Bert B. Vargas, 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

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.