Dee Rapposelli

Calcitonin gene-related peptide (CGRP) inhibitors may help prolong the therapeutic effect of onabotulinumtoxinA (ONA), according to findings presented during a poster session at the 61st Annual Meeting of the 

 The poster was presented by Heidi Yuan, BA, study coordinator in the Headache Division, Neurology, at the 

 in Salt Lake City. Ms Yuan is working with a team under the direction of Seniha Ozudogru, MD, who is Assistant Clinical Professor of Neurology at the university.

Both ONA and CGRP inhibitors are indicated for the treatment of chronic migraine, with CGRP inhibitors being the newest to join the migraine treatment armamentarium. Both are injectables; ONA is administered intramuscularly every 12 weeks, and the three currently available CGRP inhibitors-erenumab, fremanezumab, and galcanezumab-are given subcutaneously every 4 weeks. A fourth CGRP inhibitor, eptinezumab, which is expected to enter the market in 2020, is an intravenous infusion meant to be administered every 12 weeks.

Among the currently available CGRP inhibitors, erenumab has a Level A recommendation for migraine prophylaxis and is recommended by the 

 for patients who have not had success with other preventive therapies.

 ONA also has a Level A recommendation for the same indication, although its effectiveness may wane within 1 to 3 weeks before the next injection.

“Our current research is to put in the spotlight the possibility of exploring concurrent therapies as a better way to address onabotulinumtoxinA responders who do not experience the full duration of effect,” Ms Yuan told 

. She, Dr Ozudogru, and coinvestigators conducted a retrospective qualitative analysis to gauge whether add-on CGRP inhibitor therapy could provide an improved therapeutic effect in patients receiving ONA for treatment of chronic migraine.

They identified 34 patients with chronic migraine who were receiving ONA injections at the 

 and who also had been prescribed erenumab therapy. The study inclusion criterion was receipt of ONA therapy before and after erenumab, with patients having had at least two injection cycles prior to beginning anti-CGRP therapy. Most study participants (91%) were women with a diagnosis of intractable chronic migraine that had been refractory to a wide range of standard treatments.

“The study participants had gone through many referrals and unsuccessful treatments before arriving at the University of Utah Headache Clinic to see one of its specialists. They had been suffering for years-decades-with chronic migraine symptoms, and had tried and failed at least three to five therapies before coming to us,” said Ms Yuan. Comorbidities also were common among participants and included depression (n=11), anxiety (n=9), insomnia (n=9), chronic tension-type headache (n=4), idiopathic neuropathy or neuropathic pain (n=4), concussion (n=3), autoimmune disorders (n=3), fibromyalgia (n=2), and occipital neuralgia (n=2).

Response to ONA, as recorded in patient chart data, was examined to determine ONA’s perceived efficacy before and after administration of CGRP inhibitor therapy. Criteria examined included number of headaches while ONA provided a therapeutic effect, number of weeks for the ONA injection to wear off, and number of headaches after the injection wore off before administration of the next subsequent injection.

Erenumab appeared to boost ONA efficacy and sustained effects in a significant proportion of participants. About half (53%) reported improvement in at least one of the three criteria indicative of ONA efficacy at their first or second injection visit following initiation of erenumab therapy. These patients reported an average increase of about 2 weeks before the ONA injection wore off. Twenty-nine percent of participants reported no change in ONA efficacy following the addition of erenumab, and 18% reported greater headache burden or decreased ONA efficacy following initiation of erenumab.

When asked about cost constraints regarding concurrent use of these therapies, Ms Yuan explained that some specialists in the clinic have been looking into extending the ONA treatment cycle and that treatment cycle adjustments might be a way to provide some cost savings for some patients.

The study is ongoing. The team plans to continue observing the clinical progress of the study participants across additional cycles of ONA and erenumab to determine whether CGRP antibodies are effective in improving and prolonging the therapeutic effect of ONA. The data may also give insight into optimal patient selection for concurrent ONA and erenumab therapy in the treatment of intractable chronic migraine. Further prospective studies are warranted.

1. Yuan H, Baggaley S, Digre, K, Ozudogru S. CGRP antibodies as adjunctive prophylactic therapy for prolonging the therapeutic effect of onabotulinumtoxinA injections among chronic migraine patients (ongoing project). Poster presented at: 

61st Annual Meeting of the American Headache Society

2. US Food and Drug Administration accepts biologics license application for eptinezumab [press release]. 

https://www.globenewswire.com/news-release/2019/04/22/1807504/0/en/U-S-Food-and-Drug-Administration-Accepts-Biologics-License-Application-for-Eptinezumab.html

. Bothell, WA: Alder Biopharmaceuticals; April 22, 2019. Accessed July 19, 2019.

The American Headache Society Position Statement on Integrating New Migraine Treatments Into Clinical Practice

Migraine headache: diagnosis and current and emerging preventive treatments

Articles

For years, study participants had been suffering with migraine symptoms and had failed at least three to five therapies before enrolling in the trial.

Concurrent CGRP Inhibitor and OnabotulinumtoxinA Therapy Boosts Relief in Severe Chronic Migraine

A large percentage of the US population is contending with undiagnosed migraine and suboptimal care, according to results from the Observational Survey of the Epidemiology, Treatment and Care of Migraine (OVERCOME).

 The findings were presented at the 61st 

 of the American Headache Society, held July 11 to 14 in Philadelphia. The survey results also determined that 30% of patients with migraine may qualify for novel medications for acute migraine relief regardless of how many migraine headache days (MHD) they have per month.

OVERCOME is a web-based survey that was conducted in a representative US sample of 21,143 persons with migraine. A migraine diagnosis was identified based on 

The International Classification of Headache Disorders 3rd edition (ICHD-3)

 criteria. The data were presented by Richard B. Lipton, MD, the Edwin S. Lowe Professor and Vice Chair of Neurology, Professor of Epidemiology and Population Health, and Professor of Psychiatry and Behavioral Sciences at the 

Here, we report on two assessments of OVERCOME data presented by Dr Lipton at the AHS meeting. The purpose of the first assessment was to update understanding of migraine diagnosis, consultation, and treatment in the United States. The second was to estimate the percentage of patients who meet 

American Headache Society (AHS) consensus criteria

 for acute treatment with novel therapies either because triptan therapy is contraindicated or because of failure to respond to or tolerate at least two oral triptans.

 The assessment stratified participants into those who experienced three or fewer MHD per month (n=12,299; 58%) and those who experienced four or more (n=8844; 42%).

Persons who experienced three or fewer MHD per month but met ICHD-3 criteria for migraine were particularly vulnerable to going without a diagnosis, although the percentage of those with four or more MHD per month who had not received a diagnosis was considerable.

 Thirty-one percent of those with four or more MHD per month had not received a diagnosis and 45% of those with three or fewer MHD had not. Meanwhile, 73% of those with three or fewer MHD and 86% with four or more reported ever seeking medical care for headache or migraine, largely consulting with a primary care physician or neurologist, or receiving care in the emergency department. Diagnostic testing was reported by 50% of those with three or fewer MHD and 68% of those with four or more. Twelve percent of survey participants in the three-or-fewer MHD-per-month group and 21% of those in the four-or-more group reported ever visiting a headache specialist.

The researchers alarmingly found that opioid use rivaled that of triptan use: 41% of the three-or-fewer MHD group and 55% of the four-or-more MHD group reported having ever used an opioid for migraine management. Thirty percent and 42%, respectively, reported ever using a triptan.

Dr Lipton stressed that migraine in a significant percentage of the population sample remained undiagnosed. He noted that although primary care is the main source of patient diagnosis and treatment, more than 30% of surveyed patients with four or more monthly MHD had sought emergency care for a migraine. Also, he called the preponderance of opioid use relative to triptan use and the low rate of preventive medication use among prevention-eligible patients concerning.

The second assessment employed the migraine Treatment Optimization Questionnaire (mTOQ), which measures the adequacy of acute therapy. The study population was divided into three groups:
	• Persons not currently on an oral triptan but with a history of use and discontinuation of at least 2 of them
	• Persons currently using an oral triptan with mTOQ sum score <6 (poor/very poor treatment efficacy) and history of failing at least one oral triptan
	• Persons with potential contraindications to triptans (eg, cardiovascular conditions or procedures)

Overall, the researchers found that, irrespective of group designation, 27% of persons with three or fewer MHD per month and 33% of those with four or more appeared to be eligible for novel medications designed for acute treatment of migraine. A quarter of the eligible population with three or fewer monthly MHD were currently using an oral triptan despite it being either contraindicated or providing poor/very poor effectiveness. The same percentage reported using opioids.

A third of persons with four or more monthly MHD were using oral triptans and about 30% were using opioids. Barbiturates were used by 13% of those with three or fewer and 16% of those with four or more MHD.

1. Lipton RB, Araujo AB, Nicholson RA, et al. Patterns of diagnosis, consultation, and treatment of migraine in the US: results of the OVERCOME Study. (2017-229-001).

2. Lipton RB, Pohl GM, Araujo AB, et al. Who is eligible for novel medications designed for the acute treatment of migraine and what are their unmet needs? Results of the OVERCOME Study. (2017-6229-004).

Nearly one-third of persons with four or more migraine headache days per month have not received a diagnosis.

Survey Reveals Major Gaps in Migraine Care

Noninvasive transdermal vagus nerve stimulation (nVNS) appears to be as effective as triptan therapy for relief of episodic migraine but provides that relief through a different mechanism of action, according to Paul L. Durham, PhD, Director of Cell Biology at the 

 at Missouri State University in Springfield.

 Findings reported by Dr Durham and his team on July 11 at the 61st 

Annual Meeting of the American Headache Society

 in Philadelphia may be particularly promising for patients who do not respond well to triptans or who would like to avoid pharmacotherapy.

The FDA approved nVNS for treatment of episodic migraine in adults in January 2018, which expanded its use beyond an indication for episodic cluster headache. The nVNS device is a portable, handheld item that a patient applies to the cervical area of the vagus nerve. Results from the 

 (NCT02686034), which provided the evidence for FDA approval, found that, compared with a sham control, nVNS provided significantly better pain relief at 30 and 60 minutes (

<.03); decreased intensity of pain at 30, 60, and 120 minutes; reduced use of rescue medication; and provided consistent, predictable pain relief with use over time.

To compare the inhibitory actions of nVNS and sumatriptan on trigeminal nociception, Dr Durham and his team measured nocifensive responses in Sprague Dawley rats. To induce nociception in the rats, complete Freund’s adjuvant (CFA) was injected at 10 neck muscle sites to induce inflammation, which developed over the course of 8 days. Trigeminal neurons were then activated by exposing the rats to one of two substances known to induce migraine in humans: the volatile aroma of California bay leaf oil extract (CBL) or sodium nitroprusside (SNP). Rats randomized to CBL were exposed for 10 minutes, and those randomized to SNP were intraperitoneally injected with a dose of 0.01 mg/kg. After 2 hours, nocifensive behavior, in the form of head withdrawal in response to mechanical stimulation of the temporalis and masseter muscles, was examined. Sensitized rats displayed increased nocifensive responses at 2 hours postexposure, and the number of responses was similar between groups.

To then ameliorate nociception, either nVNS (1 ms pulses of 5 kHz sine waves, repeated at 25 Hz for 2 minutes twice at 5-minute intervals) or sumatriptan, delivered subcutaneously at a dose of 0.3 mg/kg, was administered to a subset of the rats. Head withdrawal response was again examined beginning at about 1 hour and 20 minutes after treatment. “Nociceptive response was effectively attenuated by administration of nVNS or sumatriptan 2 hours post-trigger and remained repressed at 24 hours,” according to Dr Durham.

To explore the mechanism of action of nVNS in this same study, the research team intracisternally injected those rats exposed to CBL with the GABA

 receptors were targeted because of the strong evidence of their involvement in descending pain modulation, explained Dr Durham in conversation with 

. “They are known to cause release of the inhibitory neurotransmitters GABA and glycine from inhibitory neurons to block ascending pain signaling.” The injection of GABA

 antagonists in a subset of rats did block the analgesic effect of nVNS.

The nVNS pathway differs from that of triptans, which bind to and stimulate 5-HT

 and block pain signaling neurotransmitters ascending toward the thalamus.

 “The triptans are believed to block the release of CGRP and glutamate from primary trigeminal nerves that project into the spinal cord and thus inhibit activation of second order neurons involved in the ascending pain pathway,” noted Dr Durham. The “take-home,” according to him is that “VNS provides a viable alternative therapy for episodic migraine patients that do not respond to triptans or when triptans are contraindicated,” adding that the use of nVNS may be more beneficial in patients with impaired descending pain modulation.

In addition, nVNS may have value in preventing transformed migraine if initiated early enough. “We have evidence in our lab from animal studies that daily nVNS can prevent the development of chronic trigeminal sensitization in our chronic migraine model when administered early in the transition to a more sensitized system,” said Dr Durham.

1. Cornelison LE, Woodman SE, Durham PL. 

Noninvasive vagus nerve stimulation inhibits trigeminal nociception in two episodic migraine models by enhancing descending pain modulation

. Presented at: 61st Annual Meeting of the American Headache Society; July 11-14, 2019; Philadelphia, PA.

2. Tassorelli C, Grazzi L, de Tommaso M, et al; PRESTO Study Group. 

Noninvasive vagus nerve stimulation as acute therapy for migraine: the randomized PRESTO study

3. Grazzi L, Tassorelli C, de Tommaso M, et al; PRESTO Study Group. 

Practical and clinical utility of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of migraine: a post hoc analysis of the randomized, sham-controlled, double-blind PRESTO trial

Overview of triptans in the treatment of acute migraine

A promising alternative for patients who do not respond well to triptans or who wish to avoid pharmacotherapy.

Vagus Nerve Stimulation on Par With Triptan in Episodic Migraine

 to migraine than are men, with US incidence rates of 18% versus 6%.

 that men with migraine are at risk for being underdiagnosed and 

But why are women so much more susceptible to migraine than men?

A group of  researchers from Shandong University in Jian, Shandong, China, theorized that differences in neurocognitive functioning might be relevant.

 pointed out that besides sex differences, neurocognitive deficits have been implicated in migraine pathophysiology.

The study sought to characterize the effect of gender on migraine and possible interactions between it and neurocognitive processing. They hypothesized that migraineurs, in general, have attentive processing impairment and would demonstrate attentional event-related potential (ERP) abnormalities such as reduced P3 amplitude and/or prolonged P3 latency on EEG. The researchers also suspected that differences in emotional health and attentional processing would be observed between male and female migraineurs.

The team recruited 46 patients with migraine without aura: 23 women and 23 men (average age 33 years) and 46 age- and sex-matched healthy controls. The patients with migraine were interictal when enrolled. Use of migraine prophylaxis and a history of analgesic overuse were among the exclusionary criteria.

All study participants underwent neurologic and psychiatric evaluation for study-inclusion suitability. Emotional characteristics of participants were evaluated via self-rate anxiety and depression scales (SAS and SDS, respectively) and attentive processing was analyzed via ERP examinations using a three-stimulus visual oddball paradigm.

Peak ERP amplitudes and latencies were measured relative to pre-stimulus baseline measures. The positive peak between 300 and 500 ms post-stimulus, the negative peak between 50 and 190 ms, the positive peak between 110 and 270 ms, and the negative peak between 210 and 370 ms were respectively used to define P3, N1, P2 and N2 components.

Components that showed significant sex differences in patients with migraine were further analyzed. The researchers involved in conducting and assessing the EEGs were blinded to study participants’ diagnosis and sex.

The research team found that the patients with migraine were much more apt to have emotional (

 < .001) and visual cognitive processing abnormalities (

 < .001) than healthy controls, including higher levels of anxiety and a reduced P3 amplitude.

These parameters were modulated by sex in patients with migraine but not in the healthy controls. Female migraineurs demonstrated higher levels of anxiety but not depression, as measured via the Self-Rating Anxiety Scale and Self-Rating Depression Scale. Female migraineurs also demonstrated greater impairment in attentive processing of visual stimuli than their male counterparts, as evidenced by ERP waveform analyses.

The findings confirmed that patients with migraine have attentive processing abnormalities. It went on to show that women are more vulnerable than men. The research team stressed that, given their findings, cognitive behavioral therapy that addresses anxiety burdens and a focus on sex difference in migraine should be more strongly emphasized to improve outcomes. They called for more studies aimed at clarifying gender-related discrepancies of migraine and their mechanisms.

1. Migraine Research Foundation (MRF). Migraine Facts. 

https://migraineresearchfoundation.org/about-migraine/migraine-facts

2. Lipton RB, Serrano D, Holland S, et al. 

Barriers to the diagnosis and treatment of migraine: effects of sex, income, and headache features

3. Dodick DW, Loder EW, Manack Adams A, et al. 

Assessing barriers to chronic migraine consultation, diagnosis, and treatment: Results from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study

Female versus male migraine: an event-related potential study of visual neurocognitive processing

Women are three times more susceptible to migraine than are men. The difference is so pronounced that men with migraine are at risk for being underdiagnosed and undertreated. Why such a discrepancy?

Dee Rapposelli

Articles

Concurrent CGRP Inhibitor and OnabotulinumtoxinA Therapy Boosts Relief in Severe Chronic Migraine

Survey Reveals Major Gaps in Migraine Care

Vagus Nerve Stimulation on Par With Triptan in Episodic Migraine

Gender Disparities in Migraine