Drug safety and tolerability in prophylactic migraine treatment

Introduction: Migraine is a frequent, disabling primary headache disorder, whose pathomechanism is not yet fully understood. Prophylactic treatment is advisable for migraineurs with severe or highly frequent attacks, which impair the quality of life.

Areas covered: The different types of prophylactic migraine drugs are discussed, with particular regard to potential adverse effects and safety issues. β-Adrenergic blockers, antiepileptic drugs and calcium-channel blockers are drugs widely used for migraine prevention, whereas complementary medicine and onabotulinumtoxin A can be used in selected cases.

Expert opinion: The background of the recurrence and chronification of migraine attacks has not been fully clarified, and causative preventive therapy is therefore not currently available. The tolerability and adverse effects of the currently used medications often limit their use. β-Adrenergic receptor blockers may induce adverse cardiovascular events, whereas flunarizine is frequently associated with a weight gain and depression. As most migraine sufferers are young women of child-bearing age, the use of valproate is limited. Topiramate is associated with central nervous system-related side effects. There is a need for future development of pathomechanism-based preventive drugs, and personalized therapy tailored to the patient.     

Migraine with aura and reproductive life events: a case control study

The course of migraine without aura (MO) is greatly influenced by the events of female reproductive life. Much less is known about migraine with aura (MA). The aim of this study was to evaluate the relationship between MA and the milestones of reproductive life. A retrospective case control study was carried out on 100 women affected by migraine with typical aura (cases) and 200 age-matched women with MO (controls). Premenstrual syndrome was found to be much more common among the patients with MA (odds ratio (OR) 6.0; confidence interval (CI) 3.1-11.6). Menstrually triggered migraine was more frequently encountered among MO than among MA patients (MA 15.0%; MO 53.5%; OR 0.1; CI 0.1-0.3). In both forms of migraine, pregnancy had a favourable effect; however, a lower percentage of MA (43.6%) than MO patients (76.8%; OR 0.2; CI 0.1-0.5) showed improvement or remission. The use of oral contraceptives worsened migraine in MA more frequently than in MO patients (MA 56.4%; MO 25.3%; OR 3.8; CI 1.6-9.3). The course of MA seems to be influenced by female reproductive life events, but in a different way with respect to MO.     

Familial hemiplegic migraine type 2 does not share hypersensitivity to nitric oxide with common types of migraine

Familial hemiplegic migraine type 2 (FHM-2) and common types of migraine show phenotypic similarities which may indicate a common neurobiological background. The nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway plays a crucial role in migraine pathophysiology. Therefore, we tested the hypothesis that ATP1A2 mutations in patients with FHM-2 are associated with hypersensitivity to NO-cGMP pathway. Eight FHM-2 patients with R202Q, R763C, V138A and L764P mutations and nine healthy controls received intravenous infusions of 0.5 mug kg(-1) min(-1) glyceryl trinitrate (GTN) over 20 min. We recorded the following variables: headache intensity on a verbal rating scale; mean flow velocity in the middle cerebral artery (V(meanMCA)) by transcranial Doppler; diameter of the superficial temporal artery (STA) by ultrasound. The primary end-points were differences in incidence of migraine headache and area under the curve (AUC) for headache score during an immediate phase (0-120 min) and a delayed phase (2-14 h) after start of infusion. We found no difference in the incidence of reported migraine between FHM-2 patients, 25% (two out of eight), and controls, 0% (0 out of nine) (95% confidence interval -0.06, 0.56) (P = 0.21). The AUC(headache) in the immediate (P = 0.37) and delayed (P = 0.09) phase was not different between patients and controls. The GTN infusion resulted in a biphasic response in patients. During the immediate phase, the median peak headache occurred at 30 min and tended to be higher in patients, 1 (0, 3.8), than in controls, 0 (0, 1) (P = 0.056). During the delayed phase, the median peak headache occurred 4 h after the start of the infusion and was significantly higher in patients, 2.5 (0, 3), than in controls, 0 (0, 0) (P = 0.046). We found no difference in the AUC(VmeanMCA) (P = 0.77) or AUC(STA) (P = 0.53) between FHM-2 patients and controls. GTN infusion failed to induce more migraine in FHM-2 patients than in controls. The pathophysiological pathways underlying migraine headache in FHM-2 may be different from the common types of migraine.     

Evaluation and proposal for optimalization of neurophysiological tests in migraine: part 1--electrophysiological tests

Neurophysiological testing has become a valuable tool for investigating brain excitability and nociceptive systems in headache disorders. Previous reviews have suggested that most neurophysiological tests have limited value for headache diagnosis, but a vast potential for exploring the pathophysiology of headaches, the central effects of certain pharmacological treatments and phenotype-genotype correlations. Many protocols, however, lack standardization. This meta-analytical review of neurophysiological methods in migraine was initiated by a task force within the EUROHEAD project (EU Strep LSHM-CT-2004–5044837-Workpackage 9). Most of the neurophysiological approaches that have been used in headache patients are reviewed, i.e. evoked potentials, nociception-specific blink reflex, single-fibre electromyography, neuroimaging methods (functional MRI, PET, and voxel-based morphometry) and the nitroglycerin attack-provoking test. For each of them, we summarize the results, analyse the methodological limitations and propose recommendations for improved methodology and standardization of research protocols. The first part is devoted to electrophysiological methods, the second to neuroimaging techniques and the NTG test.     

Infrequent or non-response to oral sumatriptan does not predict response to other triptans--review of four trials

A migraineur can claim to be an infrequent responder ('non-responder') to an oral triptan independent of which triptan he or she is presently using. Four trials of an alternative triptan (zolmitriptan/rizatriptan; eletriptan; naratriptan; almotriptan) in patients with a history of infrequent response to oral sumatriptan were compared and contrasted in terms of study design, patient characteristics, and efficacy and tolerability of the triptan under investigation. Unfortunately, none of the reported studies used an appropriate parallel design, which would have had the non-responding triptan (oral sumatriptan) in one arm and without encapsulation. While the four trials differed in terms of study design (open-label vs. placebo-controlled), definition of sumatriptan 'non-responder' (retrospective vs. prospective) and pain intensity at baseline (30% severe to 70% severe), all four demonstrated that lack of response to sumatriptan did not predict lack of response to an alternative triptan. Changing triptans resulted in 2-h pain-relief rates of 25-81% in patients with a history of poor response to sumatriptan. It can be concluded that migraine patients who respond infrequently to sumatriptan should be switched to a different triptan, as lack of response to one triptan does not predict likelihood of responsiveness to another. A review of the available evidence suggests that almotriptan may be one of the most appropriate choices for an alternative triptan.     

Sumatriptan Relieves Migrainelike Headaches Associated With Carbon Monoxide Exposure

We report a 58-year-old woman with long-standing migraine who developed a pattern of weekend headaches which occurred only while staying at her Connecticut vacation home The headaches promptly responded to sumatriptan. Investigation revealed a high carbon monoxide level in her home due to a defective furnace. Replacing the furnace eliminated the headaches. This case highlights the importance of searching for secondary causes of headache even in patients responsive to sumatriptan. It also suggests that carbon monoxide may trigger headaches mediated by trigeminovascular inflammation.     

Combined therapy for migraine prevention? Clinical experience with a beta-blocker plus sodium valproate in 52 resistant migraine patients

The aim was to explore whether combining a beta-blocker and sodium valproate could lead to an advantage in efficacy in patients with migraine previously resistant to the two medications in monotherapy. Fifty-two patients (43 women) with a history of episodic migraine with or without aura, and previously unresponsive to beta-blockers and sodium valproate in monotherapy, were treated with a combination of propranolol or nadolol and sodium valproate in an open-label fashion. Eight patients (15%) discontinued due to adverse events. Fifteen (29%) did not respond. The remaining 29 cases (56%) showed response (> 50% reduction in migraine days). The response was excellent in nine (17%). From this open trial, combination therapy with a beta-blocker and sodium valproate appears to be a good migraine preventative in some previously resistant migraine cases. Controlled trials are now necessary to determine the true advantage in efficacy of this combination in difficult to treat migraineurs.     

Testing of variants of the MTHFR and ESR1 genes in 1798 Finnish individuals fails to confirm the association with migraine with aura

Among the few independently replicated genetic associations in migraine are polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) and oestrogen receptor (ESR1) genes. We studied the contribution of these genes to migraine susceptibility by genotyping six MTHFR and 26 ESR1 polymorphisms in 898 unrelated migraine with aura (MA) patients and in 900 unrelated healthy controls. There were no differences in the genotype distributions of the previously migraine-associated SNPs C677T (MTHFR) and G2014A (ESR1) between cases and controls (P-values 0.83 and 0.55, respectively). Thus, we were not able to replicate the previous findings, although our study had considerable power. However, five of the ESR1 SNPs (rs6557170, rs2347867, rs6557171, rs4870062 and rs1801132) that were in strong linkage disequilibrium were nominally associated with MA (uncorrected P-values 0.007-0.034). These results did not, however, remain significant after taking multiple testing into account. Thus it seems unlikely that the studied genes are involved in migraine susceptibility, at least in this sample.     

The effect of circulating adenosine on cerebral haemodynamics and headache generation in healthy subjects

Adenosine is an endogenous neurotransmitter that is released from the brain during hypoxia and relaxes isolated human cerebral arteries. Many cerebral artery dilators cause migraine attacks. However, the effect of intravenous adenosine on headache and cerebral artery diameter has not previously been investigated in man and reports regarding the effect of intravenous adenosine on cerebral blood flow are conflicting. Twelve healthy participants received adenosine 80, 120 microg kg(-1) min(-1) and placebo intravenously for 20 min, in a double-blind, three-way, crossover, randomized design. Headache was rated on a verbal scale (0-10). Regional cerebral blood flow (rCBF) with 133Xe inhalation and single-photon emission computed tomography (SPECT) and MCA flow velocity (V(MCA)) with transcranial Doppler, were measured in direct sequence. Six participants developed headache during 80 microg kg(-1) min(-1) and six during 120 microg kg(-1) min(-1) compared with none on placebo (P = 0.006). The headache was very mild and predominantly described as a pressing sensation. When correcting data for adenosine-induced hyperventilation, no significant changes in rCBF (P = 0.22) or V(MCA) (P = 0.16) were found between treatments. A significant dilation of the superficial temporal artery (STA) was seen (P < 0.001). These results show that circulating adenosine has no effect on rCBF or V(MCA), while it dilates the STA and causes very mild headache.     

Chemical mediators of migraine: preclinical and clinical observations

Migraine is a neurovascular disorder, and although the pathophysiology of migraine has not been fully delineated, much has been learned in the past 50 years. This knowledge has been accompanied by significant advancements in the way migraine is viewed as a disease process and in the development therapeutic options. In this review, we will focus on 4 mediators (nitric oxide, histamine, serotonin, and calcitonin gene-related peptide) which have significantly advanced our understanding of migraine as a disease entity. For each mediator we begin by reviewing the preclinical data linking it to migraine pathophysiology, first focusing on the vascular mechanisms, then the neuronal mechanisms. The preclinical data are then followed by a review of the clinical data which support each mediator's role in migraine and highlights the pharmacological agents which target these mediators for migraine therapy.