Migraine/Headache

Migraine is the most common acute primary headache in children and adolescents. In 2014, topiramate became the first preventive drug for migraine, approved by the Food and Drug Administration (FDA) for adolescents. This meta-analysis was aimed to evaluate the efficacy and safety of topiramate in the prevention of pediatric migraine. We searched the PubMed, EMBASE, Cochrane Library, and Chinese National Knowledge Infrastructure (CNKI) databases up to June 2019 for eligible randomized controlled trials (RCTs). The primary outcomes were mean migraine days per month, ≥50% reduction rate, and Pediatric Migraine Disability Assessment Scale (PedMIDAS) scores. RevMan5.3 software was performed for statistical analysis. Overall, 5 RCTs recruiting 531 patients (6-17 years of age) were included in the meta-analysis. The target dose of topiramate was 2 mg/kg (the maintenance phase was 12 weeks), 2-3 mg/kg, 50 mg/day, and 100 mg/day (maintaining for 16 weeks), respectively, in the included studies. Our results demonstrate that participants receiving topiramate had a significant advantage in remitting the monthly migraine days than those receiving placebo, with a mean difference (MD) of -0.78 ( = 531; 95% CI, -1.23 to -0.32; = 3.37; = 0.0008). Topiramate could also reduce the mean PedMIDAS scores ( = 238; 95% CI, -16.53 to -0.49; = 2.43; = 0.04). However, there was no significant difference in the percentage of patients experiencing a ≥50% reduction in monthly headache days between topiramate and placebo groups ( = 531; 95% CI, 0.94-1.77; = 1.58; = 0.11). Topiramate was associated with higher rates of side effects such as weight decrease ( = 395; 95% CI, 2.73-22.98; = 3.81; < 0.01) and paresthesia ( = 531; 95% CI, 3.05-13.18; = 4.94; < 0.01). Topiramate can significantly decrease monthly headache days and migraine-related burden in migraine patients <18 years old. However, it failed to increase 50% response rate. Adverse events seem to be more frequent in topiramate-treated children.

Recent findings suggested that Clinical Endocannabinoid Deficiency underlies the pathophysiology of pain disorders, including migraine and headache. In models of medication overuse headache induced by sustained administration of sumatriptan or morphine, 2-AG levels were selectively depleted in the periaqueductal gray (PAG) and anandamide (AEA) increased in the cortex suggesting distinct regulation of the endocannabinoid system during headache pain. These results led to the hypothesis that blockade of DAGL, to reduce 2-AG levels would induce headache-like behaviors as a new, translationally relevant model of episodic headache. Our study investigated whether non-selective and selective blockade of DAGL, the main biosynthetic enzyme for 2-AG, induced periorbital and hind-paw allodynia, photophobia, anxiety-like behaviors, responsivity to abortive anti-migraine agents, and 2-AG/AEA levels. Injection of non-selective DAGL (DH376, 10 mg/kg, IP) and selective DAGLα (LEI106, 20 mg/kg, IP) inhibitors, but not DAGLβ agents, induced facial sensitivity in 100% and ∼60% of female and male rats, respectively, without induction of peripheral sensitivity. Notably, male rats showed significantly less sensitivity than female rats after DAGLα inhibition, suggesting sexual dimorphism in this mechanism. Importantly, LEI106 induced periorbital allodynia was attenuated by administration of the clinically available abortive antimigraine agents, sumatriptan and olcegepant. Selective DAGLα inhibition induced significant photophobia as measured by the light-dark box, without anxiety like behaviors or changes in voluntary movement. Analysis of AEA and 2-AG levels at the time of peak pain sensitivity revealed reductions in 2-AG in the visual cortex and periaqueductal gray (PAG), without altering anandamide or significantly increasing diacylglycerol levels. These results provide foundational evidence for DAGL-2AG in the induction of headache-like pain and photophobia without extracephalic allodynia, thus modeling the clinical episodic migraine. Mechanistically, behavioral measures of headache sensitivity after DAGL inhibition suggests that reduced 2-AG signaling in the cortex and PAG, but not the trigeminal nucleus caudalis or trigeminal ganglia, drives headache initiation. Therefore, episodic DAGL inhibition, which reduces the time, cost, and invasiveness of currently accepted models of headache, may fill the need for episodic migraine/headache models mirroring clinical presentation. Moreover, use of this approach may provide an avenue to study the transition from episodic to chronic headache.

The earliest descriptions of botulism were in the early 19th century, and was reported by the German physician Justinus Kerner. The term "botulism" was derived from the Latin word botulus, indicating its original association with sausages. It took another 150 years or so to come into clinical use. The first clinical application was strabismus, and was developed by the American ophthalmologist Alan B. Scott, whose effort led to the pharmaceutical product known as onabotulinumtoxinA today. The therapeutic benefit in migraine was an incidental finding in a report by the American plastic surgeon William J. Binder, which inspired a series of clinical studies in headache disorders. The doses and injection techniques in the earlier reports were variable, so were the results. It was until the Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) 1 and 2 studies when its efficacy and safety, as well as the indication, i.e., chronic migraine (CM), were ascertained. Even though there were criticisms regarding the heterogeneities in the results between the PREEMPT 1 and 2 studies, the data on efficacy endpoints and safety were generally consistent, which were subsequently confirmed by the open-label extension of the PREEMPT 1 and 2 studies, and three open-label studies, namely the Chronic Migraine OnabotulinuMtoxinA Prolonged Efficacy open Label (COMPEL), the REal-life use of botulinum toxin for the symptomatic treatment of adults with chronic migraine, measuring healthcare resource utilization, and Patient-reported OutcomeS observed in practice (REPOSE) studies, and the CM Post-Authorization Safety Study (CM PASS) studies. On the other hand, the results were challenged by the Chronification and Reversibility of Migraine (CHARM) study, which involved CM patients with medication overuse. It was concluded that the clinical improvement was attributed to early withdrawal of the overused acute medications, rather than onabotulinumtoxinA injections. However, fundamental differences in the patient profile and methodology between the CHARM and PREEMPT studies existed, and cautious should be exercised when interpreting and comparing the results. According to the practical guidelines and reimbursement regulations in many countries, its use is limited to CM patients, and is reserved for those who fail at least 2-3 preventive medications, due to either lack of efficacy or intolerability. Cessation of treatment is recommended in patients who do not respond to 2-3 injection cycles, or in patients whose headache frequency has dropped to <10-15 days a month. Even in the era of calcitonin-gene-related peptide monoclonal antibodies, onabotulinumtoxinA injection remains a treatment option of reasonable cost-effectiveness in carefully selected patients.

Lasmiditan, a highly selective 5-hydroxytryptamine receptor 1F (5-HT) agonist, is the first drug in its class and is lacking triptan-like vasoactive properties. The US Food and Drug Administration (FDA) has recently approved lasmiditan for the acute treatment of migraine in adults based on positive results of two pivotal phase III trials, which showed a significant difference to placebo in the proportion of patients achieving total migraine freedom within 2 h. More patients with lasmiditan achieved headache freedom and, in addition, freedom from the most bothersome symptom, that is, photophobia, than with placebo. Treatment-related side effects seem to be related to the rapid penetration of the drug into the brain and include dizziness, paresthesia and drowsiness, mostly of mild to moderate intensity. Interim results from an ongoing long-term phase III trial suggest a decrease in the frequency of adverse events after multiple lasmiditan use. Lasmiditan is a promising acute anti-migraine therapy, in particular for patients with cardiovascular risk factors, contraindications, or unwanted side effects to triptans.