Chronic migraine: a therapeutic challenge for clinicians

Abstract

Chronic migraine is a common disabling condition. Severe migraine attacks should be treated with triptans, but these agents are contraindicated in patients with vascular problems and may not be effective or tolerated in around one third of the patients. New acute migraine therapies without vasoconstrictive activity and triptan-specific side effects are emerging. For the prophylaxis of chronic migraine, only topiramate and OnabotulinumtoxinA have been shown to be effective in placebo-controlled randomized trials, so novel therapeutic strategies are needed. The growing understanding of the pathophysiology of chronic migraine will contribute to the identification of new treatment targets.

Keywords::

• acute treatment
• CGRP
• chronic migraine
• onabotulinumtoxinA
• prophylaxis
• refractory

Chronic migraine is a common debilitating disorder that causes greater interference with patients' daily activities and greater reduction in their quality of life than episodic migraine [1]. Data from a large international survey of persons with migraine showed that chronic migraine imposes a greater burden on both the individual and the health care system than episodic migraine [2]. In recent years, neurologists have tried to define the concept of chronic migraine [3], to determine what causes a patient with episodic migraine to evolve to chronic migraine [4] and, particularly, to find out how to reduce the number of headache days and improve the quality of life for patients who suffer this complication [5]. In the excellent article on which this editorial comments, there is an in-depth review of the forms of treatment that have emerged in recent years for chronic migraine [6].

Treatment of chronic migraine can be divided into three well differentiated sections: identification and handling of risk factors that lead to the development of chronic migraine, acute treatment of migraine attacks and preventive treatment to reduce the frequency and severity of migraine headaches.

Various studies have identified several modifiable risk factors that predispose migraineurs to develop chronic migraine, including the number of migraine attacks, stress, sleep disorders (mainly sleep apnoea), obesity, depression and abuse of analgesics or caffeine [4]. Identification and treatment of these modifiable risk factors may be helpful to ensure the success of treatment. One of the most relevant risk factors for migraine chronification is obesity [4], which is often associated with sleep apnoea. Therefore, losing weight for overweight or obese migraine sufferers should be recommended. Depression and anxiety symptoms are also more common in patients with chronic migraine than in those who suffer from episodic migraines [1], and these often require specific treatment. Another factor associated with development of chronic migraine is overuse of analgesics [4]. Excessive and continuous analgesic consumption may worsen migraines and lead to the onset of daily pain, which significantly improves or disappears after discontinuing the overused drugs. Currently, medication overuse headache can be diagnosed if the patient takes ergotics, triptans and opiates more than 10 days a month or takes simple analgesics or combinations of analgesics more than 15 days a month [7]. For patients with chronic migraine who suffer from headaches almost every day, it is easy to understand that they need frequent analgesic intake. However, it does not appear that taking analgesics is the cause of the chronic migraine in most cases, but rather the consequence of suffering from migraine on a daily basis.

Treatment of migraine attacks should be prescribed to all patients to relieve the pain and associated symptoms. Triptans and ergotics are the only migraine-specific drugs for acute treatment. These agents are contraindicated in migraineurs with vascular problems, and specifically triptans are not effective or not tolerated in around one third of the patients [8]. For these reasons, new methods of delivering triptans and ergots to increase their efficacy and reduce their side effects have been developed [9]. Furthermore, new drugs without vasoactive properties, such as calcitonin gene-related peptide (CGRP) receptor antagonists or gepants, serotonin 5-HT1F receptor agonists and α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA)/kainate receptor antagonists, are currently under evaluation [6,9]. The efficacy of lasmiditan, a highly selective 5-HT1F agonist [10,11], and various gepants [9], appears comparable to that of triptans. Adverse events with lasmiditan and gepants are qualitatively different from those reported with triptans [9-11]. However, a preventive study of telcagepant in migraine given twice daily for 3 months was terminated early due to increased liver transaminases levels in some patients, and concerns about possible liver toxicity of gepants remain unresolved.

The use of preventive drugs is probably the key treatment in chronic migraine. Any of the oral preventive drugs indicated for episodic migraine may be prescribed to patients with chronic migraine [5]. However, only topiramate and botulinum toxin Type-A, have demonstrated their efficacy specifically in patients with chronic migraine in randomized, placebo-controlled trials [5], and the only currently approved treatment by the Federal Drug Administration for the preventive treatment of chronic migraine is onabotulinumtoxinA (BoNT-A). Either topiramate or BoNT-A may be a good choice in overweight or obese patients, a risk factor for migraine chronification, because these drugs will not cause weight gain. Because most of the patients may requiere prophylactic drugs, and current treatments may be ineffective or not tolerated in many migraineurs, development of novel therapies for patients with chronic migraine is a priority.

Botulinum toxin Type-A has been used for different types of pain including migraine for two decades, but its efficacy in patients with chronic migraine was not established until 2010 when the results of the PREEMPT study were published [12]. Treatment with BoNT-A was superior to placebo for reducing both the number of episodes and days with headache. It was also confirmed that this treatment made it possible to reduce triptan consumption [12] and may be effective in refractory chronic migraine patients [13]. The benefit of BoNT-A for chronic chronic migraines is modest considering the effect on the reduction of headache frequency [14]. However, the reduction in the number of headaches in absolute terms may not adequately describe the potential benefits of BoNT-A on chronic migraines in clinical practice. The improvement of disability and quality of life has emerged as a useful measurement of treatment benefit in chronic pain syndromes such as chronic migraine. Recent studies have demonstrated that the treatment of chronic migraine patients with BoNT-A was associated with significant improvements in functioning and quality of life [15]. On the other hand, migraine prophylaxis may reduce headache frequency and associated disability and could be an important approach for containing medical costs. Future studies with preventive drugs in patients with chronic migraine should also evaluate the improvement in disability and quality of life, and the impact on headache-related medical costs, as the true clinical benefit achieved with prophylactic agents can be regarded as going beyond a reduction in headache frequency.

Another interesting conclusion of the PREEMPT trials [12], as previously observed with topiramate, is that discontinuing analgesics was not absolutely essential for BoNT-A to be effective [5]. It was traditionally considered that taking analgesics continuously rendered preventive treatments ineffective and withdrawal of these drugs was recommended even before starting any preventive treatment. Approximately three quarters of the patients included in both PREEMPT studies overused analgesics (according to the stringent criteria established in the International Classification of Headache Disorders), and they were allowed to continue taking painkillers on demand throughout follow-up without this reducing the efficacy of BoNT-A [12]. Although prophylactics may be effective in analgesic overusers, it seems advisable to start the preventive treatment of migraine while simultaneously reducing analgesics. We also recommend prescribing prophylactic treatment to those patients with chronic migraine who do not manage to reduce their analgesic consumption.

Other preventive drugs such as amitryptiline, gabapentine, fluoxetine, tizanidine and valproate have demonstrated their efficacy in placebo-controlled trials that included patients with chronic daily headache [5]. It is likely that a high proportion of the patients with chronic daily headache included in these trials suffered from chronic migraine, and therefore all of these drugs could be useful in this group of patients. However, in the absence of controlled trials, no valid recommendations can be made.

Other preventive treatments for chronic migraine continue to be tested and proposed in light of the promising results of some drugs obtained in both open-label studies or small clinical trials (such as levetiracetam or lacosamide) and the new evidence on the involvement of other receptors (melatonin-1, orexin) in migraine pathophysiology [6]. Neurostimulation could be useful to patients with refractory chronic migraine [5,6]. The primary efficacy endpoints in the most recent randomized placebo-controlled trials with occipital nerve stimulation in patients with refractory chronic migraine were negative, although some benefits were observed in several secondary endpoints. Further studies are required to clearly demonstrate the efficacy of neurostimulation in refractory chronic migraine patients. The technique of implanting electrodes is being improved continuously and smaller-sized, longer-acting generators are increasingly available.

The work by Lionetto L, et al. [6] shows that the future for migraine treatment, and specifically for chronic migraine, is very promising. In addition to current treatments, among which BoNT-A is noteworthy for chronic migraine, new therapies are emerging for acute treatment and migraine prophylaxis. The growing understanding of the mechanisms involved in migraine chronification will open up new directions in the treatment of these challenging patients.

Declaration of interest

P. I. has received payment for lectures from Allergan. The authors have received no payment in preparation of this manuscript.