Effect of noninvasive vagus nerve stimulation on acute migraine: An open-label pilot study

Abstract

Background

We sought to assess a novel, noninvasive, portable vagal nerve stimulator (nVNS) for acute treatment of migraine.

Methods

Participants with migraine with or without aura were eligible for an open-label, single-arm, multiple-attack study. Up to four migraine attacks were treated with two 90-second doses, at 15-minute intervals delivered to the right cervical branch of the vagus nerve within a six-week time period. Subjects were asked to self-treat at moderate or severe pain, or after 20 minutes of mild pain.

Results

Of 30 enrolled patients (25 females, five males, median age 39), two treated no attacks, and one treated aura only, leaving a Full Analysis Set of 27 treating 80 attacks with pain. An adverse event was reported in 13 patients, notably: neck twitching (n = 1), raspy voice (n = 1) and redness at the device site (n = 1). No unanticipated, serious or severe adverse events were reported. The pain-free rate at two hours was four of 19 (21%) for the first treated attack with a moderate or severe headache at baseline. For all moderate or severe attacks at baseline, the pain-free rate was 12/54 (22%).

Conclusions

nVNS may be an effective and well-tolerated acute treatment for migraine in certain patients.

Keywords

Migraine acute treatment neuromodulation vagus nerve

Introduction

Migraine is the most common neurological cause of disability worldwide (1). It is costly to the tune of billions of dollars (2) or euros (3). Migraine is fundamentally an inherited brain disorder (4,5) and thus at various stages requires management of attacks in terms of both prevention and acute attack therapy (6). The most effective acute therapy class in migraine, triptans—serotonin 5-HT_1B/1D receptor agonists (7), while certainly a milestone development, deliver, at best, 35% pain-free rates at two hours in oral formulations (8), and commonly are associated with nonserious adverse events (9). It is generally accepted that more options for acute and preventive migraine treatment are needed.

A possible effect of vagal nerve stimulation in migraine was first suggested from clinical practice. A 42-year-old male with medically refractory complex partial seizures who had a vagal nerve stimulator (VNS) implanted had a history of migraine from his teens, and reported that although the VNS had not been useful for his seizures, his migraine attacks had stopped after the implantation (10). The authors carefully reviewed his outpatient notes, including data from emergency room visits. They noted the reduction in migraine had been reported some eight weeks after the stimulator implant by the patient. This was corroborated by noting that 90% of his attacks had previously been treated in the emergency room, and these visits had indeed ceased.

With the development of a noninvasive VNS device, and based on the clinical reports, and some anecdotal observations as the device was being developed for another indication, it was considered appropriate to perform a pilot study of noninvasive VNS in migraine. We report here the data that suggest this novel modality should be studied in placebo-controlled trials. The data have been reported in preliminary form (11).

Methods

Thirty subjects (25 female) with migraine with and without aura (12) were invited to participate in this open-label, single-arm, multiple-attack study.

The study was conducted at four United States headache centers by advertising for patients (University of California San Francisco (UCSF)) or enrolling patients already attending the clinic. Subjects were recruited between February 23, 2012 and May 21, 2012, and the study was completed by July 25, 2012.

The study was approved by institutional review boards appropriate to the investigators.

The study was performed under an Investigational Device Exemption (United States Food and Drug Administration; G110224) and registered as NCT01532830.

Inclusion criteria

Potential subjects needed to meet the following criteria:

Aged between the ages of 18 and 55 years.

Previously diagnosed with migraine with and without aura by the criteria of the International Classification of Headache Disorders-second edition (ICHD-II) (12).

Experiences at least two migraines per month, and less than 15 headache days per month over the previous three months.

Age of onset of migraine less than 50 years old.

Able to distinguish migraine from other headaches, e.g. tension-type headache.

Agrees to withhold usual migraine medications until two hours after stimulation treatment with the GammaCore® device.

Capable of completing headache pain self-assessments.

Agreed to use the GammaCore® device as intended and follow all of the requirements of the study, including follow-up visit requirements.

Agrees to report use of the GammaCore device®, study data, and any adverse device effects to the study center within 24 hours of treatment(s), and agrees to schedule an office visit 7 ± 3 days after the third and final at-home treatment, or when six weeks has passed, whichever comes first.

Is able to give written informed consent.

Exclusion criteria

Potential subjects meeting any of the following criteria were excluded from the study:

Has a history of aneurysm, intracerebral hemorrhage, brain tumors or significant head trauma.

Has a lesion, including lymphadenopathy, at the GammaCore® treatment site.

Has known or suspected severe atherosclerotic cardiovascular disease, severe carotid artery disease (e.g. bruits or history of transient ischemic attack (TIA) or cerebral vascular attack (CVA)) or congestive heart failure (CHF)).

Has a history or baseline electrocardiogram (ECG) that identifies the presence of a clinically significant unstable cardiac arrhythmia, second-degree heart block type II, history of ventricular tachycardia or ventricular fibrillation, or known cardiac syndromes that may be associated with increased risk of sudden death in otherwise healthy people.

Has a previous bilateral or right cervical vagotomy.

Has a clinically significant irregular heart rate or rhythm.

Has uncontrolled high blood pressure.

Is currently implanted with an electrical and/or neurostimulator device, including but not limited to cardiac pacemaker, vagal neurostimulator, deep brain stimulator, spinal stimulator, bone growth stimulator, or cochlear implant.

Has a history of carotid endarterectomy or vascular neck surgery on the right side.

Has been implanted with metal cervical spine hardware.

Has a recent or repeated history of syncope.

Has a recent or repeated history of seizure.

Has a history or suspicion of substance abuse.

Takes medication for acute headaches more than 10 days per month.

Has had a change in medications for migraine prophylaxis in the previous 30 days.

Has previously failed to respond to more than two classes of treatment for episodic migraine.

In the opinion of the investigator/research staff the subject is incapable of operating the GammaCore® device as intended and performing the data collection procedures.

Is pregnant or is thinking of becoming pregnant in the next three months.

Is participating in any other therapeutic clinical investigation or has participated in a clinical trial in the preceding 30 days.

Belongs to a vulnerable population or has any condition such that his or her ability to provide informed consent, comply with follow-up requirements, or provide self-assessments is compromised (e.g. homeless, developmentally disabled, prisoner).

Is a relative of or an employee of the investigator or the clinical study site.

Study design

Subjects were asked to treat up to four acute migraine attacks with the device within six weeks.

Headache pain was reported as: none, mild, moderate or severe.

The treatment consisted of two, 90-second doses, at 15-minute intervals delivered to the right cervical branch of the vagus nerve, based on earlier work in airways disease in animals. Subjects were asked to self-treat once pain became moderate or severe, or after 20 minutes of mild pain (Figure 1).

Figure 1.

Disposition of patients.

Data collection

Data were collected with a subject diary. Data on tolerability and safety was collected to assess onset, type, severity, and frequency of any anticipated or unanticipated adverse events, including a determination of device-relatedness. The collection for effectiveness included: headache pain on a scale of none, mild, moderate or severe; nausea on a scale of none, mild, moderate or severe; presence of photophobia or phonophobia; functional disability on a four-point scale; ease of use of the device on a four-point scale; subject satisfaction; duration of treatment effect out to 24 hours by measuring use of rescue medication in the 24 hours after treatment and time to meaningful relief.

Analysis

Data are presented with summary measures as appropriate to the scale of measurement and were compiled and calculated from the study report data tables with Excel (PJG). The primary endpoint was device safety as determined by the reporting of any serious device-related adverse events to test the hypothesis that the device was well tolerated in patients experiencing an acute migraine. For efficacy we report the efficacy outcome based on the first attack alone and then on all attacks, to minimize bias, to test the hypothesis that the pain-free rates would be clinically relevant to support placebo-controlled trials. Within that analysis, attacks with a baseline of moderate or severe pain (13), or of mild pain (14) are reported separately, given the data from the triptan development programs (15) and evidence that placebo rates for patients with moderate or severe pain at baseline are less (16). Pain free was used as the endpoint as development programs with this endpoint consistently report lower placebo rates than for the headache response outcome (for example, Ferrari et al. (8), Ho et al. (17), and Farkkila et al. (18)), and it is the current International Headache Society guidance (19). Pain relief (13), moderate or severe pain at baseline reduced to nil or mild pain at two hours is also reported. We explored a patient or site effect using a Multilevel approach (MLwiN 2.25, Goldstein (20)). Sample size was in line with a pilot study for a device in migraine.

Results

Thirty subjects, 25 female, with migraine with (n = 10) and without aura (n = 20) were recruited, with two subjects treating no attacks, and one patient treating aura on all four occasions and provided no headache data, leaving the full analysis set on an intention-to-treat principle of 27 subjects treating at least one attack and providing some efficacy data (21). These patients treated 80 attacks. Their median age was 39 years; seven patients documented an aura with a treated attack.

Safety

There were no unanticipated adverse events.

Of anticipated adverse events none were serious and all were judged mild or moderate in severity. An adverse event was reported in 13 of the 28 treated patients. It is appropriate to highlight neck twitching (n = 1), raspy voice (n = 1), and redness over the site of device application on the neck (n = 1), which were the clearest adverse events associated with the stimulator.

All adverse events are listed in Table 1.

Table 1.

All adverse events.^a

Event	Severity^b	n
Stiff neck	Mild	4
Stiff neck	Moderate	1
Neck twitch	Mild	1
Lip or facial drooping	Mild	2
Frequent urination	Mild	4
Raspy voice	Mild	1
Neck redness	Mild	1
Neck redness	Moderate	1
Neck swelling	Mild	1
Shoulder pain or spasm	Moderate	2
Cough, sneeze, fatigue, achy, sinus headache	Moderate	1
Mild confusion for two hours	Mild	1
Dizziness	Moderate	1
Dizziness for up to sixty minutes	Mild	1
Tinnitus left ear	Moderate	1
Fever: 102°F	Moderate	1
Joint pain	Moderate	1

All adverse events (AEs) resolved without treatment, save a patient who took an over-the-counter (OTC) analgesic for neck stiffness.

Adverse event severity: Mild: The AE is noticeable to the patient but does not interfere with routine activity and does not require medical treatment. Moderate: The AE interferes with routine activity but responds to symptomatic therapy or rest. Usually requires medical treatment. Severe: The AE significantly limits the patient’s ability to perform routine activities despite symptomatic therapy.

Efficacy

Pain

First attack

For patients with a baseline of moderate or severe headache, four of 19 reported being pain free at two hours after treatment (21%), while nine of 19 reported pain relief (47%). Five of eight patients with mild pain at baseline were pain free at two hours (63%).

All attacks

For patients with attacks with a baseline of moderate or severe headache, on 12 of 54 attacks they reported being pain free at two hours after treatment (22%), while on 23 of 54 attacks they reported pain relief (43%). On 10 of 26 attacks with mild pain they reported being pain free at two hours (38%).

Consistency of response

Of attacks with pain 18 subjects treated at least three attacks and six were pain free on two of three occasions (33%). Of 13 patients who treated four attacks, six were pain free on two of four attacks (46%).

Site or patient effect

Using a Multilevel modeling approach, there was no significant site or patient effect on the pain-free responses when all attacks were used as the dependent variable.

Efficacy

Associated features

Associated symptoms are here reported on an all-attack basis.

Nausea

In 29 attacks there was nausea, measured as mild, moderate or severe, at baseline with 11 (38%) having relief at two hours.

Photophobia

In 53 attacks there was photophobia, measured as present or absent, at baseline with 16 (30%) having no photophobia at two hours.

Phonophobia

In 33 attacks there was phonophobia, measured as present or absent, at baseline with 17 (52%) having no phonophobia at two hours.

Functional disability

Of attacks with pain treated and in whom we had two-hour assessments, 26 subjects treated 79 attacks, of which 20 (25%) had an improvement of at least one grade in functional disability. Worsening of function was reported in nine attacks (11%) while no change was seen in 50 attacks (63%).

Discussion

The data demonstrate use of a noninvasive, portable transcutaneous vagal nerve stimulator (nVNS) is well tolerated in patients with acute migraine. There were no unanticipated adverse events, no serious adverse events, and no adverse event deemed severe. Based on pain-free rates at two hours from both the first attack and by pooling all attacks, the efficacy results are comparable to other well-tolerated oral formulations of acute migraine treatments. Given the substantial unmet need in acute migraine therapy, nVNS should be progressed to placebo-controlled studies.

Subsequent to the report of Sadler and colleagues (10), where VNS implantation led to improvement in headache and had no effect on seizures, others have noted effects on migraine with implanted VNS. In patients with medically refractory migraine and not epilepsy, there were encouraging suggestions of a preventive effect, and indeed perhaps some effect on cluster headache (22). Two other seizure cohorts have been reported in whom migraine was also seen to improve (23,24), although with some change in seizure frequency, the basis for change is less clear. Finally, in patients with chronic migraine and depression, a useful effect of VNS, again with an implanted VNS device, has been reported (25). These clinical results are broadly in line with the data reported here, and with anti-nociceptive effects of implanted VNS in humans (26), such that VNS has promise in migraine. Similar and encouraging results have been seen in cluster headache (27), supporting a view to move this approach to systematic clinical trials.

How does the effect seen here compare with other standard therapies?

The two-hour pain-free rate of 21% for the first attack and 22% for all attacks treated with nVNS that had a baseline of moderate or severe pain seems consistent. It is notable that the rate is similar to that of naratriptan 2.5 mg, which is also well tolerated (8). Moreover, it is similar to that reported for naproxen 500 mg at 23% and 25%, respectively, for each of the two parallel studies (28), and for the powder formulation of diclofenac potassium at 25% (29,30). It is certainly less than eletriptan 80 mg (31) or sumatriptan 6 mg by injection (32). Moreover, based on this limited population, nVNS seems much better tolerated than the more potent triptans, and does not have comparable cardiovascular or cerebrovascular issues (9).

The response rates are, naturally, simply a reflection of the potential herd effect. Here nVNS is as useful to the 21% who are pain free, as sumatriptan 6 mg by injection is to any similar patient; it notably has less adverse event potential. Even if recurrence rates were greater, and there is no indication of this here, retreatment with the stimulator could be preferential to re-injection by many. Comparing nVNS to other noninvasive approaches, specifically transcranial magnetic stimulation, is more difficult. The two-hour pain-free rate was 39%, and all grades of pain could be treated in a population enriched for migraine with aura (33). Notably the placebo response rate was 22% (n = 99) in that study, which is similar if not less than what has been seen with oral study outcomes in which triptans could be used during mild pain in that range, such as 24% (n = 155) (34), 25% (n = 107) (16), and 31% (n = 177) (35). It would be fair to say that development of noninvasive neuromodulation approaches is justified by the enormous potential gain for the responding population with almost no downside risk.

Is an effect of VNS on migraine plausible?

The vagus nerve is a remarkable nerve by any standards, and would even fascinate other organ-based specialists as it innervates important structures very broadly. The vagus nerve has inputs to the nucleus of the tractus solitarius (NTS) for taste and with visceral afferents. From nucleus ambiguous it has efferent projections to the larynx, which would beautifully explain the adverse event of a raspy voice, and preganglionic parasympathetic cardiac neurons, which provide the main safety concern of cardiac effects that we did not observe. The dorsal motor nucleus of the vagus provides visceral parasympathetic outputs, and lastly, some part of the dura mater of the posterior fossa and afferents from the ear and larynx traverse the vagus before terminating in the trigeminal nucleus caudalis (36). We have seen interactions between dural nociceptive afferents and the NTS (37), and interestingly, as far as it has been studied in the cat, the vagus is largely an afferent, 80% of its fibers, rather than an efferent nerve (38,39).

Is this simply cutaneous skin stimulation?

It is challenging to consider how the placement activates ophthalmic division afferents. Any trigeminal input would be predominantly mandibular and given what we know of intracranial innervation (40,41), and the very uncommon expression of migraine pain as mandibular pain, ophthalmic division stimulation seems unlikely. Moreover, an animal study demonstrates that nVNS with the GammaCore® signal has similar effects as direct, implanted stimulation of the vagus nerve (42). Additionally, an animal model of bronchoconstriction demonstrated the same degree of efficacy in relieving the bronchoconstriction with stimulating the vagus nerve directly as with noninvasive stimulation (43). The networks seem in place; how best to understand any potential action of nVNS in primary headache disorders will require some very careful physiological studies in experimental animals and humans.

Limitations

The study was open label and uncontrolled, so must be considered with all the associated caveats. The pain-free rates are in keeping with other well-tolerated therapies, such as naratriptan or nonsteroidal anti-inflammatory drugs (NSAIDs). Assuming a 10% placebo response rate as a general guide when considering attacks with a moderate or severe headache at treatment (8), the therapeutic gain here would be modest, although given the excellent tolerability and the option to simply hand the device back if it does not work or is bothersome, many patients may see the overall profile as desirable. It has been said that devices attract higher placebo effects; this may be so. However, the transdermal sumatriptan device 9% (n = 228) (44), the inhaled dihydroergotamine device 10% (n = 397) (45), and the reducing placebo of the breath-powered transnasal sumatriptan device with larger studies from 25% (n = 38) to 17% (n = 111) (46,47) and a comparison with the original sumatriptan nasal spray study 11% (n = 64) (48) or zolmitriptan nasal spray 7% (n = 226) (49), all suggest this may not be correct. Our study was undoubtedly small, although effects seen in small studies are worth pursuing when compared to small effects in very large studies. Overall, it is clear a blinded study is required to establish or refute the suggestion raised by the data here of an effect of nVNS in acute migraine.

The data from this open-label pilot study of transcutaneous VNS (nVNS) demonstrate a 21% pain-free rate at two hours in patients with a baseline of moderate- or severe-intensity pain. The device was very well tolerated with no unanticipated, serious or severe adverse events. Patients with migraine need more and better tolerated therapies, and nVNS certainly deserves exploration in a placebo-controlled study.

Clinical implications

Noninvasive vagal nerve stimulation (nVNS) offers a novel approach to acute migraine treatment.

In this open-label, single-arm study, nVNS was well tolerated in acute migraine.

nVNS had a pain-free rate at two hours comparable to similarly tolerated triptans.

nVNS requires study with randomized placebo-controlled trials.

Footnotes

Manuscript providence

The final clinical trial report was supplied to all named authors. The first author (PJG) extracted all data for the analysis using Excel and performed all analyses reported herein. These were check by KAS for accuracy. The first author wrote the first draft of the manuscript and prepared the figure. The manuscript was circulated to all authors, who had input and agreed the final draft. The manuscript represents the authors’ views and not necessarily the sponsors’.

Funding

The study was sponsored by electroCore LLC.

Conflicts of interest

PJG has consulted for the sponsor, direct payments less than $5000 in the year of the study, and received grant support to study the device in cluster headache (see Kirchner et al. ()). Unrelated directly to this manuscript, PJG is on advisory boards for Allergan, Colucid, MAP Pharmaceuticals, Merck, Sharpe and Dohme, eNeura, Autonomic Technologies Inc, Boston Scientific, Eli Lilly, Medtronic, Linde gases, Arteaus, AlderBio, and Bristol-Myers Squibb. PJG has consulted for Pfizer, Nevrocorp, Lundbeck, Zogenix, Impax, Zosano, and Dr Reddy, and has been compensated for expert legal testimony. He has grant support from Allergan, Amgen, and Merck. PJG has received honoraria for editorial work from Journal Watch Neurology and for developing educational materials and teaching for the American Headache Society. BMG served on a scientific advisory board for Kowa Pharmaceuticals America Inc and Tribute Pharmaceuticals; has received speaker honoraria from Zogenix; receives research support from Allergan Inc, Boston Scientific, and electroCore; and has been compensated for expert legal testimony. AM was a paid participant in the clinical trial of GammaCore® and consultant to electroCore LLC, owner of Migralex Inc. RC currently serves on several advisory boards: Allergan, Boston Scientific, Merck & Co Inc, Nautilus Neuroscience, Novartis, NuPathe, Optinose, and Zogenix. He also receives research grants from Allergan, Amgen, Arteaus, AstraZeneca, Boston Scientific, Bristol-Myers Squibb, electroCore, EpiQ, Forest Pharmaceuticals, Fortis Spectrum, GlaxoSmithKline, Merck & Co Inc, Nico Worldwide, NuPathe, OptiNose, Pearl Therapeutics, PuraMed Bioscience, Theravance, Tian Medical, Transcept, and Zogenix. Dr Cady has provided consulting services for Allergan, Amgen, Avanir, Evidera Inc, GlaxoSmithKline, Meda Pharmaceuticals, Merck & Co. Inc, Novartis, Transcept, and Zogenix. KAS is an employee of electroCore.

References

Murray

Vos

Lozano

. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2197–2223.

Bigal

Rapoport

Tepper

. The classification of chronic daily headache in adolescents—a comparison between the second edition of the International Classification of Headache Disorders and alternative diagnostic criteria. Headache 2005; 45: 582–589.

Olesen

Gustavsson

Svensson

. The economic cost of brain disorders in Europe. Eur J Neurol 2012; 19: 155–162.

Goadsby

Lipton

Ferrari

. Migraine—current understanding and treatment. N Engl J Med 2002; 346: 257–270.

Akerman

Holland

Goadsby

. Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci 2011; 12: 570–584.

Lance

Goadsby

. Mechanism and Management of Headache, 7th edn. New York: Elsevier, 2005.

Goadsby

. The pharmacology of headache. Progr Neurobiol 2000; 62: 509–525.

Ferrari

Roon

Lipton

. Oral triptans (serotonin, 5-HT_1B/1D agonists) in acute migraine treatment: A meta-analysis of 53 trials. Lancet 2001; 358: 1668–1675.

Dodick

Lipton

Martin

. Consensus statement: Cardiovascular safety profile of triptans (5-HT_1B/1D agonists) in the acute treatment of migraine. Headache 2004; 44: 414–425.

10.

Sadler

Purdy

Rahey

. Vagal nerve stimulation aborts migraine in patient with intractable epilepsy. Cephalalgia 2002; 22: 482–484.

11.

Goadsby

Grosberg

Mauskop

. Non-invasive vagus nerve stimulation (nVNS) for acute treatment of migraine: An open-label pilot study. Neurology 2013, pp. S40.004–S40.004.

12.

Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders. Cephalalgia 2004; 24, 2nd edn. Suppl 1): 1–160.

13.

Pilgrim

. Methodology of clinical trials of sumatriptan in migraine and cluster headache. Eur Neurol 1991; 31: 295–299.

14.

Lipton

Stewart

Cady

. Sumatriptan for the range of headaches in migraine sufferers: Results of the Spectrum Study. Headache 2000; 40: 783–791.

15.

Ferrari

Goadsby

Roon

. Triptans (serotonin, 5-HT_1B/1D agonists) in migraine: Detailed results and methods of a meta-analysis of 53 trials. Cephalalgia 2002; 22: 633–658.

16.

Goadsby

Zanchin

Geraud

. Early vs. non-early intervention in acute migraine—‘Act when Mild (AwM)'. A double-blind placebo-controlled trial of almotriptan. Cephalalgia 2008; 28: 383–391.

17.

Ferrari

Dodick

. Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: A randomised, placebo-controlled, parallel-treatment trial. Lancet 2008; 372: 2115–2123.

18.

Farkkila

Diener

Geraud

. Efficacy and tolerability of lasmiditan, an oral 5-HT(1F) receptor agonist, for the acute treatment of migraine: A phase 2 randomised, placebo-controlled, parallel-group, dose-ranging study. Lancet Neurol 2012; 11: 405–413.

19.

Tfelt-Hansen

Pascual

Ramadan

. Guidelines for controlled trials of drugs in migraine: Third edition. A guide for investigators. Cephalalgia 2012; 32: 6–38.

20.

Goldstein

. Multilevel statistical models, 4th edn. London: John Wiley & Sons, 2011.

21.

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Statistical Principles for Clinical Trials. In: European Medicines Agency Geneva: International conference on harmonisation, 1998.

22.

Mauskop

. Vagus nerve stimulation relieves chronic refractory migraine and cluster headaches. Cephalalgia 2005; 25: 82–86.

23.

Hord

Evans

Mueed

. The effect of vagus nerve stimulation on migraines. J Pain 2003; 4: 530–534.

24.

Lenaerts

Oommen

Couch

. Can vagus nerve stimulation help migraine? Cephalalgia 2008; 28: 392–395.

25.

Cecchini

Mea

Tullo

. Vagus nerve stimulation in drug-resistant daily chronic migraine with depression: Preliminary data. Neurol Sci 2009; 30(Suppl 1): S101–S104.

26.

Kirchner

Birklein

Stefan

. Left vagus nerve stimulation suppresses experimentally induced pain. Neurology 2000; 55: 1167–1171.

27.

Nesbitt

Marin

JCA

Tomkins

. Non-invasive vagus nerve stimulation for the treatment of cluster headache: A cohort study. Cephalalgia 2013; 33(Suppl 8): 107–107.

28.

Brandes

Kudrow

Stark

. Sumatriptan-naproxen for acute treatment of migraine: A randomized trial. JAMA 2007; 297: 1443–1454.

29.

Diener

Montagna

Gacs

. Efficacy and tolerability of diclofenac potassium sachets in migraine: A randomized, double-blind, cross-over study in comparison with diclofenac potassium tablets and placebo. Cephalalgia 2006; 26: 537–547.

30.

Lipton

Grosberg

Singer

. Efficacy and tolerability of a new powdered formulation of diclofenac potassium for oral solution for the acute treatment of migraine: Results from the International Migraine Pain Assessment Clinical Trial (IMPACT). Cephalalgia 2010; 30: 1336–1345.

31.

Diener

Dodick

Goadsby

. Identification of negative predictors of pain-free response to triptans: Analysis of the eletriptan database. Cephalalgia 2008; 28: 35–40.

32.

The Subcutaneous Sumatriptan International Study Group. Treatment of migraine attacks with sumatriptan. N Engl J Med 1991; 325: 316–321.

33.

Lipton

Dodick

Silberstein

. Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: A randomised, double-blind, parallel-group, sham-controlled trial. Lancet Neurol 2010; 9: 373–380.

34.

Mathew

Finlayson

Smith

. Early intervention with almotriptan: Results of the AEGIS trial (AXERT Early Migraine Intervention Study). Headache 2007; 47: 189–198.

35.

Cady

Martin

Mauskop

. Symptoms of cutaneous sensitivity pre-treatment and post-treatment: Results from the rizatriptan TAME studies. Cephalalgia 2007; 27: 1055–1060.

36.

Gray

. Anatomy of the human body (www.bartleby.com/107/), Philadelphia, PA: Lea & Febiger, 1918.

37.

Kaube

Keay

Hoskin

. Expression of c-Fos-like immunoreactivity in the caudal medulla and upper cervical cord following stimulation of the superior sagittal sinus in the cat. Brain Res 1993; 629: 95–102.

38.

Foley

DuBois

. Quantitative studies of the vagus nerve in the cat. J Comp Neurol 1937; 67: 49–67.

39.

Agostoni

Chinnock

De Daly

. Functional and histological studies of the vagus nerve and its branches to the heart, lungs and abdominal viscera in the cat. J Physiol 1957; 135: 182–205.

40.

Feindel

Penfield

McNaughton

. The tentorial nerves and localization of intracranial pain in man. Neurology 1960; 10: 555–563.

41.

Goadsby

Hoskin

. The distribution of trigeminovascular afferents in the nonhuman primate brain Macaca nemestrina: A c-fos immunocytochemical study. J Anat 1997; 190: 367–375.

42.

Hoffmann

Simon

Zhang

. Low voltage vagal nerve stimulation reduces bronchoconstriction in guinea pigs through catecholamine release. Neuromodulation 2012; 15: 527–536.

43.

Hoffmann

Mendez

Staats

. Inhibition of histamine-induced bronchoconstriction in guinea pig and swine by pulsed electrical vagus nerve stimulation. Neuromodulation 2009; 12: 261–269.

44.

Goldstein

Smith

Pugach

. A sumatriptan iontophoretic transdermal system for the acute treatment of migraine. Headache 2012; 52: 1402–1410.

45.

Aurora

Silberstein

Kori

. MAP0004, orally inhaled DHE: A randomized, controlled study in the acute treatment of migraine. Headache 2011; 51: 507–517.

46.

Djupesland

Docekal

. Czech Migraine Investigators Group. Intranasal sumatriptan powder delivered by a novel breath-actuated bi-directional device for the acute treatment of migraine: A randomised, placebo-controlled study. Cephalalgia 2010; 30: 933–942.

47.

Cady

Messina

Carothers

. Efficacy and safety of a novel Breath-Powered™ powder sumatriptan intranasal treatment for acute migraine. Cephalalgia 2013; 33(Suppl 8): 21–22.

48.

Peikert

Becker

Ashford

. Sumatriptan nasal spray: A dose-ranging study in the acute treatment of migraine. Eur J Neurol 1999; 6: 43–49.

49.

Charlesworth

Dowson

Purdy

. Speed of onset and efficacy of zolmitriptan nasal spray in the acute treatment of migraine: A double-blind, placebo-controlled, dose-ranging study versus zolmitriptan tablet. CNS Drugs 2003; 17: 653–667.