The main objective of basic treatment , also called prophylactic treatment, is to reduce the frequency of attacks, then their intensity. It is therefore not necessary to prescribe basic treatment if the frequency or intensity of the attacks do not have an impact on the patient's personal and socio-professional life.
In general, basic treatment for migraine is considered in subjects who regularly present at least 4 attacks per month (Massiou et al. 2005). Likewise, it is essential in patients who take crisis treatment more than two days a week, due to the risk of progression towards the chronicization of migraines. It is considered effective when it reduces the frequency of seizures by at least 50%, with a difference of at least 30% compared to placebo (Géraud et al. 2015).
A basic treatment must be evaluated over a period of at least 3 months . There are many molecules that are used in the basic treatment of migraines, but few of them are specific. Most of these molecules are old and have not been evaluated in therapeutic trials with sufficient methodology. They were classified into three categories: grade A for demonstrated effectiveness, grade B or C for probable or doubtful effectiveness.
List of basic treatments according to their grade (Géraud et al. 2015) : Grade A: Sodium valproate and divalproate, Metoprolol, Propranolol, Topiramate For grade B: Amitriptyline, Atenolol, Candesartan, Flunarizine, Methysergide (MAH suspended), Naproxen sodium, Nebivolol, Oxetorone, Pizotifen, Timolol, Venlafaxine With grade C: Dihydroergotamine (MAD removed), Verapamil, Gabapentin
The choice of basic treatment for migraine is essentially conditioned by the benefit-risk ratio , because no molecule has demonstrated superior effectiveness compared to the others, and the allocation of grades corresponds more to the methodology applied than to the others. to the real effectiveness of the molecule. Using non-specific treatments implies secondary activity of the molecule and therefore, potentially, long-term side effects (Massiou et al. 2005)
1. Beta blockers as background treatmentThere are several beta-blockers which have demonstrated their effectiveness in the basic treatment of migraine, but only propranolol marketed under the name Avlocardyl® and Hémipralon® has obtained marketing authorization (AMM) for basic treatment of migraine, with metoprolol marketed under the name Seloken® and Lopressor®. Several other beta-blockers, such as acebutolol and aprenolol, which have sympathomimetic activity (which stimulates the sympathetic system), have shown no effectiveness in preventing migraines (Danesh et al. 2019). These molecules are old, their marketing authorizations dating back more than 50 years , and their mode of operation is still not elucidated. It seems that their “pure” agonist effect on β-receptors is essential for their antimigraine action.
Indeed, beta-blockers that have shown no effectiveness are essentially partial agonists. Additionally, they are very lipophilic and therefore easily cross the blood-brain barrier . They could therefore act by reducing catecholaminergic hyperactivity of the central nervous system (Fumagalli et al. 2020).
In the background treatment of migraine, no beta-blocker has shown superiority over the other (Jackson et al. 2015). If one is not effective for a patient, another beta blocker may be. In addition, the effectiveness of the basic treatment may vary over time and may no longer be suitable at a given moment. The dosage must be adjusted on a case-by-case basis, starting with a minimum dose (10 mg for Avlocardyl®). Due to their action on blood pressure, the best indication for beta-blockers is migraine without aura , in stressed subjects or subjects with a hypertensive tendency (Donnet et al. 2018). If the side effects remain minimal, the most common are asthenia (fatigue) and insomnia. This is long-term use which can sometimes cause problems . By reducing blood pressure in patients who do not need it, stopping the drug becomes difficult due to a risk of rebound hypertension (Géraud et al. 2015).
2. AntiserotonergicsThis group of drugs brings together several molecules with an affinity for serotonin (5-HT 2) receptors. However, it seems that it is not this anti-serotonergic activity which is responsible for their effectiveness. Indeed, powerful specific anti-5-HT 2 agents have been synthesized, such as ketanserin or mianserin, but have proven to be ineffective in migraine (Kaumann et al. 1985; Shukla et al. 2001). There are three drugs in this class, used to treat migraine attacks: methysergide (Désernil®), pizotifen (Sanmigran®) and oxetorone (Nocertone®).
Methysergide is an ergot derivative that has shown efficacy comparable to propranolol (Tfelt-Hansen et al. 2006). Its action would be essentially due to a vasoconstrictor effect through its agonist activity on 5-HT 1 B receptors. Its use is however limited, because it cannot be combined with triptans , because of the exceptional but serious risk of retroperitoneal fibrosis. , endocardial or pleuropulmonary. It is therefore reserved as an alternative treatment in severe forms of migraine that no longer respond to any treatment. The unfavorable benefit-risk assessment for this basic treatment forced the cancellation of its Marketing Authorization in France , but it still remains widely used in other countries. Pizotifen also has an antihistamine and weakly anticholinergic action. In some studies it was found to be more effective than methysergide (Jackson et al. 2015). On the other hand, it exerts a slight antidepressant effect , which makes it the most popular basic treatment in this category. Oxetorone has, in addition to its anti-serotonergic effects, antihistamine, antiemetic and neuroleptic effects. Its use is relatively limited by its side effects, particularly drowsiness that is sometimes very disabling in patients.
3. Calcium antagonists as background treatmentCalcium channel blockers inhibit membrane transfer of calcium in cardiac and vascular muscle cells. They are therefore the cause of significant vasodilation which allows them to be classified in the first three intended treatments against arterial hypertension. In the basic treatment of migraine, in addition to the vasodilator effect, their effectiveness is also due to a cytoprotective action , during the excessive release of calcium ions during cerebral ischemia (Bentué-Ferrer et al. 1989) .
They also interfere in the production of NO (Nitric Oxide) and the release of neuropeptides such as CGRP. The three main molecules marketed to treat migraine are: flunarizine (Sibélium®), verapamil (Isoptine®) and nimodipine (Nimotop®). However, verapamil and nimodipine have not obtained Marketing Authorization in the treatment of migraine. This is mainly due to very disparate and inconclusive results in clinical studies, or to significant side effects, such as hypotension, lower limb edema or bradycardia. Concerning flunarizine, its anticalcic effect is associated with an antihistamine and anti-serotonergic activity. In controlled studies, its efficacy has been found to be comparable to that of propranolol (Gawel et al. 1992). The use of this molecule is however limited, mainly because of the anxiodepressive effects and significant weight gain in certain patients.
The cortical hyperexcitability of the brain recorded in migraine justifies the theory of the use of antiepileptics in migraine prophylaxis (Cuvellier et al. 2009). Valproate and topiramate are those with demonstrated efficacy and moderate adverse effects in the treatment of migraine. Topiramate (Épitomax®) has marketing authorization in the treatment of migraine, but no reimbursement from Social Security for this indication, with the aim of directing treatment towards drugs with fewer side effects. Indeed, if the efficacy of topiramate is comparable to that of propranolol (Diener et al. 2004), the dose with the best efficacy-tolerance balance of 100 mg is not always sufficient; however, the side effects are dose-dependent and mainly concern neurological disorders such as psychomotor slowing, the onset of mood disorders or uncontrollable aggressiveness. Valproate marketed under the name Dépakine® and Dépakote® did not obtain Marketing Authorization either in this indication for the same reasons.
5. Antidepressants as basic treatment for migraineWe have already mentioned in pathophysiology the interest of antidepressants , capable of increasing the level of free serotonin in the basic treatment of migraine (Lôo and Olié 2004). Even if there is an increase in headaches at the start of treatment, due to the transient increase in the level of free serotonin , the gradual normalization of this level confers a protective effect on the patient (Azimova et al. 2016). Tricyclic antidepressants were the first molecules used in headache prophylaxis in 1964 and have long been the most common treatment for migraine prevention (X. Xu et al. 2017). They were quickly put in competition with selective serotonin reuptake inhibitors, and several studies showed lower effectiveness of the latter, despite fewer side effects (Jackson et al. 2010).
Amitriptyline (Laroxyl®) is the only antidepressant that has demonstrated efficacy in migraine prophylaxis . Its effectiveness is equivalent to that of propranolol and it is interesting to note that no correlation between the antidepressant effect and the antimigraine effect has been found. Venlafaxine (Effexor®) is a serotonin and norepinephrine reuptake inhibitor and is the only one in its class to have demonstrated effectiveness in migraine prophylaxis (Jackson et al. 2010).
6. Gepans and anti-CGRP monoclonal antibodies
It was in 1980 that the role of CGRP was highlighted in the pathophysiology of migraine (Sandor et al. 2019). Since that day, pharmaceutical companies have continued to develop antagonists directed against components of the CGRP system for the treatment of migraine. The first CGRP antagonists to be evaluated in the treatment of migraine attacks were called “ gepans ”. They attracted great interest initially, as they had shown similar efficacy to triptans , while being better tolerated (Ho et al. 2008). They also had the advantage of having no vasoconstrictor effect, which allowed their prescription in patients with a vascular history. In addition, no chronicization had been observed, thus limiting the appearance of headaches due to drug abuse. However, some subsequent studies showed hepatotoxicity, which forced pharmaceutical companies to abandon the gepan route (Ho et al. 2016; Xu et al. 2016). For several years, no disease-modifying treatment of this class was offered. There is currently renewed interest in developing new gepans that do not cause liver toxicity . Several of them are in the development phase, such as ubrogepant for episodic migraines, which is currently in phase 3 (Lipton et al. 2019); rimegepant for chronic migraines, which is also in this same phase, and atogepant is in phase 2 for the prevention of migraines.
In the phase 3 ACHIEVE I study, randomized, multicenter and double-blind, the efficacy, safety and tolerability of ubrogepant were evaluated (Dodick et al. 2020). Administered orally (50 mg or 100 mg), it was compared to placebo during acute migraine attacks of moderate to severe intensity. Of the 1327 patients treated with the disease-modifying treatment, an absence of pain was observed two hours after taking it, in a much higher proportion than in the placebo group. The results were in the same direction concerning the secondary criteria, ie the absence of the most bothersome symptoms associated with migraine, such as photophobia, phonophobia or nausea. The most frequently observed side effects are nausea, drowsiness and dry mouth.
Thus, the new gepans seem to be able to provide a useful alternative to triptans, particularly in patients suffering from cardiovascular risk or not responding to triptans. Another promising development is that of monoclonal antibodies directed against CGRP (eptinezumab, fremanezumab and galcanezumab) or its receptor. (erenumab) (Sandor et al. 2019). Depending on the substance, this background treatment is administered subcutaneously or intravenously, every 1 to 3 months.
The LIBERTY study , which aims to evaluate the effectiveness of erenumab against a placebo treatment (Reuter et al. 2018), showed that at 12 weeks, the number of patients having achieved a reduction of at least 50 % number of migraine days per month (primary endpoint) was 30% in the erenumab group versus 14% on placebo (p = 0.002). The proportion of those achieving a 75% or 100% reduction was 12% versus 4% (p=0.025) and 6% versus 0%, respectively.
Erenumab is the first molecule to be authorized on the market, its Marketing Authorization having been granted in May 2018 in the United States, and in September 2018 in the European area. It is available as an auto-injector for home use, and its tolerability is excellent and comparable to that of placebo for almost all adverse effects, and no hepatotoxicity has been reported to date. The phase 3 PROMISE study evaluated the efficacy of eptinezumab against placebo (Ashina et al. 2020; Lipton et al. 2020). About half of the patients receiving the treatment achieved a reduction of more than 50% in monthly migraines. These promising results are also found in studies concerning the two other molecules (Ferrari et al. 2019; Silberstein et al. 2017; Lamb 2018).
However, there are no direct comparative studies between these four molecules or in comparison with another prophylactic treatment, but overall, the effectiveness described in the studies is comparable to that of other established antimigraine prophylactic agents (topiramate by example) and does not seem to depend on the frequency of headaches at the start of treatment (Brandes et al. 2004; Sandor et al. 2019). Since erenumab, marketed under the name Aimovig®, other molecules have gradually obtained their marketing authorization. This is the case of Emgality (galcanezumab) from Eli Lilly laboratories or even Ajovy (fremanezumab) from Teva. Eptinezumab was authorized by the FDA in April 2020 and is expected to quickly be authorized on the European market.
Currently, the main restriction is the cost of treatment, estimated between 3000 and 5000 euros per year per patient (Sandor et al. 2019). To date, no reimbursement by payers has been approved, therefore this treatment will not be available to all patients. The American Headache Society (AHS) unveiled the recommendations for use in March 2019 and only includes patients suffering at least 15 days of headache per month, including 8 meeting the criteria for migraine (photophobia, digestive signs, increased pain). exercise, etc.), and after failure of at least 2 conventional treatments (American Headache Society 2018).Although these specific migraine prophylactic treatments cannot be prescribed to all migraine patients, they nevertheless constitute a major advance for patients refractory to current treatments.