exercise cardiovascular responses; heart rate (a), systolic blood pressure (b), and diastolic blood pressure (c) expressed relative to exercise work-rate in pregabalin responders, nonresponders, and controls. ∗ indicates significant difference, p < 0.05. ∗∗ indicates significant difference, p < 0.01.

References

    1. Wolfe F., Smythe H. A., Yunus M. B., et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis and Rheumatism. 1990;33(2):160–172. doi: 10.1002/art.1780330203.
    1. Smith H. S., Harris R., Clauw D. Fibromyalgia: an afferent processing disorder leading to a complex pain generalized syndrome. Pain Physician. 2011;14(2):E217–E245.
    1. Aaron L. A., Burke M. M., Buchwald D. Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Archives of Internal Medicine. 2000;160(2):221–227. doi: 10.1001/archinte.160.2.221.
    1. Cole J. A., Rothman K. J., Cabral H. J., Zhang Y., Farraye F. A. Migraine, fibromyalgia, and depression among people with IBS: a prevalence study. BMC Gastroenterology. 2006;6, article 26 doi: 10.1186/1471-230x-6-26.
    1. White K. P., Speechley M., Harth M., Østbye T. Co-existence of chronic fatigue syndrome with fibromyalgia syndrome in the general population. A controlled study. Scandinavian Journal of Rheumatology. 2000;29(1):44–51. doi: 10.1080/030097400750001798.
    1. Crofford L. J., Rowbotham M. C., Mease P. J., et al. Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis and Rheumatism. 2005;52(4):1264–1273. doi: 10.1002/art.20983.
    1. Russell I. J., Crofford L. J., Leon T., et al. The effects of pregabalin on sleep disturbance symptoms among individuals with fibromyalgia syndrome. Sleep Medicine. 2009;10(6):604–610. doi: 10.1016/j.sleep.2009.01.009.
    1. Arnold L., Mease P., Silverman S. Pregabalin: an alpha2-delta (alpha2-delta) ligand for the management of fibromyalgia. The American Journal of Managed Care. 2010;16(5):S138–S143.
    1. Smith M. T., Moore B. J. Pregabalin for the treatment of fibromyalgia. Expert Opinion on Pharmacotherapy. 2012;13(10):1527–1533. doi: 10.1517/14656566.2012.687373.
    1. Hooten W. M., Qu W., Townsend C. O., Judd J. W. Effects of strength vs aerobic exercise on pain severity in adults with fibromyalgia: a randomized equivalence trial. Pain. 2012;153(4):915–923. doi: 10.1016/j.pain.2012.01.020.
    1. Nüesch E., Häuser W., Bernardy K., Barth J., Jüni P. Comparative efficacy of pharmacological and non-pharmacological interventions in fibromyalgia syndrome: network meta-analysis. Annals of the Rheumatic Diseases. 2013;72(6):955–962. doi: 10.1136/annrheumdis-2011-201249.
    1. Gavi M. B., Vassalo D. V., Amaral F. T., et al. Strengthening exercises improve symptoms and quality of life but do not change autonomic modulation in fibromyalgia: a randomized clinical trial. PLoS ONE. 2014;9(3) doi: 10.1371/journal.pone.0090767.e90767
    1. Ang D. C., Kaleth A. S., Bigatti S., et al. Research to encourage exercise for fibromyalgia (REEF): use of motivational interviewing, outcomes from a randomized-controlled trial. Clinical Journal of Pain. 2013;29(4):296–304. doi: 10.1097/ajp.0b013e318254ac76.
    1. van Eijk-Hustings Y., Kroese M., Tan F., Boonen A., Bessems-Beks M., Landewé R. Challenges in demonstrating the effectiveness of multidisciplinary treatment on quality of life, participation and health care utilisation in patients with fibromyalgia: a randomised controlled trial. Clinical Rheumatology. 2013;32(2):199–209. doi: 10.1007/s10067-012-2100-7.
    1. Nijs J., Roussel N., Van Oosterwijck J., et al. Fear of movement and avoidance behaviour toward physical activity in chronic-fatigue syndrome and fibromyalgia: state of the art and implications for clinical practice. Clinical Rheumatology. 2013;32(8):1121–1129. doi: 10.1007/s10067-013-2277-4.
    1. Meeus M., Hermans L., Ickmans K., et al. Endogenous pain modulation in response to exercise in patients with rheumatoid arthritis, patients with chronic fatigue syndrome and comorbid fibromyalgia, and healthy controls: a double-blind randomized controlled trial. Pain Practice. 2015;15(2):98–106.
    1. Light A. R., Bateman L., Jo D., et al. Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome. Journal of Internal Medicine. 2012;271(1):64–81. doi: 10.1111/j.1365-2796.2011.02405.x.
    1. White A. T., Light A. R., Hughen R. W., Vanhaitsma T. A., Light K. C. Differences in metabolite-detecting, adrenergic, and immune gene expression after moderate exercise in patients with chronic fatigue syndrome, patients with multiple sclerosis, and healthy controls. Psychosomatic Medicine. 2012;74(1):46–54. doi: 10.1097/PSY.0b013e31824152ed.
    1. Fukuda K., Straus S. E., Hickie I., Sharpe M. C., Dobbins J. G., Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Annals of Internal Medicine. 1994;121(12):953–959. doi: 10.7326/0003-4819-121-12-199412150-00009.
    1. Noble B. J., Borg G. A. V., Jacobs I., Ceci R., Kaiser P. A category-ratio perceived exertion scale: relationship to blood and muscle lactates and heart rate. Medicine and Science in Sports and Exercise. 1983;15(6):523–528.
    1. Pauer L., Winkelmann A., Arsenault P., et al. An international, randomized, double-blind, placebo-controlled, phase III trial of pregabalin monotherapy in treatment of patients with fibromyalgia. Journal of Rheumatology. 2011;38(12):2643–2652. doi: 10.3899/jrheum.110569.
    1. Bushmakin A. G., Cappelleri J. C., Chandran A. B., Zlateva G. Evaluation of the fibromyalgia impact questionnaire at baseline as a predictor for time to pain improvement in two clinical trials of pregabalin. International Journal of Clinical Practice. 2013;67(1):52–59. doi: 10.1111/ijcp.12035.
    1. Choy E., Marshall D., Gabriel Z. L., Mitchell S. A., Gylee E., Dakin H. A. A systematic review and mixed treatment comparison of the efficacy of pharmacological treatments for fibromyalgia. Seminars in Arthritis and Rheumatism. 2011;41(3):335–345.e6. doi: 10.1016/j.semarthrit.2011.06.003.
    1. Roth T., Arnold L. M., Garcia-Borreguero D., Resnick M., Clair A. G. A review of the effects of pregabalin on sleep disturbance across multiple clinical conditions. Sleep Medicine Reviews. 2014;18(3):261–271. doi: 10.1016/j.smrv.2013.07.005.
    1. Sarzi-Puttini P., Atzeni F., Diana A., Doria A., Furlan R. Increased neural sympathetic activation in fibromyalgia syndrome. Annals of the New York Academy of Sciences. 2006;1069:109–117. doi: 10.1196/annals.1351.009.
    1. Martínez-Martínez L.-A., Mora T., Vargas A., Fuentes-Iniestra M., Martínez-Lavín M. Sympathetic nervous system dysfunction in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis: a review of case-control studies. Journal of Clinical Rheumatology. 2014;20(3):146–150. doi: 10.1097/rhu.0000000000000089.
    1. Becker S., Schweinhardt P. Dysfunctional neurotransmitter systems in fibromyalgia, their role in central stress circuitry and pharmacological actions on these systems. Pain Research and Treatment. 2012;2012:10. doi: 10.1155/2012/741746.741746
    1. Kulshreshtha P., Deepak K. K. Autonomic nervous system profile in fibromyalgia patients and its modulation by exercise: a mini review. Clinical Physiology and Functional Imaging. 2013;33(2):83–91. doi: 10.1111/cpf.12000.
    1. Light K. C., Bragdon E. E., Grewen K. M., Brownley K. A., Girdler S. S., Maixner W. Adrenergic dysregulation and pain with and without acute beta-blockade in women with fibromyalgia and temporomandibular disorder. Journal of Pain. 2009;10(5):542–552. doi: 10.1016/j.jpain.2008.12.006.
    1. Micheva K. D., Taylor C. P., Smith S. J. Pregabalin reduces the release of synaptic vesicles from cultured hippocampal neurons. Molecular Pharmacology. 2006;70(2):467–476. doi: 10.1124/mol.106.023309.
    1. Han D. W., Kweon T. D., Lee J. S., Lee Y.-W. Antiallodynic effect of pregabalin in rat models of sympathetically maintained and sympathetic independent neuropathic pain. Yonsei Medical Journal. 2007;48(1):41–47. doi: 10.3349/ymj.2007.48.1.41.
    1. Harris R. E., Napadow V., Huggins J. P., et al. Pregabalin rectifies aberrant brain chemistry, connectivity, and functional response in chronic pain patients. Anesthesiology. 2013;119(6):1453–1464. doi: 10.1097/aln.0000000000000017.
    1. Bote M. E., Garcia J. J., Hinchado M. D., Ortega E. Fibromyalgia: anti-inflammatory and stress responses after acute moderate exercise. PLoS ONE. 2013;8(9) doi: 10.1371/journal.pone.0074524.e74524
    1. da Cunha Ribeiro R. P., Roschel H., Artioli G. G., et al. Cardiac autonomic impairment and chronotropic incompetence in fibromyalgia. Arthritis Research and Therapy. 2011;13(6, article R190) doi: 10.1186/ar3519.
    1. Rastogi B., Gupta K., Gupta P. K., Agarwal S., Jain M., Chauhan H. Oral pregabalin premedication for attenuation of haemodynamic pressor response of airway instrumentation during general anaesthesia: a dose response study. Indian Journal of Anaesthesia. 2012;56(1):49–54. doi: 10.4103/0019-5049.93344.
    1. Pollak K. A., Swenson J. D., Vanhaitsma T. A., et al. Exogenously applied muscle metabolites synergistically evoke sensations of muscle fatigue and pain in human subjects. Experimental Physiology. 2014;99(2):368–380. doi: 10.1113/expphysiol.2013.075812.
    1. Amann M., Runnels S., Morgan D. E., et al. On the contribution of group III and IV muscle afferents to the circulatory response to rhythmic exercise in humans. Journal of Physiology. 2011;589(15):3855–3866. doi: 10.1113/jphysiol.2011.209353.
    1. Kaufman M. P., Hayes S. G. The exercise pressor reflex. Clinical Autonomic Research. 2002;12(6):429–439. doi: 10.1007/s10286-002-0059-1.
    1. Kaufman M. P. The exercise pressor reflex in animals. Experimental Physiology. 2012;97(1):51–58. doi: 10.1113/expphysiol.2011.057539.

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