Thomas P. Bravo, MD

Another topic important to our understanding of the pathophysiology of migraine was presented at AAN 2015 by Henrik Schytz, MD.* Dr Schytz has recently been involved in the investigation of pituitary adenylate cyclase-activating peptide (PACAP)--a potent migraine inducer, which offers potential insight into a new therapeutic target for migraine. PACAP is present in the trigeminocervical complex and is elevated acutely during a migraine attack. Recent work has also confirmed that when migraine is effectively treated with sumatriptan, PACAP levels return to baseline.

PACAP has been the subject of a number of recent studies. Dr Schytz has been involved in current efforts to better characterize its physiological, biochemical, and migraine-inducing effects.

This double-blind crossover study recruited 24 females who had episodic migraine without aura and randomly allocated them to receive either PACAP38 or vasoactive intestinal peptide (VIP). Subjects were monitored closely for development of migraine symptoms over the next 24 hours. Serum levels of PACAP, VIP, and tryptase were measured at baseline and at 60 min, and 300 min. If migraine was triggered, subcutaneous sumatriptan was administered. MRA of selected intra- and extracranial arteries of the head was also conducted at baseline, 2 hours post-infusion, at onset of migraine, and 30 min after resolution of migraine (or at 5 hours if migraine did not occur). The goal was to characterize PACAP38 with regard to its potential migraine-inducing effects, associated plasma levels, and evidence of mast cell degranulation as an associated mechanism (elevated tryptase) as well as the peptide's potential vascular effects.

The results demonstrated that PACAP38 was a potent aggravator of migraine. 73% of patients reported migraine-like attacks with a median onset of 4h 15 min after infusion compared with 18% after VIP infusion (p=0.0020). Measured PACAP38 serum concentration was significantly higher at 60 min than expected from infusion alone in those with migraine attacks compared with those who were headache free, suggesting potential de novo release. Arterial imaging of intracranial vessels showed no change in circumference at any time point. However dilation of the extracranial arteries was demonstrated in both infusion groups: greater dilation was seen in the superficial temporal arteries and middle meningeal arteries in the PACAP38 group. This dilation subsequently reversed after sumatriptan administration. There was no significant change in tryptase levels in any group, which suggests that widespread mast cell degranulation did not occur.

Overall, this study supports the hypothesis that PACAP38 is involved in the migraine pathway via mechanisms similar to those of CGRP. Not only do levels of the peptide rise and fall with the onset and treatment of the attack, but now it has now been demonstrated that administration of PACAP38 induces attacks in migraineurs. This provides several new potential therapeutic targets --  most prominently a specific PACAP receptor PAC1. With additional study, the development of a PAC1 antagonist may potentially lead to a new class of migraine treatment.

*Dr Schytz was the winner of the Harold Wolff-John Graham Award, an annual award sponsored by the AAN for outstanding research in the area of Headache and Facial Pain Research.

1. Zagami AS, Edvinsson L, Goadbsy PJ. Pituitary adenylate cyclase activating polypeptide and migraine. 

2014;1:1036-1040.
2. Amin FM, Hougaard A, Schytz HW, et al. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. 

Articles

 PACAP38 is a potent aggravator of migraine, a new study shows. This provides several new potential therapeutic targets -- most prominently a specific PACAP receptor PAC1.

PACAP: Lessons From A Potent Migraine Inducer?

At a plenary session at AAN2015, Todd Schwedt, MD, presented intriguing research that is helping to shape our understanding of the functional connectivity and brain structure of migraineurs.

We know that migraineurs demonstrate abnormal sensory processing-including abnormal pain integration, modulation, and affective processing. Even between attacks, migraineurs exhibit increased sensitivity to light, sound, and smell. They also have increased rates of pain disorders that may have altered central processing, such as irritable bowel syndrome and fibromyalgia. This suggests that abnormal sensory processing in migraine is potentially the result of altered brain function.

Recent research using resting state functional connectivity MRI supports the presence of abnormal functional connections in those with chronic migraine.

 Functional connections between the anterior insula, amygdala, pulvinar, mediodorsal thalamus, middle temporal cortex, and periaqueductal gray have been described: functional connections between the anterior insula and both the mediodorsal thalamus and periaqueductal gray specifically correlate with the length of time a person has experienced chronic migraine. Dr Schwedt presented additional research which demonstrated abnormal functional connectivity in these areas, as well as evidence that cortical thickness of the temporal parietal junction region may be abnormal.

A study compared 31 adults with episodic migraine with 32 healthy controls utilizing quantitative sensory testing (QST) and regional cortical thickness using 3 Tesla MRI. Each subject’s heat pain threshold was quantified at the left forearm using QST. Cortical thickness was measured next using T1-weighted sequences by general linear model whole-brain vertex-wise analysis. Subjects were grouped by pain threshold and those with migraine were then compared to controls.

Healthy controls with low heat pain thresholds had a thicker cortex in left superior temporal/inferior parietal region. Migraineurs with low pain heat thresholds had thinner cortex in this area (

<.01). There was no change in this area among the migraineur group despite disease-varied severity, which suggests that this may be an underlying trait of those with migraine. This region is involved in the cognitive aspect of pain, specifically directing attention toward or away from environmental or painful stimuli. One could hypothesize that having this trait may explain why someone with migraine may have a difficult time distracting himself or herself from pain and other nonpainful stimuli.

The potential implications of this research may lead us to an imaging biomarker for migraine using volume, surface area, and thickness of specified brain regions on standard MRI. While migraine remains a clinical diagnosis, structural imaging may eventually become a helpful adjunctive clinical tool.

1. Schwedt TJ, Schlaggar BL, Mar S, et al. Atypical resting-state functional connectivity of affective pain regions in chronic migraine. 

2013;53:737-751.
2. Schwedt TJ, Chong CD. Correlations between brain cortical thickness and cutaneous pain thresholds are atypical in adults with migraine.

 2014;9(6).
3. Schwedt T, Chong C. Abstract PL1.001. Adults with migraine have atypical correlations between brain cortical thickness and pain thresholds. Presented at: AAN2015 Washington, DC.

Intriguing research is helping to shape our understanding of the functional connectivity and brain structure of migraineurs.

An Imaging Biomarker for Migraine?

The American Academy of Neurology annual meeting this year began by showcasing several important findings in concussion and associated post-traumatic headache (PTH).

Sports-related concussion is a prevalent problem: between 1.6 to 3.8 million occur annually-often in young athletes. Headache is by far the most common symptom of concussion and is a persistent and disabling feature. PTH occurs in between 85% to 94% of concussed athletes and is a risk factor for prolonged recovery.

Despite this, there are no randomized clinical trials of treatment of PTH and limited prospective studies.

Dr Karen Barlow presented at AAN on sports-related concussion and PTH, including the first large study to describe the characteristics of PTH and treatment response in children.

A cohort of 670 children with concussion in an acute care setting was followed monthly until symptom resolution. Among this cohort, 11% had PTH at 2 weeks following injury; in 7.8%, PTH persisted at 3 months. 100% of children who had continued post-concussive syndrome at 12 months had headache. 54% of those with PTH met criteria for migraine: medication overuse headache and tension type headache were uncommon. Between 44% and 61% of those with PTH had headache daily; however, those with daily headache were also were more likely to have responded to a preventative medication.

The PTH treatment cohort received amitriptyline, nortriptyline, flunarizine, topiramate, or melatonin chosen based on clinical symptoms. 64% of children improved on treatment: responses to amitriptyline, melatonin, and flunarizine were notable. A particularly interesting finding among the cohort is that a personal history or family history of migraine was present in 82% of those with PTH. This provides additional supporting evidence that a history of migraine is an independent risk factor for prolonged recovery following concussion.

Overall, this study demonstrates that PTH is a common problem and supports consideration of early referral to a headache specialist. It also suggests the potential positive impact of early treatment for PTH in addition to the standard concussion recommendation of some degree of physical and cognitive rest with a plan for graduated return to play and to learning.

1. Seifert TD. Sports concussion and associated post-traumatic headache. 

 2013;53:726-736.
2. Kuczynski A, Crawford S, Bodell L, et al. Characteristics of post-traumatic headaches in children following mild traumatic brain injury and their response to treatment: a prospective cohort. 

Highlights of the first large study to describe the characteristics of post-traumatic headache and treatment response in children are summarized here.

New Insights on Post-Traumatic Headache

Attendees at the AAN 2015 conference got a look at a novel drug-device for acute migraine treatment. AVP-825 is a breath-powered intranasal delivery system of lower-dose powdered sumatriptan. This drug-device combination is designed as a potential non-oral treatment option with the goal of faster and more effective systemic absorption and pain relief without the need for injection.

A meta-analysis of the pooled results of phase 2 and phase 3 clinical trials of AVP-825 was presented, which demonstrated efficacy in a cohort of patients with episodic migraine without either sumatriptan or 2 or more triptan failures and with normal palate and nasal function. Beginning at 30 minutes, significant pain relief occurred compared with placebo (44.8% vs 27.9%). Pain freedom at 2 hours was noted in 40% compared with 19.21% in the placebo group. 46.9% of treated patients reported no clinical disability at 2 hours vs 27.9% in the placebo group (

<.01). No significant adverse events were noted: 1 patient reported paresthesias; 20% noted abnormal taste; and 11% reported mild nasal discomfort.

Overall this meta-analysis is consistent with the prior phase 2 and 3 clinical trials, which demonstrated efficacy of AVP-825 as a non-oral acute migraine treatment option.

This poster session comes as a precursor to the presentation of data from the COMPASS study (Breath Powered™ Nasal Delivery of 22 mg Sumatriptan Powder (AVP-825) Versus 100-mg Oral Sumatriptan in Acute Migraine: A Comparative Clinical Trial).

 This is a recently completed multicenter, double-dummy, crossover, 12-week study that compares AVP-825, 100-mg oral sumatriptan, and placebo for acute migraine treatment. COMPASS demonstrated that for 2 or more attacks, AVP-825 was superior to oral sumatriptan at 30 minutes pain relief (37.6% vs 18.8%, 

<.0001) and 30 minutes pain freedom (15.7% vs 6.4%, 

Overall, this study suggests that AVP-825 may not only be a promising non-oral triptan acute treatment, but may be more efficacious than its oral counterpart.

1. Cady R, et al. Abstract p1.315. Pooled analyses of randomized, double-blind, placebo-controlled studies of a Breath Powered™ Nasal Delivery Device Containing 22 mg Sumatriptan Powder (AVP-825) in the treatment of episodic migraine. Presented at: AAN 2015 Washington DC.

2. Lipton R, et al. Presentation S23.003. Consistency of response in the COMPASS Study [Breath Powered™ Nasal Delivery of 22 mg Sumatriptan Powder (AVP-825) versus 100 mg oral sumatriptan in acute migraine: a comparative clinical trial]. Presented at: AAN 2015 Washington DC.

A novel drug-device may not only be a promising non-oral triptan acute migraine treatment, but may be more efficacious than its oral counterpart.

A Novel Acute Migraine Treatment

Recently, sphenopalatine ganglion (SPG) block has been generating interest as another extracranial nerve block that may be used as part of treatment for migraine. The SPG is a group of neurons within the pterygopalatine fossa that lies behind the nasopharynx posterior to the middle turbinate and inferior to the sphenoid sinus.

 The SPG contains sensory and sympathetic fibers but is largely a parasympathetic structure and the largest extracranial parasympathetic ganglion of the head.

The SPG receives parasympathetic innervation from the superior salivatory nucleus in the pons and projects ipsilaterally to extracerebral and intracerebral arteries, the lacrimal gland, nasal mucosa, conjunctiva, and Muller muscle in the upper eyelid.

 The SPG is crucial for mediating the cranial autonomic symptoms produced by primary headache disorders, particularly trigeminal autonomic cephalalgias.

SPG activation in these disorders produces unilateral eye redness, rhinorrhea, eyelid edema, facial flushing/sweating, ear fullness, and ptosis. It also has been proposed that because the SPG provides parasympathetic input to cranial blood vessels, its stimulation, through the superior salivatory nucleus, causes plasma protein extravasation in the dura and may activate meningeal nociceptors and trigger a migraine through neurogenic inflammation.

 This provides a rationale for targeting the SPG as a potential migraine treatment.

SPG blockade was pioneered in 1908. Among primary headache disorders, it has been reported most often in the treatment of cluster headaches. SPG blockade can be performed topically by placing an anesthetic-soaked cotton-tipped applicator at the middle turbinate, by transnasal injection with endoscopic guidance, by lateral-infratemporal injection with fluoroscopic guidance, or by oral injection routes.

 Recently, several new devices have been marketed as a noninvasive way to deliver anesthetics topically to the nasal mucosa for SPG blockade.

To date, there is only 1 trial investigating the role of SPG blocks in the treatment of migraine. A recent small, industry-funded, placebo-controlled, randomized clinical trial evaluated an SPG block device, the Tx360®, as a treatment for chronic migraine.

The trial randomized 38 subjects with International Classification of the Headache Disorders 2 criteria for chronic migraine to either treatment with 0.5% bupivacaine or placebo (normal saline) with the device. The Tx360® device allows a small flexible catheter to advance intranasally below the middle turbinate and 0.3 mL of anesthetic or saline to be sprayed topically on the mucosa superficial to area of the SPG. In this trial, both groups received bilateral treatment twice weekly for 6 weeks. The primary outcome of the study compared numeric rating scale scores (NRS) following treatment at 15 minutes, 30 minutes, and 24 hours posttreatment with pretreatment baseline.

The results of the study showed that the treatment group had a significant decrease in pain at 15 minutes, 30 minutes, and 24 hours posttreatment (

<.001). In addition, the NRS showed a mild drop from a pooled baseline of 3.18 to 2.53 at 15 minutes, 2.41 at 30 minutes, and 2.85 at 24 hours in the active-treatment group.

Comparison between the two groups over the 6-week time course did not show a statistically significant decrease in NRS scores from baseline; however, the authors noted a trend toward improvement. No significant change in utilization of acute migraine medication was noted over the course of treatment between the two groups. There were no serious adverse effects in either group. Headache impact test scores (HIT-6) were lower in the active-treatment group by -4.5 points (

In a follow-up study, no significant differences in headache days, average pain, acute medication use, or quality-of-life measures were seen at 1 and 6 months posttreatment between active treatment and placebo.

 However, a trend of improvement in these areas was noted in the active-treatment group as compared with baseline.

The study had several limitations, including small sample size and difficulty with true blinding. Although the acute treatment results were statistically significant, the small magnitude of pain improvement combined with the feasibility of twice weekly procedures is of uncertain clinical relevance.

It is possible that a subgroup of migraineurs with more prominent cranial autonomic features may have a more robust response, and this would be an interesting future area of study. In addition, comparative studies with simple intranasal lidocaine spray, which has several small previous studies showing effectiveness in acute migraine treatment,

 would be important, because it is unclear from the current literature whether a directed device is truly required.

 The SPG is a promising target for migraine treatment. However, noninvasive device–mediated SPG blockade currently lacks robust evidence of efficacy for routine use as a migraine preventative and further study is warranted.

1. Piagkou M, Demesticha T, Troupis T, et al. 

The pterygopalatine ganglion and its role in various pain syndromes: from anatomy to clinical practice. 

Sphenopalatine ganglion neuromodulation in migraine: what is the rationale? 

Unitary hypothesis for multiple triggers of the pain and strain of migraine. 

4. Cady R, Saper J, Dexter K, Manley HR. 

A double-blind, placebo-controlled study of repetitive transnasal sphenopalatine ganglion blockade with Tx360® as acute treatment for chronic migraine. 

5. Cady RK, Saper J, Dexter K, et al. Long-term efficacy of a double-blind, placebo-controlled, randomized study for repetitive sphenopalatine blockade with bupivacaine vs saline with the Tx360® device for treatment of chronic migraine. 

2015 Mar 31. doi:10.1111/head.12546. [Epub ahead of print]

Intranasal lidocaine for treatment of migraine: a randomized, double-blind, controlled trial. 

Intranasal lidocaine for migraine: a randomized trial and open-label follow-up [published correction appears in 

The SPG is a promising target for migraine treatment, but robust evidence of efficacy for routine use of noninvasive device–mediated SPG blockade is needed. 

Sphenopalatine Ganglion Block for Migraine?

Chronic migraine (CM), a severe and disabling neurologic disease, occurs with a worldwide prevalence of about 2%.

 The International Classification of Headache Disorders (ICHD)-3 beta defines CM as 15 or more headache days per month over at least 3 months’ time, with at least 8 days per month on which headaches and associated symptoms meet diagnostic criteria for migraine.

 CM has a significant negative impact on individuals and society; 90% of persons with CM have moderate or greater levels of migraine-related disability.

 The total average cost of CM is estimated at $7750 per person annually-4.4 times greater than the cost of episodic migraine (EM)-with the majority of the cost due to loss of productive time.

Why EM transforms to CM is not fully understood, but many risk factors have been identified.

 Among the proposed mechanisms is that a higher frequency of migraine attacks produces sensitization of the trigeminal system and affected neuronal networks, reducing the overall threshold for activation. To further investigate this proposed mechanism, a recent large longitudinal observational study examined the effect acute treatment response has on transformation to CM.

The study followed selected participants from the American Migraine Prevalence and Prevention Study. From that study, 5681 individuals meeting ICHD 2 criteria for EM, determined by standardized survey, were identified and followed for 1 year. Variables collected included sociodemographic data, headache frequency, disability due to migraine, depression, and acute treatment type and efficacy.

Treatment efficacy was assessed using a validated self-administered survey (the Migraine-Treatment Optimization Questionnaire) that grades the acute treatment into 1 of 4 response categories: very poor, poor, moderate, or maximum treatment efficacy. At 1 year, participants who had transformed to CM were identified. Multivariate modeling was used to calculate the overall risk of self-reported efficacy of acute treatments on conversion to CM.

The results showed that 3.1% of participants transformed from EM to CM. Participants who were graded as having very poor response to acute treatment were at significantly higher risk for developing CM compared with those who had maximum acute treatment response. Across all 3 models used, adjusting for sociodemographic, headache frequency/disability, and acute medication class, very poor response to treatment remained a consistent marker for progression to CM (OR=3.39, 95% CI, 1.98-5.8; OR=2.39, 95% CI, 1.33-4.28; OR=2.55, 95% CI, 1.42-4.61, respectively).

Overall, this suggests that individuals with very poor acute treatment response had roughly 2.5- to 3.5-fold greater odds of developing CM. Those with moderate or better acute treatment efficacy did not have a significant increased risk.

A weakness of this study’s observational design is that it cannot demonstrate a direct casual effect. It’s possible that very poor acute treatment response may be a marker for more severe/resistant disease and may not be a cause for the transformation to CM. Although this possibility cannot be excluded, the authors did adjust for headache days/month and headache-related disability and very poor treatment response remained a significant risk for transformation (OR=2.39, 95% CI, 1.33-4.28).

Among the types of acute treatments, no single medication class was associated with a higher risk of transformation to CM. Although the study was not designed for head-to-head treatment comparisons, individuals who used triptans were more likely to have a moderate or maximum acute treatment response and patients who used NSAIDs or simple analgesics were less likely to be in the high efficacy categories.

Overall, the study provides supporting evidence that efficacy of acute medication matters beyond just treating a single migraine and may have an impact on the risk of developing worsened disease. Although the individual effectiveness of acute medications was not addressed in this study, that has been addressed in a recent 

 Ineffective acute migraine treatment is associated with a 2.5- to 3.5-fold increased risk of transformation to chronic migraine.

Global prevalence of chronic migraine: a systematic review. 

2. Headache Classification Committee of the International Headache Society (IHS). 

The International Classification of Headache Disorders, 3rd edition (beta version). 

Headache impact of chronic and episodic migraine: results from the American Migraine Prevalence and Prevention study. 

4. Munakata J, Hazard E, Serrano D, et al. 

Economic burden of transformed migraine: results from the American Migraine Prevalence and Prevention (AMPP) study. 

6. Lipton RB, Fanning KM, Serrano D, et al. 

Ineffective acute treatment of episodic migraine is associated with new-onset chronic migraine. 

7. Marmura MJ, Silberstein SD, Schwedt TJ. 

The acute treatment of migraine in adults: the american headache society evidence assessment of migraine pharmacotherapies. 

Efficacy of acute medication matters beyond just treating a single migraine. It may increase the risk of worsened disease.

Poor Acute Treatment May Lead to Chronic Migraine

Butterbur, a popular over-the-counter nutraceutical used for the prevention of migraine, has recently been associated with serious safety concerns. Common butterbur (

) is a perennial plant that contains chemotypes, termed “petasins,” that are thought to be positively pharmacologically active and may have an anti-inflammatory effect. Butterbur has long been used in herbal medicine for the treatment of many conditions, including allergic rhinitis; as an antispasmodic; and in the prevention of migraine.

A specific proprietary butterbur extract, Petadolex (produced by Germany-based Weber & Weber), has been studied as a migraine preventative in several randomized clinical trials. The first placebo-controlled, randomized clinical trial with this extract was conducted in 2001. A  group of 33 adult subjects given a dose of 50 mg BID demonstrated a decrease in migraine frequency from a  baseline of 3.4 per month to 1.8 per month after 12 weeks of treatment (p=0.0024). No significant adverse effects, including elevation of liver function tests, were reported during the treatment period.

This was followed by a larger placebo-controlled RCT in 2004 in which 233 adult subjects with episodic migraine were randomized to doses of 50 mg BID or 75 mg BID of Petadolex versus placebo over a 16-week treatment period. The 75 mg BID group saw a reduction of migraine frequency of 45% (p=0.04). The 50 mg BID group had a reduction of 32% and the placebo group 28%, both of which were not statistically significant (p=0.43). No significant adverse effects, including elevation of liver function tests, were reported during the treatment period, and the authors noted burping as the only unique adverse effect. They concluded that Petadolex at 75 mg BID was more effective than placebo in migraine prevention.

These two studies were together evaluated as part of the American Academy of Neurology evidence-based guideline update for NSAIDs and other complementary treatments for episodic migraine prevention in adults in 2012. The review categorized the studies as class 1 trials, and 

 received Level A classification, establishing it as effective for migraine prevention. Despite this recommendation, the guideline does note that the safety of prolonged use of 

Unfortunately, butterbur extract has been shown to contain pyrrolizidine alkaloids (PAs), a toxic substance that causes hepatoxicity in humans and has been shown to be mutagenic and carcinogenic in animal studies. The extract must be manufactured carefully and consistently to remove PAs.

In a recent review of 21 commercial butterbur products, 7 of the 21 products (33%) contained PAs. In addition, only 7 (33%) showed an amount of petasins consistent with each product’s labeling. Of note in this study, Petadolex contained petasins in the amount disclosed on the product labeling with no detectable PAs in the sample provided.

Petadolex was previously registered by the German health authority BfArM, which regulates drugs, medical devices, and herbal supplements in Germany, and was the only butterbur compound to be approved by a governmental regulatory body. Although Petadolex is still commercially available, it has since lost this approval in 2009 and is now unavailable in Germany. Reportedly this was due to a change in the manufacturing process, occurring prior to the above studies, for which BfArm required reregistration as a new drug and which the company has not completed.

 In addition, due to reports of human hepatoxicity associated with the use of butterbur-containing compounds, all butterbur supplements have since been banned in Switzerland.

Despite butterbur’s potential efficacy, doubts are increasing about the long-term safety of this supplement given of the risk of liver damage and the lack of an actively regulated preparation. Due to the mounting concerns, the American Headache Society is currently evaluating a position statement cautioning against its use.

1. Aydin AA, Zerbes, V, Parlar H, et al. 

The medical plant butterbur (Petasites): analytical and physiological (re)view. 

An extract of Petasites hybridus is effective in the prophylaxis of migraine. 

The first placebo-controlled trial of a special butterbur root extract for the prevention of migraine: reanalysis of efficacy criteria. 

4. Lipton RB, GÃ¶bel H, EinhÃ¤upl KM, et al. 

Petasites hybridus root (butterbur) is an effective preventive treatment for migraine. 

5. Holland S, Silberstein SD, Freitag F, et al. 

Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. 

Simultaneous determination of sesquiterpenes and pyrrolizidine alkaloids from the rhizomes of Petasites hybridus (L.) G.M. et Sch. and dietary supplements using UPLC-UV and HPLC-TOF-MS methods. 

Petadolex capsules formal registration expires. Weber and Weber company website. 

Despite butterbur’s potential efficacy, doubts are increasing about its long-term safety given of the risk of liver damage and the lack of an actively regulated preparation.

Migraine Preventative Butterbur Has Safety Concerns

Migraine is a primary headache disorder that affects over 1 billion worldwide.

 Despite its prevalence, there are a small number of treatment options, each with side effects and contraindications. Recently, single-pulse transcranial magnetic stimulation (sTMS)-a novel nonpharmacologic, well-tolerated, and safe therapy-has shown promise for the treatment of migraine.

The sTMS device (

) works via an external stimulator placed behind the occipital aspect of the head; it is activated by a single click for acute treatment of migraine attacks. When fired, it creates a 0.9T 180ms magnetic pulse that induces an anticlockwise flow of current at the target area cortex. In initial animal models, sTMS has been shown to block cortical spreading depression (CSD)

-the underlying pathophysiology in migraine aura and possibly migraine without aura. Additionally, sTMS may lead to long term modulation of cortico-thalamic activation as well as evoked activity in the sensory thalamus that occurs after CSD.

 These potential mechanisms may explain how sTMS may be effective as not only an acute treatment option, but also a preventive option for migraine.

 The first large clinical trial evaluating sTMS treatment in migraine was a randomized, double-blind, sham-controlled multicenter trial of 267 adults with episodic migraine with aura.

Participants met international criteria of headache disorders II (ICHD-II) criteria for episodic migraine with aura and had visual aura before 30% of their attacks. Individuals were excluded with medication overuse headache, prolonged (>60 min) aura, history of seizure or presence of metal with in the head or neck.  

After a phase 1 run in period, a remainder 201 individuals were randomized to either sham or treatment stimulation devices. The sham device was said to be identical in appearance and created an equivalent discharge sound. Adequate blinding was confirmed on a post study survey where 67% of sham and 72% of active participants believed they had received active treatment. The participants were instructed to use the device at the onset of aura consisting of 2 treatments 30 seconds apart. Up to 3 attacks were to be treated and rescue medication was allowed 2 hours after treatment if needed.

The primary end point was pain freedom at 2 hours. 39% of treatment group was pain free at 2 hours as compared to 22% for sham stimulation (p=0.0179, 95%CI 3-31%). Additionally 29% of participants in the active group remained pain free at 24 hours compared to 16% in the sham group. No significant adverse events were reported.

The authors concluded that sTMS was a promising option for the acute treatment of migraine with aura. A subsequent comparison of sTMS response versus acute treatment with triptans showed a similar total migraine freedom rate at 2 hours5 and a much better side effect profile.

The device received FDA approval for the acute treatment of migraine with aura in December 2013,6 but is not yet currently available for clinical use in the US pending further study.

sTMS is currently undergoing evaluation as a preventive option for migraine with and without aura. In an open label post-market study recently presented at an American Headache Society meeting, sTMS of two pulses twice to three times daily in addition to use as acute treatment was associated with reduction in headache days after 12 weeks of treatment without serious adverse events. In a population (n=122) comprising both chronic and episodic migraine with and without aura, 72% reported that sTMS use reduced pain.7 An exciting finding was that headache day reduction was more prominent in the chronic migraine group-an often difficult-to-treat population.  A large multi-site observational study, the eNeura Spring TMS post-market observational study of migraine or ESPOUSE Study, is underway to further to examine the potential preventive and acute treatment effects in both episodic and chronic migraine.

Bottom line: sTMS is a promising, effective, well-tolerated and safe treatment option for migraine with and without aura, episodic or chronic.

1. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. 

2. Holland PR, Schembri C, et al. Transcranial magnetic stimulation for the treatment of migraine aura? 

3. Andreou AP, Sprenger T, et al. Cortical modulation of thalamic function during cortical spreading depression- Unraveling a new central mechanism involved in migraine aura. 

4. Lipton RB, Dodick DW, et al. Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomized, double-blind, parallel-group, sham-controlled trial. 

5. Starling AJ, Bravo TP, et al. Total migraine freedom (TMF) for single pulse transcranial magnetic stimulation (sTMS) versus triptans for the early acute treatment of migraine. 

: FDA allows marketing of first device to relieve migraine headache pain.

7. Bhola R, Kinsella E et al. Update of the UK post market pilot programme with single pulse transcranial magnetic stimulation (STMS) for the acute treatment of migraine. 

Transcranial magnetic stimulation is a promising, effective, well-tolerated and safe treatment option for migraine with and without aura, episodic or chronic.

sTMS: Promising Migraine Therapy

Migraine is a prevalent and often debilitating condition with highly variable individual responses to prophylactic therapy. Selecting an effective prophylactic treatment for an individual patient often is a process of trial and error, without clear clinical factors to guide selection of effective therapy.

Several recent studies have examined whether patient description of headache “direction” may predict treatment response, specifically to onabotulinumtoxinA (Botox) injections.

The association between headache directionality and response to Botox was first published in a triple-blinded prospective and retrospective study in 2006.

This study examined a variety of neurologic symptoms associated with migraine, in both episodic and chronic forms, in responders and nonresponders to 100 units of Botox given for migraine prophylaxis. In the prospective portion of the study, 27 of the 42 patients were categorized as either “clear responders” or “clear nonresponders” based on patient headache logs between weeks 4 and 12 after initial injection.

Between these 2 groups, factors such as presence of aura, photophobia, phonophobia, nausea, vomiting, neck muscle tenderness, and presence of cutaneous allodynia were not correlated with response to onabotulinumtoxinA. However, the description of perceived direction of the origin of the headache was the sole characteristic studied that correlated strongly with response.

Subjects with migraine who described their headache as 

 or a perceived buildup of pressure “as if their skull was about to split open,” were much more likely to be nonresponders. None of the patients with exploding headache were described as responding to Botox in the prospective portion of the study, and those with exploding headaches comprised 89% of the nonresponders in the retrospective portion.

 or “assaulted by external forces, typically described as crushing, clamping or stubbing,” and 

 or “eye popping pain,” were more likely to report response to Botox. Of the responders in the prospective and retrospective portions, 93% and 84%, respectively, described their headache as being either imploding or ocular.

A follow-up study confirmed the correlation with description of headache directionality and Botox response in a retrospective study of 82 patients with subjects meeting International Classification of Headache Disorders 2 (ICHD2) diagnostic criteria for migraine.

 Patients who had received Botox for migraine prophylaxis were interviewed, and a number of clinical characteristics, including headache directionality, were recorded. Patients who had a self-reported drop in headache days by more than 66% were considered responders; less than 33%, nonresponders; and between 33% and 66%, questionable responders.

Those who described their headaches as imploding or ocular accounted for the majority of responders (70%). Those who described their headache as exploding accounted for the majority of nonresponders (78%).

However, obtaining a consistent description of the direction of a patient’s headache may not be straightforward. In an attempt to standardize assessment of directionality, a recent study examined different methods of determining headache directionality in an outpatient women’s health clinic for patients who met ICHD2 criteria for migraine.

 The study compared 3 methods of determining headache direction: (1) a pictorial representation of their headache,(2)  a standardized survey designed to allow the patient to express directionality, and (3) a clinician’s blinded assessment using standardized questions.

Surprisingly, the study demonstrated poor concordance among the different methods, with descriptions of directionally varying widely within subjects when the different methods of assignment were used. The authors suggest that this may be the result of most patients’ unfamiliarity with the concept of headache directionality given that physicians question this infrequently. This represents a potentially significant challenge in using the approach clinically.

While the description of headache directionality may help clinicians better select patients with migraine who may respond to Botox or potentially other prophylactic therapies, the best way to determine this in a consistent manner is as of yet unclear. Furthermore, why the description of the direction from which the pain originates would be predictive in treatment response and what this tells us about the potential pathophysiology also are unknown.

It’s hypothesized that those patients who describe their headaches as imploding may have more involvement of extracranial nociceptors and therefore may have more response to therapies that are directed at extracranial targets, such as Botox. While this cultivates many intriguing questions, further investigations are needed.

1. Jakubowski M, McAllister PJ, Bajwa ZH, et al. 

Exploding vs. imploding headache in migraine prophylaxis with Botulinum Toxin A.

Migraine prophylaxis with botulinum toxin A is associated with perception of headache.

3. Files JA, Schwedt TJ, Mayer AP, et al. 

Imploding and exploding migraine headaches: comparison of methods to diagnose pain directionality.

Knowing the direction of the headache's origin, while clinically difficult to ascertain on a consistent basis, has shown some predictive value for migraines.

Imploding or Exploding: Headache Direction May Help Select Treatment

Migraine headache accounts for at least one-third of the 5,000,000 headache visits to US emergency departments each year. In the acute care setting there is currently significant heterogeneity in the treatment of acute migraine. This practice variation can result in patients being treated with medications that may be ineffective and can contribute to prolonged ED stay, poor patient outcomes, return visits to the ED, and worsening of the migraine pattern.

Recently a systematic review examined the available literature on acute care treatments for migraine for effectiveness and tolerability, graded each medication’s level of available evidence, and gave recommendations regarding its use.

The review was limited to double-blind prospective RCTs in adults treated in an emergency department or equivalent acute care setting. Only studies that defined migraine using either International Headache Society diagnostic criteria or the Ad Hoc criteria were included. Overall 831 abstracts were screened, 120 full text articles were assessed resulting in a total of 44 studies included in the review. Each study was graded according to risk for bias and given a final rating of methodological quality using the US Preventative Task Force criteria.

Recommendations regarding use of each treatment were made at a consensus meeting of the Canadian Headache Society. This expert consensus group reviewed each treatment based on several additional factors including desirable and undesirable side effects, variability in patient values or preferences, and wise use of resources. The level of quality of evidence had partial impact on the use recommendation. Final use recommendation was graded as strong or weak based on review of these additional factors. The pertinent results are summarized in the 

Five therapies (4 available in the US) with high to low levels of evidence gained a strong recommendation for use.

Prochlorperazine (Compazine) carried the highest level of evidence based on 2 “good,” 3 “fair,” and 1”poor” trials. The authors note that although strongly effective, this should be weighed against the relative frequent occurrence of extrapyramidal symptoms (EPS). In one study, EPS occurred in both prochlorperazine and metoclopramide groups in 13% of treated subjects. To address this, consideration of coadministration with an agent such as diphenhydramine is advised.

Subcutaneous sumatriptan was the only triptan medication assessed in this review. While carrying a strong recommendation, it is more likely to be efficacious when given in the first few hours after the onset of a migraine attack and is limited to patients who have not used a triptan in the last 24 hours. Despite their effectiveness, triptans are currently underutilized; a recent analysis of a National Hospital Ambulatory Medical survey found a triptan medication was given only in 7% of acute migraine treatments in the ED. Additionally when a triptan was used, the median length of ED stay was shorter than when opiate therapy was administered.

Ketorolac (IM or IV) was strongly recommended after 2 “fair” and 2 “poor” quality studies with active comparators.

One of the more striking results of the review is the recognition that the evidence on comparative efficacy of available options is generally of low quality. Many treatments received weak recommendations based on the very limited evidence available.  

Meperidine (Demerol) received a weak recommendation based on 1 “fair” and 1 “poor” study. Despite falling softly into the "use" category, meperidine is becoming much less available due to concerns of serious adverse events, including seizure. It is recommended that this drug be used with caution.

Routine use of opioids has long been advised against for acute migraine.

The limitation in scope of this review was again demonstrated in the evaluation of dexamethasone. This medication received a strong recommendation with moderate evidence that it is 

 effective in acute treatment. However some evidence suggests that a single dose acutely will decrease the relative risk of migraine recurrence 26% over the first 72 hours, overall making it potentially beneficial outside of its immediate effect.

Overall this systematic review is a substantial step forward in establishing an evidence-based approach to migraine treatment in the acute care setting. It demonstrates that there is significant need for further research. While clinicians should exercise judgment based on each individual patient and circumstance, this review provides an excellent evidence based guide.

1. Orr SL, Aube M, Becker WJ, et al. Canadian Headache Society systematic review and recommendations on the treatment of migraine pain in emergency settings. 

 2014; Epub ahead of print. 1-14.
2. Friedman BW, West J, Vinson DR, et al. Current management of migraine in US emergency departments: An analysis of the National Hospital Ambulatory Medical Care Survey. 

2014; Epub ahead of print. 1-9.
3. Loder E, Weizenbaum E, Frishberg B, et al. Choosing wisely in headache medicine: the American Headache Society’s list of five things physicians and patients should question. 

 2013; 53: 1651–1659.
4. Colman I, Friedman BW, Brown MD, et al. Parenteral dexamethasone for acute severe migraine headache: meta-analysis of randomised controlled trials for preventing recurrence.

Here: highlights from a systematic review that these authors view as a substantial step forward in establishing an evidence-based approach to migraine treatment in the acute care setting.