Migraine ICYMI

Among military veterans with chronic posttraumatic stress disorder (PTSD) and frequent nightmares, prazosin does not alleviate distressing dreams or improve sleep quality, according to trial results published in the February 8 issue of the New England Journal of Medicine.

Prior single-center trials found that prazosin, an alpha 1-adrenoreceptor antagonist, may alleviate nightmares associated with PTSD and improve overall clinical status. The present study’s eligibility criteria may have led to selection bias that contributed to its negative results, the researchers said.

The PACT Trial

To investigate the efficacy of prazosin in patients with chronic combat-related PTSD and frequent nightmares, Murray A. Raskind, MD, and colleagues conducted the Prazosin and Combat Trauma PTSD (PACT) trial. Dr. Raskind is the Director of the Veterans Affairs (VA) Northwest Network Mental Illness Research, Education, and Clinical Center and Professor and Vice Chair of Psychiatry and Behavioral Sciences at the University of Washington School of Medicine in Seattle.

The 26-week, double-blind, randomized, controlled trial included 304 veterans from 12 VA medical centers. Participants met DSM-IV criteria for PTSD; had a total score of at least 50 on the 17-item Clinician-Administered PTSD Scale (CAPS); had been exposed to one or more traumatic, life-threatening events in a war zone before the onset of recurrent nightmares; could recall combat-related nightmares; had a frequency score of at least 2 and a cumulative score of at least 5 on CAPS item B2 (ie, “recurrent distressing dreams”); and, for at least four weeks before randomization, were receiving a stable dose of nonexcluded medications or supportive psychotherapy. Exclusion criteria included unstable medical illness, a systolic blood pressure of less than 110 mm Hg in the supine position, active suicidal or homicidal ideation with plan or intent, and psychosocial instability.

Of 413 people screened, 304 underwent randomization (about 98% male; average age, 52); 152 patients were assigned to each treatment group. The two groups’ patient characteristics did not differ significantly at baseline. Researchers administered prazosin or placebo in escalating divided doses over five weeks to a daily maximum of 20 mg in men and 12 mg in women.

Primary Outcome Measures

The three primary outcome measures were change in score from baseline to 10 weeks on the CAPS item B2, change in score from baseline to 10 weeks on the Pittsburgh Sleep Quality Index, and the Clinical Global Impression of Change score at 10 weeks. None of the primary outcome measures significantly differed between the groups at 10 weeks. The groups’ outcome measures at 26 weeks and other secondary outcomes also were not significantly different.

The number of serious adverse events did not differ significantly by group. Of the adverse events, dizziness, lightheadedness, and urinary incontinence were significantly more common in the prazosin group, compared with the placebo group, whereas new or worsening suicidal ideation was significantly less common among participants who received prazosin, compared with patients who received placebo (8% vs 15%, respectively).

The investigators enrolled patients who were mainly in clinically stable condition, which may have led the trial to include patients whose distressing dreams were unlikely to respond to prazosin, Dr. Raskind and colleagues said.

Future Directions

“The failure of this new, large, multisite trial to replicate the previous studies is surprising and disappointing,” said Kerry J. Ressler, MD, PhD, Chief of the Division of Depression and Anxiety Disorders at McLean Hospital in Belmont, Massachusetts, and Professor of Psychiatry at Harvard Medical School in Boston, in an accompanying editorial. “PTSD remains a psychiatric malady that in some respects seems understandable and treatable on the basis of known neurobiologic pathways. Yet it is a complex syndrome with innumerable subtypes and variations…. There is a need to define clinical subtypes of PTSD on the basis of biologic markers.”

Studies of prazosin for the treatment of other conditions are under way. Investigators have initiated trials to examine whether prazosin reduces the frequency of chronic postconcussive headaches, compared with placebo.

—Jake Remaly

Suggested Reading

Raskind MA, Peskind ER, Chow B, et al. Trial of prazosin for post-traumatic stress disorder in military veterans. N Engl J Med. 2018;378(6):507-517.

Raskind MA, Peterson K, Williams T, et al. A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan. Am J Psychiatry. 2013;170(9):1003-1010.

Ressler KJ. Alpha-adrenergic receptors in PTSD - Failure or time for precision medicine? N Engl J Med. 2018; 378(6):575-576.

Among military veterans with chronic posttraumatic stress disorder (PTSD) and frequent nightmares, prazosin does not alleviate distressing dreams or improve sleep quality, according to trial results published in the February 8 issue of the New England Journal of Medicine.

Prior single-center trials found that prazosin, an alpha 1-adrenoreceptor antagonist, may alleviate nightmares associated with PTSD and improve overall clinical status. The present study’s eligibility criteria may have led to selection bias that contributed to its negative results, the researchers said.

The PACT Trial

To investigate the efficacy of prazosin in patients with chronic combat-related PTSD and frequent nightmares, Murray A. Raskind, MD, and colleagues conducted the Prazosin and Combat Trauma PTSD (PACT) trial. Dr. Raskind is the Director of the Veterans Affairs (VA) Northwest Network Mental Illness Research, Education, and Clinical Center and Professor and Vice Chair of Psychiatry and Behavioral Sciences at the University of Washington School of Medicine in Seattle.

The 26-week, double-blind, randomized, controlled trial included 304 veterans from 12 VA medical centers. Participants met DSM-IV criteria for PTSD; had a total score of at least 50 on the 17-item Clinician-Administered PTSD Scale (CAPS); had been exposed to one or more traumatic, life-threatening events in a war zone before the onset of recurrent nightmares; could recall combat-related nightmares; had a frequency score of at least 2 and a cumulative score of at least 5 on CAPS item B2 (ie, “recurrent distressing dreams”); and, for at least four weeks before randomization, were receiving a stable dose of nonexcluded medications or supportive psychotherapy. Exclusion criteria included unstable medical illness, a systolic blood pressure of less than 110 mm Hg in the supine position, active suicidal or homicidal ideation with plan or intent, and psychosocial instability.

Of 413 people screened, 304 underwent randomization (about 98% male; average age, 52); 152 patients were assigned to each treatment group. The two groups’ patient characteristics did not differ significantly at baseline. Researchers administered prazosin or placebo in escalating divided doses over five weeks to a daily maximum of 20 mg in men and 12 mg in women.

Primary Outcome Measures

The three primary outcome measures were change in score from baseline to 10 weeks on the CAPS item B2, change in score from baseline to 10 weeks on the Pittsburgh Sleep Quality Index, and the Clinical Global Impression of Change score at 10 weeks. None of the primary outcome measures significantly differed between the groups at 10 weeks. The groups’ outcome measures at 26 weeks and other secondary outcomes also were not significantly different.

The number of serious adverse events did not differ significantly by group. Of the adverse events, dizziness, lightheadedness, and urinary incontinence were significantly more common in the prazosin group, compared with the placebo group, whereas new or worsening suicidal ideation was significantly less common among participants who received prazosin, compared with patients who received placebo (8% vs 15%, respectively).

The investigators enrolled patients who were mainly in clinically stable condition, which may have led the trial to include patients whose distressing dreams were unlikely to respond to prazosin, Dr. Raskind and colleagues said.

Future Directions

“The failure of this new, large, multisite trial to replicate the previous studies is surprising and disappointing,” said Kerry J. Ressler, MD, PhD, Chief of the Division of Depression and Anxiety Disorders at McLean Hospital in Belmont, Massachusetts, and Professor of Psychiatry at Harvard Medical School in Boston, in an accompanying editorial. “PTSD remains a psychiatric malady that in some respects seems understandable and treatable on the basis of known neurobiologic pathways. Yet it is a complex syndrome with innumerable subtypes and variations…. There is a need to define clinical subtypes of PTSD on the basis of biologic markers.”

Studies of prazosin for the treatment of other conditions are under way. Investigators have initiated trials to examine whether prazosin reduces the frequency of chronic postconcussive headaches, compared with placebo.

—Jake Remaly

Suggested Reading

Raskind MA, Peskind ER, Chow B, et al. Trial of prazosin for post-traumatic stress disorder in military veterans. N Engl J Med. 2018;378(6):507-517.

Raskind MA, Peterson K, Williams T, et al. A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan. Am J Psychiatry. 2013;170(9):1003-1010.

Ressler KJ. Alpha-adrenergic receptors in PTSD - Failure or time for precision medicine? N Engl J Med. 2018; 378(6):575-576.

Among military veterans with chronic posttraumatic stress disorder (PTSD) and frequent nightmares, prazosin does not alleviate distressing dreams or improve sleep quality, according to trial results published in the February 8 issue of the New England Journal of Medicine.

Prior single-center trials found that prazosin, an alpha 1-adrenoreceptor antagonist, may alleviate nightmares associated with PTSD and improve overall clinical status. The present study’s eligibility criteria may have led to selection bias that contributed to its negative results, the researchers said.

The PACT Trial

To investigate the efficacy of prazosin in patients with chronic combat-related PTSD and frequent nightmares, Murray A. Raskind, MD, and colleagues conducted the Prazosin and Combat Trauma PTSD (PACT) trial. Dr. Raskind is the Director of the Veterans Affairs (VA) Northwest Network Mental Illness Research, Education, and Clinical Center and Professor and Vice Chair of Psychiatry and Behavioral Sciences at the University of Washington School of Medicine in Seattle.

The 26-week, double-blind, randomized, controlled trial included 304 veterans from 12 VA medical centers. Participants met DSM-IV criteria for PTSD; had a total score of at least 50 on the 17-item Clinician-Administered PTSD Scale (CAPS); had been exposed to one or more traumatic, life-threatening events in a war zone before the onset of recurrent nightmares; could recall combat-related nightmares; had a frequency score of at least 2 and a cumulative score of at least 5 on CAPS item B2 (ie, “recurrent distressing dreams”); and, for at least four weeks before randomization, were receiving a stable dose of nonexcluded medications or supportive psychotherapy. Exclusion criteria included unstable medical illness, a systolic blood pressure of less than 110 mm Hg in the supine position, active suicidal or homicidal ideation with plan or intent, and psychosocial instability.

Of 413 people screened, 304 underwent randomization (about 98% male; average age, 52); 152 patients were assigned to each treatment group. The two groups’ patient characteristics did not differ significantly at baseline. Researchers administered prazosin or placebo in escalating divided doses over five weeks to a daily maximum of 20 mg in men and 12 mg in women.

Primary Outcome Measures

The three primary outcome measures were change in score from baseline to 10 weeks on the CAPS item B2, change in score from baseline to 10 weeks on the Pittsburgh Sleep Quality Index, and the Clinical Global Impression of Change score at 10 weeks. None of the primary outcome measures significantly differed between the groups at 10 weeks. The groups’ outcome measures at 26 weeks and other secondary outcomes also were not significantly different.

The number of serious adverse events did not differ significantly by group. Of the adverse events, dizziness, lightheadedness, and urinary incontinence were significantly more common in the prazosin group, compared with the placebo group, whereas new or worsening suicidal ideation was significantly less common among participants who received prazosin, compared with patients who received placebo (8% vs 15%, respectively).

The investigators enrolled patients who were mainly in clinically stable condition, which may have led the trial to include patients whose distressing dreams were unlikely to respond to prazosin, Dr. Raskind and colleagues said.

Future Directions

“The failure of this new, large, multisite trial to replicate the previous studies is surprising and disappointing,” said Kerry J. Ressler, MD, PhD, Chief of the Division of Depression and Anxiety Disorders at McLean Hospital in Belmont, Massachusetts, and Professor of Psychiatry at Harvard Medical School in Boston, in an accompanying editorial. “PTSD remains a psychiatric malady that in some respects seems understandable and treatable on the basis of known neurobiologic pathways. Yet it is a complex syndrome with innumerable subtypes and variations…. There is a need to define clinical subtypes of PTSD on the basis of biologic markers.”

Studies of prazosin for the treatment of other conditions are under way. Investigators have initiated trials to examine whether prazosin reduces the frequency of chronic postconcussive headaches, compared with placebo.

—Jake Remaly

Suggested Reading

Raskind MA, Peskind ER, Chow B, et al. Trial of prazosin for post-traumatic stress disorder in military veterans. N Engl J Med. 2018;378(6):507-517.

Raskind MA, Peterson K, Williams T, et al. A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan. Am J Psychiatry. 2013;170(9):1003-1010.

Ressler KJ. Alpha-adrenergic receptors in PTSD - Failure or time for precision medicine? N Engl J Med. 2018; 378(6):575-576.

Headaches that reach peak intensity in less than one second of onset are significantly more common in patients with subarachnoid hemorrhage (SAH) than in patients who present to a hospital with headaches caused by other conditions, according to a prospective, observational study published in the March issue of Headache. Other headache characteristics, including occipital location and a stabbing quality, also are more likely in patients with SAH.

“Our study suggests a number of features of the clinical history that may aid in identifying those patients presenting with headache at high likelihood of having an SAH,” said Brian Mac Grory, MB, BCh, BAO, Assistant Professor of Neurology at Warren Alpert Medical School of Brown University in Providence, Rhode Island, and colleagues. “This points to the possibility that we may be able to more accurately triage patients in the acute setting based on readily obtainable clinical metrics, which has the potential to reduce the number of expensive and invasive diagnostic tests performed, as well as the number of missed diagnoses.”

SAH is a life-threatening emergency. Patients most commonly present with a severe headache, but the presentation of SAH varies and is often subtle, the researchers said.

To characterize the headache associated with SAH, Dr. Mac Grory and colleagues performed a prospective, observational study examining the clinical features of the presenting headache in people with and without SAH in the emergency department and in the neurosciences intensive care unit of a tertiary referral center. They sought to assess whether any easily obtainable features of the clinical history might allow clinicians to predict whether a person has an SAH in the acute setting. The investigators documented clinical features of the headache, including the time to peak intensity, location, associated symptoms, and activities that caused worsening.

The researchers enrolled 158 subjects, of whom 20 had SAH. Distinguishing features included occipital location (55% in the SAH group vs 22% in the non-SAH group), stabbing quality (35% in the SAH group vs 5% in the non-SAH group), presence of prior headache (50% in the SAH group vs 83% in the non-SAH group), associated meningismus (80% in the SAH group vs 42% in the non-SAH group), and headache that reached peak intensity within 1 second (65% in the SAH group vs 10% in the non-SAH group).

—Jake Remaly

Suggested Reading

Mac Grory B, Vu L, Cutting S, et al. Distinguishing characteristics of headache in nontraumatic subarachnoid hemorrhage. Headache. 2018;58(3):364-370.

Headaches that reach peak intensity in less than one second of onset are significantly more common in patients with subarachnoid hemorrhage (SAH) than in patients who present to a hospital with headaches caused by other conditions, according to a prospective, observational study published in the March issue of Headache. Other headache characteristics, including occipital location and a stabbing quality, also are more likely in patients with SAH.

“Our study suggests a number of features of the clinical history that may aid in identifying those patients presenting with headache at high likelihood of having an SAH,” said Brian Mac Grory, MB, BCh, BAO, Assistant Professor of Neurology at Warren Alpert Medical School of Brown University in Providence, Rhode Island, and colleagues. “This points to the possibility that we may be able to more accurately triage patients in the acute setting based on readily obtainable clinical metrics, which has the potential to reduce the number of expensive and invasive diagnostic tests performed, as well as the number of missed diagnoses.”

SAH is a life-threatening emergency. Patients most commonly present with a severe headache, but the presentation of SAH varies and is often subtle, the researchers said.

To characterize the headache associated with SAH, Dr. Mac Grory and colleagues performed a prospective, observational study examining the clinical features of the presenting headache in people with and without SAH in the emergency department and in the neurosciences intensive care unit of a tertiary referral center. They sought to assess whether any easily obtainable features of the clinical history might allow clinicians to predict whether a person has an SAH in the acute setting. The investigators documented clinical features of the headache, including the time to peak intensity, location, associated symptoms, and activities that caused worsening.

The researchers enrolled 158 subjects, of whom 20 had SAH. Distinguishing features included occipital location (55% in the SAH group vs 22% in the non-SAH group), stabbing quality (35% in the SAH group vs 5% in the non-SAH group), presence of prior headache (50% in the SAH group vs 83% in the non-SAH group), associated meningismus (80% in the SAH group vs 42% in the non-SAH group), and headache that reached peak intensity within 1 second (65% in the SAH group vs 10% in the non-SAH group).

—Jake Remaly

Suggested Reading

Mac Grory B, Vu L, Cutting S, et al. Distinguishing characteristics of headache in nontraumatic subarachnoid hemorrhage. Headache. 2018;58(3):364-370.

Headaches that reach peak intensity in less than one second of onset are significantly more common in patients with subarachnoid hemorrhage (SAH) than in patients who present to a hospital with headaches caused by other conditions, according to a prospective, observational study published in the March issue of Headache. Other headache characteristics, including occipital location and a stabbing quality, also are more likely in patients with SAH.

“Our study suggests a number of features of the clinical history that may aid in identifying those patients presenting with headache at high likelihood of having an SAH,” said Brian Mac Grory, MB, BCh, BAO, Assistant Professor of Neurology at Warren Alpert Medical School of Brown University in Providence, Rhode Island, and colleagues. “This points to the possibility that we may be able to more accurately triage patients in the acute setting based on readily obtainable clinical metrics, which has the potential to reduce the number of expensive and invasive diagnostic tests performed, as well as the number of missed diagnoses.”

SAH is a life-threatening emergency. Patients most commonly present with a severe headache, but the presentation of SAH varies and is often subtle, the researchers said.

To characterize the headache associated with SAH, Dr. Mac Grory and colleagues performed a prospective, observational study examining the clinical features of the presenting headache in people with and without SAH in the emergency department and in the neurosciences intensive care unit of a tertiary referral center. They sought to assess whether any easily obtainable features of the clinical history might allow clinicians to predict whether a person has an SAH in the acute setting. The investigators documented clinical features of the headache, including the time to peak intensity, location, associated symptoms, and activities that caused worsening.

The researchers enrolled 158 subjects, of whom 20 had SAH. Distinguishing features included occipital location (55% in the SAH group vs 22% in the non-SAH group), stabbing quality (35% in the SAH group vs 5% in the non-SAH group), presence of prior headache (50% in the SAH group vs 83% in the non-SAH group), associated meningismus (80% in the SAH group vs 42% in the non-SAH group), and headache that reached peak intensity within 1 second (65% in the SAH group vs 10% in the non-SAH group).

—Jake Remaly

Suggested Reading

Mac Grory B, Vu L, Cutting S, et al. Distinguishing characteristics of headache in nontraumatic subarachnoid hemorrhage. Headache. 2018;58(3):364-370.

STOWE, VT—The development of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) has made migraine prevention a hot topic. Although FDA approval of these therapies could transform the field in the months ahead, the guiding principles and mainstays of preventive therapy remain unchanged. At the Headache Cooperative of New England’s 28th Annual Stowe Headache Symposium, Robert E. Shapiro, MD, PhD, reviewed the goals, principles, and current options for preventive migraine therapy. Dr. Shapiro is Professor of Neurological Sciences at the Larner College of Medicine at the University of Vermont in Burlington.

The goals of migraine prevention, Dr. Shapiro said, are to decrease attack frequency, severity, and duration; improve responsiveness to acute treatment; improve function and reduce disability; prevent acute analgesic overuse; and possibly reduce the total cost of treatment. “Achieving zero headaches and zero symptoms of migraine,” he said, “is an emerging goal … but we are not there yet.”

First Things First

Before considering what to prescribe, a neurologist should keep certain guiding principles in mind. Using headache calendars to follow treatment compliance and effects is essential, said Dr. Shapiro. To prevent patients from fixating on their symptoms, Dr. Shapiro advised that documentation be kept to a minimum. He asks his patients to record at the end of each day whether they had a headache and what the severity of the headache was at its worst.

Behavioral therapies also are essential. “Part of this [regimen] is simple cognitive restructuring,” Dr. Shapiro said. He recommended stabilizing bedtime and waking hours, mealtime, and exercise time. “Keep surprises to a minimum, in terms of daily schedule.” Avoiding exposures such as odors or food triggers can be helpful, as long as patients do not obsess over these exposures.

Cognitive behavioral therapy, yoga, and other types of behavioral therapies have demonstrated significant benefit. Likewise, sleep modification can be helpful. Incorporating these techniques into a prevention plan is important, Dr. Shapiro said. It also is important to treat relevant comorbid conditions. Dr. Shapiro also recommends tapering analgesics and caffeine.

Keeping Things in Perspective

There are several “inconvenient truths” about what can be achieved with preventive medications, Dr. Shapiro said. “Only four medications are FDA-approved for prevention of episodic migraine, and one for chronic migraine. None of them were developed for migraine. We are hopeful that later this year there will be FDA-approved medications that were developed for the prevention of migraine.” Additionally, the FDA cleared a few devices for migraine prevention. The caveat is that the standards for approval differ between drugs and devices. “Whenever a device is cleared … it is important to go back and look with some level of higher scrutiny at what the evidence base is for efficacy,” Dr. Shapiro advised.

All available drugs have limited tolerability. There is no clear and obviously superior medication, from the standpoint of efficacy. “A 50% reduction in headache days in half the patients is considered a pretty good outcome,” Dr. Shapiro said. Treatment choice needs to take efficacy, comorbid conditions, cost, side effects, convenient formulations, patient preferences, and prior history into account.

Another basic principle is slow titration to the optimal dose. The dose–response curve for some medications reaches a plateau, Dr. Shapiro said. If the therapeutic window is exceeded, the efficacy begins to decrease. Analgesic overuse is another potential problem. “It is important to have a trial at the appropriate dose for at least two months before you can make a judgment as to whether the medication is helpful. Individual responses are hard to predict.” Finally, Dr. Shapiro suggested tapering a medication off after 12 months. “There is some sense that with a reduction in the frequency of events, there may be a stabilizing effect. That is not based on a lot of evidence. It is based, rather, on clinical experience. Successful preventive medications may be tapered off, and there may be a durable benefit after it has been there for a while,” he said.

The most sobering fact about preventive medications, Dr. Shapiro said, is that “83% of patients started on a preventive medication are not taking it one year later.”

Starting Preventive Treatment

The consensus among a panel of experts was that headache at six days or more per month should be the threshold for offering a patient a preventive therapy, whereas it should be considered for patients experiencing four to five days with headache per month. “Based on this [principle], a 2007 study found that 13% of migraine patients were on preventive medications, while an additional 26% should be offered preventive medications, and in 13% preventives should be considered,” Dr. Shapiro said.

Based on the 2012 American Headache Society/American Academy of Neurology guideline for episodic migraine preventive drugs, there is Level A (established as effective) evidence for divalproex sodium ER (1,000 mg daily), topiramate (50 mg bid), propranolol (120 mg to 160 mg daily), timolol (10 mg to 15 mg bid), metoprolol (100 mg bid), and petasites (ie, butterbur). The first four medicines are FDA-approved for migraine, and metoprolol is included based on the evidence available, even though it is not FDA-approved for this indication. “Butterbur is effective, but there is an almost universal sense that we should not be offering this to patients because of the concern about potential liver toxicity and insufficient assurance from manufacturers that the agents that might cause that toxicity have been removed,” Dr. Shapiro said.

Several studies comparing efficacy, defined as the 50% responder rate, have indicated that valproate, topiramate, and propranolol all have approximately the same level of efficacy. Approximately 45% of patients receiving these therapies had 50% reduction in attack frequency or severity.

Level B (probably effective) evidence exists for several agents that are in common use, such as amitriptyline, candesartan, lisinopril, amlodipine and zonisamide. Other agents with Level B evidence include nutraceuticals and vitamin agents, such as megadoses of riboflavin and magnesium.

As previously mentioned, selection of a preventive agent may be guided by comorbidity. If a patient has hypertension, for example, angiotensin receptor blockers, ACE inhibitors, beta blockers, or calcium channel blockers are worth considering. In its evaluation of medications for migraine prevention, the Agency for Healthcare Research and Quality issued its own evaluation of medications for migraine prevention and suggested that even though angiotensin receptor blockers such as candesartan, or angiotensin converting enzyme inhibitors such as lisinopril, are not FDA-approved to treat migraine, their relative tolerability suggests that they could be first-line agents for this purpose. For depression, venlafaxine could be an appropriate choice. If a patient is obese, topiramate or zonisamide should be considered. If epilepsy is comorbid with migraine, obvious choices would be topiramate, divalproate, or zonisamide. For neuropathic pain or insomnia, tricyclic antidepressants are appropriate.

Game Changer?

“We are all excited about the new developments” related to the CGRP agents in clinical trials, Dr. Shapiro said, “but how much these drugs may improve clinical outcomes remains to be seen.” Independent lines of evidence suggest that CGRP is involved during migraine attacks and that blocking the effects of CGRP can have therapeutic benefit.

The four medications in late-stage clinical development are erenumab, fremanezumab, galcanezumab, and eptinezumab. Three of them have been submitted to the FDA for review. They are all either fully human or humanized antibodies. All of them have been studied in clinical trials for episodic and chronic migraine. Galcanezumab and fremanezumab are being studied for episodic and chronic cluster headache. Erenumab is an antibody directed against the CGRP receptor, whereas the other three treatments target CGRP itself. Erenumab, fremanezumab, and galcanezumab are delivered by monthly or quarterly subcutaneous injections. Eptinezumab has been studied as a quarterly IV infusion. The dosage and frequency of administration will remain uncertain until the FDA approves specific regimens for these therapies, Dr. Shapiro said.

Regulatory news is pending. The PDUFA date for FDA reporting on erenumab is May 17, 2018. Unexpected problems at the manufacturing plant in South Korea have raised questions about the timing of fremanezumab availability, but the FDA is still expected to render a judgment on its approvability by this summer. For galcanezumab, an FDA decision is expected by late September 2018. Eptinezumab has not yet been submitted for approval.

Other Options

Botox is approved for prevention of chronic migraine. Neurologists administer 155 units to 31 injection sites. In clinical trials, baseline monthly headache frequency of 20 days was reduced to 11.5 days among patients receiving onabotulinumtoxinA and to 13 days among controls. The therapeutic gain was about 9%, or about 1.7 days, during the 28-day trial period. At least 78% of the improvement associated with Botox was attributed to the placebo effect, Dr. Shapiro noted. “But that does not mean that this is not a helpful thing to do…. This helps a lot of people, even though the placebo effect is substantial.”

The Cefaly transcutaneous electrical nerve stimulation (TENS) device has been cleared for marketing by the FDA. In clinical trials, the device did not significantly reduce the number of headache days at three months, compared with sham treatment, but the FDA cleared the device nevertheless. “This [treatment] is of variable benefit,” Dr. Shapiro said. “Evidence of that is that only about half of the patients who tried it were willing to buy the device after two months.”

The sTMS mini transcranial magnetic stimulation device was cleared for marketing in the summer of 2017. In clinical trials, this device reduced headache frequency by two to three days per month when used for prevention of episodic or chronic migraine. The clinical trial, however, was open-label and used a “performance goal” comparator that was estimated from placebo responses in several other clinical trials, rather than a sham control; this design raises concerns about the validity of the efficacy claims. “This [device] is another potential option, but again, the evidence that the FDA accepted for clearing this device was not what we would prefer,” Dr. Shapiro said.

—Glenn S. Williams

Suggested Reading

Shamliyan TA, Choi JY, Ramakrishnan R, et al. Preventive pharmacologic treatments for episodic migraine in adults. J Gen Intern Med. 2013;28(9):1225-1237.

Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337-1345.

STOWE, VT—The development of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) has made migraine prevention a hot topic. Although FDA approval of these therapies could transform the field in the months ahead, the guiding principles and mainstays of preventive therapy remain unchanged. At the Headache Cooperative of New England’s 28th Annual Stowe Headache Symposium, Robert E. Shapiro, MD, PhD, reviewed the goals, principles, and current options for preventive migraine therapy. Dr. Shapiro is Professor of Neurological Sciences at the Larner College of Medicine at the University of Vermont in Burlington.

The goals of migraine prevention, Dr. Shapiro said, are to decrease attack frequency, severity, and duration; improve responsiveness to acute treatment; improve function and reduce disability; prevent acute analgesic overuse; and possibly reduce the total cost of treatment. “Achieving zero headaches and zero symptoms of migraine,” he said, “is an emerging goal … but we are not there yet.”

First Things First

Before considering what to prescribe, a neurologist should keep certain guiding principles in mind. Using headache calendars to follow treatment compliance and effects is essential, said Dr. Shapiro. To prevent patients from fixating on their symptoms, Dr. Shapiro advised that documentation be kept to a minimum. He asks his patients to record at the end of each day whether they had a headache and what the severity of the headache was at its worst.

Behavioral therapies also are essential. “Part of this [regimen] is simple cognitive restructuring,” Dr. Shapiro said. He recommended stabilizing bedtime and waking hours, mealtime, and exercise time. “Keep surprises to a minimum, in terms of daily schedule.” Avoiding exposures such as odors or food triggers can be helpful, as long as patients do not obsess over these exposures.

Cognitive behavioral therapy, yoga, and other types of behavioral therapies have demonstrated significant benefit. Likewise, sleep modification can be helpful. Incorporating these techniques into a prevention plan is important, Dr. Shapiro said. It also is important to treat relevant comorbid conditions. Dr. Shapiro also recommends tapering analgesics and caffeine.

Keeping Things in Perspective

There are several “inconvenient truths” about what can be achieved with preventive medications, Dr. Shapiro said. “Only four medications are FDA-approved for prevention of episodic migraine, and one for chronic migraine. None of them were developed for migraine. We are hopeful that later this year there will be FDA-approved medications that were developed for the prevention of migraine.” Additionally, the FDA cleared a few devices for migraine prevention. The caveat is that the standards for approval differ between drugs and devices. “Whenever a device is cleared … it is important to go back and look with some level of higher scrutiny at what the evidence base is for efficacy,” Dr. Shapiro advised.

All available drugs have limited tolerability. There is no clear and obviously superior medication, from the standpoint of efficacy. “A 50% reduction in headache days in half the patients is considered a pretty good outcome,” Dr. Shapiro said. Treatment choice needs to take efficacy, comorbid conditions, cost, side effects, convenient formulations, patient preferences, and prior history into account.

Another basic principle is slow titration to the optimal dose. The dose–response curve for some medications reaches a plateau, Dr. Shapiro said. If the therapeutic window is exceeded, the efficacy begins to decrease. Analgesic overuse is another potential problem. “It is important to have a trial at the appropriate dose for at least two months before you can make a judgment as to whether the medication is helpful. Individual responses are hard to predict.” Finally, Dr. Shapiro suggested tapering a medication off after 12 months. “There is some sense that with a reduction in the frequency of events, there may be a stabilizing effect. That is not based on a lot of evidence. It is based, rather, on clinical experience. Successful preventive medications may be tapered off, and there may be a durable benefit after it has been there for a while,” he said.

The most sobering fact about preventive medications, Dr. Shapiro said, is that “83% of patients started on a preventive medication are not taking it one year later.”

Starting Preventive Treatment

The consensus among a panel of experts was that headache at six days or more per month should be the threshold for offering a patient a preventive therapy, whereas it should be considered for patients experiencing four to five days with headache per month. “Based on this [principle], a 2007 study found that 13% of migraine patients were on preventive medications, while an additional 26% should be offered preventive medications, and in 13% preventives should be considered,” Dr. Shapiro said.

Based on the 2012 American Headache Society/American Academy of Neurology guideline for episodic migraine preventive drugs, there is Level A (established as effective) evidence for divalproex sodium ER (1,000 mg daily), topiramate (50 mg bid), propranolol (120 mg to 160 mg daily), timolol (10 mg to 15 mg bid), metoprolol (100 mg bid), and petasites (ie, butterbur). The first four medicines are FDA-approved for migraine, and metoprolol is included based on the evidence available, even though it is not FDA-approved for this indication. “Butterbur is effective, but there is an almost universal sense that we should not be offering this to patients because of the concern about potential liver toxicity and insufficient assurance from manufacturers that the agents that might cause that toxicity have been removed,” Dr. Shapiro said.

Several studies comparing efficacy, defined as the 50% responder rate, have indicated that valproate, topiramate, and propranolol all have approximately the same level of efficacy. Approximately 45% of patients receiving these therapies had 50% reduction in attack frequency or severity.

Level B (probably effective) evidence exists for several agents that are in common use, such as amitriptyline, candesartan, lisinopril, amlodipine and zonisamide. Other agents with Level B evidence include nutraceuticals and vitamin agents, such as megadoses of riboflavin and magnesium.

As previously mentioned, selection of a preventive agent may be guided by comorbidity. If a patient has hypertension, for example, angiotensin receptor blockers, ACE inhibitors, beta blockers, or calcium channel blockers are worth considering. In its evaluation of medications for migraine prevention, the Agency for Healthcare Research and Quality issued its own evaluation of medications for migraine prevention and suggested that even though angiotensin receptor blockers such as candesartan, or angiotensin converting enzyme inhibitors such as lisinopril, are not FDA-approved to treat migraine, their relative tolerability suggests that they could be first-line agents for this purpose. For depression, venlafaxine could be an appropriate choice. If a patient is obese, topiramate or zonisamide should be considered. If epilepsy is comorbid with migraine, obvious choices would be topiramate, divalproate, or zonisamide. For neuropathic pain or insomnia, tricyclic antidepressants are appropriate.

Game Changer?

“We are all excited about the new developments” related to the CGRP agents in clinical trials, Dr. Shapiro said, “but how much these drugs may improve clinical outcomes remains to be seen.” Independent lines of evidence suggest that CGRP is involved during migraine attacks and that blocking the effects of CGRP can have therapeutic benefit.

The four medications in late-stage clinical development are erenumab, fremanezumab, galcanezumab, and eptinezumab. Three of them have been submitted to the FDA for review. They are all either fully human or humanized antibodies. All of them have been studied in clinical trials for episodic and chronic migraine. Galcanezumab and fremanezumab are being studied for episodic and chronic cluster headache. Erenumab is an antibody directed against the CGRP receptor, whereas the other three treatments target CGRP itself. Erenumab, fremanezumab, and galcanezumab are delivered by monthly or quarterly subcutaneous injections. Eptinezumab has been studied as a quarterly IV infusion. The dosage and frequency of administration will remain uncertain until the FDA approves specific regimens for these therapies, Dr. Shapiro said.

Regulatory news is pending. The PDUFA date for FDA reporting on erenumab is May 17, 2018. Unexpected problems at the manufacturing plant in South Korea have raised questions about the timing of fremanezumab availability, but the FDA is still expected to render a judgment on its approvability by this summer. For galcanezumab, an FDA decision is expected by late September 2018. Eptinezumab has not yet been submitted for approval.

Other Options

Botox is approved for prevention of chronic migraine. Neurologists administer 155 units to 31 injection sites. In clinical trials, baseline monthly headache frequency of 20 days was reduced to 11.5 days among patients receiving onabotulinumtoxinA and to 13 days among controls. The therapeutic gain was about 9%, or about 1.7 days, during the 28-day trial period. At least 78% of the improvement associated with Botox was attributed to the placebo effect, Dr. Shapiro noted. “But that does not mean that this is not a helpful thing to do…. This helps a lot of people, even though the placebo effect is substantial.”

The Cefaly transcutaneous electrical nerve stimulation (TENS) device has been cleared for marketing by the FDA. In clinical trials, the device did not significantly reduce the number of headache days at three months, compared with sham treatment, but the FDA cleared the device nevertheless. “This [treatment] is of variable benefit,” Dr. Shapiro said. “Evidence of that is that only about half of the patients who tried it were willing to buy the device after two months.”

The sTMS mini transcranial magnetic stimulation device was cleared for marketing in the summer of 2017. In clinical trials, this device reduced headache frequency by two to three days per month when used for prevention of episodic or chronic migraine. The clinical trial, however, was open-label and used a “performance goal” comparator that was estimated from placebo responses in several other clinical trials, rather than a sham control; this design raises concerns about the validity of the efficacy claims. “This [device] is another potential option, but again, the evidence that the FDA accepted for clearing this device was not what we would prefer,” Dr. Shapiro said.

—Glenn S. Williams

Suggested Reading

Shamliyan TA, Choi JY, Ramakrishnan R, et al. Preventive pharmacologic treatments for episodic migraine in adults. J Gen Intern Med. 2013;28(9):1225-1237.

Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337-1345.

STOWE, VT—The development of monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) has made migraine prevention a hot topic. Although FDA approval of these therapies could transform the field in the months ahead, the guiding principles and mainstays of preventive therapy remain unchanged. At the Headache Cooperative of New England’s 28th Annual Stowe Headache Symposium, Robert E. Shapiro, MD, PhD, reviewed the goals, principles, and current options for preventive migraine therapy. Dr. Shapiro is Professor of Neurological Sciences at the Larner College of Medicine at the University of Vermont in Burlington.

The goals of migraine prevention, Dr. Shapiro said, are to decrease attack frequency, severity, and duration; improve responsiveness to acute treatment; improve function and reduce disability; prevent acute analgesic overuse; and possibly reduce the total cost of treatment. “Achieving zero headaches and zero symptoms of migraine,” he said, “is an emerging goal … but we are not there yet.”

First Things First

Before considering what to prescribe, a neurologist should keep certain guiding principles in mind. Using headache calendars to follow treatment compliance and effects is essential, said Dr. Shapiro. To prevent patients from fixating on their symptoms, Dr. Shapiro advised that documentation be kept to a minimum. He asks his patients to record at the end of each day whether they had a headache and what the severity of the headache was at its worst.

Behavioral therapies also are essential. “Part of this [regimen] is simple cognitive restructuring,” Dr. Shapiro said. He recommended stabilizing bedtime and waking hours, mealtime, and exercise time. “Keep surprises to a minimum, in terms of daily schedule.” Avoiding exposures such as odors or food triggers can be helpful, as long as patients do not obsess over these exposures.

Cognitive behavioral therapy, yoga, and other types of behavioral therapies have demonstrated significant benefit. Likewise, sleep modification can be helpful. Incorporating these techniques into a prevention plan is important, Dr. Shapiro said. It also is important to treat relevant comorbid conditions. Dr. Shapiro also recommends tapering analgesics and caffeine.

Keeping Things in Perspective

There are several “inconvenient truths” about what can be achieved with preventive medications, Dr. Shapiro said. “Only four medications are FDA-approved for prevention of episodic migraine, and one for chronic migraine. None of them were developed for migraine. We are hopeful that later this year there will be FDA-approved medications that were developed for the prevention of migraine.” Additionally, the FDA cleared a few devices for migraine prevention. The caveat is that the standards for approval differ between drugs and devices. “Whenever a device is cleared … it is important to go back and look with some level of higher scrutiny at what the evidence base is for efficacy,” Dr. Shapiro advised.

All available drugs have limited tolerability. There is no clear and obviously superior medication, from the standpoint of efficacy. “A 50% reduction in headache days in half the patients is considered a pretty good outcome,” Dr. Shapiro said. Treatment choice needs to take efficacy, comorbid conditions, cost, side effects, convenient formulations, patient preferences, and prior history into account.

Another basic principle is slow titration to the optimal dose. The dose–response curve for some medications reaches a plateau, Dr. Shapiro said. If the therapeutic window is exceeded, the efficacy begins to decrease. Analgesic overuse is another potential problem. “It is important to have a trial at the appropriate dose for at least two months before you can make a judgment as to whether the medication is helpful. Individual responses are hard to predict.” Finally, Dr. Shapiro suggested tapering a medication off after 12 months. “There is some sense that with a reduction in the frequency of events, there may be a stabilizing effect. That is not based on a lot of evidence. It is based, rather, on clinical experience. Successful preventive medications may be tapered off, and there may be a durable benefit after it has been there for a while,” he said.

The most sobering fact about preventive medications, Dr. Shapiro said, is that “83% of patients started on a preventive medication are not taking it one year later.”

Starting Preventive Treatment

The consensus among a panel of experts was that headache at six days or more per month should be the threshold for offering a patient a preventive therapy, whereas it should be considered for patients experiencing four to five days with headache per month. “Based on this [principle], a 2007 study found that 13% of migraine patients were on preventive medications, while an additional 26% should be offered preventive medications, and in 13% preventives should be considered,” Dr. Shapiro said.

Based on the 2012 American Headache Society/American Academy of Neurology guideline for episodic migraine preventive drugs, there is Level A (established as effective) evidence for divalproex sodium ER (1,000 mg daily), topiramate (50 mg bid), propranolol (120 mg to 160 mg daily), timolol (10 mg to 15 mg bid), metoprolol (100 mg bid), and petasites (ie, butterbur). The first four medicines are FDA-approved for migraine, and metoprolol is included based on the evidence available, even though it is not FDA-approved for this indication. “Butterbur is effective, but there is an almost universal sense that we should not be offering this to patients because of the concern about potential liver toxicity and insufficient assurance from manufacturers that the agents that might cause that toxicity have been removed,” Dr. Shapiro said.

Several studies comparing efficacy, defined as the 50% responder rate, have indicated that valproate, topiramate, and propranolol all have approximately the same level of efficacy. Approximately 45% of patients receiving these therapies had 50% reduction in attack frequency or severity.

Level B (probably effective) evidence exists for several agents that are in common use, such as amitriptyline, candesartan, lisinopril, amlodipine and zonisamide. Other agents with Level B evidence include nutraceuticals and vitamin agents, such as megadoses of riboflavin and magnesium.

As previously mentioned, selection of a preventive agent may be guided by comorbidity. If a patient has hypertension, for example, angiotensin receptor blockers, ACE inhibitors, beta blockers, or calcium channel blockers are worth considering. In its evaluation of medications for migraine prevention, the Agency for Healthcare Research and Quality issued its own evaluation of medications for migraine prevention and suggested that even though angiotensin receptor blockers such as candesartan, or angiotensin converting enzyme inhibitors such as lisinopril, are not FDA-approved to treat migraine, their relative tolerability suggests that they could be first-line agents for this purpose. For depression, venlafaxine could be an appropriate choice. If a patient is obese, topiramate or zonisamide should be considered. If epilepsy is comorbid with migraine, obvious choices would be topiramate, divalproate, or zonisamide. For neuropathic pain or insomnia, tricyclic antidepressants are appropriate.

Game Changer?

“We are all excited about the new developments” related to the CGRP agents in clinical trials, Dr. Shapiro said, “but how much these drugs may improve clinical outcomes remains to be seen.” Independent lines of evidence suggest that CGRP is involved during migraine attacks and that blocking the effects of CGRP can have therapeutic benefit.

The four medications in late-stage clinical development are erenumab, fremanezumab, galcanezumab, and eptinezumab. Three of them have been submitted to the FDA for review. They are all either fully human or humanized antibodies. All of them have been studied in clinical trials for episodic and chronic migraine. Galcanezumab and fremanezumab are being studied for episodic and chronic cluster headache. Erenumab is an antibody directed against the CGRP receptor, whereas the other three treatments target CGRP itself. Erenumab, fremanezumab, and galcanezumab are delivered by monthly or quarterly subcutaneous injections. Eptinezumab has been studied as a quarterly IV infusion. The dosage and frequency of administration will remain uncertain until the FDA approves specific regimens for these therapies, Dr. Shapiro said.

Regulatory news is pending. The PDUFA date for FDA reporting on erenumab is May 17, 2018. Unexpected problems at the manufacturing plant in South Korea have raised questions about the timing of fremanezumab availability, but the FDA is still expected to render a judgment on its approvability by this summer. For galcanezumab, an FDA decision is expected by late September 2018. Eptinezumab has not yet been submitted for approval.

Other Options

Botox is approved for prevention of chronic migraine. Neurologists administer 155 units to 31 injection sites. In clinical trials, baseline monthly headache frequency of 20 days was reduced to 11.5 days among patients receiving onabotulinumtoxinA and to 13 days among controls. The therapeutic gain was about 9%, or about 1.7 days, during the 28-day trial period. At least 78% of the improvement associated with Botox was attributed to the placebo effect, Dr. Shapiro noted. “But that does not mean that this is not a helpful thing to do…. This helps a lot of people, even though the placebo effect is substantial.”

The Cefaly transcutaneous electrical nerve stimulation (TENS) device has been cleared for marketing by the FDA. In clinical trials, the device did not significantly reduce the number of headache days at three months, compared with sham treatment, but the FDA cleared the device nevertheless. “This [treatment] is of variable benefit,” Dr. Shapiro said. “Evidence of that is that only about half of the patients who tried it were willing to buy the device after two months.”

The sTMS mini transcranial magnetic stimulation device was cleared for marketing in the summer of 2017. In clinical trials, this device reduced headache frequency by two to three days per month when used for prevention of episodic or chronic migraine. The clinical trial, however, was open-label and used a “performance goal” comparator that was estimated from placebo responses in several other clinical trials, rather than a sham control; this design raises concerns about the validity of the efficacy claims. “This [device] is another potential option, but again, the evidence that the FDA accepted for clearing this device was not what we would prefer,” Dr. Shapiro said.

—Glenn S. Williams

Suggested Reading

Shamliyan TA, Choi JY, Ramakrishnan R, et al. Preventive pharmacologic treatments for episodic migraine in adults. J Gen Intern Med. 2013;28(9):1225-1237.

Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337-1345.

OJAI, CA—Infusion of the neuropeptide pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) induces headache and vasodilatation in healthy subjects and migraineurs. Among migraineurs, PACAP38 infusion also may induce migraine-like attacks that are associated with sustained dilatation of extracranial arteries and elevated plasma PACAP38 before attack onset. Taken together, research indicates that PACAP38 is involved in migraine pathophysiology and may have implications for migraine therapy, according to a presentation at the 11th Annual Headache Cooperative of the Pacific Winter Conference.

Investigators at the University of Copenhagen’s Danish Headache Center, including Jes Olesen, MD, Professor of Neurology, have studied PACAP38. Dr. Olesen compared their work on PACAP38 to their prior studies of calcitonin gene-related peptide (CGRP), which contributed to the development of a new class of migraine drugs known as selective CGRP antagonists.

Similar Peptides With Different Effects

PACAP38 is structurally and functionally related to vasoactive intestinal polypeptide (VIP), but their effects on headache differ. Rahmann et al in 2008 studied 12 patients with migraine without aura who received infusions of VIP. None of the subjects reported a migraine attack after VIP infusion. The few instances of headache were mild. The investigators concluded that VIP does not trigger migraine attacks in migraineurs.

Similar studies of PACAP38, however, found that infusion of PACAP38 does induce headache and migraine-like attacks. Schytz et al in 2009 reported that PACAP38 infusion caused headache in all healthy subjects (n = 12) and in 11 of 12 patients with migraine, seven of whom experienced migraine-like attacks. None of the participants had headache after receiving placebo. Half of the migraineurs reported that onset of migraine-like attacks occurred several hours (mean, six hours) after the start of the PACAP38 infusions. “It’s a long-lasting effect, and there is a tendency for most of the headaches to come pretty late,” Dr. Olesen said.

With such observations in mind, Amin et al in 2014 undertook a head-to-head comparison of PACAP38 and VIP in a double-blind crossover study of female patients with migraine without aura. Patients were randomly allocated to IV infusion of PACAP38 or VIP over 20 minutes. Patients then received the other infusion at least one week later. Of the 22 patients who completed the study (mean age, 24), 16 patients (73%) reported migraine-like attacks after PACAP38 infusion, whereas four patients (18%) reported migraine-like attacks after VIP infusion. Three of the four patients who reported migraine-like attacks after VIP infusion also reported migraine-like attacks after PACAP38 infusion. Some of the migraine attacks could have been spontaneous and unrelated to the infusions, Dr. Olesen noted. Nevertheless, “it is clear that highly significantly more patients got a migraine attack with PACAP than with VIP,” Dr. Olesen said.

Is the PAC₁ Receptor Key?

Further insights into PACAP38 have emerged from animal studies, one of which involves the potentially important role of the PAC₁ receptor in migraine. PACAP38 works on the three most prominent receptors in the cerebral vasculature: PAC₁, VPAC₁, and VPAC₂. VIP, by contrast, works on VPAC₁ and VPAC₂, but not on PAC₁. The two compounds have the same affinity to VPAC₁ and VPAC₂. “So, isn’t it almost obvious that since PACAP causes a migraine attack and VIP does not, it must be via the PAC₁ receptor?” Dr. Olesen asked. “Well, we think so, but how can we be sure? That is the logic of the data until somebody comes up with something else.”

A study led by Dr. Olesen’s colleague and wife, Inger Jansen-Olesen, DMSc, suggests another difference between VIP and PACAP38 that may be relevant to migraine. Dr. Jansen-Olesen and colleagues compared the effect of PACAP38 and VIP on CGRP release in the trigeminal nucleus caudalis in rats. Increasing doses of PACAP38 increased release of CGRP, whereas increasing doses of VIP did not. “VIP does not liberate CGRP. That is at least one difference between PACAP and VIP that may be relevant,” Dr. Olesen said.

Whether the PAC₁ receptor is responsible for migraine induction is the “million-dollar question,” Dr. Olesen said. Several companies, based on their experience with CGRP, have the ability to develop human antibodies against PACAP38 or any of its three receptors relatively quickly, he said. “We would put our money on an antibody that blocks the PAC₁ receptor because you like a drug to be as specific as possible,” said Dr. Olesen. “We do not want to block three receptors if we only have to block one receptor.”The same philosophy applies to blocking the PACAP38 molecule itself. “You … take away the signals to all three kinds of receptors, so it is likely that you would have more side effects,” Dr. Olesen said. On the other hand, whether migraine induction involves the PAC₁ receptor or other mechanisms remains unclear. “I think [studies] will show in the not-too-distant future whether antibodies against the PAC₁ receptor will be effective in migraine,” said Dr. Olesen.

—Fred Balzac

Suggested Reading

Amin FM, Hougaard A, Magon S, et al. Change in brain network connectivity during PACAP38-induced migraine attacks: a resting-state functional MRI study. Neurology. 2016;86(2):180-187.

Amin FM, Hougaard A, Schytz HW, et al. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain. 2014;137(Pt 3):779-794.

Guo S, Vollesen AL, Hansen RD, et al. Part I: Pituitary adenylate cyclase-activating polypeptide-38 induced migraine-like attacks in patients with and without familial aggregation of migraine. Cephalalgia. 2017;37(2):125-135.

Guo S, Vollesen AL, Hansen YB, et al. Part II: Biochemical changes after pituitary adenylate cyclase-activating polypeptide-38 infusion in migraine patients. Cephalalgia. 2017;37(2):136-147.

Guo S, Vollesen AL, Olesen J, Ashina M. Premonitory and nonheadache symptoms induced by CGRP and PACAP38 in patients with migraine. Pain. 2016;157(12):2773-2781.

Jansen-Olesen I, Baun M, Amrutkar DV, et al. PACAP-38 but not VIP induces release of CGRP from trigeminal nucleus caudalis via a receptor distinct from the PAC1 receptor. Neuropeptides. 2014;48(2):53-64.

Rahmann A, Wienecke T, Hansen JM, et al. Vasoactive intestinal peptide causes marked cephalic vasodilation, but does not induce migraine. Cephalalgia. 2008;28(3):226-236.

Schytz HW, Birk S, Wienecke T, et al. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain. 2009;132(Pt 1):16-25.

OJAI, CA—Infusion of the neuropeptide pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) induces headache and vasodilatation in healthy subjects and migraineurs. Among migraineurs, PACAP38 infusion also may induce migraine-like attacks that are associated with sustained dilatation of extracranial arteries and elevated plasma PACAP38 before attack onset. Taken together, research indicates that PACAP38 is involved in migraine pathophysiology and may have implications for migraine therapy, according to a presentation at the 11th Annual Headache Cooperative of the Pacific Winter Conference.

Investigators at the University of Copenhagen’s Danish Headache Center, including Jes Olesen, MD, Professor of Neurology, have studied PACAP38. Dr. Olesen compared their work on PACAP38 to their prior studies of calcitonin gene-related peptide (CGRP), which contributed to the development of a new class of migraine drugs known as selective CGRP antagonists.

Similar Peptides With Different Effects

PACAP38 is structurally and functionally related to vasoactive intestinal polypeptide (VIP), but their effects on headache differ. Rahmann et al in 2008 studied 12 patients with migraine without aura who received infusions of VIP. None of the subjects reported a migraine attack after VIP infusion. The few instances of headache were mild. The investigators concluded that VIP does not trigger migraine attacks in migraineurs.

Similar studies of PACAP38, however, found that infusion of PACAP38 does induce headache and migraine-like attacks. Schytz et al in 2009 reported that PACAP38 infusion caused headache in all healthy subjects (n = 12) and in 11 of 12 patients with migraine, seven of whom experienced migraine-like attacks. None of the participants had headache after receiving placebo. Half of the migraineurs reported that onset of migraine-like attacks occurred several hours (mean, six hours) after the start of the PACAP38 infusions. “It’s a long-lasting effect, and there is a tendency for most of the headaches to come pretty late,” Dr. Olesen said.

With such observations in mind, Amin et al in 2014 undertook a head-to-head comparison of PACAP38 and VIP in a double-blind crossover study of female patients with migraine without aura. Patients were randomly allocated to IV infusion of PACAP38 or VIP over 20 minutes. Patients then received the other infusion at least one week later. Of the 22 patients who completed the study (mean age, 24), 16 patients (73%) reported migraine-like attacks after PACAP38 infusion, whereas four patients (18%) reported migraine-like attacks after VIP infusion. Three of the four patients who reported migraine-like attacks after VIP infusion also reported migraine-like attacks after PACAP38 infusion. Some of the migraine attacks could have been spontaneous and unrelated to the infusions, Dr. Olesen noted. Nevertheless, “it is clear that highly significantly more patients got a migraine attack with PACAP than with VIP,” Dr. Olesen said.

Is the PAC₁ Receptor Key?

Further insights into PACAP38 have emerged from animal studies, one of which involves the potentially important role of the PAC₁ receptor in migraine. PACAP38 works on the three most prominent receptors in the cerebral vasculature: PAC₁, VPAC₁, and VPAC₂. VIP, by contrast, works on VPAC₁ and VPAC₂, but not on PAC₁. The two compounds have the same affinity to VPAC₁ and VPAC₂. “So, isn’t it almost obvious that since PACAP causes a migraine attack and VIP does not, it must be via the PAC₁ receptor?” Dr. Olesen asked. “Well, we think so, but how can we be sure? That is the logic of the data until somebody comes up with something else.”

A study led by Dr. Olesen’s colleague and wife, Inger Jansen-Olesen, DMSc, suggests another difference between VIP and PACAP38 that may be relevant to migraine. Dr. Jansen-Olesen and colleagues compared the effect of PACAP38 and VIP on CGRP release in the trigeminal nucleus caudalis in rats. Increasing doses of PACAP38 increased release of CGRP, whereas increasing doses of VIP did not. “VIP does not liberate CGRP. That is at least one difference between PACAP and VIP that may be relevant,” Dr. Olesen said.

Whether the PAC₁ receptor is responsible for migraine induction is the “million-dollar question,” Dr. Olesen said. Several companies, based on their experience with CGRP, have the ability to develop human antibodies against PACAP38 or any of its three receptors relatively quickly, he said. “We would put our money on an antibody that blocks the PAC₁ receptor because you like a drug to be as specific as possible,” said Dr. Olesen. “We do not want to block three receptors if we only have to block one receptor.”The same philosophy applies to blocking the PACAP38 molecule itself. “You … take away the signals to all three kinds of receptors, so it is likely that you would have more side effects,” Dr. Olesen said. On the other hand, whether migraine induction involves the PAC₁ receptor or other mechanisms remains unclear. “I think [studies] will show in the not-too-distant future whether antibodies against the PAC₁ receptor will be effective in migraine,” said Dr. Olesen.

—Fred Balzac

Suggested Reading

Amin FM, Hougaard A, Magon S, et al. Change in brain network connectivity during PACAP38-induced migraine attacks: a resting-state functional MRI study. Neurology. 2016;86(2):180-187.

Amin FM, Hougaard A, Schytz HW, et al. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain. 2014;137(Pt 3):779-794.

Guo S, Vollesen AL, Hansen RD, et al. Part I: Pituitary adenylate cyclase-activating polypeptide-38 induced migraine-like attacks in patients with and without familial aggregation of migraine. Cephalalgia. 2017;37(2):125-135.

Guo S, Vollesen AL, Hansen YB, et al. Part II: Biochemical changes after pituitary adenylate cyclase-activating polypeptide-38 infusion in migraine patients. Cephalalgia. 2017;37(2):136-147.

Guo S, Vollesen AL, Olesen J, Ashina M. Premonitory and nonheadache symptoms induced by CGRP and PACAP38 in patients with migraine. Pain. 2016;157(12):2773-2781.

Jansen-Olesen I, Baun M, Amrutkar DV, et al. PACAP-38 but not VIP induces release of CGRP from trigeminal nucleus caudalis via a receptor distinct from the PAC1 receptor. Neuropeptides. 2014;48(2):53-64.

Rahmann A, Wienecke T, Hansen JM, et al. Vasoactive intestinal peptide causes marked cephalic vasodilation, but does not induce migraine. Cephalalgia. 2008;28(3):226-236.

Schytz HW, Birk S, Wienecke T, et al. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain. 2009;132(Pt 1):16-25.

OJAI, CA—Infusion of the neuropeptide pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) induces headache and vasodilatation in healthy subjects and migraineurs. Among migraineurs, PACAP38 infusion also may induce migraine-like attacks that are associated with sustained dilatation of extracranial arteries and elevated plasma PACAP38 before attack onset. Taken together, research indicates that PACAP38 is involved in migraine pathophysiology and may have implications for migraine therapy, according to a presentation at the 11th Annual Headache Cooperative of the Pacific Winter Conference.

Investigators at the University of Copenhagen’s Danish Headache Center, including Jes Olesen, MD, Professor of Neurology, have studied PACAP38. Dr. Olesen compared their work on PACAP38 to their prior studies of calcitonin gene-related peptide (CGRP), which contributed to the development of a new class of migraine drugs known as selective CGRP antagonists.

Similar Peptides With Different Effects

PACAP38 is structurally and functionally related to vasoactive intestinal polypeptide (VIP), but their effects on headache differ. Rahmann et al in 2008 studied 12 patients with migraine without aura who received infusions of VIP. None of the subjects reported a migraine attack after VIP infusion. The few instances of headache were mild. The investigators concluded that VIP does not trigger migraine attacks in migraineurs.

Similar studies of PACAP38, however, found that infusion of PACAP38 does induce headache and migraine-like attacks. Schytz et al in 2009 reported that PACAP38 infusion caused headache in all healthy subjects (n = 12) and in 11 of 12 patients with migraine, seven of whom experienced migraine-like attacks. None of the participants had headache after receiving placebo. Half of the migraineurs reported that onset of migraine-like attacks occurred several hours (mean, six hours) after the start of the PACAP38 infusions. “It’s a long-lasting effect, and there is a tendency for most of the headaches to come pretty late,” Dr. Olesen said.

With such observations in mind, Amin et al in 2014 undertook a head-to-head comparison of PACAP38 and VIP in a double-blind crossover study of female patients with migraine without aura. Patients were randomly allocated to IV infusion of PACAP38 or VIP over 20 minutes. Patients then received the other infusion at least one week later. Of the 22 patients who completed the study (mean age, 24), 16 patients (73%) reported migraine-like attacks after PACAP38 infusion, whereas four patients (18%) reported migraine-like attacks after VIP infusion. Three of the four patients who reported migraine-like attacks after VIP infusion also reported migraine-like attacks after PACAP38 infusion. Some of the migraine attacks could have been spontaneous and unrelated to the infusions, Dr. Olesen noted. Nevertheless, “it is clear that highly significantly more patients got a migraine attack with PACAP than with VIP,” Dr. Olesen said.

Is the PAC₁ Receptor Key?

Further insights into PACAP38 have emerged from animal studies, one of which involves the potentially important role of the PAC₁ receptor in migraine. PACAP38 works on the three most prominent receptors in the cerebral vasculature: PAC₁, VPAC₁, and VPAC₂. VIP, by contrast, works on VPAC₁ and VPAC₂, but not on PAC₁. The two compounds have the same affinity to VPAC₁ and VPAC₂. “So, isn’t it almost obvious that since PACAP causes a migraine attack and VIP does not, it must be via the PAC₁ receptor?” Dr. Olesen asked. “Well, we think so, but how can we be sure? That is the logic of the data until somebody comes up with something else.”

A study led by Dr. Olesen’s colleague and wife, Inger Jansen-Olesen, DMSc, suggests another difference between VIP and PACAP38 that may be relevant to migraine. Dr. Jansen-Olesen and colleagues compared the effect of PACAP38 and VIP on CGRP release in the trigeminal nucleus caudalis in rats. Increasing doses of PACAP38 increased release of CGRP, whereas increasing doses of VIP did not. “VIP does not liberate CGRP. That is at least one difference between PACAP and VIP that may be relevant,” Dr. Olesen said.

Whether the PAC₁ receptor is responsible for migraine induction is the “million-dollar question,” Dr. Olesen said. Several companies, based on their experience with CGRP, have the ability to develop human antibodies against PACAP38 or any of its three receptors relatively quickly, he said. “We would put our money on an antibody that blocks the PAC₁ receptor because you like a drug to be as specific as possible,” said Dr. Olesen. “We do not want to block three receptors if we only have to block one receptor.”The same philosophy applies to blocking the PACAP38 molecule itself. “You … take away the signals to all three kinds of receptors, so it is likely that you would have more side effects,” Dr. Olesen said. On the other hand, whether migraine induction involves the PAC₁ receptor or other mechanisms remains unclear. “I think [studies] will show in the not-too-distant future whether antibodies against the PAC₁ receptor will be effective in migraine,” said Dr. Olesen.

—Fred Balzac

Suggested Reading

Amin FM, Hougaard A, Magon S, et al. Change in brain network connectivity during PACAP38-induced migraine attacks: a resting-state functional MRI study. Neurology. 2016;86(2):180-187.

Amin FM, Hougaard A, Schytz HW, et al. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain. 2014;137(Pt 3):779-794.

Guo S, Vollesen AL, Hansen RD, et al. Part I: Pituitary adenylate cyclase-activating polypeptide-38 induced migraine-like attacks in patients with and without familial aggregation of migraine. Cephalalgia. 2017;37(2):125-135.

Guo S, Vollesen AL, Hansen YB, et al. Part II: Biochemical changes after pituitary adenylate cyclase-activating polypeptide-38 infusion in migraine patients. Cephalalgia. 2017;37(2):136-147.

Guo S, Vollesen AL, Olesen J, Ashina M. Premonitory and nonheadache symptoms induced by CGRP and PACAP38 in patients with migraine. Pain. 2016;157(12):2773-2781.

Jansen-Olesen I, Baun M, Amrutkar DV, et al. PACAP-38 but not VIP induces release of CGRP from trigeminal nucleus caudalis via a receptor distinct from the PAC1 receptor. Neuropeptides. 2014;48(2):53-64.

Rahmann A, Wienecke T, Hansen JM, et al. Vasoactive intestinal peptide causes marked cephalic vasodilation, but does not induce migraine. Cephalalgia. 2008;28(3):226-236.

Schytz HW, Birk S, Wienecke T, et al. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain. 2009;132(Pt 1):16-25.

Greater occipital nerve (GON) block seems to be an effective option for acute management of migraine headache, with promising reductions in pain scores, a recent study found. This retrospective cohort study was undertaken between January 2009 and August 2014 and included patients who underwent at least 1 GON block and attended at least 1 follow-up appointment. Change in the 11-point numeric pain rating scale (NPRS) was used to assess the response to GON block. A total of 562 patients met inclusion criteria; 423 were women (75%); mean age was 58.6 ± 16.7 years. Response was defined as “minimal” (less than 30% NPRS point reduction), “moderate” (31% to 50% NPRS point reduction), or “significant” ( greater than 50% NPRS point reduction). Researchers found:

• Of total patients, 459 (82%) rated their response to GON block as moderate or significant.
• No statistically significant relationship existed between previous treatment regimens and response to GON block.
• GON block was equally effective across the different age and sex groups.

Greater occipital nerve block for acute treatment of migraine headache: A large retrospective cohort study. J Am Board Fam Med. 2018;31(2):211-218. doi:10.3122/jabfm.2018.02.170188.

Greater occipital nerve (GON) block seems to be an effective option for acute management of migraine headache, with promising reductions in pain scores, a recent study found. This retrospective cohort study was undertaken between January 2009 and August 2014 and included patients who underwent at least 1 GON block and attended at least 1 follow-up appointment. Change in the 11-point numeric pain rating scale (NPRS) was used to assess the response to GON block. A total of 562 patients met inclusion criteria; 423 were women (75%); mean age was 58.6 ± 16.7 years. Response was defined as “minimal” (less than 30% NPRS point reduction), “moderate” (31% to 50% NPRS point reduction), or “significant” ( greater than 50% NPRS point reduction). Researchers found:

• Of total patients, 459 (82%) rated their response to GON block as moderate or significant.
• No statistically significant relationship existed between previous treatment regimens and response to GON block.
• GON block was equally effective across the different age and sex groups.

Greater occipital nerve block for acute treatment of migraine headache: A large retrospective cohort study. J Am Board Fam Med. 2018;31(2):211-218. doi:10.3122/jabfm.2018.02.170188.

Greater occipital nerve (GON) block seems to be an effective option for acute management of migraine headache, with promising reductions in pain scores, a recent study found. This retrospective cohort study was undertaken between January 2009 and August 2014 and included patients who underwent at least 1 GON block and attended at least 1 follow-up appointment. Change in the 11-point numeric pain rating scale (NPRS) was used to assess the response to GON block. A total of 562 patients met inclusion criteria; 423 were women (75%); mean age was 58.6 ± 16.7 years. Response was defined as “minimal” (less than 30% NPRS point reduction), “moderate” (31% to 50% NPRS point reduction), or “significant” ( greater than 50% NPRS point reduction). Researchers found:

• Of total patients, 459 (82%) rated their response to GON block as moderate or significant.
• No statistically significant relationship existed between previous treatment regimens and response to GON block.
• GON block was equally effective across the different age and sex groups.

Greater occipital nerve block for acute treatment of migraine headache: A large retrospective cohort study. J Am Board Fam Med. 2018;31(2):211-218. doi:10.3122/jabfm.2018.02.170188.

A recent study identifies early cerebral diffusion changes in children with tension-type and migraine-type headaches compared with controls. The hypothesized mechanisms of nociception in migraine-type and tension-type headaches may explain the findings as a precursor to structural changes seen in adult patients with chronic headache. Patients evaluated for tension-type or migraine-type headache without aura from May 2014 to July 2016 in a single center were retrospectively reviewed. Thirty-two patients with tension-type headache and 23 with migraine-type headache at an average of 4 months after diagnosis were enrolled. All patients underwent diffusion weighted imaging at 3T before the start of pharmacotherapy. Researchers found:

• There were no significant differences in regional brain volumes between the groups.
• Patients with tension-type and migraine-type headaches showed significantly increased apparent diffusion coefficient (ADC) in the hippocampus and brain stem compared with controls.
• Additionally, only patients with migraine-type headache showed significantly increased ADC in the thalamus and a trend toward increased ADC in the amygdala compared with controls.

Brain diffusion abnormalities in children with tension-type and migraine-type headaches. [Published online ahead of print March 15, 2018]. AJNR Am J Neuroradiol. doi:10.3174/ajnr.A5582.

A recent study identifies early cerebral diffusion changes in children with tension-type and migraine-type headaches compared with controls. The hypothesized mechanisms of nociception in migraine-type and tension-type headaches may explain the findings as a precursor to structural changes seen in adult patients with chronic headache. Patients evaluated for tension-type or migraine-type headache without aura from May 2014 to July 2016 in a single center were retrospectively reviewed. Thirty-two patients with tension-type headache and 23 with migraine-type headache at an average of 4 months after diagnosis were enrolled. All patients underwent diffusion weighted imaging at 3T before the start of pharmacotherapy. Researchers found:

• There were no significant differences in regional brain volumes between the groups.
• Patients with tension-type and migraine-type headaches showed significantly increased apparent diffusion coefficient (ADC) in the hippocampus and brain stem compared with controls.
• Additionally, only patients with migraine-type headache showed significantly increased ADC in the thalamus and a trend toward increased ADC in the amygdala compared with controls.

Brain diffusion abnormalities in children with tension-type and migraine-type headaches. [Published online ahead of print March 15, 2018]. AJNR Am J Neuroradiol. doi:10.3174/ajnr.A5582.

A recent study identifies early cerebral diffusion changes in children with tension-type and migraine-type headaches compared with controls. The hypothesized mechanisms of nociception in migraine-type and tension-type headaches may explain the findings as a precursor to structural changes seen in adult patients with chronic headache. Patients evaluated for tension-type or migraine-type headache without aura from May 2014 to July 2016 in a single center were retrospectively reviewed. Thirty-two patients with tension-type headache and 23 with migraine-type headache at an average of 4 months after diagnosis were enrolled. All patients underwent diffusion weighted imaging at 3T before the start of pharmacotherapy. Researchers found:

• There were no significant differences in regional brain volumes between the groups.
• Patients with tension-type and migraine-type headaches showed significantly increased apparent diffusion coefficient (ADC) in the hippocampus and brain stem compared with controls.
• Additionally, only patients with migraine-type headache showed significantly increased ADC in the thalamus and a trend toward increased ADC in the amygdala compared with controls.

Brain diffusion abnormalities in children with tension-type and migraine-type headaches. [Published online ahead of print March 15, 2018]. AJNR Am J Neuroradiol. doi:10.3174/ajnr.A5582.

Migraine disease has a higher prevalence in an otolaryngologic cohort than in the general population, according to a recent study, presenting with a high rate of sinonasal and otologic symptoms that may be due to or exacerbated by migraines. In a cross-sectional study utilizing the CHEER (Creating Healthcare Excellence through Education and Research) network, patients were recruited in 14 CHEER sites between June 2015 and March 2017. Those included were aged 18 years or older and had been seen for any concern that was not head and neck cancer. Patients with any history of brain abnormality or headaches that began within 2 weeks of a medical illness, trauma, or head injury were excluded. If they screened positive on the Migraine Assessment Tool (MAT+), the subjects also filled out questionnaires for sinonasal, otologic, and migraine-specific symptoms. Researchers found:

• Of 1458 patients screened, 235 (16.1%) screened positive for migraine (MAT+), which is higher than the general population (13%).
• The MAT+ group was significantly younger (47.2 vs 55.6 years of age) and predominantly women (80.0% vs 55.9%).

Patterns of migraine disease in otolaryngology: A CHEER network study. [Published online ahead of print March 20, 2018]. Otolaryngol Head Neck Surg. doi:10.1177/0194599818764387.

Migraine disease has a higher prevalence in an otolaryngologic cohort than in the general population, according to a recent study, presenting with a high rate of sinonasal and otologic symptoms that may be due to or exacerbated by migraines. In a cross-sectional study utilizing the CHEER (Creating Healthcare Excellence through Education and Research) network, patients were recruited in 14 CHEER sites between June 2015 and March 2017. Those included were aged 18 years or older and had been seen for any concern that was not head and neck cancer. Patients with any history of brain abnormality or headaches that began within 2 weeks of a medical illness, trauma, or head injury were excluded. If they screened positive on the Migraine Assessment Tool (MAT+), the subjects also filled out questionnaires for sinonasal, otologic, and migraine-specific symptoms. Researchers found:

• Of 1458 patients screened, 235 (16.1%) screened positive for migraine (MAT+), which is higher than the general population (13%).
• The MAT+ group was significantly younger (47.2 vs 55.6 years of age) and predominantly women (80.0% vs 55.9%).

Patterns of migraine disease in otolaryngology: A CHEER network study. [Published online ahead of print March 20, 2018]. Otolaryngol Head Neck Surg. doi:10.1177/0194599818764387.

Migraine disease has a higher prevalence in an otolaryngologic cohort than in the general population, according to a recent study, presenting with a high rate of sinonasal and otologic symptoms that may be due to or exacerbated by migraines. In a cross-sectional study utilizing the CHEER (Creating Healthcare Excellence through Education and Research) network, patients were recruited in 14 CHEER sites between June 2015 and March 2017. Those included were aged 18 years or older and had been seen for any concern that was not head and neck cancer. Patients with any history of brain abnormality or headaches that began within 2 weeks of a medical illness, trauma, or head injury were excluded. If they screened positive on the Migraine Assessment Tool (MAT+), the subjects also filled out questionnaires for sinonasal, otologic, and migraine-specific symptoms. Researchers found:

• Of 1458 patients screened, 235 (16.1%) screened positive for migraine (MAT+), which is higher than the general population (13%).
• The MAT+ group was significantly younger (47.2 vs 55.6 years of age) and predominantly women (80.0% vs 55.9%).

Patterns of migraine disease in otolaryngology: A CHEER network study. [Published online ahead of print March 20, 2018]. Otolaryngol Head Neck Surg. doi:10.1177/0194599818764387.