Herbert G. Markley

Analgesic rebound headache in clinical practice: data from a physician survey.

Background: Frequent, excessive use of over‐the‐counter or prescription analgesics may lead to analgesic rebound headache. Little is known about the magnitude of the health problem posed by analgesic rebound headache, its epidemiology, the characteristics of analgesic rebound headache sufferers, or about physicians’ approaches to treatment.

Defining Refractory Migraine and Refractory Chronic Migraine: Proposed Criteria From the Refractory Headache Special Interest Section of the American Headache Society

Certain migraines are labeled as refractory, but the entity lacks a well‐accepted operational definition. This article summarizes the results of a survey sent to American Headache Society members to evaluate interest in a definition for RM and what were considered necessary criteria. Review of the literature, collaborative discussions and results of the survey contributed to the proposed definition for RM. We also comment on our considerations in formulating the criteria and any issues in making the criteria operational. For the proposed definition for RM and refractory chronic migraine, patients must meet the International Classification of Headache Disorders, Second Edition criteria for migraine or chronic migraine, respectively. Headaches need to cause significant interference with function or quality of life despite modification of triggers, lifestyle factors, and adequate trials of acute and preventive medicines with established efficacy. The definition requires that patients fail adequate trials of preventive medicines, alone or in combination, from at least 2 of 4 drug classes including: beta‐blockers, anticonvulsants, tricyclics, and calcium channel blockers. Patients must also fail adequate trials of abortive medicines, including both a triptan and dihydroergotamine (DHE) intranasal or injectable formulation and either nonsteroidal anti‐inflammatory drugs (NSAIDs) or combination analgesic, unless contraindicated. An adequate trial is defined as a period of time during which an appropriate dose of medication is administered, typically at least 2 months at optimal or maximum‐tolerated dose, unless terminated early due to adverse effects. The definition also employs modifiers for the presence or absence of medication overuse, and with or without significant disability.

Verapamil and migraine prophylaxis: mechanisms and efficacy

Calcium channel blockers have demonstrated efficacy in investigative use for prophylaxis of migraine and cluster headaches. In particular, verapamil, with its low side-effect profile, appears to be a promising alternative to the currently available agents for prophylactic treatment of chronic recurring headaches. Although its exact mechanisms of action in this application are unknown, verapamil exerts a vasodilatory effect on cerebral arteries and interacts with serotonergic systems involved in migraine pathogenesis. A review of studies from the past decade indicates that verapamil may be as effective as traditional therapies as prophylaxis for the major types of chronic recurring headache.

Defining refractory migraine: Results of the rhsis survey of american headache society members

Objectives.— To gauge consensus regarding a proposed definition for refractory migraine proposed by Refractory Headache Special Interest Section, and where its use would be most appropriate.

CoEnzyme Q10 and riboflavin: the mitochondrial connection.

Objective.— We conducted a short review of relevant literature which contends that migraine is associated with a wide‐spread metabolic abnormality of mitochondrial oxidative metabolism, leading to the use of riboflavin and coenzyme Q10 as prophylactic therapy for migraine.

New Daily Persistent Headache and Potential New Therapeutic Agents

New daily persistent headache is a form of a chronic daily headache with a unique temporal profile. Patients can recall the exact day when their headache started. It can be one of the most refractory types of headache to treat. Recent publications have highlighted different subtypes and heterogeneity in presentation. Referring to it as a syndrome versus a distinct disorder has also been suggested. Several different classes of medications have been used for the treatment, with mixed results. The underlying pathophysiology of new daily persistent headache is unclear, but tumor necrosis factor may play a role. The clinical features, differential diagnosis and potential new therapeutic agents will be discussed.

Editorial for Therapeutic Monoclonal Antibodies: What Headache Specialists Need to Know.

For many years, investigators studying the neurochemistry of migraine researched neurotransmitters in serum, urine, cerebrospinal fluid, and jugular venous drainage. There was no consistent pattern of elevation or depression of the standard catecholamine neurotransmitters such as epinephrine, norepinephrine, and dopamine that could be reconciled with the premonitory or acute phases of migraine attacks. It was not until researchers began studying 5-hydroxytriptamine (serotonin) that consistent changes were seen. 5-hydroxyindoleacetic acid (5-HIAA) levels increased in urine during a migraine attack, and decreased in the interictal period. Serotonin came to be considered the preeminent neurotransmitter involved in migraine after Federico Sicuteri demonstrated that infusion of intravenous serotonin could abort an acute migraine attack. However, serotonin also caused prominent cardiovascular changes, which made it unsuitable as a therapeutic agent. With research focusing upon serotonin as the principle migraine neurotransmitter, Patrick Humphrey of Glaxo synthesized the first serotonin agonist that bound to a subset of serotonin receptors on presynaptic neurons and cerebral blood vessels, GR43175, later named sumatriptan (Imitrex, Imigran, GlaxoSmithKline, Research Triangle Park, NC, USA). Subcutaneous GR43175 could abort an established migraine attack within only a few minutes, with no apparent cardiovascular adverse effects associated with serotonin itself. This discovery launched what has been called “The Age of the Triptans” and generated intense competition among pharmaceutical companies, popularly known as “The Triptan Wars.” Seven different triptans were developed over several years, all of which demonstrated efficacy in large randomized controlled trials and were FDA approved for the acute abortive treatment of migraine attacks. However, after several years it became apparent that serotonin was not the Holy Grail of migraine as had been first believed. For one thing, not every migraine patient responded to the serotonin agonists. For another, these compounds seemed to have no utility in the prophylaxis of migraine because of their short half-life and property of producing coronary artery constriction. For these and other reasons, researchers turned toward other neurotransmitters. Calcitonin gene related peptide (CGRP) was reported by Goadsby and Edvinsson to produce intense vascular dilation and inflammation. Infusion of CGRP was shown to produce a severe migraine-like headache in migraine patients, but produced a less impressive headache in nonmigraineurs. Edvinsson’s beautiful work tracing the pathways of CGRP-containing neurons throughout the central nervous system and the rest of the body gave us a road map of the various tissues that could be affected by this peptide. Even today, however, the effects of CGRP upon many of these end organs have not been completely clarified. With reasoning similar to the development of the triptan class of medications, neurochemists began studying CGRP, discovered CGRP receptors, defined their kinetics, and began developing CGRP receptor antagonists. The first antagonist reported, BIBN4096BS (olcegepant, Boehringer-Ingelheim), was shown to abort migraine attacks when given intravenously. After that, a series of small-molecule CGRP antagonists was synthesized by Merck Laboratories, the best studied being MK-0974 (telcagepant). This compound was found to be as equally effective at aborting acute migraine attacks as the FDA-approved triptan, zolmitriptan. Aside from the possible therapeutic benefit, these discoveries forced a rewriting of the theory of migraine pain and inflammation. The central role of serotonin has been reduced to that of a secondary role. The principle origin of pain in migraine is now believed to be the release of CGRP from presynaptic neurons synapsing on dural and epidural blood vessels. CGRP induces both vasodilation and neurovascular inflammation with an inflammatory cascade of prostaglandins and cytokines. As CGRP is also active at the postsynaptic site of second-order neurons in the trigeminal nucleus caudalis, it is thought to play a role in inducing the central sensitization seen in the later stages of the migraine attack. The role of serotonin is to block the release of CGRP from presynaptic neurons, and also to decrease neurovascular inflammation which has been initiated by CGRP. Many researchers now believe that we should think of CGRP as the most important neurotransmitter involved in the pathogenesis of migraine pain, instead of serotonin. Because of concerns about hepatotoxicity with the smallmolecule CGRP receptor antagonists, attention has now turned From the New England Regional Headache Center, Worcester, MA, USA; University of Massachusetts Medical School, Worcester, MA, USA. Address all correspondence to H.G. Markley, New England Regional Headache Center, 85 Prescott Street Suite 101, Worcester, MA 01605, USA, email: markleyh@nerhc.org Accepted for publication July 21, 2015. ............. Headache