This study showed that a short course of sublingual vitamin B12, 1000 mcg daily, can significantly improve the severity of FM as well as the anxiety score of FM patients. However, we did not find any improvement in the depression score and health status scales after vitamin B12 treatment.
It seems that vitamin B12 can potentially exert its analgesic effect and psychological modulation through several complex pathways. Preclinical studies have shown that cobalamin inhibits glutamate exocytosis, as an excitatory pain neurotransmitter, and when infused intracerebroventricularly, increases GABA cell contents, as an inhibitory pain neurotransmitter [6, 9]. The inhibitory effects of chronic exposure of vitamin B12 on glutamate-induced neurotoxicity were determined in cell culture, probably by altering the membrane properties through S-adenosylmethionine (SAM)-mediated methylation [26, 27]. SAM is one of the major methyl donors for methylation reactions throughout the body, including the methylation of myelin basic protein. Vitamin B12 in the form of methylcobalamin is required for the formation of methionine, known as a precursor of SAM, from homocysteine [28]. Furthermore, SAM is a precursor in the synthesis of melatonin and is also an enzymatic cofactor of glutathione production [29]. Melatonin has an antioxidant role, like glutathione. Studies show that SAM synthesis can enhance cognitive performance. SAM is an essential cofactor in the pathway of synthesis of epinephrine, which is involved in learning processes and memory consolidation [29, 30].
Moreover, increased homocysteine levels due to vitamin B12 deficiency could induce neurotoxicity caused by oxidative stress. Interestingly, Regland et al. showed the increased CSF level of homocysteine in FM patients and its correlation with patients’ fatiguability [16]. Increased level of homocysteine is also an independent risk factor for developing pain by inducing peripheral neuropathy [31]. Vitamin B12 also upregulates brain-derived neurotrophic factor (BDNF) and increases nerve conduction velocity, which may reflect part of the regeneration process and brain plasticity [32]. Another potential mechanism of action for the pain-reducing properties of vitamin B12 comes from interactions with prostaglandin synthesis, including cyclooxygenase (COX) enzymes. Animal studies showed simultaneous anti-inflammatory along analgesic effects on both peripherally and centrally induced pain models [10].
So, the preclinical and clinical studies showed that vitamin B12 is an essential micronutrient involved in the preservation of pain inhibitory and excitatory neurotransmitters balance, inflammation moderation, and consequently in the diverse behavioral process including sleep, learning, memory, and sensation of pain [7, 19]. Based on this, vitamin B12 could be an adjunctive therapy in FM patients who suffer from nociplastic pain and other central symptoms such as fatigue, sleep, and cognitive disturbance. To the best of our knowledge, no research has investigated the therapeutic effect of vitamin B12 on the disease impact and psychological profile of FM patients. Given the high proclivity of vitamin B12 to neural tissue and the fundamental role of this micronutrient in neuroplasticity, it would be conceivable to have a moderator effect on pain neurobiology and integrated psychological process. This is the first prospective study addressing this issue and supporting this viewpoint. Although mean pain VAS didn’t improve significantly in our FM patients after taking vitamin B12, the total and all domains of FIQR score improved significantly up to nearly 10 points. FIQR is a holistic indicator of FM impact in terms of pain, function, and other common symptoms of FM. The decrease in FIQR score to 10 points after vitamin B12 treatment in our study indicates significant improvement of the FM impact both statistically and clinically. Interestingly, the FIQR improvement was independent of demographic and psychological profiles and preserved after adjusting for these potential confounding factors. Congruent with our result, Regland et al. showed positive dose–response and long-lasting effects of vitamin B12 injection in FM/chronic fatigue syndrome (CFS). They compared the patients (good responders versus mild responders) who had already been taking vitamin B12 shots for at least six months to twenty years [17]. In this study of FM/chronic fatigue syndrome, patients who were good responders were found to be using a higher and more frequent doses of vitamin B12 for a longer period [17]. Decrease in pain scores after vitamin B12 supplementation have been also reported in other types of pain such as peripheral neuropathy and post-chemotherapy musculoskeletal pain. Although pain mechanisms are different in neuropathic or nociceptive pain, vitamin B12 as a pain killer has had positive effects in these studies, similar to our studied FM patients [11, 12].
Interestingly, despite promising reports of vitamin B12 effect on various types of pain, existing studies has implied that serum levels of vitamin B12 in FM patients are not altered in comparison with control group [13]. In Regland et al.’s study, all patients had normal serum levels of vitamin B12 and homocysteine, however, levels of B12 in CSF correlated significantly with fatigue and items of a psychopathological scale [16]. This discrepancy indicates a correlation between central vitamin B12 levels, not peripheral/serum level, with pain and fatigue. There is scarce data on this issue, thereby vitamin B12 measurement is not recommended for FM patients.
Although our results were promising in reducing anxiety scores after vitamin B12 treatment, the patients’ depression scores were not diminished post-treatment in our patients. However, this finding doesn’t indicate the ineffectiveness of vitamin B12 in the treatment of depression. It may be because of the short treatment course in our study (50 ± 2 days) or continuing of FM medications such as duloxetine or tricyclic antidepressants in the study time which could attenuate the vitamin B12 effect. Previous data support the role of vitamin B12 supplementation in preventing or improving depressive symptoms and cognitive dysfunction [19]. Given this, we surmise the achievement of positive effects need the application of vitamin B12 in a larger population and with a longer treatment duration.
Interestingly, lower baseline depression, single status, and shorter duration of diagnosis are significantly correlated with FIQR scores improvement after vitamin B12 treatment. These baseline characteristics favor the effectiveness of vitamin B12 treatment. It may indicate some psychological status, and demographic characteristics may influence the treatment response.
Our study had some limitations. First, only female patients from one tertiary care center with a relatively small sample size were recruited; thus, the study findings cannot be extrapolated to the general FM population. Secondly, we did not have a placebo arm to compare with the treatment arm. Providing the placebo form of sublingual vitamin B12 similar to the original drug was very difficult. So, we decided the study design be based on the pre-post intervention model. Although the study design is not randomized, the results of this type of study as a quasi-experimental study could still give us a relatively high level of evidence. Thirdly, this study was an open label trial delimiting our results for the interpretation with high confidence. Furthermore, we used vitamin B12 as an adjuvant drug with patients’ current treatment regimen such as FDA-approved FM drugs. It may change or attenuate the effect of vitamin B12 on the outcomes. So, future randomized control trial needs to address this potential confounding factor in evaluating more realized vitamin B12 effect. Finally, our study duration was short and approximately two months. Given the safety of vitamin B12, it would be more favorable to treat FM patients with a longer duration to achieve a larger effect on pain and psychological illness improvement. It appears that long-term treatment for the moderation of the nociplastic alterations in the FM nervous system is needed.
This study can be a node for developing more mature and controlled studies to evaluate the effect of vitamin B12 as a safe and potentially important moderator of nociplastic pain and psychological illness in FM. This prospective study was the first study trying to clarify the effect of vitamin B12 in FM patients regarding symptom severity and psychological profiles.