There are a multitude of treatments used in migraine prophylaxis, but few of them have been properly evaluated methodologically.
1. Angiotensin II converting enzyme inhibitors
Angiotensin II converting enzyme inhibitors are still being evaluated. Preliminary results support the efficacy of these molecules (Tronvik et al. 2003). Lisinopril®, initially used against arterial hypertension, proved to be effective in reducing the intensity and frequency of seizures by up to 20% on average (Schrader et al. 2001). Its mechanism of action is not fully established. It could block the conversion of angiotensin I to angiotensin II, modulate sympathetic activity and oppose the release of free radicals. Botulinum toxin (Botox®) has been widely publicized in the prophylactic treatment of migraines and particularly chronic migraines. This enthusiasm is to be considered in moderation. Besides the few studies showing a decrease of almost two days per month in headaches in chronic migraine (Herd et al. 2018), many other clinical trials do not demonstrate tangible efficacy (Jackson et al. 2012; Puljak et al. 2019). In addition, this drug has serious side effects. It would block the release of acetylcholine at neuromuscular junctions or other cholinergic junctions. The European Medicines Agency and the French Health Products Safety Agency have recommended that this substance not be prescribed for this indication. However, Botox benefits from an MA in the treatment of migraines in England.
2. Coenzyme Q10
Coenzyme Q10 is the recommended treatment (in combination with L-carnitine and L-arginine) to treat MELAS syndrome. It is also an essential cofactor in the mechanism of the respiratory chain. Its effectiveness in the prevention of migraines has been demonstrated (Parohan et al. 2019) and is today the most widely used natural alternative treatment. Also known as ubiquinone, it is one of the substances necessary for the production of energy in the cells of almost all living things. It plays an important antioxidant role, protects cells against ROS and the oxidation of nucleic acids or the peroxidation of membrane lipids.
It is also attributed anti-inflammatory effects, a role in DNA replication, in the RNA repair process and in the respiratory chain. More particularly at the level of the mitochondria, where it changes from its oxidized form to its reduced form, making it possible to transfer electrons from one enzymatic complex (NADH dehydrogenase) to another (cytochrome reductase). Thanks to its multiple effects, ubiquinone is recommended as a dietary supplement in several neurological pathologies. Such as Parkinson's disease, amyotrophic lateral sclerosis or multiple sclerosis. Its essential role in mitochondrial function and the respiratory chain makes ubiquinone the perfect candidate to treat metabolic energy failures in migraine attacks. A recent randomized double-blind, placebo-controlled study (Dahri et al. 2019) in migraine patients measured the evolution of inflammatory markers following the administration of 400 mg per day of ubiquinone. After measurement of CGRP, interleukins IL-6 and IL-10 and TNF-α, the results show a significant reduction in CGRP and TNF-α in treated patients, as well as a decrease in the frequency and severity of migraine attacks (Dahri et al. 2019).
3. Magnesium against migraine
If several studies have shown a magnesium deficiency in migraine patients (Mauskop et al. 2002; Ramadan et al. 1989; Trauninger et al. 2002), the question of treatment based on Mg2+ now arises. A recent meta-analysis published in “Headache” examined 204 clinical studies on the effectiveness of Mg2+ between 1990 and 2016 (Von Luckner et al. 2018). Often biased methodologies or conflicts of interest with pharmaceutical laboratories only allowed the analysis of 5 studies, considered methodologically reliable. On average, the number of seizures decreases by 22 to 43% with high-dose magnesium treatment. Compared to preventive treatments, such as propranolol, which recorded reductions of between 30 and 60%, the effectiveness of Mg2+ was classified as grade C, that is to say “presumed effectiveness”. However, we must take a step back from these results, as the number of studies analyzed is still small and the methodologies used vary. The interest of Mg2+ in the preventive treatment of migraines perhaps lies in an association with conventional treatments, or in a complex combining coenzyme Q10. There are also other natural treatments to treat migraine
4. Vitamin B2 or riboflavin
Results from several clinical trials support the prophylactic effect of high-dose riboflavin supplementation on migraine attacks. In an open study (Boehnke et al. 2004), high-dose riboflavin supplementation (400 mg/day) for 6 months resulted in a reduction in the frequency of migraine attacks. Nambiar and colleagues reported that riboflavin supplementation (100 mg/day) is equally effective and better tolerated than 80 mg/day of propranolol (golden prophylactic drug) in reducing headache frequency, duration, and severity ( Nambiar et al. 2011). Several other studies also go in this direction (Maizels et al. 2004; Sandor et al. 2000). Based on this evidence, the American Academy of Neurology Guideline considered riboflavin to be “probably effective” (grade B) in the prophylaxis of migraine in adults (Holland et al. 2012). The “Canada Headache Society” has also included the vitamin in the list of highly recommended preventive treatments (Pringsheim et al. 2012). Studies in children use often unreliable methodologies, with low doses of riboflavin and small group sizes. All of the trials report inconsistent results. A first uncontrolled study indicated that high riboflavin supplementation is effective in the prophylaxis of pediatric migraines (Condò et al. 2009), while two other randomized controlled trials show no significant difference between the treated group and the group control (Bruijn et al. 2010; MacLennan, et al. 2008). However, it is specified that the placebo response is greater in children compared to adults (Ho et al. 2009). According to the WHO, the recommended doses of vitamin B2 are around 1 mg per day in children and 1.5 mg per day in adults, without any maximum dose being mentioned to regulate supplementation. Riboflavin-based treatments marketed for the treatment of migraine range from 40 mg/day to 400 mg. Riboflavin being a water-soluble vitamin, it is naturally eliminated by the body in the urine in case of excess. Known side effects include diarrhea and yellow urine.
5. Neurostimulation against migraine
Neurostimulation is used in neurology for the treatment of diseases such as Parkinson's, for example. This is a surgically installed neurostimulator which, using electrical impulses, will oppose the transmission of pain. This technology has recently been adapted to stimulate Arnold's greater occipital nerve. An electrode is implanted under the skin at the back of the head, at the base of the occiput. This is connected to a small box implanted in the abdomen, which permanently stimulates the greater occipital nerve. In 60% of patients, this treatment leads to a clear reduction in the number of seizures and a significant improvement in quality of life (Reed 2012; Stanak et al. 2020). The neurostimulation of the greater occipital nerve in refractory chronic daily headaches has made it possible to make a great advance at the therapeutic level. This neurostimulation is called internal, because it requires a surgical procedure to implant the electrode. It is only intended for patients who do not respond to any drug treatment. In addition, no reimbursement by Social Security has been coded in France. Following this discovery and the first positive results, several models of external neurostimulation, in which the electrodes are affixed directly to the skin, have been developed (Lanteri-Minet 2018). In 2017, the GammaCore® neurostimulator obtained marketing authorization for cluster headaches and in January 2018, the American health authorities validated an extended use to relieve pain related to migraines in adults. More recently, Belgian company Cefaly Technology also received approval from the Food and Drug Administration (FDA). In this device, the electrodes are located at the temples and stimulate the trigeminal nerve. The device costs the patient between approximately 400 and 600 euros (Stanak et al. 2020).
6. Relaxation, hypnosis, feedback and manual therapies
Relaxation and biofeedback have proven themselves
In addition to basic crisis medications, all the natural techniques that help to relax during the crisis make it possible to reduce the pain. They also make it possible to better manage stress and potentially reduce the frequency of seizures (Fauconnier et al. 2015). Relaxation techniques are multiple and include meditation, yoga or sophrology breathing exercises. Sport is also one of the calming activities and a recent study showed that regular sports practice helped reduce the frequency of attacks (Amin et al. 2018). Regularity seems to be the essential point, because isolated intense physical activity can also be a triggering factor. Retrocontrol (biofeedback) is increasingly used and is based on the measurement of organic functions. The goal is to teach the patient to identify physiological variations in their body, such as pulse, skin temperature, muscle activity, then to control them to soothe them.
Numerous publications conclude that biofeedback is effective in relieving migraines (Nestoriuc et al. 2007). Whether accompanied by relaxation or combined with behavioral treatment, the results indicate greater effectiveness than the placebo group. The meta-analysis of the US Headache Consortium published in 2000 (Campbell et al. 2000) shows that relaxation, feedback combined with relaxation, cognitive and behavioral therapies have significant effectiveness in preventing seizures compared to placebo, with a 30 to 50% reduction in their intensity. Moreover, these effects seem to be maintained over several years and are accentuated as long as the patient exercises. Many authors question the reliability of these studies, mainly due to the fact that the placebo group is easily identifiable among patients. Either way, calming the mind has a daily beneficial effect in managing stress and pain. Moreover, its effectiveness was described as early as the second century by Galen (Sacks 1999) and continues to be used today in almost all chronic pain management services.
Medical hypnosis to control pain
Medical hypnosis has often been studied in chronic pain and migraine (Michaux et al. 2004). It intervenes on two axes: to allow the migraine sufferer to control his emotions, which constitute powerful triggers of the crises, and when these settle, to allow him to modulate his pain to reduce its intensity. Several studies have shown the effectiveness of hypnosis in the management of chronic pain. Its effectiveness is essentially linked to the significant production of endorphins which act as natural analgesics. After a more or less long training period, the patient can use self-hypnosis. By exercising regularly, he is able to relax his body and modulate his pain alone.
