The Role of Vitamin D in the Management of Chronic Pain in Fibromyalgia: A Narrative Review
Introduction
Fibromyalgia (FM) is a complex disorder characterized primarily by chronic, widespread musculoskeletal pain. Currently, the Food and Drug Administration (FDA) has approved the use of three medications to treat FM: pregabalin, duloxetine, and milnacipran. The pharmaceutical intervention has lacked consistent pain relief among all patients. Therefore, the investigation into alternative treatment options has grown in interest. This narrative review aims to evaluate the evidence regarding vitamin D for the treatment of FM.
Methods
Narrative review.
Results
Low serum vitamin D has been linked to various chronic pain states. An association between vitamin D deficiency and FM has been reported but is controversial in the literature. Some studies have documented the beneficial effects of vitamin D supplementation on reducing pain symptoms and improving the overall quality of life in those with FM. Despite these positive findings, many of the studies regarding this topic lack adequate power to make substantial conclusions about the effects of vitamin D on FM.
Conclusion
Existing studies provide promising results. However, additional high-quality data on vitamin D supplementation is needed before recommendations for pain management can be made. Vitamin D supplementation is inexpensive, has minimal side effects, and can benefit FM patients regardless of its efficacy in pain control. Additionally, high-quality studies are warranted to fully elucidate the potential of vitamin D to manage chronic pain in FM.
1. Hauser W, Ablin J, Fitzcharles MA, et al.Fibromyalgia. Nat Rev Dis Primers.2015;1:15022. doi:10.1038/nrdp.2015.22
2. Galvez-Sánchez CM, Duschek S, Reyes Del Paso GA. Psychological impact of Fibromyalgia: current perspectives. Psychol Res Behav Manag. 2019;12:117-127. doi:10.2147/prbm.s178240
3. Kaltsas G, Tsiveriotis K. Fibromyalgia. In: Feingold KR, Anawalt B, Boyce A, et al., eds. End Text. MDText.com, Inc;2020.
4. Casale R, Sarzi-Puttini P, Botto R, et al. Fibromyalgia and the concept of resilience. Clin Exp Rheumatol. 2019;37 Suppl 116(1):105-113.
5. Wolfe F, Walitt B, Perrot S, Rasker JJ, Hauser W. Fibromyalgia diagnosis and biased assessment: Sex, prevalence and bias. PLoS ONE. 2018;13(9):e0203755. doi:10.1371/journal.pone.0203755
6. Understanding Fibromyalgia and its related disorders. Prim Care Companion J Clin Psychiatry. 2008;10(2):133-144. doi:10.4088/pcc.v10n0208
7. Clauw DJ. Fibromyalgia and related conditions. Mayo Clin Proc. 2015;90(5):680-692. doi:10.1016/j.mayocp.2015.03.014
8. Jahan F, Nanji K, Qidwai W, Qasim R. Fibromyalgia syndrome: an overview of pathophysiology, diagnosis and management. Oman Med J. 2012;27(3):192-195. doi:10.5001/omi.2012.44
9. Petzke F, Brückle W, Eidmann U, et al. Allgemeine Behandlungsgrundsatze, Versorgungskoordination und Patientenschulung beim Fibromyalgiesyndrom: Aktualisierte Leitlinie 2017 und Ubersicht von systematischen Ubersichtsarbeiten[General treatment principles, coordination of care and patient education in fibromyalgia syndrome: Updated guidelines 2017 and overview of systematic review articles]. Schmerz. 2017;31(3):246-254. doi:10.1007/s00482-017-0201-6
10. Neumann L, Buskila D. Epidemiology of Fibromyalgia. Curr Pain Headache Rep. 2003;7(5):362-368. doi:10.1007/s11916-003-0035-z
11. Queiroz LP. Worldwide epidemiology of fibromyalgia. Curr Pain Headache Rep. 2013;17(8):356. doi:10.1007/s11916-013-0356-5
12. McCarberg BH. Clinical overview of Fibromyalgia. Am J Ther. 2012;19(5):357-368.doi:10.1097/mjt.0b013e3181ff7bee
13. Bennett RM, Jones J, Turk DC, Russell IJ, Matallana L. An internet survey of 2,596 people with Fibromyalgia. BMC Musculoskelet Disord. 2007;8:27. doi:10.1186/1471-2474-8-27
14. Mohammad A, Carey JJ, Storan E, Scarry M, Coughlan RJ, Lee JM. Prevalence of Fibromyalgia among patients with chronic hepatitis C infection: relationship to viral characteristics and quality of life. J Clin Gastroenterol. 2012;46(5):407-412. doi:10.1097/mcg.0b013e3182485528
15. Da Costa D, Dobkin PL, Fitzcharles MA, et al. Determinants of health status in Fibromyalgia: a comparative study with systemic lupus erythematosus. J Rheumatol. 2000;27(2):365-372.
16. McBeth J, Jones K. Epidemiology of chronic musculoskeletal pain. Best Pract Res Clin Rheumatol. 2007;21(3):403-425. doi:10.1016/j.berh.2007.03.003
17. Hauser W, Wolfe F. Diagnosis and diagnostic tests for Fibromyalgia(syndrome). Rheumatism. 2012;64(4):194-205. doi:10.4081/reumatismo.2012.194
18. Wallace DJ, Gavin IM, Karpenko O, Barkhordar F, Gillis BS. Cytokine and chemokine profiles in Fibromyalgia, rheumatoid arthritis and systemic lupus erythematosus: a potentially useful tool in differential diagnosis. Rheumatol Int. 2015;35(6):991-996. doi:10.1007/s00296-014-3172-2
19. Choy EH. The role of sleep in pain and Fibromyalgia. Nat Rev Rheumatol. 2015;11(9):513-520. doi:10.1038/nrrheum.2015.56
20. Nebel MB, Gracely RH. Neuroimaging of Fibromyalgia. Rheum Dis Clin North Am. 2009;35(2):313-327. doi:10.1016/j.rdc.2009.06.004
21. van Tilburg MAL, Parisien M, Boles RG, et al. A genetic polymorphism that is associated with mitochondrial energy metabolism increases risk of Fibromyalgia. Pain. 2020;161(12):2860-2871.doi:10.1097/j.pain.0000000000001996
22. Ablin JN, Buskila D. Update on the genetics of the fibromyalgia syndrome. Best Pract Res Clin Rheumatol. 2015;29(1):20-28. doi:10.1016/j.berh.2015.04.018
23. Wolfe F, Russell IJ, Vipraio G, Ross K, Anderson J. Serotonin levels, pain threshold, and fibromyalgia symptoms in the general population. J Rheumatol. 1997;24(3):555-559.
24. Bjersing JL, Lundborg C, Bokarewa MI, Mannerkorpi K. Profile of cerebrospinal microRNAs in Fibromyalgia. PLoS ONE. 2013;8(10):e78762. doi:10.1371/journal.pone.0078762
25. Williams DA, Clauw DJ. Understanding fibromyalgia: lessons from the broader pain research community. JPain. 2009;10(8):777-791. doi:10.1016/i.jpain.2009.06.001
26. Diatchenko L, Slade GD, Nackley AG, et al. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet. 2005;14(1):135-143. doi:10.1093/hmg/ddi013
27. Baek D, Villén J, Shin C, Camargo FD, Gygi SP, Bartel DP. The impact of microRNAs on protein output. Nature. 2008;455(7209):64-71. doi:10.1038/nature07242
28. Feng J, Zhang Z, Wu X, et al. Discovery of potential new gene variants and inflammatory cytokine associations with fibromyalgia syndrome by whole-exome sequencing. PLoS ONE. 2013;8(6):e65033. doi:10.1371/journal.pone.0065033
29. Clauw DJ. Fibromyalgia: an overview. Am JMed. 2009;122(12 Suppl):S3-S13. doi:10.1016/j.amjmed.2009.09.006
30. González-Vives S, Diaz-Marsá M, De la Vega I, et al. Hypothalamic-pituitary axis response to a 0.25-MG dexamethasone test in women with Fibromyalgia. Stress. 2020;23(3):284-289. doi:10.1080/10253890.2019.1678024
31. Demitrack MA, Crofford LJ. Evidence for and pathophysiologic implications of hypothalamic-pituitary-adrenal axis dysregulation in fibromyalgia and chronic fatigue syndrome. Ann N Y Acad Sci. 1998;840:684-697. doi:10.1111/j.1749-6632.1998.tb09607.x
32. Crofford LJ. The hypothalamic-pituitary-adrenal stress axis in fibromyalgia and chronic fatigue syndrome. Z Rheumatol. 1998;57(Suppl 2):67-71. doi:10.1007/s003930050239
33. Mease P. Fibromyalgia syndrome: review of clinical presentation, pathogenesis, outcome measures, and treatment[published correction appears in J Rheumatol Suppl. 2005 Oct;32(10):2063]. J Rheumatol Suppl. 2005;75:6-21.
34. Sánchez-Domínguez B, Bullón P, Román-Malo L, et al. Oxidative stress, mitochondrial dysfunction and inflammation common events in skin of patients with Fibromyalgia. Mitochondrion. 2015;21:69-75. doi:10.1016/j.mito.2015.01.010
35. Girdle B, Ghafouri B, Lund E, et al. Evidence of Mitochondrial Dysfunction in Fibromyalgia: Deviating Muscle Energy Metabolism Detected Using Microdialysis and Magnetic Resonance. J Clin Med. 2020;9(11):3527. doi:10.3390/jcm9113527
36. Coskun Benlidayi I. Role of inflammation in the pathogenesis and treatment of Fibromyalgia. Rheumatol Int. 2019;39(5):781-791. doi:10.1007/s00296-019-04251-6
37. Rodriguez-Pintó I, Agmon-Levin N, Howard A, Shoenfeld Y. Fibromyalgia and cytokines. Immunol Lett. 2014;161(2):200-203. doi:10.1016/j.imlet.2014.01.009
38. Tsilioni I, Russell IJ, Stewart JM, Gleason RM, Theoharides TC. Neuropeptides CRH, SP, HK-1, and Inflammatory Cytokines IL-6 and TNF Are Increased in Serum of Patients with Fibromyalgia Syndrome, Implicating Mast Cells. J Pharmacol Exp Ther. 2016;356(3):664-672. doi:10.1124/jpet.115.230060
39. Hamilton NA, Affleck G, Tennen H, et al. Fibromyalgia: the role of sleep in affect and in negative event reactivity and recovery. Health Psychol. 2008;27(4):490-497. doi:10.1037/0278-6133.27.4.490
40. Arnold LM, Clauw DJ. Challenges of implementing fibromyalgia treatment guidelines in current clinical practice. Postgrad Med. 2017;129(7):709-714. doi:10.1080/00325481.2017.1336417
41. Macfarlane GJ, Kronisch C, Dean LE, et al. EULAR revised recommendations for the management of Fibromyalgia. Ann Rheum Dis. 2017;76(2):318-328. doi:10.1136/annrheumdis-2016-209724
42. Chinn S, Caldwell W, Gritsenko K. Fibromyalgia Pathogenesis and Treatment Options Update. Curr Pain Headache Rep. 2016;20(4):25. doi:10.1007/s11916-016-0556-x
43. Taylor CP, Angelotti T, Fauman E. Pharmacology and mechanism of action of pregabalin: the calcium channel α2-δ (alpha2-delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res. 2007;73(2):137-150. doi:10.1016/j.eplepsyres.2006.09.008
44. Crofford LJ, Rowbotham MC, Mease PJ, et al. Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2005;52(4):1264-1273. doi:10.1002/art.20983
45. Sumpton JE, Moulin DE. Fibromyalgia. Handb Clin Neurol. 2014;119:513-527. doi:10.1016/b978-0-7020-4086-3.00033-3
46. Jay GW, Barkin RL. Fibromyalgia. Dis Mon. 2015;61(3):66-111. doi:10.1016/j.disamonth.2015.01.002
47. Arnold LM, Clauw D, Wang F, Ahl J, Gaynor PJ, Wohlreich MM. Flexible dosed duloxetine in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled trial. J Rheumatol. 2010;37(12):2578-2586. doi:10.3899/jrheum.100365
48. Russell JI, Mease PJ, Smith TR, et al. Efficacy and safety of duloxetine for treatment of fibromyalgia in patients with or without major depressive disorder: Results from a 6-month, randomized, double-blind, placebo-controlled, fixed-dose trial. Pain. 2008;136(3):432-444. doi:10.1016/j.pain.2008.02.024
49. Bidari A, Moazen-Zadeh E, Ghavidel-Parsa B, Rahmani S, Hosseini S, Hassankhani A. Comparing duloxetine and pregabalin for treatment of pain and depression in women with Fibromyalgia: an open-label randomized clinical trial. Daru. 2019;27(1):149-158. doi:10.1007/s40199-019-00257-4
50. Hauser W, Urrütia G, Tort S, Uceyler N, Walitt B. Serotonin and noradrenaline reuptake inhibitors(SNRIs) for fibromyalgia syndrome. Cochrane Database Syst Rev. Published online January 31,2013:CD010292. doi:10.1002/14651858.cd010292
51. Vitton O, Gendreau M, Gendreau J, Kranzler J, Rao SG. A double-blind placebo-controlled trial of milnacipran in the treatment of Fibromyalgia. Hum Psychopharmacol. 2004;19(Suppl 1):S27-S35. doi:10.1002/hup.622
52. Cording M, Derry S, Phillips T, Moore RA, Wiffen PJ. Milnacipran for pain in fibromyalgia in adults. Cochrane Database Syst Rev. 2015;2015;2015(10):CD008244. doi:10.1002/14651858.cd008244.pub3
53. Yunus MB, Masi AT, Aldag JC. Short term effects of ibuprofen in primary fibromyalgia syndrome: a double-blind, placebo-controlled trial[published correction appears in J Rheumatol 1989 Jun;16(6):855]. JRheumatol.1989;16(4):527-532.
54. Russell IJ, Kamin M, Bennett RM, Schnitzer TJ, Green JA, Katz WA. Efficacy of tramadol in treatment of pain in Fibromyalgia. J Clin Rheumatol. 2000;6(5):250-257. doi:10.1097/00124743-200010000-00004
55. da Rocha AP, Mizzaci CC, Nunes Pinto ACP, da Silva Vieira AG, Civile V, Trevisani VFM. Tramadol for management of fibromyalgia pain and symptoms: Systematic review. Int J Clin Pract.2020;74(3):e13455. doi:10.1111/ijcp.13455
56. Kia S, Choy E. Update on Treatment Guideline in Fibromyalgia Syndrome with Focus on Pharmacology. Biomedicines.2017;5(2):20. doi:10.3390/biomedicines 5020020
57. Borchers AT, Gershwin ME. Fibromyalgia: A Critical and Comprehensive Review. Clin Rev Allergy Immunol.2015;49(2):100-151. doi:10.1007/s12016-015-8509-4
58. Krasselt M, Baerwald C. Fibromyalgie-Syndrom: Aktuelle Empfehlungen zu Diagnostik und Therapie. Dtsch Med Wochenschr.2018;143(15):1103-1108. doi:10.1055/a-0542-9531
59. El-Shewy KM, Kunbaz A, Gad MM, et al. Hyperbaric oxygen and aerobic exercise in the long-term treatment of Fibromyalgia: A narrative review. Biomed Pharmacother.2019;109:629-638. doi:10.1016/j.biopha.2018.10.157
60. Straube S, Derry S, Straube C, Moore RA. Vitamin D for the treatment of chronic painful conditions in adults. Cochrane Database Syst Rev.2015;2015(5):CD007771. doi:10.1002/14651858.cd007771.pub3
61. Daniel D, Pirotta MV. Fibromyalgia--should we be testing and treating for vitamin D deficiency? Aust Fam Physician.2011;40(9):712-716.
62. von Kanel R, Müller-Hartmannsgruber V, Kokinogenis G, Egloff N. Vitamin D and central hypersensitivity in patients with chronic pain. Pain Med.2014;15(9):1609-1618. doi:10.1111/pme.12454
63. Leung L, Cahill CM. TNF-α and neuropathic pain-a review. J Neuroinflammation.2010;7:27. doi:10.1186/1742-2094-7-27
64. Mensah-Nyagan AG, Meyer L, Schaeffer V, Kibaly C, Patte-Mensah C. Evidence for a key role of steroids in the modulation of pain. Psychoneuroendocrinology.2009;34(Suppl 1):S169-S177. doi:10.1016/j.psyneue n.2009.06.004
65. Marchand F, Perretti M, McMahon SB. Role of the immune system in chronic pain. Nat Rev Neurosci.2005;6(7):521-532. doi:10.1038/nrn1700
66. Garcion E, Wion-Barbot N, Montero-Menei CN, Berger F, Wion D. New clues about vitamin D functions in the nervous system. Trends Endocrinol Metab.2002;13(3):100-105. doi:10.1016/s1043-2760(01)00547-1
67. Tague SE, Clarke GL, Winter MK, McCarson KE, Wright DE, Smith PG. Vitamin D deficiency promotes skeletal muscle hypersensitivity and sensory hyperinnervation. J Neurosci. 2011;31(39):13728-13738. doi:10.1523/jneurosci.3637-11.2011
68. Wu Z, Camargo CA Jr, Sluyter JD, et al. Association between serum 25-hydroxyvitamin D levels and self-reported chronic pain in older adults: A cross-sectional analysis from the ViDA study. J Steroid Biochem Mol Biol.2019;188:17-22. doi:10.1016/j.jsbm b.2018.11.018
69. Huang W, Shah S, Long Q, Crankshaw AK, Tangpricha V. Improvement of pain, sleep, and quality of life in chronic pain patients with vitamin D supplementation. Clin J Pain.2013;29(4):341-347. doi:10.1097/aip.0b013e318255655d
70. Yong WC, Sanguankeo A, Upala S. Effect of vitamin D supplementation in chronic widespread pain: a systematic review and meta-analysis. Clin Rheumatol.2017;36(12):2825-2833. doi:10.1007/s10067-017-3754-y
71. Mateos F, Valero C, Olmos JM, et al. Bone mass and vitamin D levels in women with a diagnosis of Fibromyalgia. Osteoporos Int.2014;25(2):525-533. doi:10.1007/s00198-013-2434-2
72. Beserra SR, Souza FIS, Sarni ROS, Pereira MM de M. Association Between Low Vitamin D Levels and the Greater Impact of Fibromyalgia. J Clin Med Res.2020;12(7):436-442. doi:10.14740/jocmr4136
73. Okyay R, Kocyigit B, Girsoy S. Vitamin D levels in women with Fibromyalgia and relationship between pain, tender point count and disease activity. Acta Med Mediterr.2016;32:243-247.
74. Abokrysha NT. Vitamin D deficiency in women with Fibromyalgia in Saudi Arabia. Pain Med.2012;13(3):452-458. doi:10.1111/j.1526-4637.2011.01304.x
75. Joustra ML, Minovic I, Janssens KAM, Bakker SJL, Rosmalen JGM. Vitamin and mineral status in chronic fatigue syndrome and fibromyalgia syndrome: A systematic review and meta-analysis. PLoS ONE.2017;12(4):e0176631. doi:10.1371/journal.pone.0176631
76. Maafi AA, Ghavidel-Parsa B, Haghdoost A, et al. Serum Vitamin D Status in Iranian Fibromyalgia Patients: according to the Symptom Severity and Illness Invalidation. Korean J Pain.2016;29(3):172-178. doi:10.3344/kjp.2016.29.3.172
77. de Rezende Pena C, Grillo LP, das Chagas Medeiros MM. Evaluation of 25-hydroxyvitamin D serum levels in patients with Fibromyalgia. J Clin Rheumatol.2010;16(8):365-369. doi:10.1097/rhu.0b013e3181fe8a 90
78. Matthana MH. The relation between vitamin D deficiency and fibromyalgia syndrome in women. Saudi Med J.2011;32(9):925-929.
79. Wepner F, Scheuer R, Schuetz-Wieser B, et al. Effects of vitamin D on patients with fibromyalgia syndrome: a randomized placebo-controlled trial. Pain.2014;155(2):261-268. doi:10.1016/j.pain.2013.10.002
80. de Carvalho JF, da Rocha Araújo FAG, da Mota LMA, Aires RB, de Araujo RP. Vitamin D Supplementation Seems to Improve Fibromyalgia Symptoms: Preliminary Results. Isr Med Assoc J.2018;20(6):379-381.
81. Yilmaz R, Salli A, Cingoz HT, Kucuksen S, Ugurlu H. Efficacy of vitamin D replacement therapy on patients with chronic nonspecific widespread musculoskeletal pain with vitamin D deficiency. Int J Rheum Dis.2016;19(12):1255-1262. doi:10.1111/1756-185x.12960
82. Mirzaei A, Zabihiyeganeh M, Jahed SA, Khiabani E, Nojomi M, Ghaffari S. Effects of vitamin D optimization on quality of life of patients with fibromyalgia: A randomized controlled trial. Med J Islam Repub Iran.2018;32:29. doi:10.14196/mjiri.32.29
83. Abou-Raya S, Abou-Raya A, Helmii M. THU0327 Efficacy of Vitamin D Supplementation in the Treatment of Fibromyalgia: Randomized Controlled Trial. Ann Rheum Dis.2014;73:295.3-295. doi:10.1136/annrheumdis-2014-eular.2767
84. McKenna MJ, Murray BF. Vitamin D dose response is underestimated by Endocrine Society's Clinical Practice Guideline. Endocr Connect.2013;2(2):87-95. doi:10.1530/ec-13-0008
85. Jesus CA, Feder D, Peres MF. The role of vitamin D in pathophysiology and treatment of Fibromyalgia. Curr Pain Headache Rep.2013;17(8):355. doi:10.1007/s11916-013-0355-6
86. Scheuer R. Fibromyalgia: could vitamin D help? Int J Clin Rheumtol.2014;9(3):237-239. doi:10.2217/ij r.14.16
87. Baygutalp NK, Baygutalp F, Seferoglu B, Bakan E. The relation between serum vitamin D levels and clinical findings of fibromyalgia syndrome. Dicle Med J.2014;41(3):446-450. doi:10.5798/diclemedj.0921.2014.03.0452
88. Okumus M, Koybasi M, Tuncay F, et al. Fibromyalgia syndrome: is it related to vitamin D deficiency in premenopausal female patients? Pain Manag Nurs.2013;14(4):e156-e163. doi:10.1016/j.pm n.2011.09.006