The pathophysiology of migraine involves dysfunction of subcortical structures modulating sensory input in the trigeminovascular system. As a result, vasoactive peptides, such as calcitonin gene-related peptide (CGRP) and substance P, are released from trigeminovascular neurons, thereby exacerbating vasodilation and generating neurogenic inflammation.18,19 Mitochondrial dysfunction, increased calcitonin, matrix metalloproteinase 9 (MMP-9), and nitric oxide (NO) levels, as well as decreased level of metabolic enzymes are also considered among the significant factors generating migraine.20 Additionally, genetic and environmental factors might also be involved in triggering the
onset of migraine attacks.21
Various conventional pharmacological treatments for migraine prevention are currently in use, aiming to reduce afferent traffic or stabilizing these above-mentioned abnormal pathways.18 Nonetheless, many patients respond poorly to, or experience adverse events with these treatments.8 In addition, many patients are noncompliant with these medications; unsatisfactory efficacy, safety or tolerability issues, and concerns about long-term safety are among the reasons.9
As such, there is a growing therapeutic shift over the last years towards treatments with lower adverse event rate, including onabotulinum toxin–A, monoclonal antibodies, external neurostimulators22-24 and nutraceuticals. Nutraceuticals is a non-pharmacological approach that includes vitamins, minerals, and herbs in the prevention of migraines. The level of evidence to support use of nutrients is low or moderate, mainly because of lack of rigorous clinical trials. Nonetheless, patients often prefer nutraceutical treatment over traditional pharmacological approaches in migraine prophylaxis to diminish possible side effects and intolerance, but also based on the belief that herbal remedies or nutrients are much safer than drugs.25,26
The use of nutraceuticals is included or accepted by various guidelines despite the rather poor or moderate level of evidence, in both the EU and US,6,17 based on the luck of significant adverse events and the potential of an individual or synergistic ability to target significant factors involved in migraine pathogenesis.25 Interestingly, the Canadian Headache Society Guideline for Migraine Prophylaxis27 includes riboflavin, coenzyme Q10, and magnesium citrate to the list of prophylactic drugs that received a strong recommendation for use, along with topiramate, propranolol and amitriptyline, among others. This recommendation comes despite the rather poor or moderate level of evidence, as authors of the Canadian Headache Society Guideline for Migraine Prophylaxis acknowledge, and is mainly based on the safety and tolerability profile, an approach which seems rational and reflecting the real-world situation.
Indeed, existing knowledge shows that magnesium, vitamin B2, feverfew and coenzyme Q10 are helpful in migraine prophylaxis with minimal safety issues, as these nutrients might be able to target some of the processes involved in migraine pathogenesis.28 Specifically, magnesium blocks glutamate receptors, modulates ATP production and glucose metabolism and as such high dose supplementation is able to decrease glutamate-activated cortical spreading depression. Likewise, high dose supplementation with vitamin B2 and coenzyme Q10 may augment activity of mitochondrial complexes to prevent mitochondrial dysfunction. Finally, the use of feverfew is attributed to its properties to inhibit serotonin release from platelets and evoke vascular smooth muscle relaxation (Tepper et al, 2006; Nattagh-Eshtivani et al, 2018).25,29
In the current setting, we documented a significant improvement in all primary and secondary efficacy variables after 3 months of supplementation with a proprietary fixed combination of magnesium, vitamin B2, feverfew, coenzyme Q10 and androgrpahis paniculata. A total of 64/113 (56.6%) enrolled patients obtained a response rate at ≥50%, which was associated with improved HIT-6, MIDAS, and MSQ-QOL scores (p<0.001). An even larger group of patients (n=70; 62%) remained satisfied from Vivinor® and wished to continue supplementation, thoroughly bolstering the view that some migraineurs prefer nutraceutical over pharmacological approaches in order to avoid side effects even if the response is less clinically significant, i.e. at 30%. Notably, more than half of our patients had tried up to five previous prophylactic pharmacological medications before being supplemented with Vivinor® and either experienced modest efficacy or poor tolerance due to side effects. As such, based on their experience, they
preferred to use a potentially less effective but completely safe complementary medication as monotherapy. Patient satisfaction and a decision to continue a specific preventive migraine treatment is important in clinical practice and may not always be completely related to outcomes usually used in clinical trials. In other words, patients experiencing modest improve, less than the 50%, may be satisfied and willing to continue or repeat a treatment if they experience little or no side effects and are confident that severe side effects are unlikely in the future. On the other hand, a patient experiencing significant improvement may be reluctant to continue or repeat a treatment because of concerns with current or potential side effects or long-term safety.
Finally, another main observation of the current study is that none of the enrolled patients discontinued supplementation early throughout the process due to intolerable adverse events. Our results, overall, are in agreement with a previously published study applying a similar study design to test a proprietary supplement containing feverfew, magnesium and Q10.30 Improvement of migraine symptoms with a proprietary supplement containing riboflavin, magnesium and Q10 was also noted in a randomized, placebo-controlled, double-blind, multicenter trial enrolling 130 migraineurs, although reduction of migraine frequency showed only a trend towards statistical significance between active and placebo arms.31 Different dosages and formulations as well methodological issues in the study design (observational open-label vs placebo-controlled study design) may account for the discrepancy between results of the latter trials.
To conclude, our real-world experience with Vivinor® showed that this supplementation may be an effective and well tolerated complementary treatment in EM prophylaxis. However, the pilot open-label design of this trial, the lack of a control group. and the potential for selection or response bias, also present in other similar studies, can be acknowledged as significant limitations. Nevertheless, and to best possibly support the positive outcomes of Vivinor® supplementation, we used migraine-specific tools as endpoints to assess changes in disability, psychological burden, QOL, and satisfaction in close relation to the intervention we tested. Further larger placebo-controlled trials are warranted to confirm our results on the potential beneficial effect of this proprietary supplement (Vivinor®; Brain Therapeutics, Greece), containing magnesium, vitamin B2, feverfew, coenzyme Q10 and andrographis paniculata in EM prophylaxis.