Sensitization of the Trigeminovascular Pathway: Perspective and Implications to Migraine Pathophysiology

Migraine headache is commonly associated with signs of exaggerated intracranial and extracranial mechanical sensitivities. Patients exhibiting signs of intracranial hypersensitivity testify that their headache throbs and that mundane physical activities that increase intracranial pressure (such as bending over or coughing) intensify the pain. Patients exhibiting signs of extracranial hypersensitivity testify that during migraine their facial skin hurts in response to otherwise innocuous activities such as combing, shaving, letting water run over their face in the shower, or wearing glasses or earrings (termed here cephalic cutaneous allodynia). Such patients often testify that during migraine their bodily skin is hypersensitive and that wearing tight cloth, bracelets, rings, necklaces and socks or using a heavy blanket can be uncomfortable and/or painful (termed her extracephalic cutaneous allodynia). This review summarizes the evidence that support the view that activation of the trigeminovascular pathway contribute to the headache phase of a migraine attack, that the development of throbbing in the initial phase of migraine is mediated by sensitization of peripheral trigeminovascular neurons that innervate the meninges, that the development of cephalic allodynia is propelled by sensitization of second-order trigeminovascular neurons in the spinal trigeminal nucleus which receive converging sensory input from the meninges as well as from the scalp and facial skin, and that the development of extracephalic allodynia is mediated by sensitization of third-order trigeminovascular neurons in the posterior thalamic nuclei which receive converging sensory input from the meninges, facial and body skin.

Migraine in the triptan era: progresses achieved, lessons learned and future developments / Migrânea na era dos triptanos: progressos alcançados, lições aprendidas e desenvolvimentos futuros

Triptans, serotonin 5-HT1B/1D receptor agonists, more than revolutionizing the treatment of migraine, stimulated also ground breaking research that provided insights into the anatomy, physiology, and molecular pharmacology of migraine. This knowledge, in turn, is stimulating research on new mechanisms of action for the treatment of migraine. Accordingly, it is opportune to critically review the main advances in migraine science that happened in the triptan era. Herein we first review and conceptualize some of the progresses achieved in migraine science during the triptan era. We then review the class of the triptans - mechanism of action and clinical evidence. We close by briefly discussing the class of CGRP receptor antagonists, which is currently being developed for the acute treatment of migraine.

Os triptanos, agonistas serotoninérgicos 5-HT1B/1D, revolucionaram o tratamento da migrânea promovendo pesquisas que evidenciaram aspectos da anatomia, fisiologia e farmacologia molecular deste tipo prevalente de cefaléia primária. Esse conhecimento, por sua vez vem estimulando ainda mais a descoberta de novos mecanismos de ação para drogas anti-migranosas. Assim, é oportuno rever de forma crítica, os maiores avanços na ciência das cefaléias ocorridos durante a era dos triptanos. Inicialmente reveremos e conceituaremos alguns dos progressos obtidos nesta fase seguido de uma revisão profunda dos mecanismos de ação e evidências clínicas para o uso desta classe de fármacos. Finalmente, discutiremos a nova classe dos antagonistas dos receptores do peptideo geneticamente relacionado à calcitonina (CGRP) atualmente em desenvolvimento.

Triptanes / Triptans

La migraña es un trastorno frecuente que genera altos costos directos e indirectos a los sistemas de salud. En su fisiopatología intervienen factores genéticos, ambientales, neurofisiológicos y bioquímicos. Los triptanes son agonistas de la 5HT-1 y constituyen la terapia abortiva más importante de la migraña, sus principales mecanismos de acción son: vasoconstricción, inhibición neuronal periférica, e inhibición de la transmisión de impulsos a través de las neuronas de segundo orden del complejo trigeminocervical. En esta revisión se analizan las características farmacológicas y se hace una comparación de la eficacia clínica de los diferentes triptanes, su seguridad, sus efectos adversos, los costos del tratamiento y el impacto que tienen en la productividad laboral.

Migraine is a common disorder that generates direct and indirect costs to health systems. In the pathiphysiology of migraine there are involved genetic, environmental, neurophysiological, and biochemical factors. Triptans are 5HT-1 receptor agonists and they constitute the most important abortive therapy for migraine, their main mechanisms of action are: vasoconstriction, peripheral neuronal inhibition, and inhibition of the transmission of impulses through the second order neurons in the trigeminocervical complex. This review provides a comparison between the clinical effectiveness of the different triptans and discusses their pharmacological characteristics, adverse effects, security, the costs of the treatment and their impact on the labor productivity.

Drug Therapy for Migraine

Migraine significantly disturbs the quality of life of the patients by causing severe throbbing headache associated with neurological, autonomic, and gastrointestinal symptoms. Management of migraine starts from the correct diagnosis based on the classification proposed by the International Headache Society in 2004. Treatment failure and medication overuse and abuse commonly result from misdiagnosis of specific type of headache. Treatment includes: (1) nonpharmacological therapy (patient education, regular exercise, abstinence of caffeine and alcohol drinking, avoidance of fasting, and regular sleep), (2) acute pharmacological therapy (simple analgesics, NSAIDs, ergotamines, triptans, etc.), and (3) prophylactic pharmacological therapy (beta- blockers, calcium channel blockers, antidepressants, and anticonvulsants). Because individual drugs have their unique properties and drug interactions, careful selection and combination of the drugs must be made on the basis of the patient's migraine type, associated symptoms, and comorbidities. One of the complications of migraine drug therapy is transformation of episodic migraine into chronic daily headache that is caused by abuse or overuse of anti-migraine drugs. So the correct diagnosis of migraine and appropriate pharmacological and non-pharmacological treatments are of utmost importance in improving the patient's quality of life and prevention of medication-overuse headache.

Pharmacological management of migraine / 中国实用内科杂志

Pharmacological management of migraine should be evidence-based and individualized,combined with patient's education and non-pharmacological management.For acute therapy,simple or combination analgesics (non-steroidal anti-inflammatory drugs) or migraine specific drugs (ergotamines and triptans) are recommended and should be administrated following the concept of stratification or stepwise treatment.For preventive therapy,flunarizine,antidepressant (amitriptyline),antiepileptics (valproic acids and topiramate),and beta-blockers (propranolol and metoprolol) are drugs of first choice and should be chosen individually.Prophylaxis therapy should be evaluated for 4～8 weeks and last for 3～6 months whenever it is effective.