Recent Developments in Headache Medicine

Emerging therapeutic targets and new modalities highlight a bright future.

By Deborah I. Friedman, MD, MPH

New therapeutic targets and neuromodulation treatments for migraine and cluster headache, and completion of a clinical trial investigating the treatment of idiopathic intracranial hypertension, highlight major recent advances in the field of headache medicine.

Anti-calcitonin gene related peptide (CGRP) antibodies

CGRP is an attractive candidate for migraine therapy. Stimulation of the trigeminal ganglion in humans leads to release of GCRP from perivascular sensory axons to mediate vasodilation of extracerebral intracranial arteries and arteriovenous anastomoses. CGRP is also involved in pain transmission within the trigeminal system in the CNS. CGRP levels are elevated in jugular venous blood samples during migraine, and sumatriptan reduces levels of CGRP in experimental animal models of migraine. If ultimately proven safe, effective and marketed, these treatments would herald an era of migraine preventive therapy using medications specifically designed for this specific purpose. The results of two phase 2, randomized trials of CGRP antibodies for episodic migraine were presented at the 2014 American Academy of Neurology annual meeting:

  • ALD403 (Alder Pharmaceuticals), administered as a single intravenous infusion, was compared to placebo infusion in 163 patients.1 At 24 weeks, those receiv­ing active treatment had 5.6 fewer migraine days per month (a 66 percent decrease) vs. 4.6 fewer days for those receiving place­bo. Sixteen percent of participants receiving ALD403 had no migraine days at 12 weeks (no one in the placebo group be­came headache free). The treatment was well tolerated with comparable side effects between the two groups.
  • LY2951742 (Arteus Therapeutics) was compared to placebo in 217 patients who received biweekly subcutaneous injec­tions for 12 weeks.2 Those receiving ac­tive treatment had 4.2 fewer migraine days per month at 12 weeks (a 64 percent decrease) vs. three fewer days in the placebo group (a 42 percent decrease). There were more side effects with active treatment, such as injection site pain, upper respiratory in­fections and abdominal pain) but overall, the medication was safe and well tolerated.

Clinical trials of a CGRP receptor antibody are underway for acute and chronic for cluster headache.


Transcutaneous supraorbital nerve stimulation. Transcutaneous supraorbital nerve stimulation (Cefaly) was approved by the FDA for prevention of migraine with and without aura. A randomized, double-blinded, sham-controlled study (PREMICE) of 67 patients was reported in 2013.3 Subjects underwent daily sham or verum neurostimulation for 20 minutes. The primary outcome was change in monthly migraine days and the 50 percent responder rate. The therapeutic gain of the device was 26 percent, separating from placebo stimulation after the first month. By month three, the mean number of migraine days decreased by 6.94 to 4.88 days, compared to 6.54 vs. 6.22 in the sham group). Monthly migraine attacks, headache days, and acute antimigraine drug intake were also statistically significantly decreased in the active group but not the sham group. There was no effect in pain severity or associated migraine symptoms. Seventy percent of participants were “very or moderately satisfied” and the device was well tolerated.

Practical Pointers

New advances in the field of headache medicine are rapidly shaping the therapeutic armamentarium. In the field of neuromodulation, new research on transcutane- ous supraorbital nerve stimulation, implanted occipital nerve stimulation, and external vagal nerve stimulation offer a glimpse of new directions in the treatment of migraine. Outside the neurotoxin realm, the develop- ment of new sumatriptan systems—such as the use of the OptiNose device as well as Iontophoretic trans- dermal products—and recent research on a idiopathic intracranial hypertensions treatment may further shape the future of headache management.

Implanted occipital nerve stimulation. A randomized, double blind, multicenter study of 157 patients was performed to assess implanted occipital nerve stimulation (ONS).4 One hundred twenty-five patients had chronic migraine. Subjects were randomized to active or control groups for 12 weeks, then received open label active stimulation for 40 weeks. Outcomes were assessed at 52 weeks. Headache days were reduced by 6.7 + 8.4 days overall and 7.7 + 8.4 days in the chronic migraine group. More than half of patients were satisfied with treatment. However, there were 183 device or procedure-related adverse events; 8.6 percent required hospitalization, 40.7 percent required surgery and 70 percent of subjects had some type of adverse event.

External vagal nerve stimulation (VNS). The results from two studies were presented at the European Headache and Migraine Trust International Congress in 2014:

  • The Prevention of Chronic Migraine (EVENT) Study (Elec­trocore) randomized subjects to receive either VNS or sham treatment (low-voltage device generating an electric field and audible feedback) administered three times daily at specified time intervals. Each treatment was two 90-second stimulations administered five to 10 minutes apart.5 The primary endpoint was safety and tolerability with secondary clinical efficacy endpoints. The average num­ber of headache days per 28 days was 21.1 in the active group and 22.3 in the sham group. At month two, VNS reduced head­ache days by a mean of two per 28 days with no change in the sham group. At month eight, there was an average reduction of nine days in the active group compared to six in the sham group, although the number of participants in the trial decreased by half. Longer duration of treatment was associated with fewer migraine days per month. A US study is in progress.
  • Non-invasive VNS was studied in the PREVA (Prevention and Acute Treatment of Chronic Cluster Headache) study (Electrocore).6 One hundred fourteen patients with chronic cluster headache received standard of care treatment for two weeks, and were randomized to standard of care (SOC) or SOC plus VNS for four weeks. In the third phase, all participants received SOC plus open-label VNS. The primary end point was reduc­tion of CH attacks weekly in the last two weeks of the random­ized phase. The mean number of CH attacks in the four weeks prior to enrollment was 67.3 in the SOC + VNS group and 73.9 in the SOC group. About 70 percent of subjects used oxygen for an acute attack. There was a statistically significant reduc­tion in CH attacks in the VNS group compared to SOC alone (-7.6 vs. -2.0, p=0.002). After the transition to open label, the group initially assigned to receive SOC alone had a reduction of 3.3 CH attacks per week (p=0.0001) and the VNS group had an addition improvement of 1.9 attacks per week (p=.0032). 37.8 percent of subjects randomized to VNS had at least a 50 percent re­sponse rate vs. 8.3 percent randomized to SOC. As in the migraine study, longer duration of treatment during the study was as­sociated with a continued reduction in CH attacks. There were no serious adverse events associated with treatment. A US study was recently completed and results are pending.

Sphenopalatine Ganglion Stimulation. The SPG is located in the pterygopalatine fossa and contains sympathetic and parasympathetic fibers. Low frequency SPG stimulation can induce cluster attacks which are aborted with high frequency stimulation. An implanted SPG stimulator with a wireless, rechargeable, remote control system is in clinical trials by Autonomic Technologies Inc. The device is inserted via trans-gingival approach by an oromaxillofacial surgeon.

A European study (CH-1) of refractory chronic CH was performed in 32 subjects with full stimulation, sub-stimulation or sham stimulation.7 Twenty-eight participants completed the study. The primary outcome was pain relief in 15 minutes or a serious adverse event. 67.1 percent of patients receiving full stimulation had pain relief vs. seven percent of those receiving the other stimulation paradigms. Sixty eight percent had clinically significant improvement, 25 percent had pain relief in at least 50 percent of attacks, and 35 percent had at least a 50 percent reduction in attack frequency. Recruitment for a similar study is underway in the US and a larger trial for migraine is being conducted in Europe.8

New Sumatriptan Delivery Systems

  • A breath-actuated delivery of powdered sumatriptan using the OptiNose device (AVP-825, Avanir) was tested in a phase 3 pla­cebo-controlled, parallel group study of 212 participants. Active treatment was 15 mg of intranasal sumatriptan. Pain relief in two hours was achieved in 68 percent of patients receiving active treatment vs. 45 percent of controls (p<0.01), with pain relief in 30 minutes in 42 percent of participants taking sumatriptan vs. 27 percent of controls (p<0.05).
  • Iontophoretic transdermal sumatriptan, studied in a random­ized, parallel-group, placebo-controlled phase 3 trial of 530 subjects (6.5 mg/four hours), showed two-hour pain free response in 18 percent with active treatment vs. nine percent of controls which was sus­tained for 12 hours.9 Two-hour pain relief occurred in 52.9 percent with su­matriptan vs. 28.6 percent of controls and was also sustained for 12 hours. There was no statistical difference in the one-hour nau­sea free rate between the two groups. Most adverse events were related to application site reactions, occurring in 56.8 percent. The product, marketed as Zecuity (Teva Pharmaceuticals), was FDA-approved in 2013 with recent availability.

Idiopathic Intracranial Hypertension Treatment Trial

Despite longstanding and common usage, the effectiveness of acetazolamide for IIH treatment had never been previously demonstrated in a clinical trial. The IIHTT (National Eye Institute) studied acetazolamide vs. placebo with a supervised medical weight loss program in 165 subjects with mild visual loss from IIH.10 The primary outcome was change in perimetric mean deviation on Humphrey automated perimetry. The central 24 degrees of visual field were assessed, as is standard with this method of visual field testing in clinical practice. The perimetric mean deviation (PMD) is a summary variable that represents the average of light intensity (measured in decibels, dB) perceived at predetermined test locations spaced six degrees apart. Patients with PMD from -2 to -7 dB were included (normal is greater than -2 dB and most normal individuals have PMD between -2 and zero).

IIH was diagnosed using standard criteria, including the presence of papilledema, an elevated lumbar puncture opening pressure, no apparent secondary cause and a normal brain MRI. Potential subjects could not have received previous treatment for IIH, other than a short course of acetazolamide which was washed out prior to the baseline evaluation. Eligible participants were randomly assigned to receive either acetazolamide 500mg BID or matching placebo tablets. The dose was gradually escalated by 250mg weekly as tolerated to a maximum of 4,000mg daily of acetazolamide or the equivalent of placebo tablets; the minimum allowed dose was 125mg daily. All participants had access to a supervised weight loss program administered via telephone by weight loss coaches at the New York Obesity Nutrition and Research Center. The primary outcome was PMD in the most affected eye at six months.

There were 161 women and four men in the study.11 The improvement in PMD was greater in participants receiving acetazolamide than placebo (1.43 dB vs. 0.71 dB) with a therapeutic gain of 0.71 dB (p=0.05). While the overall improvement did not meet predetermined endpoints for clinical significance, greater gains were seen in patients who had more severe visual loss at baseline. Acetazolamide was also associated with greater improvements in the less affected eye, in papilledema grade in both eyes, vision-related quality of life, general quality of life, reduction in weight (-7.50 kg vs. -3.45 kg) and CSF pressure. A total of 16 participants withdrew in each treatment group, including one treatment failure in the acetazolamide group vs. six in the placebo group. Headache disability (HIT-6) improved slightly in both groups with no difference between groups at six months. Acetazolamide was well tolerated and safe. n

Deborah I. Friedman, MD, MPH is Professor of Neurology & Neurotherapeutics and Ophthalmology at the University of Texas Southwestern Medical Center.

Article reprinted with permission from the Texas Neurological Society Broca’s Area Newsletter (Summer 2015).

1. AAN 2014 Poster. Dodick, 2014 #1830

2. AAN 2014 Poster. Dodick, 2014 #1831

3. Magis D, Sava S, d’Elia TS, Baschi R, Schoenen J. Safety and patients’ satisfaction of transcutaneous supraorbital neurostimulation (tSNS) with the Cefaly® device in headache treatment: a survey of 2,313 headache sufferers in the general population. J Headache Pain. 2013 Dec 1;14:95.

4. Dodick DW, Silberstein SD, Reed KL, et al. Safety and efficacy of peripheral nerve stimulation of the occipital nerves for the management of chronic migraine: Long-term results from a randomized, multicenter, double-blinded, controlled study. Cephalalgia 2014 pii: 0333102414543331.

5. Schoenen J, Gaul C, Silber­stein S. Presented at the 4th European Headache and Mi­graine Trust International Congress, Copehagen, September 20, 2014

6. Schoenen J, Jensen RH, Lantéri-Minet M, et al. Stimulation of the spheno­papatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: A randomized, sham-controlled study. Cepha­lalgia 2013;33:816-30.

7. Schoenen J, Jensen RH, Lantéri-Minet M, et al. Stimulation of the sphenopapatine ganglion (SPG) for cluster headache treatment. Pathway CH-1: A randomized, sham-controlled study. Cephalalgia 2013;33:816-30.

8. Nagy AJ, Rapoport AM. Update on future headache treatments. Neurol Sci 2013;34(suppl 1): S101-108.

9. Pierce M, O’Neill C, Felker E, Sebree T. Sumatriptan iontophoretic transdermal system: History, study results, and use in clinical practice. Headache 2013;53(Suppl S2):34-42.

10. Friedman DI, McDermott MP, Kieburtz K, Kupersmith M, Stoutenburg A, Keltner J, Feldon SE, Corbett JJ, Schron E, for the NORDIC IIHTT Study Group. The Idiopathic Intracranial Hypertension Treatment Trial: Design considerations and methods. J Neuro-Ophthalmol 2014;34:107-117.

11. Wall M, McDermott MP, Kieburtz KD, Corbett JJ, Feldon SE, Friedman DI, Katz DM, Keltner JL, Scron EB, Kupersmith MJ. Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss. JAMA Neurol 2014;13(16):1641-51


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