Montelukast in the prophylaxis of migraine: a potential role for leukotriene modifiers

OBJECTIVE: Clinical observation of a decrease in migraine frequency in patients with comorbid asthma taking montelukast, a specific D4 leukotriene receptor antagonist, or zafirlukast, another leukotriene receptor antagonist, prompted us to explore a possible role for leukotriene modifiers in the treatment of migraine. (A further prompt was a pharmacist colleague's observation that a number of patients on these agents reported a decreased sensitivity to perfume triggers and improvement in migraine.) BACKGROUND: Nonsteroidal anti-inflammatory agents have been used widely in the treatment of migraine. Another class of anti-inflammatory agents, known as leukotriene modifiers, have not been studied to date with regard to their possible role in the treatment of migraine. The name "leukotriene is derived both from the parent molecule, which was originally isolated from leukocytes, and from its three double-bond carbon backbone or triene structure. Both prostaglandins and leukotrienes are derived from the metabolism of arachidonic acid, with prostaglandins coming off the cyclooxygenase pathway and leukotrienes derived via the enzyme 5-lipoxygenase. Both prostaglandins and leukotrienes mediate inflammatory responses. The latter have been studied with regard to their role in the pathophysiology of asthma. METHODS: A prospective, open-label study evaluating the efficacy of montelukast, 10 mg or 20 mg, in the prophylaxis of migraine in 17 patients is presented in this paper. All 17 patients completed the study that consisted of a 2-month baseline run-in period and a 3-month treatment phase. RESULTS: Montelukast was extremely well tolerated, and no adverse events were reported by any of the patients. Fifty-three percent showed a reduction of greater than 50% (P<.025) in the frequency of severe attacks, with 41% showing a reduction of greater than 60%. Responders, including modest responders, rated the drug as excellent. CONCLUSIONS: We conclude, given the limitations of an open-label study design and the small sample size, that montelukast shows potential as an effective, well-tolerated prophylactic agent in migraine. Double-blinded, placebo-controlled studies are warranted. In addition, the leukotrienes, as suggested previously in the literature, may play a role in the pathogenesis of migraine.     

MAP0004, orally inhaled DHE: a randomized, controlled study in the acute treatment of migraine

(Headache 2011;51:507‐517) Objective.— To evaluate the efficacy and tolerability of MAP0004 compared with placebo for a single migraine in adult migraineurs: The FREEDOM‐301 Study. Background.— Acute treatment of migraine remains a clinical challenge despite the availability of triptans and other agents. Injectable dihydroergotamine, although effective, is considered invasive and inconvenient, and intranasal dihydroergotamine is associated with inconsistent systemic dosage delivery. MAP0004 is an orally inhaled formulation of dihydroergotamine delivered to the systemic circulation. In a phase 2 study, MAP0004 provided significant early onset of pain relief (10 minutes, P < .05) and sustained pain relief for up to 48 hours with a favorable adverse event profile. Methods.— A phase 3, randomized, double‐blind, placebo‐controlled, parallel‐group, single‐attack, outpatient study of MAP0004, an inhaled dihydroergotamine was conducted at 102 sites in 903 adults with a history of episodic migraine. Patients were randomized (1:1) to receive MAP0004 (0.63 mg emitted dose; 1.0 mg nominal dose) or placebo, administered after onset of a migraine headache with moderate to severe pain. The co‐primary endpoints were patient‐assessed pain relief and absence of photophobia, phonophobia, and nausea at 2 hours after treatment. Results.— A total of 903 patients (450 active, 453 placebo) were randomized, and 792 (395 active, 397 placebo) experienced a qualifying migraine. MAP0004 was superior to placebo in all 4 co‐primary endpoints: pain relief (58.7% vs 34.5%, P < .0001), phonophobia free (52.9% vs 33.8%, P < .0001), photophobia free (46.6% vs 27.2%, P < .0001), and nausea free (67.1% vs 58.7%, P = .0210). Additionally, significantly more patients were pain‐free at 2 hours following treatment with MAP0004 than with placebo (28.4% vs 10.1%, P < .0001). MAP0004 was well tolerated; no drug‐related serious adverse events occurred. Conclusions.— In this study, MAP0004 was effective and well tolerated for the acute treatment of migraine with or without aura, providing statistically significant pain relief and freedom from photophobia, phonophobia, and nausea in adults with migraine compared with placebo.     

Symptomatic pharmacotherapy of migraine.

This review summarizes data on the effectiveness of various symptomatic migraine pharmacotherapies and makes recommendations for treatment. A wide variety of agents are available for the symptomatic treatment of migraine headache, including over-the-counter analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), combination products, opiates, ergot alkaloids, corticosteroids, dopamine antagonists, and triptans. In the stepped-care approach, simple analgesics and NSAIDs are the recommended first step for the treatment of mild-to-moderate migraine headaches. Patients who do not respond to first-step treatments may be given ergots, combination products, dopamine antagonists, or triptans as the second step. Corticosteroids or opiates may be used as rescue treatment in patients who do not respond to second-step treatment. A stratified approach to care individualizes treatment based on the severity of the headache and other patient-specific factors. In a stratified approach, dihydroergotamine or triptans may be the first-step treatment for patients who present with a history of severe migraines that have responded poorly to previous treatments. Sumatriptan was the first triptan approved for the symptomatic treatment of migraine headache; newer triptans include zolmitriptan, naratriptan, and rizatriptan. Since sumatriptan is rapidly absorbed by the subcutaneous route, its time to onset of effect is shortest. Among triptan drugs that are administered orally, the relative time to onset may be shorter with rizatriptan than sumatriptan. Naratriptan has a longer time to onset but is associated with a lower rate of migraine recurrence than other triptans. graine headache, ergot alkaloids, triptans,     

DHE in the Pharmacotherapy of Migraine: Potential for a Larger Role

Despite a large array of currently marketed, frequently effective drugs for the acute treatment of migraine headache, comprising various classes and formulations, predictably reliable treatment for most headache types is often lacking. Dihydroergotamine mesylate (DHE) is a comparatively safe and effective therapy for migraine headache that could potentially be used for a broader range of headache types than occurs at present. The features of DHE supporting this assertion include (1) effectiveness in terminating severe, long-lasting headaches, (2) rapid onset of action, (3) very low rates of headache recurrence, (4) minimal risk of medication-overuse headache, and (5) in the nasal spray formulation, suitability for outpatients (especially patients who are very nauseated or vomiting, potentially obviating the need for an office or hospital visit for acute care). Conditions or circumstances for which there are data supporting the expanded use of DHE include menstrual migraine, migraine with central sensitization and cutaneous allodynia, medication-overuse headache, migraine recurrence, and status migrainosus. The introduction of the intranasal formulation of DHE provides both pharmacologic and patient-convenience advantages for use in migraine therapy. This article reviews the rationale for the use of DHE in these common, often difficult-to-treat migraine forms.     

Brain barriers and their potential role in migraine pathophysiology

Migraine is a ubiquitous neurologic disease that afflicts people of all ages. Its molecular pathogenesis involves peptides that promote intracranial vasodilation and modulate nociceptive transmission upon release from sensory afferents of cells in the trigeminal ganglion and parasympathetic efferents of cells in the sphenopalatine ganglion. Experimental data have confirmed that intravenous infusion of these vasoactive peptides induce migraine attacks in people with migraine, but it remains a point of scientific contention whether their site of action lies outside or within the central nervous system. In this context, it has been hypothesized that transient dysfunction of brain barriers before or during migraine attacks might facilitate the passage of migraine-inducing peptides into the central nervous system. Here, we review evidence suggestive of brain barrier dysfunction in migraine pathogenesis and conclude with lessons learned in order to provide directions for future research efforts.     

Neurological mechanisms of migraine: potential of the gap-junction modulator tonabersat in prevention of migraine

Migraine is a neurovascular disorder characterized by recurrent episodic headaches, and is caused by abnormal processing of sensory information due to peripheral and/or central sensitization. The exact pathophysiological mechanism underlying migraine is not fully understood; however, cortical spreading depression (CSD) is thought to provide the basis for migraine aura and may serve as a trigger of migraine pain. CSD depends on neuronal–glial cell communication, which is mediated by intercellular transfer of messengers through connexin-containing gap junctions, as well as messengers released into the extracellular space by non-junctional connexin-containing hemichannels. These processes are believed to be important in peripheral sensitization within the trigeminal ganglion and to lead to central sensitization. The novel benzopyran compound tonabersat binds selectively to a unique site in the brain. In preclinical studies, tonabersat markedly reduced CSD and CSD-associated events and inhibited gap-junction communication between neurons and satellite glial cells in the trigeminal ganglion. Together, these findings suggest that tonabersat should have clinical application in preventing migraine attacks.     

The role of cervical dysfunction in migraine: a systematic review

This systematic review evaluates the strength of the evidence for the role of cervical musculoskeletal dysfunction in migraine. In this review, cervical musculoskeletal dysfunction will refer to the abnormal sensory afferentation from cervical region structures contained within the receptive field of the trigeminocervical nucleus. Electronic database searches using MEDLINE, PubMed and CINAHL were performed, and 17 studies investigating cervical musculoskeletal dysfunction in people with migraine were selected for review. The methodological quality of the included studies was assessed by two independent reviewers using a customized checklist. The review found that intersubject differences were inadequately reported and controlled, which resulted in grouping of participants with varying pathologies and symptoms. A diverse range of assessment procedures was used by the reviewed studies, which made comparison of their findings difficult. The assessment procedures were mainly used to quantify the degree of cervical musculoskeletal dysfunction, rather than to identify a cause and effect relationship between cervical structure and migrainous pain. Although animal study evidence proposes a role for cervical musculoskeletal dysfunction in migraine, this systematic review of the literature found that there is currently no convincing evidence to confirm this phenomenon in humans.     

The role of estrogen in migraine: a review and hypothesis

The epidemiological, clinical and basic science evidence for a role of estrogen in migraine is reviewed. The hypothesis is put forward that estrogen exerts its influence by modulating sympathetic control of the cerebral vasculature.     

Neurovascular headache and a midbrain vascular malformation: evidence for a role of the brainstem in chronic migraine

Migraine is a common, disabling form of primary headache that has been linked by functional imaging studies to activation in the rostral brainstem. In specialty clinics migraine is most commonly seen in association with frequent less feature full headache that has been called transformed migraine or more recently termed chronic migraine. A patient is described with frequent migraine, 3 days per week, and less feature full headaches on other days. The patient has a cavernoma in the midbrain that has bled. She was previously headache free and now has contralateral daily headache. The patient supports the functional imaging observations from positron emission tomography (PET) that the rostral brainstem is pivotal in migraine pathophysiology, particularly the contralateral midbrain periaqueductal grey matter. Moreover, the patient's lesion provides biologically plausible support that a single entity causes her clinical presentation: chronic migraine, not two-disorders, migraine and tension-type headache.     

Clinical significance of serum sex hormones in postmenopausal women with vestibular migraine: potential role of estradiol

ObjectiveThis study aimed to investigate the role of sex hormones in postmenopausal women with vestibular migraine.MethodsThis observational study included 242 female patients with vestibular migraine who were postmenopausal during April 2017 to December 2019. Serum levels of sex hormones, including estradiol, progesterone, testosterone, follicle-stimulating hormone, luteinizing hormone, and prolactin, were determined by radioimmunoassay. The duration and frequency (every month) of onset of vestibular migraine were recorded. The degree of vestibular migraine was measured by the visual analogue scale.ResultsSerum levels of estradiol, progesterone, and testosterone were significantly lower, while serum prolactin levels were significantly higher in postmenopausal patients with vestibular migraine compared with healthy controls. Serum estradiol levels were negatively correlated with the duration, frequency, and severity of onset of vestibular migraine. Patients with higher serum estradiol levels showed a longer disease-free survival time.ConclusionSex hormones are correlated with vestibular migraine in postmenopausal women. Additionally, estradiol levels are correlated with the duration, frequency, and severity of onset of vestibular migraine, as well as the disease-free survival time.     

The new role of pharmacotherapy for weight reduction in obesity

Obesity is associated with an increased risk for a wide variety of chronic health conditions. Despite this fact, less than half of obese patients are advised by healthcare professionals to lose weight. Creating a viable plan for losing weight and maintaining weight loss is difficult. Lifestyle change is always the cornerstone of treatment, but two new therapeutic agents approved for long-term use, sibutramine and orlistat, can help maximise success. Increased weight loss can lead to reductions in the risk of obesity-related co-morbidities. Sibutramine and orlistat offer new weight reduction opportunities for obese patients.     

Maternal characteristics and migraine pharmacotherapy during pregnancy: cross-sectional analysis of data from a large cohort study

Little is known about factors associated with migraine pharmacotherapy during pregnancy. Of 60 435 pregnant women in a population-based cohort, 3480 (5.8%) reported having migraine during the first 5 months of pregnancy. Of these, 2525 (72.6%) reported using migraine pharmacotherapy, mostly non-narcotic analgesics (54.1%) and triptans (25.4%). After adjustment for sociodemographic factors and comorbidities in logistic regression analysis, high pregestational body mass index [odds ratio (OR) 1.3, 95% confidence interval (CI) 1.2, 1.4], sleep < 5 h (OR 1.6, 95% CI 1.3, 1.9), being on sick-leave (OR 1.3, 95% CI 1.2, 1.5) and acute back/shoulder/neck pain (OR 0.6, 95% CI 0.6, 0.7) were associated with migraine pharmacotherapy during pregnancy. Many women need drug treatment for migraine during pregnancy, and the choice of pharmacotherapy during this period may be influenced by maternal sociodemographic factors and comorbidities.     

CGRP may play a causative role in migraine

Calcitonin gene-related peptide (CGRP) has been detected in increased amounts in external jugular venous blood during migraine attacks. However, it is unknown whether this is secondary to migraine or whether CGRP may cause headache. In a double-blind crossover study, the effect of human alphaCGRP (2 microg/min) or placebo infused intravenously for 20 min was studied in 12 patients suffering from migraine without aura. Headache intensity was scored on a scale from 0 to 10. Two patients were excluded due to severe hypotension and one because she had an infection. In the first hour median peak headache score was 1.0 in the halphaCGRP group vs. 0 in the placebo group (P < 0.01). During the following 11 h all patients experienced headaches after halphaCGRP vs. one patient after placebo (P = 0.0004). The median maximal headache score was 4 after CGRP and 0 after placebo (P = 0.006). In three patients after halphaCGRP, but in no patients after placebo, the delayed headache fulfilled the IHS criteria for migraine without aura. As intravenous administration of halphaCGRP causes headache and migraine in migraineurs, our study suggests that the increase in CGRP observed during spontaneous migraine attacks may play a causative role.