Chronic Pain: Beneficial Supplements for Fibromyalgia
Last year, colleagues (Dr. Bisleen Attli, ND, et al.) and I (Dr. Christilynn Aycho/Guerin, ND), published a retrospective record review of the most common supplements that fibromyalgia (FM) patients were prescribed at the Robert Schad Naturopathic Clinic (RSNC), among other things (ie. common comorbid conditions among these patients, etc.). This blog goes into detail as to WHY, according to current literature, these patients were most commonly prescribed vitamin D, magnesium, omega-3 fish oil, vitamin B12, and probiotics, for their FM diagnosis.
Vitamin D
Vitamin D was the most prescribed supplement in our patient cohort. Interestingly enough, deficiency of this vitamin has previously been linked to the onset, and progression FM symptoms. A meta-analysis, which included 12 studies and a total of 862 participants, found that vitamin D levels are lower in patients diagnosed with FM (1). It found a standardized mean difference of -0.56 between the control group and those diagnosed with the FM (1). In another study, 70 patients who had a diagnosis of FM were required to fill out the Fibromyalgia Impact Questionnaire (FIQ), Arizona Sexual Experiences Scale (ASEX), Beck Depression Inventory (BDI), Visual Analog Scale (VAS), and short-form-36 (SF-36) (2). Overall vitamin D deficiencies were observed in over 60% of patients (2). The patients who were deficient were given vitamin D replacement therapy according to their baseline levels (2). The study found a statistically significant difference in FIQ, BDI, VAS and SF-36 scores compared with pre-treatment values (2). To further support these findings, a randomized controlled trial (RCT) of 74 patients diagnosed with FM was conducted (3). In this study, the participants were split into Group A, where they received 25mg of trazodone and 50,000IU of vitamin D, and Group B, where they were prescribed 25mg trazodone with a placebo (3). There were statistically significant findings in both groups with regard to their FIQ, Widespread Pain Index (WPI), and Pittsburgh Sleep Quality Index (PSQI) (3). However, Group A had significantly more pronounced improvement in pain-related indices (3).
Pain was found to be the most significant symptom that decreased in severity with vitamin D supplementation (2,3). Vitamin D’s role in pain modulation can be attributed to a number of factors (4). It is known to upregulate the synthesis of neurotrophins such as neural growth factor, neurotrophin 3 and glial cell derived neurotrophic factor (4). The upregulation of neurotrophins further support growth, survival and differentiation of neurons (4). Vitamin D has been shown to inhibit the synthesis of nitric oxide, which can contribute to central sensitization (4). Furthermore, it helps to downregulate neutrophil function (4). This is an important finding as neutrophils are released post-tissue injury and are linked to neuropathic pain (4). Other mechanisms of action include, but are not limited to, modulating neuronal excitability, influencing inflammatory pathways and providing neuroprotection (4).
There is a clear correlation between vitamin D and the symptomatic progression of FM (1,2,3). In our cohort, vitamin D was a common supplement of choice due to deficiencies that were found in specific patients. Vitamin D should be considered as an option with regard to treatment in patients diagnosed with FM as it may have the potential to improve overall quality of life and reduce debilitating pain that is a characteristic of this illness (2,3). The indication for the use of vitamin D should be heightened in patients who are symptomatic in pain presentation and should prompt a lab investigation to assess for deficiency.
Magnesium
Magnesium was prescribed as a treatment for 54% of our observed patient population. Magnesium comes in different supplement forms (ie. citrate, glycinate, etc) and therefore caution should be taken when using this information to prescribe a specific form. Magnesium’s appears to have a protective role in FM and has been linked to decreasing excessive excitation of neurons that can lead to neuronal cell death (5). Furthermore, it has been found that pain transmission in FM occurs through glutamate’s action on the N-methyl-D-aspartate, NMDA, receptor (5). Magnesium plays a role in modulating this pathway and therefore may have a positive impact on perceived pain in this patient population (5).
A meta-analysis identified 7 systematic reviews that analyzed the use of magnesium and malic acid in patients diagnosed with FM (6). This meta-analysis concluded that the use of magnesium and malic acid makes little or no difference on pain or depressive symptoms in FM patients (6). Another study, although not testing the effects of magnesium directly on the symptoms of FM, compared a group of women diagnosed with FM to a control group (7). The study concluded that there were significantly lower levels of calcium, magnesium, iron, copper and manganese found in the women diagnosed with FM (7). Currently, the data does not support the use of magnesium in patients diagnosed with FM, however, the mechanistic properties of magnesium and the potential for deficiency shown in this population, should warrant further investigation of FM patience via bloodwork.
Omega-3 Fish Oil
Omega-3 fish oils were prescribed to 53% of our analyzed population, most commonly for symptoms related to pain and inflammation. Omega-3 fish oils are composed of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) which are used for their therapeutic properties in FM care (8). Chronic widespread pain (CWP) is a defining feature of FM and is often associated with the pain and fatigue that accompanies this diagnosis (9). Omega-3 fatty acids may play a role in reducing the the debilitating effects of CWP (10). A twin population study attempted to identify the specific metabolic biomarkers that had a specificity toward fatigue in a population of patients suffering from CWP, compared to controls (10). Ultimately, the study concluded that there were significantly lower circulating levels of EPA in those with CWP (10). The decreased EPA was correlated to the downregulation of anti-inflammatory pathways, resulting in fatigue (10).
Inflammation in general has been considered central to the pathophysiology of chronic pain conditions, and more specifically FM (11). A study that compared 40 FM patients with controls used a multiplex protein panel where they simultaneously assessed 92 inflammation-related proteins within the two groups (11). This study concluded that there were significantly higher levels of neuroinflammation and systemic inflammation in individuals diagnosed with FM (11). They were able to identify the exact proteins that contributed to this finding, with the most prominent values resulting from increased chemokines found in the cerebrospinal fluid (11). Although specific studies on the effects of omega-3 fish oils are lacking in FM patients, they have been tested in similar inflammatory conditions. For example, in rheumatoid arthritis, supplemental EPA and DHA has been shown to decrease inflammatory cytokines, tender joint count, duration of morning stiffness and patient assessed joint pain (12, 13, 14). These results have been attributed to the ability of EPA and DHA to inhibit many aspects of inflammation, as well as give rise to anti-inflammatory and inflammation resolving mediators called resolvins, protectins and maresins (12, 13, 14, 15).
There is a clear need for more research and investigation to assess the efficacy of omega-3 fish oil in patients diagnosed with FM, its proposed link between inflammation and deficiency of EPA in FM, and its mechanism of action. It appears that omega-3 fish oil may play an important role in inflammation reduction and fatigue improvement, which has the potential to improve the quality of life in FM patients.
Vitamin B12
Vitamin B12 was another commonly prescribed therapy for at least 40% of our analyzed patient population. B12 is provided to patients during their visit as an injection, or prescribed as a post-visit treatment in sublingual tablet or spray form. Both oral and injected vitamin B12 have their advantages and the administered method is determined based on severity of the symptoms. The primary form of vitamin B12 that was prescribed to patients was methylcobalamin.
When vitamin B12 is prescribed to FM patients, it may help to modulate pain. Its mechanisms of action are attributed to its ability to provide neuronal protection (16-23). More specifically, it antagonizes glutamate-induced neurotoxicity, improves nerve conduction velocity, and inhibits ectopic spontaneous discharge from peripheral primary sensory neurons in neuropathic pain states (16-23). Although this information is convincing, results would have to be further extrapolated to justify its use in patients diagnosed with FM.
Vitamin B12 may also support the fatigue component of a FM diagnosis, as the most significant symptom of deficiency is fatigue (24, 25). In an observational study conducted on 12 outpatient women who fulfilled the criteria for both FM and chronic fatigue syndrome, were rated on 15 items of the Comprehensive Psychopathological Rating Scale (CPRS-15) (26). This study found increased homocysteine levels (HCY) in the cerebrospinal fluid (CSF). Furthermore, it concluded that levels of CSF-HCY and levels of CSF-B12 correlated with the item of fatigability of the rating scale (26). The mechanism of action that was attributed to this finding was correlated to the fact that a vitamin B12 deficiency decreases the frequency of re-methylation of HCY, which ultimately results in increased homocysteine levels (26).
In conclusion, supplementing with vitamin B12 may improve pain and fatigue in FM patients. However, based on the surrender research, it appears that higher quality studies that have a bigger FM population may be needed to favour a causal association between these findings.
Probiotics
Lastly, probiotics were used in 40% of the patients analyzed for this study and were indicated for IBS and IBD symptoms such as gas and bloating, as well as for psychological symptoms associated with depression (27). It has generally been found that 32%-80% of patients diagnosed with FM have the comorbid condition of IBS according to IBS criteria (27). To elaborate, the deficiency of Bifidobacterium spp. strains and higher amounts of Enterococcus spp. have been found in patients with FM, which has been correlated with the severity of neurological and cognitive deficits (28). Research has also found a higher prevalence of food hypersensitivity’s, and celiac disease and non-celiac gluten sensitivity present in this FM patients when compared to controls (29). In addition, higher levels of immunoglobulin A have been identified in the FM population, which has been correlated to fatigue, major depression and gastrointestinal symptoms (30, 31).
A double-blind, placebo-controlled, randomized controlled trial tested the efficacy of probiotics on patients diagnosed with FM (31). It measured pain, the impact of FM, quality of life, anxiety, and depressive symptoms, pre and post intervention (31). The participants were provided with an 8-week course of Lactobacillus rhamnosus, Lactobacillus casei, Lactobacillus acidophilus and Bifidobacterium bifidus (31). This study concluded that probiotics improve cognition, more specifically choice and decision making, but no benefits were observed in pain, quality of life, FIQ, or in anxiety or depressive symptoms (31). This is one of the first trials to observe the effects of probiotics on cognition (31).
There is a strong link between the mechanistic action of probiotics and digestive complaints in FM patients to suggest their efficacy in this population. However, further higher-quality research must be conducted to confirm this association. On the other hand, probiotics may possibly have a beneficial cognitive impact on these patients 1(32). Therefore, in patients who are particularly vulnerable to the cognitive deficits of FM, probiotics may be considered as a part of their treatment plan.
Conclusion
According to current research, these supplements may improve symptoms of pain, inflammation, deficiency fatigue, restless legs, sleep, anxiety/depression, energy and IBS/IBD (ie. gas bloating) that have been associated with fibromyalgia morbidity. Therefore, when healthcare providers are developing a treatment protocol for their FM patients, inclusion of these supplements should be considered (depending on a thorough investigation of patient history), among other emerging supplements for FM patients in the literature (ie. the importance of staying current with new research).
Resources:
1.Makrani AH, Afshari M, Ghajar M, Forooghi Z, Moosazadeh M. Vitamin D and fibromyalgia: a meta-analysis. The Korean Journal of Pain. 2017;30(4):250.
2. Dogru A, Balkarli A, Cobankara V, Tunc SE, Sahin M. Effects of Vitamin D Therapy on Quality of Life in Patients with Fibromyalgia. The Eurasian Journal of Medicine. 2017;49(2):113–
3. 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. Medical Journal of The Islamic Republic of Iran. 2018;32(1):167–72.
4. Shipton EA, Shipton EE. Vitamin D and Pain: Vitamin D and Its Role in the Aetiology and Maintenance of Chronic Pain States and Associated Comorbidities. Pain Research and Treatment. 2015;2015:1–12.
5. Kirkland A, Sarlo G, Holton K. The Role of Magnesium in Neurological Disorders. Nutrients. 2018;10(6):730.
6. Ferreira I, Ortigoza Á, Moore P. Magnesium and malic acid supplement for fibromyalgia. Suplemento de magnesio y ácido málico para fibromialgia. Medwave. 2019;19(4):e7633.
7. Kim Y-S, Kim K-M, Lee D-J, Kim B-T, Park S-B, Cho D-Y, et al. Women with Fibromyalgia Have Lower Levels of Calcium, Magnesium, Iron and Manganese in Hair Mineral Analysis. Journal of Korean Medical Science. 2011;26(10):1253.
8. Calder PC. Omega-3 fatty acids and inflammatory processes: from molecules to man. Biochemical Society Transactions. 2017;45(5):1105–15.
9. Häuser W, Perrot S, Sommer C, Shir Y, Fitzcharles M-A. Diagnostic confounders of chronic widespread pain. PAIN Reports. 2017;2(3).
10. Freidin MB, Wells HR, Potter T, Livshits G, Menni C, Williams FM. Metabolomic markers of fatigue: Association between circulating metabolome and fatigue in women with chronic widespread pain. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2018;1864(2):601–6.
11. Bäckryd E, Tanum L, Lind A-L, Larsson A, Gordh T. Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma. Journal of Pain Research. 2017;Volume 10:515–25.
12. Ierna M, Kerr A, Scales H, Berge K, Griinari M. Supplementation of diet with krill oil protects against experimental rheumatoid arthritis. BMC Musculoskeletal Disorders. 2010;11(1).
13. Miles EA, Calder PC. Influence of marinen-3 polyunsaturated fatty acids on immune function and a systematic review of their effects on clinical outcomes in rheumatoid arthritis. British Journal of Nutrition. 2012;107(S2).
17. Fortin PR, Lew RA, Liang MH, Wright EA, Beckett LA, Chalmers TC, et al. Validation of a meta-analysis: The effects of fish oil in rheumatoid arthritis. Journal of Clinical Epidemiology. 1995;48(11):1379–90.
14. Goldberg RJ, Katz J. A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain. 2007;129(1):210–23.
15. Kong X, Sun X, Zhang J, Yan Ke Xue Bao. The protective role of Mecobalamin following optic nerve crush in adult rats. 2004 Sep; 20(3):171.
16. Kikuchi M, Kashii S, Honda Y, Tamura Y, Kaneda K, Akaike A. Protective effects of methylcobalamin, a vitamin B12 analog, against glutamate-induced neurotoxicity in retinal cell culture. Invest Ophthalmol Vis Sci. 1997 Apr; 38(5):848.
17. Akaike A, Tamura Y, Sato Y, Yokota T. Protective effects of a vitamin B12 analog, methylcobalamin, against glutamate cytotoxicity in cultured cortical neurons. Eur J Pharmacol. 1993 Sep 7; 241(1):1.
18. Devathasan G, Teo W-L, Mylvaganam A. Methylcobalamin in chronic diabetic neuropathy. A double-blind clinical and electrophysiological study. Clinical Trials Journal. 1986;23(2):130.
19. Kuwabara S, Nakazawa R, Azuma N, Suzuki M, Miyajima K, Fukutake T, et al. Intravenous Methylcobalamin Treatment for Uremic and Diabetic Neuropathy in Chronic Hemodialysis Patients. Internal Medicine. 1999;38(6):472.
20. Ishihara H, Yoneda M, Yamamoto W, et al. Efficacy of intravenous administration of methycobalamin for diabetic peripheral neuropathy. Med Consult N Remedies. 1992;29(1):1720.
21. Sonobe M, Yasuda H, Hatanaka I, et al. Methylcobalamin improves nerve conduction in streptozotocin-diabetic rats without affecting sorbitol and myo-inositol contents of sciatic nerve. Hormone and Metabolic Research. 1988;20(11):717.
22. Watanabe T, Kaji R, Oka N, Bara W, Kimura J. Ultra-high dose methylcobalamin promotes nerve regeneration in experimental acrylamide neuropathy. Journal of the Neurological Sciences. 1994;122(2):140.
23. Zhang M, Han W, Hu S, Xu H. Methylcobalamin: A Potential Vitamin of Pain Killer. Neural Plasticity. 2013;2013:1.
24. Ankar A. Vitamin B12 Deficiency (Cobalamin) [Internet]. StatPearls [Internet]. U.S. National Library of Medicine; 2020 [cited 2020Sep18]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441923/
25. Regland B, Andersson M, Abrahamsson L, Bagby J, Dyrehag LE, Gottfries CG. Increased Concentrations of Homocysteine in the Cerebrospinal Fluid in Patients with Fibromyalgia and Chronic Fatigue Syndrome. Scandinavian Journal of Rheumatology. 1997;26(4):301–7.
26. Roman P, Carrillo-Trabalón F, Sánchez-Labraca N, Cañadas F, Estévez A, Cardona D. Are probiotic treatments useful on fibromyalgia syndrome or chronic fatigue syndrome patients? A systematic review. Beneficial Microbes. 2018;9(4):603–11.
27. Butt, H., Dunstan, R., McGregor, N. and Roberts, T., 2001. Bacterial colonosis in patients with persistent fatigue. Myalgic encephalopathy: chronic fatigue syndrome meeting. Sydney, Australia.
28. Slim, M., Calandre, E.P. and Rico-Villademoros, F., 2015. An insight into the gastrointestinal component of fibromyalgia: clinical manifestations and potential underlying mechanisms. Rheumatology International 35: 433-444.
29. Michalsen, A., Riegert, M., Lüdtke, R., Bäcker, M., Langhorst, J., Schwickert, M. and Dobos, G.G.J., 2005. Mediterranean diet or extended fasting’s influence on changing the intestinal microflora, immunoglobulin A secretion and clinical outcome in patients with rheumatoid arthritis and fibromyalgia: an observational study. BMC Complementary and Alternative Medicine 5: 22.
30. Maes, M., Kubera, M. and Leunis, J.-C., 2008. The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinology Letters 29: 117-124.
31. Roman P, Estévez AF, Miras A, Sánchez-Labraca N, Cañadas F, Vivas AB, et al. A Pilot Randomized Controlled Trial to Explore Cognitive and Emotional Effects of Probiotics in Fibromyalgia. Scientific Reports. 2018;8(1).
Disclaimer: It is best to consult with your naturopathic doctor or healthcare provider before implementing anything new into yours or your child's healthcare plan. This information is not intended to treat or diagnose, and should not replace any currently prescribed protocols from your healthcare team. All information here is presented in an easy to read format; for those interested in evidence that supports this information, please contact us at ca@nadarra.health for citations or book an appointment to learn more.
