Headache highlights 2017

In 2017, preclinical and clinical research on headache disorders has seen substantial contributions that enhance our understanding of their pathobiology. Migraine research has been particularly fruitful as the efficacy of antibodies against calcitonin gene–related peptide (CGRP) and its receptor are effective in the treatment of migraine. Milestones in this advancement are the publication of phase 3 clinical trials of fremanezumab ¹ and erenumab ² (both awaiting approval by the FDA [US Food and Drug Administration] and EMA [European Medicines Agency]).

Herein, we give an overview of the publications that, in our opinion, has provided an outstanding contribution to the headache field in 2017. There were many significant publications and the decision to some extent is subjective and without the intention of being complete. Even so, we hope that our selection will stimulate scientists and clinicians alike for discussions and future research. The topics highlighted include the role of CGRP in photophobia, the mechanism of action of monoclonal CGRP antibodies, new insights into mechanisms of intracranial hypertension, and lastly a discussion of opioid use in acute migraine treatment.

The role of CGRP in migraine: New insights

The vasoactive action of CGRP as well as its ability to facilitate nociceptive neuronal activity in peripheral and central neurons is well known. What has been largely neglected in past years is its influence on some of the accompanying symptoms of migraine. In this context, Mason et al. set out to investigate the influence of CGRP on photophobia in a mouse model and dissect its peripheral and central component. ³ The study showed that light aversive behavior may be elicited by peripheral (intraperitoneal) and central (intracerebroventricular) administration of CGRP. In line with data from a previous study from the same group, ⁴ the authors showed that light aversive behavior induced by peripheral or central CGRP administration can be attenuated by triptans. In addition, the authors showed that in contrast to wild-type mice, transgenic mice carrying a conditional overexpression of the human receptor activity–modifying protein 1 subunit of the CGRP receptor in the nervous system (nestin/hRAMP1) already show light aversive behavior at dim light when CGRP was administered centrally. ⁴ This effect was not observed after peripheral ³ CGRP administration. Taken together, these data indicate that CGRP may elicit photophobia through an action at peripheral and central sites of action through distinct mechanisms.

The impact of fremanezumab on nociceptive signaling was examined using electrophysiological single unit recordings of brainstem neurons with dural (trigeminovascular neurons), cutaneous or corneal receptive fields in an animal model of migraine. In this preclinical study, ⁵ fremanezumab selectively inhibited high threshold but not wide dynamic range trigeminovascular neurons. However, there was no fremanezumab-induced inhibition of neurons innervating facial skin or cornea. Fremanezumab prevented cortical spreading depression (CSD)-induced sensitization of high threshold trigeminovascular neurons and prevented CSD-mediated expansion of dural and cutaneous receptive fields. These data raise the possibility that monoclonal antibodies against CGRP take advantage of peripheral CGRP mechanisms of migraine unique to the dural afferent population. In a recently published subsequent study, ⁶ fremanezumab preferentially inhibited thin myelinated Aδ but not unmyelinated C-fiber neurons; the former contributing greater input to high threshold second-order neurons and the latter to wide dynamic range neurons. This differential effect may explain in part why fremanezumab selectively inhibits high threshold neuronal responses and not that of wide dynamic range neurons and generates hypotheses for peripheral mechanisms that could explain the clinical observation of nonresponders to monoclonal CGRP antibodies.

Pathophysiology of idiopathic intracranial hypertension

The pathophysiology underlying idiopathic intracranial hypertension (IIH) is still largely unknown and from a preclinical perspective, this disorder has been neglected. One of the main reasons for this situation is the lack of preclinical models that recreate this clinical condition. Botfield et al. aimed to shed some light on the relevant mechanisms by developing a rat model of hydrocephalus as a basis to investigate the significance of glucagon-like peptide 1 (GLP-1) in modulating CSF secretion and therefore intracranial pressure. ⁷ After demonstrating the presence of GLP-1 receptors in the choroid plexus, the authors showed in their study that exendin-4, a GLP-1 receptor agonist, reduces intracranial pressure in conscious rats, while the GLP-1 receptor antagonist exendin 9-39 reversed this effect. This GLP-1-induced effect is likely to be mediated through a reduction in the activity of Na⁺ K⁺ ATPase located in the choroid plexus and a resulting inhibition of CSF production. The pressure-reducing effect of exendin-4 was then reproduced under conditions of abnormally elevated intracranial pressure. The findings therefore suggest that GLP-1 receptor agonists may be effective in lowering intracranial pressure in conditions such as IIH.

Use of opioid medication as abortive therapy in the emergency department for migraine

Young et al. ⁸ looked at the prevalence of opioid orders, for 931 patients, during visits (n = 1222) in three different settings in Connecticut (United States), an academic medical center (n = 390), a nonacademic urban (n = 675) emergency department (ED), and a community ED (n = 175). The observation period was 14 months. Migraine medications, number of visits, length of stay, door to provider time, and total provider time were compared between sites. The average age for females was 35 and 37.5 years for males, the proportion of females was 82.7%. Opioids were ordered in 35.5% of the visits but when looking at orders by setting, opioids were given in 68.6% of visits in the community ED, 40.9% in the urban ED, and 12.3% in the academic ED medical centers. Similarly, opioids were given 58.2% of the time as first-line agents in the community ED, compared to 35.3% in the urban ED and 6.9% in the academic center. Patients who received opioids had more repeat visits, 1.79 versus 1.30 visits. The academic ED center and urban ED both found greater than 30% decrease in length of stay in visits where opioids were not given. ⁸

The difference in the prevalence of opioid orders by treatment center is striking 68.6% in the community ED versus 12.3% in the academic ED center. Guidelines published before this study was conducted did not recommend opioids as first-line treatment, ⁹ in fact key recommendations for general practice were that “Opiates and barbiturate-containing compounds should not be routinely used for abortive treatment of migraine.” ¹⁰ Results from a US population–based longitudinal study had already shown opioids to increase the transition from episodic to chronic migraine. ¹¹ The results from the study by Young et al. indicate that the prevalence of opioid orders in some ED centers remains high despite increasing evidence showing opioids to be less effective and in some cases counterproductive compared with other medications, for example, NSAIDs or triptans. Later, published studies, reviews, and guidelines have also emphasized the lack of evidence for the continuous use of opioids for treating migraine and have pointed out a number of other treatment options. ^{12 –14} We must keep in mind that translation of knowledge and changes in treatment practices are gradual processes, but these changes may be facilitated through continued education and awareness campaigns.

Closing remarks

The papers highlighted reflect the tremendous effort of the headache field to expand our understanding about the pathobiology of headache disorders and mechanisms of treatment, to explore the mechanisms of as yet understudied headache subtypes, and to highlight the growing need for effective and safe alternatives for headache abortive and preventive therapies. The horizon for headache research appears bright but could be made brighter with adequate funding and continued patient-oriented initiatives to bring awareness to those suffering from primary headache disorders. While the headache field in 2017 has been eclipsed by the monoclonal CGRP antibodies, we must also attend to lesser studied but severely disabling primary headache disorders such as cluster headache and the potential role of other neuropeptides in headache pathogenesis as well as emerging treatment strategies.