Medication Overuse Headache: an Updated Review and Clinical Recommendations on Management.

OVERVIEW: Medication overuse headache (MOH) is highly prevalent among individuals with primary headache disorders. PURPOSE OF REVIEW: (1) Provide an update on epidemiology, risk factors, and treatment strategies of MOH and (2) provide recommendations on the management of MOH. RECENT FINDINGS: The prevalence of MOH ranges from 0.5 to 7.2%. Risk factors for MOH include female sex, lower socioeconomic status, some psychiatric conditions, and substance use disorders, among others. Recent large clinical trials support preventative therapy as an integral component of MOH management. Emerging clinical trial evidence supports anti-CGRP mAbs as effective preventative treatments among individuals with migraine and MOH. Among the large clinical trials, candesartan, topiramate, amitriptyline, and onabotulinumtoxinA were the most used preventative therapies, providing further support for these agents. MOH management requires a multifaceted and patient-centered approach that involves patient education, behavioral interventions, withdrawal of the overused medication, and initiation of preventative medication.

Changes in migraine interictal burden following treatment with galcanezumab: Results from a phase III randomized, placebo-controlled study.

OBJECTIVE: To evaluate changes in interictal burden with galcanezumab versus placebo in patients with episodic (EM) or chronic migraine (CM). BACKGROUND: The disruptive effects of migraine occur both during attacks (ictal period) and between attacks (interictal period), affecting work, school, family, and social life. Migraine clinical trials typically assess ictal burden endpoints, neglecting interictal burden. METHODS: CONQUER was a 3-month, double-blind study that randomized adult patients with EM or CM who had experienced failure of two to four standard-of-care migraine preventive medication categories to receive monthly galcanezumab (n = 232) or placebo (n = 230), followed by 3 months of open-label galcanezumab. The mean change in interictal burden, a secondary objective, was measured using the four-item Migraine Interictal Burden Scale (MIBS-4). The total score for MIBS-4 can range from zero to 12, with scores ≥5 indicating severe interictal burden. Post hoc analyses evaluated shifts in MIBS-4 severity categories and item-level improvement. RESULTS: The MIBS-4 total score indicated severe interictal burden at baseline (mean [SD]: all patients, 5.5 [3.5]; EM, 5.0 [3.4]; CM, 6.2 [3.5]). Reductions in the MIBS-4 score were significantly greater with galcanezumab versus placebo at Month 3 (mean [SE]: all patients -1.9 [0.2] vs. -0.8 [0.2], p < 0.0001; EM, -1.8 [0.3] vs. -1.1 [0.3], p = 0.033; CM, -1.8 [0.4] vs. -0.3 [0.4], p < 0.001), with further improvement at Month 6 after all patients had received galcanezumab (mean [SE]: all patients, -2.4 [0.2] vs. -2.0 [0.2]; EM, -2.3 [0.3] vs. -2.2 [0.3]; CM, -2.1 [0.4] vs. -1.5 [0.4]). The percentage of patients with severe interictal burden decreased substantially for the galcanezumab-treated patients, from 59% (137/232) at baseline to 27% (58/217) at Month 6 (EM from 51% [70/137] to 23% [30/131]; CM from 71% [67/95] to 33% [28/86]). CONCLUSION: In addition to the known efficacy of galcanezumab in the ictal period, these findings suggest treatment with galcanezumab results in a significant reduction in interictal burden.

Adverse Childhood Experiences and Medication Overuse Headache: Burden and Treatment Impact.

Adverse childhood experiences (ACEs) are a risk factor for progression from episodic to chronic migraine. Risk factors for medication overuse headache (MOH) are incompletely understood, but opioid overuse may carry a higher risk than overuse of other medication types. We performed a retrospective chart review investigating the frequency and impact of ACEs in patients with MOH. Of 68 included patients, 37 (54.4%) reported ACEs. There was no significant inter-group difference in baseline migraine disability assessment (MIDAS) or monthly headache days. Patients with ACEs reported more opioid overuse, and worse headache-related disability at follow-up, despite similar monthly headache days. Patients with ACEs require complex, multidisciplinary treatment.

Preventive Treatment of Migraine.

Migraine significantly impacts individuals from all walks of life and from all around the globe. Chronic or high-frequency episodic migraine has similar disability and burden on the healthcare system and can be challenging to manage. The focus of this article is to provide an outline of the available pharmacological and nonpharmacological evidence-based strategies that clinicians can employ to build a "toolbox" for their patients.

The Impact of Shift Work on Migraine: A Case Series and Narrative Review.

OBJECTIVE: We present a case report of 2 migraine patients engaged in shift work, followed by a narrative review, to assess whether shift work influences headache-related disability and chronification of migraine. BACKGROUND: Numerous modifiable factors can lead to chronification of migraine and to higher headache-related disability. These include, among others, obesity, depression, overuse of acute medications, ineffective acute treatments, and stressful life events. Sleep disruptions and disorders are also felt to increase the risk of transitioning from episodic to chronic migraine. We hypothesize that shift work, which by definition leads to atypical or irregular sleep cycles, along with poor quality sleep, is a risk factor for chronification of migraine. METHODS: We present the case histories of 2 shift workers with migraine as per International Classification of Headache Disorders 3 criteria, seen at a large, busy academic headache center, followed by a narrative review of the literature. RESULTS: Previous literature regarding the relationship between shift work and migraine is sparse and conflicting, with more recent studies suggesting that shift work may be a risk factor for migraine-related disability. In our case series, both patients initially reported severe migraine headache-related disability and both patients had noted a worsening of their headaches after beginning night shift work. Both improved when switched back to day shifts, then worsened upon being put back on night shifts. Their headache patterns finally reverted from chronic to episodic migraine after eliminating night shifts completely and maintaining a good sleep routine. CONCLUSIONS: In the 2 cases presented, shift work appeared to be associated with chronification of migraine and higher headache-related disability despite optimal headache management and good patient adherence. A switch to only day shifts promoted transition to an episodic, less disabling pattern of migraine. It is clinically important to take a detailed sleep history in headache patients, and when appropriate, provide support for workplace accommodations. Further larger-scale, rigorous studies are needed to more clearly delineate the relationship between shift work and migraine.

Secondary Headaches During Pregnancy: When to Worry.

PURPOSE OF REVIEW: Headaches in pregnancy are a frequent cause of worry for both patients and healthcare providers. Physiological changes during this period increase the risk of a number of secondary headache disorders, and often also have an impact on primary headache disorders. This article reviews recent research into distinguishing worrisome vs non-worrisome headache presentations during pregnancy. RECENT FINDINGS: Recent research suggests that secondary causes of headache are highly prevalent during pregnancy, in between 25 and 42.4% of women seeking medical attention. Secondary causes of headache in pregnancy are most commonly homeostatic disturbances and hypertensive disorders of pregnancy, vascular problems, space-occupying lesions, and infections. Migraine itself also increases the risk of hypertensive disorders of pregnancy. Specific red flags for a secondary cause of headache in pregnancy include absence of any headache history, more severe pain, systemic features such as elevated blood pressure, and abnormal laboratory tests including thrombocytopenia or thrombocytosis, elevated liver function tests, elevated C-reactive protein, or proteinuria, in addition to traditional red flags, such as a change in headache pattern. Secondary causes of headache are common in women seeking medical attention during pregnancy. Red flags for secondary causes of headache during pregnancy may be remembered with the mnemonic PREGNANT HA (proteinuria, rapid onset, elevated blood pressure or temperature, gestational age in third trimester, neurological signs or symptoms, altered level of consciousness, no headache history or known history of a secondary headache disorder, thrombocytopenia or thrombocytosis, high liver function tests or CRP, or agonizingly severe pain). Increased education of patients and their providers may help improve selection of patients for workup of a secondary cause.

Exercise Headache: a Review.

PURPOSE OF REVIEW: Exercise headache refers to headache that is triggered by exercise or exertion. Although secondary causes must be excluded, most cases of exercise headache are benign, idiopathic, and self-limited. This article reviews the revised diagnostic criteria for primary exercise headache (PEH) and discusses recent research into the clinical presentation, epidemiology, pathophysiology, suggested workup, and treatment of this condition. RECENT FINDINGS: Recent studies estimate that PEH affects from 1 to 26% of the adult population. A secondary cause is thought to be present infrequently, but should be explored in all patients with a first or atypical presentation of exercise headache. Red flags for potential secondary causes may include older age at onset and more prolonged headache duration. There is inadequate evidence to include gender as a red flag. No recent trials have been conducted, but experts suggest that avoidance of triggers coupled with short-term NSAID and/or beta-blocker treatment may be effective for patients diagnosed with PEH. Larger studies are needed to provide high-quality evidence regarding the pathophysiology and treatment of PEH. However, recent work has shed light on the characteristics of this condition, and the ICHD-3 has provided important updates to the diagnostic criteria for this relatively common and potentially treatable condition.

Impact of Altered Cholinergic Tones on the Neurovascular Coupling Response to Whisker Stimulation.

Brain imaging techniques that use vascular signals to map changes in neuronal activity rely on the coupling between electrophysiology and hemodynamics, a phenomenon referred to as "neurovascular coupling" (NVC). It is unknown whether this relationship remains reliable under altered brain states associated with acetylcholine (ACh) levels, such as attention and arousal and in pathological conditions such as Alzheimer's disease. We therefore assessed the effects of varying ACh tone on whisker-evoked NVC responses in rat barrel cortex, measured by cerebral blood flow (CBF) and neurophysiological recordings (local field potentials, LFPs). We found that acutely enhanced ACh tone significantly potentiated whisker-evoked CBF responses through muscarinic ACh receptors and concurrently facilitated neuronal responses, as illustrated by increases in the amplitude and power in high frequencies of the evoked LFPs. However, the cellular identity of the activated neuronal network within the responsive barrel was unchanged, as characterized by c-Fos upregulation in pyramidal cells and GABA interneurons coexpressing vasoactive intestinal polypeptide. In contrast, chronic ACh deprivation hindered whisker-evoked CBF responses and the amplitude and power in most frequency bands of the evoked LFPs and reduced the rostrocaudal extent and area of the activated barrel without altering its identity. Correlations between LFP power and CBF, used to estimate NVC, were enhanced under high ACh tone and disturbed significantly by ACh depletion. We conclude that ACh is not only a facilitator but also a prerequisite for the full expression of sensory-evoked NVC responses, indicating that ACh may alter the fidelity of hemodynamic signals in assessing changes in evoked neuronal activity.SIGNIFICANCE STATEMENT Neurovascular coupling, defined as the tight relationship between activated neurons and hemodynamic responses, is a fundamental brain function that underlies hemodynamic-based functional brain imaging techniques. However, the impact of altered brain states on this relationship is largely unknown. We therefore investigated how acetylcholine (ACh), known to drive brain states of attention and arousal and to be deficient in pathologies such as Alzheimer's disease, would alter neurovascular coupling responses to sensory stimulation. Whereas acutely increased ACh enhanced neuronal responses and the resulting hemodynamic signals, chronic loss of cholinergic input resulted in dramatic impairments in both types of sensory-evoked signals. We conclude that ACh is not only a potent modulator but also a requirement for the full expression of sensory-evoked neurovascular coupling responses.

Pyramidal cells and cytochrome P450 epoxygenase products in the neurovascular coupling response to basal forebrain cholinergic input.

Activation of the basal forebrain (BF), the primary source of acetylcholine (ACh) in the cortex, broadly increases cortical cerebral blood flow (CBF), a response downstream to ACh release. Although endothelial nitric oxide and cholinoceptive GABA (γ-aminobutyric acid) interneurons have been implicated, little is known about the role of pyramidal cells in this response and their possible interaction with astrocytes. Using c-Fos immunohistochemistry as a marker of neuronal activation and laser-Doppler flowmetry, we measured changes in CBF evoked by BF stimulation following pharmacological blockade of c-Fos-identified excitatory pathways, astroglial metabolism, or vasoactive mediators. Pyramidal cells including those that express cyclooxygenase-2 (COX-2) displayed c-Fos upregulation. Glutamate acting via NMDA, AMPA, and mGlu receptors was involved in the evoked CBF response, NMDA receptors having the highest contribution (~33%). In contrast, nonselective and selective COX-2 inhibition did not affect the evoked CBF response (+0.4% to 6.9%, ns). The metabolic gliotoxins fluorocitrate and fluoroacetate, the cytochrome P450 epoxygenase inhibitor MS-PPOH and the selective epoxyeicosatrienoic acids (EETs) antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) all blocked the evoked CBF response by ~50%. Together, the data demonstrate that the hyperemic response to BF stimulation is largely mediated by glutamate released from activated pyramidal cells and by vasoactive EETs, likely originating from activated astrocytes.