Migraine and Headache Clinic, Königstein im Taunus, Germany
Division of Neurology, College Hospital Essen, Essen, Germany
Division of Neurology, College Hospital Essen, Essen, Germany
Weber & Weber GmbH & Co.KG, Medical Analysis, Inning, Germany
Summary
Background
Migraine is a practical dysfunction of the mind. The pathophysiology of migraine includes many various mechanisms together with modulation of central and peripheral ache buildings and launch of vasoactive peptides. Sufferers usually expertise episodes of complications, largely throbbing, unilateral and extreme which fluctuate inside and amongst sufferers. Complications are steadily accompanied by different signs like nausea, phonophobia and/or photophobia [1].
Acute assaults are handled with completely different analgesics or triptans. Solely a minority of migraineurs take preventive medicine to lower the frequency, length and severity of migraine assaults. Prophylactic drug remedy of migraine needs to be thought-about when the standard of life is severely impaired, when two or extra assaults happen per thirty days, when migraine assaults don’t reply to acute drug remedy or in case of intolerance to or unwanted effects of acute remedy [2].
The rules of the German Headache and Migraine Society and the American Academy of Neurology suggest primarily beta-blockers, antiepileptics (topiramate or valproic acid), and antidepressants (e.g. amitriptyline) for migraine prevention [3,4]. Vitamin B2 (riboflavin), magnesium and coenzyme Q10 are options to medicine and enchantment to sufferers with a want for extra pure remedy. As well as, micronutrients are seen by the sufferers as a “mild” type of remedy with no or minor unwanted effects [5,6].
Research revealed decreased ranges of the micronutrients riboflavin, magnesium and coenzyme in plasma and within the mind of migraine sufferers [7-9]. A deficit of those vitamins may play a task within the pathophysiology of migraine. Mitochondrial dysfunction is related to migraine [10,11]. Riboflavin, magnesium and coenzyme Q10 play an essential position within the manufacturing of power within the mitochondria [12]. Magnesium is required in numerous physiological processes which affect the pathophysiology of migraine (vasoconstriction, platelet inhibition, secretion of serotonin). Magnesium can also be wanted as a co-factor for correct functioning of the ATP-synthase which produces ATP. Moreover, Mg is the physiological antagonist on the NMDA-channel which is concerned within the regulation of neuronal excitability. Riboflavin is a precursor for flavin-mononucleotide (FMN) and flavin-adenine-dinucleotide (FAD). Each are important elements of advanced I and complicated II chargeable for electron-transport within the mitochondrial membrane. Coenzyme Q10 is a vitamin-like compound which may be synthesized by the physique from phenylalanine and tyrosine. Coenzyme Q10 is required for all mobile processes requiring power. Coenzyme Q10 is an electron-carrier, transferring electrons from advanced I/advanced II to cytochrome C. Primarily based on these observations, it appears believable {that a} substitution of those micronutrients in migraine sufferers may be capable to stop or scale back the depth of migraine assaults. Migraine remedy with a dietary complement may be of profit for sufferers with recurrent migraine who can not tolerate chemical medicine as a result of unwanted effects or contra-indications as a result of concomitant ailments.
The commercially accessible meals complement Migravent® in Germany (Dolovent® within the USA) accommodates riboflavin, magnesium and coenzyme in excessive doses together with low-dose multi-vitamins for assist of common well being. This complement has already been examined in an open scientific research with 31 migraine sufferers in Germany [13]. The current trial was performed to show the efficacy of Migravent®/Dolovent® in comparison with placebo in a bigger variety of sufferers and below randomized, double-blind and multicenter circumstances.
Strategies
Outcomes
Dialogue – “magnesium ubidecarenone and riboflavin tablets”
Medication like metoprolol, propranolol, flunarizine, valproic acid or topiramate have been proven in scientific trials to be efficient in decreasing migraine signs when administered as prophylactic brokers in episodic migraine [16-22]. All of those medicine have potential unwanted effects, typically of extreme nature. Because of this many sufferers search for a pure preventive remedy of migraine. The truth is, some scientific trials have been carried out with magnesium [23-29], riboflavin (vitamin B2) [30-35] or ubiquinone (ubichinon, coenzyme Q10) [36-38] largely as single brokers. One RCT used a mixture of magnesium, riboflavin and the botanical feverfew [31] which revealed no benefit over the management group (consumption of 25 mg riboflavin), probably as a result of the truth that 25% – 38% of the sufferers within the verum and management group took concomitant migraine prophylaxis through the research. To the very best of our information, there is no such thing as a report of a randomized, double-blind and managed trial with a triple mixture of magnesium, riboflavin and coenzyme Q10. It’s attention-grabbing to notice, {that a} pharmacogenomic research demonstrated the significance of the mitochondrial genetic background on response to riboflavin [39]. This underlines the position of the mitochondrion in migraine and the potential position of magnesium, coenzyme Q10 and riboflavin in assuaging migraine signs. It might additionally clarify why sure sufferers are non-responders.
Baseline values have been comparable between the remedy teams. The variety of sufferers who used migraine prevention earlier than research entry was barely greater within the placebo group. The numbers are too small to be vital and to have had an influence on the first endpoint. The identical, to a barely extra extent is noticed concerning medical historical past and concomitant drugs. Since sufferers have been allotted in a strict randomized style to each remedy arms this statement may be pure probability. It’s not justified to recommend that sufferers in a single group who appear to be barely extra ailing than sufferers within the different group would present a distinction within the prevention of migraine.
On this scientific trial, a mixture of three pure dietary substances, magnesium, riboflavin and Q10, was examined towards placebo within the remedy of migraine in grownup sufferers. Therapy for 3 months with this proprietary dietary complement was capable of scale back the variety of days with migraine by virtually 2 days (1.8), which is taken into account to be a clinically related discount. The discount by placebo was 1.3 days. Nevertheless, the discount in migraine days was not statistically vital.
A really related discount was achieved in a randomized, placebo-controlled research (MIGR-003) with topiramate [19]. Migraine days have been diminished by 1.8 days by topiramate 100 mg/day and by 1.1 days by placebo. This end result was statistically vital (p = 0.026). Nevertheless, the variety of sufferers within the 100 mg topiramate arm was 139 in comparison with 55 within the arm of this trial with the dietary complement containing a set mixture of magnesium, riboflavin and Q10. This means that the trial may need been underpowered with regard to the first endpoint migraine days. The truth that the 200 mg topiramate arm within the MIGR-003 research didn’t attain statistical significance even with 143 sufferers (in all probability as a result of many early drop-outs) means that 55 sufferers are merely not sufficient to indicate statistical significance of any remedy in decreasing migraine days.
In any other case, the secondary endpoints that have been analyzed along with the discount of migraine days on this trial demonstrated a statistically vital advantage of the triple mixture in comparison with placebo. Sufferers handled with verum had a statistically considerably better discount within the maximally skilled ache per migraine day in comparison with placebo (p = 0.03). Within the verum group, 70.9% of the sufferers reported extreme migraine ache previous to remedy. On the finish of the remedy, solely 52.7% had extreme ache, 7.3% had delicate ache. Within the placebo group, 73.7% sufferers had extreme ache within the baseline interval, 64.9% sufferers had extreme ache on the finish of remedy and just one.8% sufferers had delicate ache.
The helpful efficacy of verum was additionally proven by a statistically vital discount within the rating of the headache influence check questionnaire HIT-6 (p = 0.01). The sum rating of the questionnaire was diminished within the lively group after 3 months of remedy by a imply of 4.8 factors. A main care inhabitants of migraine sufferers was analyzed within the publication by Smelt. A within-person minimal essential change (MIC) was established between -2.5 and -5.5 factors relying on the statistical strategy [40]. The within-person MIC is outlined because the smallest change within the rating which sufferers understand as essential. The discount of -4.8 factors on this trial is due to this fact a clinically related enchancment which exhibits statistical significance in comparison with placebo. The HIT-6 questionnaire is a scale with 5 response choices. The response choices by no means (6 factors), hardly ever (8 factors) and all the time (13 factors) will not be represented within the research inhabitants as a result of these sufferers have been excluded from participation primarily based on the inclusion and exclusion standards. Due to this fact, typically (10 factors) and fairly often (11 factors) are left as the one doable solutions for the research inhabitants, with solely a 1-point distinction between them. This 1-point distinction within the questionnaire corresponds to a related distinction in medical phrases or when it comes to illness burden/headache influence. A 4.8 level discount interprets into almost 5 objects (questions within the questionnaire) being improved from fairly often to typically. Smelt additionally established a between-group minimally essential distinction (MID) of -1.5 factors [40]. Just like the within-person MIC, the between-group MID is the smallest distinction between scores of teams of sufferers that’s thought-about essential. The distinction between the placebo group and the verum group was -2.8 factors on this trial.
In settlement with the above end result, the analysis of efficacy of the preventive remedy was higher for verum than for placebo. The distinction was statistically vital (p = 0.01). 18.2% of the sufferers within the lively group rated the efficacy as excellent, none within the placebo group. Practically 50% (47.3%) of the sufferers rated the efficacy “very good” or “good” which was twice as many as within the placebo group. Additionally, the variety of sufferers ranking efficacy as poor was greater within the placebo group.
These outcomes point out that the research preparation may need had an influence on the frequency of migraine days and improved clinically related prespecified secondary endpoints comparable to ache depth, headache influence on life (HIT-6) and subjective analysis of effectiveness.
The triple mixture had a good adversarial occasion profile. Antagonistic occasions often noticed with medicine like weight acquire, melancholy, tiredness or dizziness weren’t noticed.
A shortcoming is the potential of unblinding sufferers within the verum group as a result of chromaturia. Nevertheless, each affected person was informed at first of the trial {that a} discoloration of the urin may seem so as to rule out that chromaturia could be related to verum solely. The one approach to keep away from this is able to have been so as to add riboflavin to placebo.
The power of this research is the possible, double-blind and placebo-controlled design. The research was powered to indicate a doable distinction for the first endpoint. The research used validated endpoints.
Conclusions
A hard and fast mixture in a each day dose of 600 mg magnesium, 400 mg riboflavin and 150 mg Q10 in a proprietary dietary complement together with additionally numerous low-dose multivitamins didn’t present statistically vital efficacy within the discount of migraine days in all probability as a result of being underpowered. It did, nevertheless, show to be superior for a number of secondary outcomes within the remedy of migraine. After 3 months of remedy with the complement, a discount of migraine ache and burden of illness was seen. Sufferers rated the efficacy of the remedy considerably superior to placebo. Antagonistic occasions related to the complement have been primarily stomach discomfort and diarrhea as a result of excessive quantities of magnesium. There have been no severe adversarial occasions reported on this trial.
Acknowledgements