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Expert outlines strategies for managing migraine in women
Understanding the hormonal changes women go through over their lives can help physicians refine migraine treatment approaches.
“It’s so critical that you know what’s going on hormonally, both endogenously and exogenously, to better evaluate treatment,” according to Susan Hutchinson, MD, director of the Orange County Migraine & Headache Center in Irvine, Calif.
In an interview, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, talks with Dr. Hutchinson about estrogen treatment for menstrual migraine, the safety of new medications during pregnancy and breastfeeding, and the importance of a collaborative approach between a patient’s primary care, neurology, and ob.gyn. providers.
Understanding the hormonal changes women go through over their lives can help physicians refine migraine treatment approaches.
“It’s so critical that you know what’s going on hormonally, both endogenously and exogenously, to better evaluate treatment,” according to Susan Hutchinson, MD, director of the Orange County Migraine & Headache Center in Irvine, Calif.
In an interview, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, talks with Dr. Hutchinson about estrogen treatment for menstrual migraine, the safety of new medications during pregnancy and breastfeeding, and the importance of a collaborative approach between a patient’s primary care, neurology, and ob.gyn. providers.
Understanding the hormonal changes women go through over their lives can help physicians refine migraine treatment approaches.
“It’s so critical that you know what’s going on hormonally, both endogenously and exogenously, to better evaluate treatment,” according to Susan Hutchinson, MD, director of the Orange County Migraine & Headache Center in Irvine, Calif.
In an interview, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, talks with Dr. Hutchinson about estrogen treatment for menstrual migraine, the safety of new medications during pregnancy and breastfeeding, and the importance of a collaborative approach between a patient’s primary care, neurology, and ob.gyn. providers.
Small-molecule CGRP receptor antagonists may pose a risk during stroke
“It turns out that these drugs make the blood vessels of the brain dysfunctional, such that the collateral channels that bring in blood to the region that is having the stroke are impaired,” explains the study’s lead author, Cenk Ayata, MD, associate professor of neurology and radiology at Harvard Medical School, Boston.
In an interview, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, talks with Dr. Ayata about his study findings, and about CGRP receptor antagonists’ potential effects if a patient has an ischemic event.
This article was updated 4/21/20.
“It turns out that these drugs make the blood vessels of the brain dysfunctional, such that the collateral channels that bring in blood to the region that is having the stroke are impaired,” explains the study’s lead author, Cenk Ayata, MD, associate professor of neurology and radiology at Harvard Medical School, Boston.
In an interview, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, talks with Dr. Ayata about his study findings, and about CGRP receptor antagonists’ potential effects if a patient has an ischemic event.
This article was updated 4/21/20.
“It turns out that these drugs make the blood vessels of the brain dysfunctional, such that the collateral channels that bring in blood to the region that is having the stroke are impaired,” explains the study’s lead author, Cenk Ayata, MD, associate professor of neurology and radiology at Harvard Medical School, Boston.
In an interview, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, talks with Dr. Ayata about his study findings, and about CGRP receptor antagonists’ potential effects if a patient has an ischemic event.
This article was updated 4/21/20.
How do neurologists choose an acute treatment for migraine?
STOWE, VT. – A large and growing number of medications is available for the acute treatment of migraine. Effective acute treatment enables patients to re-engage in their work and other daily activities, as well as reducing the likelihood that their disease will progress from episodic to chronic migraine. efficacy and tolerability according to Barbara L. Nye, MD, assistant professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H.. Dr. Nye discussed the acute treatment of migraine at the annual meeting of the Headache Cooperative of New England.
Choosing an initial treatment
Nonspecific medications are perhaps the first treatments to consider for a patient with acute migraine. This class includes NSAIDs such as naproxen sodium, piroxicam, diclofenac, celecoxib, and indomethacin. Emerging data indicate that some NSAIDs are associated with an increased risk of stroke, which is an important consideration as the population ages, said Dr. Nye. Other nonspecific options are neuroleptics such as prochlorperazine, metoclopramide, promethazine, and chlorpromazine. Many neuroleptics have sedative effects, however, so they do not necessarily help a patient return to function. Nevertheless, these drugs can be good rescue medications, said Dr. Nye.
Triptans are effective in the acute treatment of migraine, and seven drugs in this class are available. Most, such as rizatriptan, almotriptan, eletriptan, naratriptan, and frovatriptan, are available only as tablets. Other routes of delivery are available, however. Sumatriptan, for example, is available in injectable and intranasal formulations, and zolmitriptan is available as an orally dissolving tablet.
Another option to consider is dihydroergotamine (DHE), which has long been used for migraine. The injectable formulation of DHE can be cumbersome because it requires the patients with a headache to open a vial, draw the medication into a filter needle, and inject themselves, said Dr. Nye. “The nasal sprays that are available right now aren’t as effective as we’d like them to be,” she added. But overall, DHE is effective. Associated adverse events include flushing, nausea, and diarrhea.
Lasmiditan received approval from the Food and Drug Administration for the acute treatment of migraine in October 2019. Compared with placebo, the drug increases the likelihood of pain freedom and freedom from the most bothersome symptom at 2 hours. Driving tests indicated that patients were impaired for about 8 hours after treatment, and lasmiditan is a Schedule V drug. It is available in doses of 50 mg/day, 100 mg/day, and 200 mg/day.
The class of drugs known as the “gepants” provides further options. The most recently approved therapy in this class, which targets calcitonin gene–related peptide, is ubrogepant. Because the drug is metabolized through the CYP3A4 system, they are not appropriate for patients who use strong CYP3A4 inhibitors. The most common side effects are nausea, hypersensitivity reaction, and somnolence.
Neuromodulation can provide effective treatment without provoking side effects, said Dr. Nye. Options include transcutaneous supraorbital stimulation, single-pulse transcutaneous magnetic stimulation, noninvasive vagal nerve stimulation, and remote nonpainful stimulation.
If a patient presents during an acute attack, neurologists could consider using a nerve block. The latter may administer occipital nerve blocks, trigger point injections, auriculotemporal nerve blocks, and supraorbital and supratrochlear nerve blocks. This treatment can bring immediate relief, which is gratifying for patients and neurologists. But no consensus about which medications to use or how to administer them has been established. Neurologists most often use a combination of bupivacaine and lidocaine. Another possibility is a sphenopalatine ganglion nerve block, which requires treatment to be inserted through the nose. This treatment can be delivered in the office using the Sphenocath device or the Allevio device. Another device, the Tx360, is intended to enable patient self-administration.
Addressing treatment failure
If a patient returns and reports that the current treatment is ineffective, the neurologist must reevaluate the therapy. A helpful way to conduct this reassessment is to administer the Migraine Treatment Optimization Questionnaire (MTOQ), which was developed by Lipton et al., to the patient. Neurologists ask whether the patient can function normally 2 hours after treatment or whether the medication is, for example, causing a side effect that makes this outcome less likely. Other questions for the patient are whether the headache pain disappears within 2 hours and whether the medication provides consistent relief. Finally, the neurologist can ask whether the patient is comfortable taking the medication. A score lower than 2 on the MTOQ indicates that the acute treatment should be changed, said Dr. Nye.
Gastroparesis is common during migraine attacks. It is inadvisable to give an oral medication to a patient who vomits within 20 minutes of attack onset, said Dr. Nye. “It’s a little less intuitive for those people who are nauseous immediately to think that that oral tablet is probably going to sit in their stomach and not get absorbed in the intestines as intended.” Nasal sprays, injectable medicines, and oral dissolving tablets are appropriate options for patients with gastroparesis.
Treating migraine during pregnancy
Special consideration must be given to treatment when the patient is pregnant. Decreased headache frequency is common in pregnancy, but not universal. Occipital nerve blocks are a good option for prevention and acute management in pregnant patients. They may be administered every 2 weeks. Sphenopalatine ganglion nerve block is another option, and it can be administered several times per week. Data “suggest that stacking the injections 2 or 3 days per week for up to 6 weeks can eliminate headaches for up to 6 months,” said Dr. Nye.
Tylenol is appropriate for acute headache in pregnant patients, “but we do warn about medication overuse headache and limiting its use.” Ondansetron and promethazine are acceptable treatments for nausea. Although ondansetron has less central activity than promethazine, and thus does not reduce the headache, it lessens nausea, said Dr. Nye.
Triptan exposure during the first trimester is not significantly associated with major congenital malformations, which is reassuring, given that many patients take triptans before they realize that they are pregnant. During the second and third trimesters, triptan exposure is significantly associated with atonic uterus and increased blood loss during labor. In a 16-year registry, sumatriptan, naratriptan, and treximet were not associated with teratogenicity.
Nonpharmacological treatments, too, may help pregnant patients. Lifestyle management, including a regular sleep schedule, exercise routine, and diet, can be beneficial. Massage therapy may reduce stress, and cognitive-behavioral therapy and biofeedback are additional options. Behavioral therapy, however, should be initiated before the patient plans the pregnancy, said Dr. Nye. These therapies require training that a patient having an exacerbation of migraine is less likely to have the motivation to begin.
Many medications are transferred to infants through breast milk. The American Pediatric Association considers a relative infant dosing of less than 10% to be safe. A clinician or patient can look up a medication on websites such as LactMed to understand the relative infant dose and possible effects. Another helpful reference is Medications and Mothers’ Milk, said Dr. Nye. Acetaminophen, steroids, ibuprofen, riboflavin, indomethacin, ketorolac, and naproxen are generally safe during lactation. “Eletriptan is the triptan that’s least likely to be in the breast milk,” said Dr. Nye. Aspirin, atenolol, ergotamine, and lithium, however, should be given with caution. The safety of amitriptyline, nortriptyline, and SSRIs during lactation is unknown.
Dr. Nye is on advisory boards for Alder, Allergan, Biohaven, electroCore, Pernix, and Xoc.
STOWE, VT. – A large and growing number of medications is available for the acute treatment of migraine. Effective acute treatment enables patients to re-engage in their work and other daily activities, as well as reducing the likelihood that their disease will progress from episodic to chronic migraine. efficacy and tolerability according to Barbara L. Nye, MD, assistant professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H.. Dr. Nye discussed the acute treatment of migraine at the annual meeting of the Headache Cooperative of New England.
Choosing an initial treatment
Nonspecific medications are perhaps the first treatments to consider for a patient with acute migraine. This class includes NSAIDs such as naproxen sodium, piroxicam, diclofenac, celecoxib, and indomethacin. Emerging data indicate that some NSAIDs are associated with an increased risk of stroke, which is an important consideration as the population ages, said Dr. Nye. Other nonspecific options are neuroleptics such as prochlorperazine, metoclopramide, promethazine, and chlorpromazine. Many neuroleptics have sedative effects, however, so they do not necessarily help a patient return to function. Nevertheless, these drugs can be good rescue medications, said Dr. Nye.
Triptans are effective in the acute treatment of migraine, and seven drugs in this class are available. Most, such as rizatriptan, almotriptan, eletriptan, naratriptan, and frovatriptan, are available only as tablets. Other routes of delivery are available, however. Sumatriptan, for example, is available in injectable and intranasal formulations, and zolmitriptan is available as an orally dissolving tablet.
Another option to consider is dihydroergotamine (DHE), which has long been used for migraine. The injectable formulation of DHE can be cumbersome because it requires the patients with a headache to open a vial, draw the medication into a filter needle, and inject themselves, said Dr. Nye. “The nasal sprays that are available right now aren’t as effective as we’d like them to be,” she added. But overall, DHE is effective. Associated adverse events include flushing, nausea, and diarrhea.
Lasmiditan received approval from the Food and Drug Administration for the acute treatment of migraine in October 2019. Compared with placebo, the drug increases the likelihood of pain freedom and freedom from the most bothersome symptom at 2 hours. Driving tests indicated that patients were impaired for about 8 hours after treatment, and lasmiditan is a Schedule V drug. It is available in doses of 50 mg/day, 100 mg/day, and 200 mg/day.
The class of drugs known as the “gepants” provides further options. The most recently approved therapy in this class, which targets calcitonin gene–related peptide, is ubrogepant. Because the drug is metabolized through the CYP3A4 system, they are not appropriate for patients who use strong CYP3A4 inhibitors. The most common side effects are nausea, hypersensitivity reaction, and somnolence.
Neuromodulation can provide effective treatment without provoking side effects, said Dr. Nye. Options include transcutaneous supraorbital stimulation, single-pulse transcutaneous magnetic stimulation, noninvasive vagal nerve stimulation, and remote nonpainful stimulation.
If a patient presents during an acute attack, neurologists could consider using a nerve block. The latter may administer occipital nerve blocks, trigger point injections, auriculotemporal nerve blocks, and supraorbital and supratrochlear nerve blocks. This treatment can bring immediate relief, which is gratifying for patients and neurologists. But no consensus about which medications to use or how to administer them has been established. Neurologists most often use a combination of bupivacaine and lidocaine. Another possibility is a sphenopalatine ganglion nerve block, which requires treatment to be inserted through the nose. This treatment can be delivered in the office using the Sphenocath device or the Allevio device. Another device, the Tx360, is intended to enable patient self-administration.
Addressing treatment failure
If a patient returns and reports that the current treatment is ineffective, the neurologist must reevaluate the therapy. A helpful way to conduct this reassessment is to administer the Migraine Treatment Optimization Questionnaire (MTOQ), which was developed by Lipton et al., to the patient. Neurologists ask whether the patient can function normally 2 hours after treatment or whether the medication is, for example, causing a side effect that makes this outcome less likely. Other questions for the patient are whether the headache pain disappears within 2 hours and whether the medication provides consistent relief. Finally, the neurologist can ask whether the patient is comfortable taking the medication. A score lower than 2 on the MTOQ indicates that the acute treatment should be changed, said Dr. Nye.
Gastroparesis is common during migraine attacks. It is inadvisable to give an oral medication to a patient who vomits within 20 minutes of attack onset, said Dr. Nye. “It’s a little less intuitive for those people who are nauseous immediately to think that that oral tablet is probably going to sit in their stomach and not get absorbed in the intestines as intended.” Nasal sprays, injectable medicines, and oral dissolving tablets are appropriate options for patients with gastroparesis.
Treating migraine during pregnancy
Special consideration must be given to treatment when the patient is pregnant. Decreased headache frequency is common in pregnancy, but not universal. Occipital nerve blocks are a good option for prevention and acute management in pregnant patients. They may be administered every 2 weeks. Sphenopalatine ganglion nerve block is another option, and it can be administered several times per week. Data “suggest that stacking the injections 2 or 3 days per week for up to 6 weeks can eliminate headaches for up to 6 months,” said Dr. Nye.
Tylenol is appropriate for acute headache in pregnant patients, “but we do warn about medication overuse headache and limiting its use.” Ondansetron and promethazine are acceptable treatments for nausea. Although ondansetron has less central activity than promethazine, and thus does not reduce the headache, it lessens nausea, said Dr. Nye.
Triptan exposure during the first trimester is not significantly associated with major congenital malformations, which is reassuring, given that many patients take triptans before they realize that they are pregnant. During the second and third trimesters, triptan exposure is significantly associated with atonic uterus and increased blood loss during labor. In a 16-year registry, sumatriptan, naratriptan, and treximet were not associated with teratogenicity.
Nonpharmacological treatments, too, may help pregnant patients. Lifestyle management, including a regular sleep schedule, exercise routine, and diet, can be beneficial. Massage therapy may reduce stress, and cognitive-behavioral therapy and biofeedback are additional options. Behavioral therapy, however, should be initiated before the patient plans the pregnancy, said Dr. Nye. These therapies require training that a patient having an exacerbation of migraine is less likely to have the motivation to begin.
Many medications are transferred to infants through breast milk. The American Pediatric Association considers a relative infant dosing of less than 10% to be safe. A clinician or patient can look up a medication on websites such as LactMed to understand the relative infant dose and possible effects. Another helpful reference is Medications and Mothers’ Milk, said Dr. Nye. Acetaminophen, steroids, ibuprofen, riboflavin, indomethacin, ketorolac, and naproxen are generally safe during lactation. “Eletriptan is the triptan that’s least likely to be in the breast milk,” said Dr. Nye. Aspirin, atenolol, ergotamine, and lithium, however, should be given with caution. The safety of amitriptyline, nortriptyline, and SSRIs during lactation is unknown.
Dr. Nye is on advisory boards for Alder, Allergan, Biohaven, electroCore, Pernix, and Xoc.
STOWE, VT. – A large and growing number of medications is available for the acute treatment of migraine. Effective acute treatment enables patients to re-engage in their work and other daily activities, as well as reducing the likelihood that their disease will progress from episodic to chronic migraine. efficacy and tolerability according to Barbara L. Nye, MD, assistant professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H.. Dr. Nye discussed the acute treatment of migraine at the annual meeting of the Headache Cooperative of New England.
Choosing an initial treatment
Nonspecific medications are perhaps the first treatments to consider for a patient with acute migraine. This class includes NSAIDs such as naproxen sodium, piroxicam, diclofenac, celecoxib, and indomethacin. Emerging data indicate that some NSAIDs are associated with an increased risk of stroke, which is an important consideration as the population ages, said Dr. Nye. Other nonspecific options are neuroleptics such as prochlorperazine, metoclopramide, promethazine, and chlorpromazine. Many neuroleptics have sedative effects, however, so they do not necessarily help a patient return to function. Nevertheless, these drugs can be good rescue medications, said Dr. Nye.
Triptans are effective in the acute treatment of migraine, and seven drugs in this class are available. Most, such as rizatriptan, almotriptan, eletriptan, naratriptan, and frovatriptan, are available only as tablets. Other routes of delivery are available, however. Sumatriptan, for example, is available in injectable and intranasal formulations, and zolmitriptan is available as an orally dissolving tablet.
Another option to consider is dihydroergotamine (DHE), which has long been used for migraine. The injectable formulation of DHE can be cumbersome because it requires the patients with a headache to open a vial, draw the medication into a filter needle, and inject themselves, said Dr. Nye. “The nasal sprays that are available right now aren’t as effective as we’d like them to be,” she added. But overall, DHE is effective. Associated adverse events include flushing, nausea, and diarrhea.
Lasmiditan received approval from the Food and Drug Administration for the acute treatment of migraine in October 2019. Compared with placebo, the drug increases the likelihood of pain freedom and freedom from the most bothersome symptom at 2 hours. Driving tests indicated that patients were impaired for about 8 hours after treatment, and lasmiditan is a Schedule V drug. It is available in doses of 50 mg/day, 100 mg/day, and 200 mg/day.
The class of drugs known as the “gepants” provides further options. The most recently approved therapy in this class, which targets calcitonin gene–related peptide, is ubrogepant. Because the drug is metabolized through the CYP3A4 system, they are not appropriate for patients who use strong CYP3A4 inhibitors. The most common side effects are nausea, hypersensitivity reaction, and somnolence.
Neuromodulation can provide effective treatment without provoking side effects, said Dr. Nye. Options include transcutaneous supraorbital stimulation, single-pulse transcutaneous magnetic stimulation, noninvasive vagal nerve stimulation, and remote nonpainful stimulation.
If a patient presents during an acute attack, neurologists could consider using a nerve block. The latter may administer occipital nerve blocks, trigger point injections, auriculotemporal nerve blocks, and supraorbital and supratrochlear nerve blocks. This treatment can bring immediate relief, which is gratifying for patients and neurologists. But no consensus about which medications to use or how to administer them has been established. Neurologists most often use a combination of bupivacaine and lidocaine. Another possibility is a sphenopalatine ganglion nerve block, which requires treatment to be inserted through the nose. This treatment can be delivered in the office using the Sphenocath device or the Allevio device. Another device, the Tx360, is intended to enable patient self-administration.
Addressing treatment failure
If a patient returns and reports that the current treatment is ineffective, the neurologist must reevaluate the therapy. A helpful way to conduct this reassessment is to administer the Migraine Treatment Optimization Questionnaire (MTOQ), which was developed by Lipton et al., to the patient. Neurologists ask whether the patient can function normally 2 hours after treatment or whether the medication is, for example, causing a side effect that makes this outcome less likely. Other questions for the patient are whether the headache pain disappears within 2 hours and whether the medication provides consistent relief. Finally, the neurologist can ask whether the patient is comfortable taking the medication. A score lower than 2 on the MTOQ indicates that the acute treatment should be changed, said Dr. Nye.
Gastroparesis is common during migraine attacks. It is inadvisable to give an oral medication to a patient who vomits within 20 minutes of attack onset, said Dr. Nye. “It’s a little less intuitive for those people who are nauseous immediately to think that that oral tablet is probably going to sit in their stomach and not get absorbed in the intestines as intended.” Nasal sprays, injectable medicines, and oral dissolving tablets are appropriate options for patients with gastroparesis.
Treating migraine during pregnancy
Special consideration must be given to treatment when the patient is pregnant. Decreased headache frequency is common in pregnancy, but not universal. Occipital nerve blocks are a good option for prevention and acute management in pregnant patients. They may be administered every 2 weeks. Sphenopalatine ganglion nerve block is another option, and it can be administered several times per week. Data “suggest that stacking the injections 2 or 3 days per week for up to 6 weeks can eliminate headaches for up to 6 months,” said Dr. Nye.
Tylenol is appropriate for acute headache in pregnant patients, “but we do warn about medication overuse headache and limiting its use.” Ondansetron and promethazine are acceptable treatments for nausea. Although ondansetron has less central activity than promethazine, and thus does not reduce the headache, it lessens nausea, said Dr. Nye.
Triptan exposure during the first trimester is not significantly associated with major congenital malformations, which is reassuring, given that many patients take triptans before they realize that they are pregnant. During the second and third trimesters, triptan exposure is significantly associated with atonic uterus and increased blood loss during labor. In a 16-year registry, sumatriptan, naratriptan, and treximet were not associated with teratogenicity.
Nonpharmacological treatments, too, may help pregnant patients. Lifestyle management, including a regular sleep schedule, exercise routine, and diet, can be beneficial. Massage therapy may reduce stress, and cognitive-behavioral therapy and biofeedback are additional options. Behavioral therapy, however, should be initiated before the patient plans the pregnancy, said Dr. Nye. These therapies require training that a patient having an exacerbation of migraine is less likely to have the motivation to begin.
Many medications are transferred to infants through breast milk. The American Pediatric Association considers a relative infant dosing of less than 10% to be safe. A clinician or patient can look up a medication on websites such as LactMed to understand the relative infant dose and possible effects. Another helpful reference is Medications and Mothers’ Milk, said Dr. Nye. Acetaminophen, steroids, ibuprofen, riboflavin, indomethacin, ketorolac, and naproxen are generally safe during lactation. “Eletriptan is the triptan that’s least likely to be in the breast milk,” said Dr. Nye. Aspirin, atenolol, ergotamine, and lithium, however, should be given with caution. The safety of amitriptyline, nortriptyline, and SSRIs during lactation is unknown.
Dr. Nye is on advisory boards for Alder, Allergan, Biohaven, electroCore, Pernix, and Xoc.
REPORTING FROM HCNE 2020
Pandemic necessitates new strategies to treat migraine
Patients with migraine who are unable to continue preventive procedures such as onabotulinumtoxinA injections during the COVID-19 pandemic may be at risk of worsening migraine, according to an article published March 30 in Headache. To address this scenario, including monoclonal antibodies against calcitonin gene-related peptide (CGRP) or the CGRP receptor, the authors said.
“This is a particularly vulnerable time for individuals with migraine and other disabling headache disorders, with many physical and mental stressors, increased anxiety, and changes in daily routine which may serve as triggering factors for worsening headache,” said lead author Christina L. Szperka, MD, director of the pediatric headache program at Children’s Hospital of Philadelphia, and colleagues.
Acute treatment
The authors described potential treatment regimens based on their experience as headache specialists and the experiences of their colleagues. For acute therapy options, NSAIDs, triptans, and neuroleptics may be used in combination when needed. Medications within the same drug category should not be combined, however, and triptans, dihydroergotamine, and lasmiditan should not be coadministered within 24 hours. Since the 2015 American Headache Society guideline for the acute treatment of migraine, the Food and Drug Administration has approved additional acute migraine medications, including ubrogepant, rimegepant, and lasmiditan, the authors said. The agency also cleared several neuromodulation devices for the acute treatment of migraine.
Although few drugs have been studied as treatments for unusually prolonged severe headaches, headache doctors often recommend NSAIDs before patients seek care at an emergency department or infusion center, the authors said. NSAID options include indomethacin, ketorolac, naproxen, nabumetone, diclofenac, and mefenamic acid. Neuroleptics also may be used. “Long-acting triptan medications can be used as bridge therapies, as is often done in the treatment of menstrually related migraine or in the treatment of medication overuse headache,” they said. “We propose a similar strategy can be trialed as a therapeutic option for refractory or persistent migraine.”
The authors also described the use of antiepileptics and corticosteroids, as well as drugs that may treat specific symptoms, such as difficulty sleeping (hydroxyzine or amitriptyline), neck or muscle pain (tizanidine), and aura with migraine (magnesium). Clinicians should avoid the use of opioids and butalbital, they said.
Preventive treatment
“While the injection of onabotulinumtoxinA is an effective treatment for chronic migraine, the procedure can put the patient and the provider at higher risk of COVID-19 given the close contact encounter,” wrote Dr. Szperka and colleagues. “We believe that other migraine preventive treatments should be utilized first when possible.” Since the publication of a guideline on preventive migraine therapies in 2012, the FDA has approved additional preventive therapies, including the anti-CGRP monoclonal antibodies erenumab‐aooe, galcanezumab‐gnlm, fremanezumab‐vfrm, and eptinezumab‐jjmr. “The first three are intended for self‐injection at home, with detailed instructions available for each product on its website,” they said.
Among angiotensin‐converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), candesartan has evidence of efficacy and tolerability in migraine prevention. Lisinopril has been considered possibly effective. “There has been recent concern in the media about the possibility of these medications interfering with the body’s response to COVID‐19,” the authors said, although this theoretical concern was not based on experimental or clinical data. “For patients in need of a new preventive therapy, the potential for benefit with an ACE/ARB must be weighed against the theoretical increased risk of infection.”
In addition, studies indicate that melatonin may prevent migraine with few side effects and that zonisamide may be effective in patients who have an inadequate response to or experience side effects with topiramate.
Policy changes and telehealth options
Effectively treating patients with migraine during the pandemic requires policy changes, according to the authors. “Migraine preventive prior authorization restrictions need to be lifted for evidence‐based, FDA‐approved therapies; patients need to be able to access these medications quickly and easily. Patients should not be required to fail older medications,” they said. “Similarly, in order to permit the transition of patients from onabotulinumtoxinA to anti‐CGRP [monoclonal antibodies], insurers should remove the prohibition against simultaneous coverage of these drug classes.” Insurers also should loosen restrictions on the off-label use of acute and preventive medication for adolescents, Dr. Szperka and coauthors suggest.
“In the era of COVID‐19, telehealth has become an essential modality for most headache specialists, given the need for providers to take significant precautions for both their patients and themselves, limiting touch or close contact,” they said. Patients with headache may warrant additional screening for COVID-19 as well. “As headache has been reported as an early symptom of COVID‐19, patients with worsening or new onset severe headache should be reviewed for exposure risk and any other symptoms which may be consistent with COVID‐19 infection,” the authors said.
There was no direct funding for the report. Dr. Szperka and a coauthor receive salary support from the National Institutes of Health. Dr. Szperka also has received grant support from Pfizer, and her institution has received compensation for her consulting work for Allergan. Several coauthors disclosed consulting and serving on speakers’ bureaus for and receiving research support from various pharmaceutical companies.
SOURCE: Szperka CL et al. Headache. 2020 Mar 30. doi: 10.1111/head.13810.
Patients with migraine who are unable to continue preventive procedures such as onabotulinumtoxinA injections during the COVID-19 pandemic may be at risk of worsening migraine, according to an article published March 30 in Headache. To address this scenario, including monoclonal antibodies against calcitonin gene-related peptide (CGRP) or the CGRP receptor, the authors said.
“This is a particularly vulnerable time for individuals with migraine and other disabling headache disorders, with many physical and mental stressors, increased anxiety, and changes in daily routine which may serve as triggering factors for worsening headache,” said lead author Christina L. Szperka, MD, director of the pediatric headache program at Children’s Hospital of Philadelphia, and colleagues.
Acute treatment
The authors described potential treatment regimens based on their experience as headache specialists and the experiences of their colleagues. For acute therapy options, NSAIDs, triptans, and neuroleptics may be used in combination when needed. Medications within the same drug category should not be combined, however, and triptans, dihydroergotamine, and lasmiditan should not be coadministered within 24 hours. Since the 2015 American Headache Society guideline for the acute treatment of migraine, the Food and Drug Administration has approved additional acute migraine medications, including ubrogepant, rimegepant, and lasmiditan, the authors said. The agency also cleared several neuromodulation devices for the acute treatment of migraine.
Although few drugs have been studied as treatments for unusually prolonged severe headaches, headache doctors often recommend NSAIDs before patients seek care at an emergency department or infusion center, the authors said. NSAID options include indomethacin, ketorolac, naproxen, nabumetone, diclofenac, and mefenamic acid. Neuroleptics also may be used. “Long-acting triptan medications can be used as bridge therapies, as is often done in the treatment of menstrually related migraine or in the treatment of medication overuse headache,” they said. “We propose a similar strategy can be trialed as a therapeutic option for refractory or persistent migraine.”
The authors also described the use of antiepileptics and corticosteroids, as well as drugs that may treat specific symptoms, such as difficulty sleeping (hydroxyzine or amitriptyline), neck or muscle pain (tizanidine), and aura with migraine (magnesium). Clinicians should avoid the use of opioids and butalbital, they said.
Preventive treatment
“While the injection of onabotulinumtoxinA is an effective treatment for chronic migraine, the procedure can put the patient and the provider at higher risk of COVID-19 given the close contact encounter,” wrote Dr. Szperka and colleagues. “We believe that other migraine preventive treatments should be utilized first when possible.” Since the publication of a guideline on preventive migraine therapies in 2012, the FDA has approved additional preventive therapies, including the anti-CGRP monoclonal antibodies erenumab‐aooe, galcanezumab‐gnlm, fremanezumab‐vfrm, and eptinezumab‐jjmr. “The first three are intended for self‐injection at home, with detailed instructions available for each product on its website,” they said.
Among angiotensin‐converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), candesartan has evidence of efficacy and tolerability in migraine prevention. Lisinopril has been considered possibly effective. “There has been recent concern in the media about the possibility of these medications interfering with the body’s response to COVID‐19,” the authors said, although this theoretical concern was not based on experimental or clinical data. “For patients in need of a new preventive therapy, the potential for benefit with an ACE/ARB must be weighed against the theoretical increased risk of infection.”
In addition, studies indicate that melatonin may prevent migraine with few side effects and that zonisamide may be effective in patients who have an inadequate response to or experience side effects with topiramate.
Policy changes and telehealth options
Effectively treating patients with migraine during the pandemic requires policy changes, according to the authors. “Migraine preventive prior authorization restrictions need to be lifted for evidence‐based, FDA‐approved therapies; patients need to be able to access these medications quickly and easily. Patients should not be required to fail older medications,” they said. “Similarly, in order to permit the transition of patients from onabotulinumtoxinA to anti‐CGRP [monoclonal antibodies], insurers should remove the prohibition against simultaneous coverage of these drug classes.” Insurers also should loosen restrictions on the off-label use of acute and preventive medication for adolescents, Dr. Szperka and coauthors suggest.
“In the era of COVID‐19, telehealth has become an essential modality for most headache specialists, given the need for providers to take significant precautions for both their patients and themselves, limiting touch or close contact,” they said. Patients with headache may warrant additional screening for COVID-19 as well. “As headache has been reported as an early symptom of COVID‐19, patients with worsening or new onset severe headache should be reviewed for exposure risk and any other symptoms which may be consistent with COVID‐19 infection,” the authors said.
There was no direct funding for the report. Dr. Szperka and a coauthor receive salary support from the National Institutes of Health. Dr. Szperka also has received grant support from Pfizer, and her institution has received compensation for her consulting work for Allergan. Several coauthors disclosed consulting and serving on speakers’ bureaus for and receiving research support from various pharmaceutical companies.
SOURCE: Szperka CL et al. Headache. 2020 Mar 30. doi: 10.1111/head.13810.
Patients with migraine who are unable to continue preventive procedures such as onabotulinumtoxinA injections during the COVID-19 pandemic may be at risk of worsening migraine, according to an article published March 30 in Headache. To address this scenario, including monoclonal antibodies against calcitonin gene-related peptide (CGRP) or the CGRP receptor, the authors said.
“This is a particularly vulnerable time for individuals with migraine and other disabling headache disorders, with many physical and mental stressors, increased anxiety, and changes in daily routine which may serve as triggering factors for worsening headache,” said lead author Christina L. Szperka, MD, director of the pediatric headache program at Children’s Hospital of Philadelphia, and colleagues.
Acute treatment
The authors described potential treatment regimens based on their experience as headache specialists and the experiences of their colleagues. For acute therapy options, NSAIDs, triptans, and neuroleptics may be used in combination when needed. Medications within the same drug category should not be combined, however, and triptans, dihydroergotamine, and lasmiditan should not be coadministered within 24 hours. Since the 2015 American Headache Society guideline for the acute treatment of migraine, the Food and Drug Administration has approved additional acute migraine medications, including ubrogepant, rimegepant, and lasmiditan, the authors said. The agency also cleared several neuromodulation devices for the acute treatment of migraine.
Although few drugs have been studied as treatments for unusually prolonged severe headaches, headache doctors often recommend NSAIDs before patients seek care at an emergency department or infusion center, the authors said. NSAID options include indomethacin, ketorolac, naproxen, nabumetone, diclofenac, and mefenamic acid. Neuroleptics also may be used. “Long-acting triptan medications can be used as bridge therapies, as is often done in the treatment of menstrually related migraine or in the treatment of medication overuse headache,” they said. “We propose a similar strategy can be trialed as a therapeutic option for refractory or persistent migraine.”
The authors also described the use of antiepileptics and corticosteroids, as well as drugs that may treat specific symptoms, such as difficulty sleeping (hydroxyzine or amitriptyline), neck or muscle pain (tizanidine), and aura with migraine (magnesium). Clinicians should avoid the use of opioids and butalbital, they said.
Preventive treatment
“While the injection of onabotulinumtoxinA is an effective treatment for chronic migraine, the procedure can put the patient and the provider at higher risk of COVID-19 given the close contact encounter,” wrote Dr. Szperka and colleagues. “We believe that other migraine preventive treatments should be utilized first when possible.” Since the publication of a guideline on preventive migraine therapies in 2012, the FDA has approved additional preventive therapies, including the anti-CGRP monoclonal antibodies erenumab‐aooe, galcanezumab‐gnlm, fremanezumab‐vfrm, and eptinezumab‐jjmr. “The first three are intended for self‐injection at home, with detailed instructions available for each product on its website,” they said.
Among angiotensin‐converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), candesartan has evidence of efficacy and tolerability in migraine prevention. Lisinopril has been considered possibly effective. “There has been recent concern in the media about the possibility of these medications interfering with the body’s response to COVID‐19,” the authors said, although this theoretical concern was not based on experimental or clinical data. “For patients in need of a new preventive therapy, the potential for benefit with an ACE/ARB must be weighed against the theoretical increased risk of infection.”
In addition, studies indicate that melatonin may prevent migraine with few side effects and that zonisamide may be effective in patients who have an inadequate response to or experience side effects with topiramate.
Policy changes and telehealth options
Effectively treating patients with migraine during the pandemic requires policy changes, according to the authors. “Migraine preventive prior authorization restrictions need to be lifted for evidence‐based, FDA‐approved therapies; patients need to be able to access these medications quickly and easily. Patients should not be required to fail older medications,” they said. “Similarly, in order to permit the transition of patients from onabotulinumtoxinA to anti‐CGRP [monoclonal antibodies], insurers should remove the prohibition against simultaneous coverage of these drug classes.” Insurers also should loosen restrictions on the off-label use of acute and preventive medication for adolescents, Dr. Szperka and coauthors suggest.
“In the era of COVID‐19, telehealth has become an essential modality for most headache specialists, given the need for providers to take significant precautions for both their patients and themselves, limiting touch or close contact,” they said. Patients with headache may warrant additional screening for COVID-19 as well. “As headache has been reported as an early symptom of COVID‐19, patients with worsening or new onset severe headache should be reviewed for exposure risk and any other symptoms which may be consistent with COVID‐19 infection,” the authors said.
There was no direct funding for the report. Dr. Szperka and a coauthor receive salary support from the National Institutes of Health. Dr. Szperka also has received grant support from Pfizer, and her institution has received compensation for her consulting work for Allergan. Several coauthors disclosed consulting and serving on speakers’ bureaus for and receiving research support from various pharmaceutical companies.
SOURCE: Szperka CL et al. Headache. 2020 Mar 30. doi: 10.1111/head.13810.
FROM HEADACHE
When is preventive treatment of migraine appropriate?
STOWE, VT – , said Rebecca Burch, MD, staff attending neurologist at Brigham and Women’s Hospital in Boston. Clinical observation suggests that preventive treatment provides benefits for appropriately selected migraineurs, although few data confirm a modifying effect on disease course, she said at the Stowe Headache Symposium sponsored by the Headache Cooperative of New England. In her overview, Dr. Burch discussed when preventive treatment is appropriate, which patients are candidates for preventive therapy, and what the levels of evidence are for the preventive therapies. 
Identifying candidates for preventive treatment
Migraine is the second most disabling condition worldwide and imposes a large social and economic burden, said Dr. Burch. Preventive therapy reduces the disability associated with migraine. It reduces headache frequency and, thus, the risk that episodic migraine will transform into chronic migraine. By reducing the number of headache days, preventive treatment also may reduce the overuse of acute medication, which is a risk factor for migraine chronification.
Neurologists can consider preventive therapy for migraineurs with frequent headaches, but the term “frequent” is not clearly defined. Common definitions include one headache per week and two headaches per month with significant disability. These definitions are based on expert consensus and do not have strong evidential support, said Dr. Burch. Preventive therapy also may be appropriate for migraineurs who overuse acute medication or who have failed acute medications. Special cases, such as patients with exceptional anxiety or disability, may also call for preventive treatment, said Dr. Burch.
Data suggest that preventive treatment for migraine is underused. The American Migraine Prevalence and Prevention study of 2007 found that half of patients who should be offered preventive treatment are currently receiving it. In 2016, the Chronic Migraine Epidemiology and Outcomes study found that 4.5% of chronic migraineurs take both acute and preventive treatment.
Other data published in Cephalalgia in 2015 indicate that adherence to migraine preventive treatment is approximately 20%. About 45% of patients discontinue medication because of side effects, and 45% cite lack of efficacy as their reason for discontinuation. Patients also mentioned cost, interactions with other medications, and the inconvenience of daily medication as other reasons for discontinuation.
Neurologists can take several steps to increase adherence to preventive treatment, said Dr. Burch. First, neurologists should confirm that patients want preventive medication. A clear discussion of the goals of preventive treatment is helpful as well. Furthermore, neurologists should explain that they are offering patients a trial, said Dr. Burch. The medication can be titrated slowly from a low dose to minimize side effects. Patients can be reassured that ineffective medications will be stopped. Neurologists can emphasize that their relationship with the patient is a partnership and that the treatment strategy will be improved over time.
Examining the evidence on treatments’ efficacy
Many drug classes, such as antiepileptics, antidepressants, beta blockers, neurotoxins, and calcitonin gene-related peptide (CGRP) antibodies, include therapies that are used as preventive treatments for migraine. When selecting a medication, a neurologist should start with one that is supported by Level A or Level B evidence, said Dr. Burch. Medications with Level A evidence include divalproex, topiramate, metoprolol, propranolol, erenumab, galcanezumab, fremanezumab, eptinezumab, and onabotulinumtoxinA. Medications with Level B evidence include amitriptyline, venlafaxine, memantine, lisinopril, and candesartan. Neurologists sometimes prescribe gabapentin and verapamil, although the evidence for them is Level U. Duloxetine, nortriptyline, and pregabalin also are used, but the evidence for them has not been evaluated. “We need more evidence in these areas,” said Dr. Burch.
Neurologists should consider access (e.g., cost and insurance coverage), efficacy, side effects, and comorbidities and contraindications when choosing a preventive therapy, she added. Verapamil and memantine are well tolerated and appropriate choices if the goal is to avoid side effects in general. If weight gain or fatigue is a concern, then topiramate and venlafaxine should be considered. Neurologists should avoid prescribing antiepileptic drugs if cognitive symptoms are a concern, said Dr. Burch. Beta blockers and venlafaxine would be better options in this case.
In clinical trials of CGRP therapies, the rates of adverse events were similar between the active and control arms. “But it’s become fairly clear that the clinical trials did not fully capture the side-effect profile that we are seeing in clinical practice,” said Dr. Burch. In a paper currently in review, she and her colleagues retrospectively studied 241 patients that they had treated with CGRP monoclonal antibodies at their headache center. The most common adverse events were constipation (43%), injection-site reaction (24%), muscle or joint pain (17%), and fatigue (15%). Furthermore, CGRP antagonists were associated with maternal hypertension, fetal growth restriction, and fetal mortality in animal studies. The current recommendation is to avoid CGRP monoclonal antibodies during pregnancy or in any patient who is at risk of becoming pregnant, said Dr. Burch.
How should neurologists assess preventive efficacy?
The assessment of a medication’s preventive efficacy “is a moving target in the headache world,” said Dr. Burch. “Historically, we have used headache days per month, and that is still, according to the International Headache Society clinical trials guidelines, how we should be judging whether a medication is working or not. But that doesn’t necessarily tell us what’s going to happen to an individual patient in front of us.”
In 2017, the Institute for Clinical Effectiveness Research compared data for old and new migraine treatments in a network meta-analysis. They all tended to reduce the number of monthly migraine days by one to two, compared with placebo. When one analyzes clinical trials of the drugs using this criterion, “most of these treatments come out about the same,” said Dr. Burch.
More recently, investigators have examined responder rates. They commonly report the proportions of patients who had a reduction in headache days of 50%, 75%, or 100%, for example. To extrapolate responder rates from the trial participants to the general population, a neurologist must know which groups of patients got worse on treatment, said Dr. Burch. Furthermore, the responder rates for older medications are unknown, because they were not examined. This situation makes comparisons of newer and older therapies more complicated.
Phase 3 trials of the CGRP drugs included analyses of the therapies’ 50% responder rates. This rate was about 42% for the 70-mg dose of erenumab and 50% for the 140-mg dose. The 50% responder rates for fremanezumab were 47.7% for the 225-mg dose and 44.4% for the 675-mg dose. In two trials of galcanezumab, the 50% responder rate for the 120-mg dose was approximately 60%, and the rate for the 240-mg dose was about 59%. The 50% responder rates for eptinezumab were 50% for the 100-mg dose and 56% for the 300-mg dose. The 50% responder rate across all trials was around 50%-60% in the active group, which is roughly 25% over the placebo group, said Dr. Burch.
Another measurement of efficacy is the efficacy-to-harm ratio, which is derived from the number needed to treat and the number needed to harm. To calculate this ratio, however, harm needs to be assessed adequately during a clinical trial. Although the ratio can provide a clinically relevant overview of a drug’s effects, patients may differ from each other in the way they evaluate efficacy and harm.
In addition, many questions about preventive treatment of migraine have no clear answers yet. It is uncertain, for example, how long a patient should receive preventive treatment and when treatment should be withdrawn, said Dr. Burch. “Can we expect that a lot of people are going to need to be on it for life, or is there a subpopulation who will get better and [for whom] we can withdraw [treatment]?” she asked. “How do we identify them?” Also, more data are needed before neurologists can understand why a given patient responds to one treatment, but not to another. It is difficult to predict which patients will respond to which treatments. Finally, it remains unclear how much of patients’ improvement can be attributed to regression to the mean, rather than preventive treatment.
STOWE, VT – , said Rebecca Burch, MD, staff attending neurologist at Brigham and Women’s Hospital in Boston. Clinical observation suggests that preventive treatment provides benefits for appropriately selected migraineurs, although few data confirm a modifying effect on disease course, she said at the Stowe Headache Symposium sponsored by the Headache Cooperative of New England. In her overview, Dr. Burch discussed when preventive treatment is appropriate, which patients are candidates for preventive therapy, and what the levels of evidence are for the preventive therapies.
Identifying candidates for preventive treatment
Migraine is the second most disabling condition worldwide and imposes a large social and economic burden, said Dr. Burch. Preventive therapy reduces the disability associated with migraine. It reduces headache frequency and, thus, the risk that episodic migraine will transform into chronic migraine. By reducing the number of headache days, preventive treatment also may reduce the overuse of acute medication, which is a risk factor for migraine chronification.
Neurologists can consider preventive therapy for migraineurs with frequent headaches, but the term “frequent” is not clearly defined. Common definitions include one headache per week and two headaches per month with significant disability. These definitions are based on expert consensus and do not have strong evidential support, said Dr. Burch. Preventive therapy also may be appropriate for migraineurs who overuse acute medication or who have failed acute medications. Special cases, such as patients with exceptional anxiety or disability, may also call for preventive treatment, said Dr. Burch.
Data suggest that preventive treatment for migraine is underused. The American Migraine Prevalence and Prevention study of 2007 found that half of patients who should be offered preventive treatment are currently receiving it. In 2016, the Chronic Migraine Epidemiology and Outcomes study found that 4.5% of chronic migraineurs take both acute and preventive treatment.
Other data published in Cephalalgia in 2015 indicate that adherence to migraine preventive treatment is approximately 20%. About 45% of patients discontinue medication because of side effects, and 45% cite lack of efficacy as their reason for discontinuation. Patients also mentioned cost, interactions with other medications, and the inconvenience of daily medication as other reasons for discontinuation.
Neurologists can take several steps to increase adherence to preventive treatment, said Dr. Burch. First, neurologists should confirm that patients want preventive medication. A clear discussion of the goals of preventive treatment is helpful as well. Furthermore, neurologists should explain that they are offering patients a trial, said Dr. Burch. The medication can be titrated slowly from a low dose to minimize side effects. Patients can be reassured that ineffective medications will be stopped. Neurologists can emphasize that their relationship with the patient is a partnership and that the treatment strategy will be improved over time.
Examining the evidence on treatments’ efficacy
Many drug classes, such as antiepileptics, antidepressants, beta blockers, neurotoxins, and calcitonin gene-related peptide (CGRP) antibodies, include therapies that are used as preventive treatments for migraine. When selecting a medication, a neurologist should start with one that is supported by Level A or Level B evidence, said Dr. Burch. Medications with Level A evidence include divalproex, topiramate, metoprolol, propranolol, erenumab, galcanezumab, fremanezumab, eptinezumab, and onabotulinumtoxinA. Medications with Level B evidence include amitriptyline, venlafaxine, memantine, lisinopril, and candesartan. Neurologists sometimes prescribe gabapentin and verapamil, although the evidence for them is Level U. Duloxetine, nortriptyline, and pregabalin also are used, but the evidence for them has not been evaluated. “We need more evidence in these areas,” said Dr. Burch.
Neurologists should consider access (e.g., cost and insurance coverage), efficacy, side effects, and comorbidities and contraindications when choosing a preventive therapy, she added. Verapamil and memantine are well tolerated and appropriate choices if the goal is to avoid side effects in general. If weight gain or fatigue is a concern, then topiramate and venlafaxine should be considered. Neurologists should avoid prescribing antiepileptic drugs if cognitive symptoms are a concern, said Dr. Burch. Beta blockers and venlafaxine would be better options in this case.
In clinical trials of CGRP therapies, the rates of adverse events were similar between the active and control arms. “But it’s become fairly clear that the clinical trials did not fully capture the side-effect profile that we are seeing in clinical practice,” said Dr. Burch. In a paper currently in review, she and her colleagues retrospectively studied 241 patients that they had treated with CGRP monoclonal antibodies at their headache center. The most common adverse events were constipation (43%), injection-site reaction (24%), muscle or joint pain (17%), and fatigue (15%). Furthermore, CGRP antagonists were associated with maternal hypertension, fetal growth restriction, and fetal mortality in animal studies. The current recommendation is to avoid CGRP monoclonal antibodies during pregnancy or in any patient who is at risk of becoming pregnant, said Dr. Burch.
How should neurologists assess preventive efficacy?
The assessment of a medication’s preventive efficacy “is a moving target in the headache world,” said Dr. Burch. “Historically, we have used headache days per month, and that is still, according to the International Headache Society clinical trials guidelines, how we should be judging whether a medication is working or not. But that doesn’t necessarily tell us what’s going to happen to an individual patient in front of us.”
In 2017, the Institute for Clinical Effectiveness Research compared data for old and new migraine treatments in a network meta-analysis. They all tended to reduce the number of monthly migraine days by one to two, compared with placebo. When one analyzes clinical trials of the drugs using this criterion, “most of these treatments come out about the same,” said Dr. Burch.
More recently, investigators have examined responder rates. They commonly report the proportions of patients who had a reduction in headache days of 50%, 75%, or 100%, for example. To extrapolate responder rates from the trial participants to the general population, a neurologist must know which groups of patients got worse on treatment, said Dr. Burch. Furthermore, the responder rates for older medications are unknown, because they were not examined. This situation makes comparisons of newer and older therapies more complicated.
Phase 3 trials of the CGRP drugs included analyses of the therapies’ 50% responder rates. This rate was about 42% for the 70-mg dose of erenumab and 50% for the 140-mg dose. The 50% responder rates for fremanezumab were 47.7% for the 225-mg dose and 44.4% for the 675-mg dose. In two trials of galcanezumab, the 50% responder rate for the 120-mg dose was approximately 60%, and the rate for the 240-mg dose was about 59%. The 50% responder rates for eptinezumab were 50% for the 100-mg dose and 56% for the 300-mg dose. The 50% responder rate across all trials was around 50%-60% in the active group, which is roughly 25% over the placebo group, said Dr. Burch.
Another measurement of efficacy is the efficacy-to-harm ratio, which is derived from the number needed to treat and the number needed to harm. To calculate this ratio, however, harm needs to be assessed adequately during a clinical trial. Although the ratio can provide a clinically relevant overview of a drug’s effects, patients may differ from each other in the way they evaluate efficacy and harm.
In addition, many questions about preventive treatment of migraine have no clear answers yet. It is uncertain, for example, how long a patient should receive preventive treatment and when treatment should be withdrawn, said Dr. Burch. “Can we expect that a lot of people are going to need to be on it for life, or is there a subpopulation who will get better and [for whom] we can withdraw [treatment]?” she asked. “How do we identify them?” Also, more data are needed before neurologists can understand why a given patient responds to one treatment, but not to another. It is difficult to predict which patients will respond to which treatments. Finally, it remains unclear how much of patients’ improvement can be attributed to regression to the mean, rather than preventive treatment.
STOWE, VT – , said Rebecca Burch, MD, staff attending neurologist at Brigham and Women’s Hospital in Boston. Clinical observation suggests that preventive treatment provides benefits for appropriately selected migraineurs, although few data confirm a modifying effect on disease course, she said at the Stowe Headache Symposium sponsored by the Headache Cooperative of New England. In her overview, Dr. Burch discussed when preventive treatment is appropriate, which patients are candidates for preventive therapy, and what the levels of evidence are for the preventive therapies.
Identifying candidates for preventive treatment
Migraine is the second most disabling condition worldwide and imposes a large social and economic burden, said Dr. Burch. Preventive therapy reduces the disability associated with migraine. It reduces headache frequency and, thus, the risk that episodic migraine will transform into chronic migraine. By reducing the number of headache days, preventive treatment also may reduce the overuse of acute medication, which is a risk factor for migraine chronification.
Neurologists can consider preventive therapy for migraineurs with frequent headaches, but the term “frequent” is not clearly defined. Common definitions include one headache per week and two headaches per month with significant disability. These definitions are based on expert consensus and do not have strong evidential support, said Dr. Burch. Preventive therapy also may be appropriate for migraineurs who overuse acute medication or who have failed acute medications. Special cases, such as patients with exceptional anxiety or disability, may also call for preventive treatment, said Dr. Burch.
Data suggest that preventive treatment for migraine is underused. The American Migraine Prevalence and Prevention study of 2007 found that half of patients who should be offered preventive treatment are currently receiving it. In 2016, the Chronic Migraine Epidemiology and Outcomes study found that 4.5% of chronic migraineurs take both acute and preventive treatment.
Other data published in Cephalalgia in 2015 indicate that adherence to migraine preventive treatment is approximately 20%. About 45% of patients discontinue medication because of side effects, and 45% cite lack of efficacy as their reason for discontinuation. Patients also mentioned cost, interactions with other medications, and the inconvenience of daily medication as other reasons for discontinuation.
Neurologists can take several steps to increase adherence to preventive treatment, said Dr. Burch. First, neurologists should confirm that patients want preventive medication. A clear discussion of the goals of preventive treatment is helpful as well. Furthermore, neurologists should explain that they are offering patients a trial, said Dr. Burch. The medication can be titrated slowly from a low dose to minimize side effects. Patients can be reassured that ineffective medications will be stopped. Neurologists can emphasize that their relationship with the patient is a partnership and that the treatment strategy will be improved over time.
Examining the evidence on treatments’ efficacy
Many drug classes, such as antiepileptics, antidepressants, beta blockers, neurotoxins, and calcitonin gene-related peptide (CGRP) antibodies, include therapies that are used as preventive treatments for migraine. When selecting a medication, a neurologist should start with one that is supported by Level A or Level B evidence, said Dr. Burch. Medications with Level A evidence include divalproex, topiramate, metoprolol, propranolol, erenumab, galcanezumab, fremanezumab, eptinezumab, and onabotulinumtoxinA. Medications with Level B evidence include amitriptyline, venlafaxine, memantine, lisinopril, and candesartan. Neurologists sometimes prescribe gabapentin and verapamil, although the evidence for them is Level U. Duloxetine, nortriptyline, and pregabalin also are used, but the evidence for them has not been evaluated. “We need more evidence in these areas,” said Dr. Burch.
Neurologists should consider access (e.g., cost and insurance coverage), efficacy, side effects, and comorbidities and contraindications when choosing a preventive therapy, she added. Verapamil and memantine are well tolerated and appropriate choices if the goal is to avoid side effects in general. If weight gain or fatigue is a concern, then topiramate and venlafaxine should be considered. Neurologists should avoid prescribing antiepileptic drugs if cognitive symptoms are a concern, said Dr. Burch. Beta blockers and venlafaxine would be better options in this case.
In clinical trials of CGRP therapies, the rates of adverse events were similar between the active and control arms. “But it’s become fairly clear that the clinical trials did not fully capture the side-effect profile that we are seeing in clinical practice,” said Dr. Burch. In a paper currently in review, she and her colleagues retrospectively studied 241 patients that they had treated with CGRP monoclonal antibodies at their headache center. The most common adverse events were constipation (43%), injection-site reaction (24%), muscle or joint pain (17%), and fatigue (15%). Furthermore, CGRP antagonists were associated with maternal hypertension, fetal growth restriction, and fetal mortality in animal studies. The current recommendation is to avoid CGRP monoclonal antibodies during pregnancy or in any patient who is at risk of becoming pregnant, said Dr. Burch.
How should neurologists assess preventive efficacy?
The assessment of a medication’s preventive efficacy “is a moving target in the headache world,” said Dr. Burch. “Historically, we have used headache days per month, and that is still, according to the International Headache Society clinical trials guidelines, how we should be judging whether a medication is working or not. But that doesn’t necessarily tell us what’s going to happen to an individual patient in front of us.”
In 2017, the Institute for Clinical Effectiveness Research compared data for old and new migraine treatments in a network meta-analysis. They all tended to reduce the number of monthly migraine days by one to two, compared with placebo. When one analyzes clinical trials of the drugs using this criterion, “most of these treatments come out about the same,” said Dr. Burch.
More recently, investigators have examined responder rates. They commonly report the proportions of patients who had a reduction in headache days of 50%, 75%, or 100%, for example. To extrapolate responder rates from the trial participants to the general population, a neurologist must know which groups of patients got worse on treatment, said Dr. Burch. Furthermore, the responder rates for older medications are unknown, because they were not examined. This situation makes comparisons of newer and older therapies more complicated.
Phase 3 trials of the CGRP drugs included analyses of the therapies’ 50% responder rates. This rate was about 42% for the 70-mg dose of erenumab and 50% for the 140-mg dose. The 50% responder rates for fremanezumab were 47.7% for the 225-mg dose and 44.4% for the 675-mg dose. In two trials of galcanezumab, the 50% responder rate for the 120-mg dose was approximately 60%, and the rate for the 240-mg dose was about 59%. The 50% responder rates for eptinezumab were 50% for the 100-mg dose and 56% for the 300-mg dose. The 50% responder rate across all trials was around 50%-60% in the active group, which is roughly 25% over the placebo group, said Dr. Burch.
Another measurement of efficacy is the efficacy-to-harm ratio, which is derived from the number needed to treat and the number needed to harm. To calculate this ratio, however, harm needs to be assessed adequately during a clinical trial. Although the ratio can provide a clinically relevant overview of a drug’s effects, patients may differ from each other in the way they evaluate efficacy and harm.
In addition, many questions about preventive treatment of migraine have no clear answers yet. It is uncertain, for example, how long a patient should receive preventive treatment and when treatment should be withdrawn, said Dr. Burch. “Can we expect that a lot of people are going to need to be on it for life, or is there a subpopulation who will get better and [for whom] we can withdraw [treatment]?” she asked. “How do we identify them?” Also, more data are needed before neurologists can understand why a given patient responds to one treatment, but not to another. It is difficult to predict which patients will respond to which treatments. Finally, it remains unclear how much of patients’ improvement can be attributed to regression to the mean, rather than preventive treatment.
REPORTING FROM HCNE STOWE 2020
How can neurologists diagnose and treat menstrual migraine?
STOWE, VT. – , said Susan Hutchinson, MD, director of the Orange County Migraine and Headache Center in Irvine, Calif. Compared with headaches associated with nonmenstrual migraine, headaches resulting from menstrual migraine last longer and are more difficult to treat. They tend to be associated with morning awakening and with nausea and vomiting. But in younger women with regular menses, menstrual migraine is predictable. The disorder offers “an incredible chance to be preemptive and think about short-term preventive strategies,” Dr. Hutchinson said at the annual meeting of the Headache Cooperative of New England.
What is menstrual migraine?
Menstrual migraine occurs during the perimenstrual window, which begins at 2 days before onset of bleeding and ends at 3 days of menses. Migraine that occurs during this window at least two-thirds of the time satisfies the criteria for menstrual migraine. A prospective headache diary is recommended, but not required, for making the diagnosis, said Dr. Hutchinson.
Most women with migraine have perimenstrual exacerbation of their headaches, as well as headaches at other times of the month. This phenotype is called menstrually related migraine. Pure menstrual migraine is migraine associated exclusively with menses. The International Classification of Headache Disorders-3 recognizes that menstrual migraine can be with or without aura. A headache diary can help distinguish between menstrual migraine and menstrually related migraine.
For pure menstrual migraine, it is appropriate to treat during the perimenstrual window. Preventive treatment may not be necessary throughout the month, said Dr. Hutchinson. Furthermore, hormonal treatment is the type of therapy most likely to be effective, she added. Menstrually related migraine requires a broader approach.
Gathering information during the visit
A 1972 study by Somerville and colleagues indicated that a decrease in estrogen is a powerful trigger of migraine. The investigators administered estrogen (i.e., intramuscular estradiol) or progesterone during the late luteal phase to women with menstrual migraine. Among women who received estrogen, migraine onset was postponed until the estrogen level decreased. The administration of progesterone postponed bleeding, but did not affect migraine. Progesterone treatment prevents migraine effectively on occasion, but estrogen treatment is much more likely to be a successful strategy, said Dr. Hutchinson.
Neurologists should ask certain questions of women with migraine, whether the patients are new or not, to gather information needed to make treatment decisions. For example, it is advisable to ask a woman whether she often has a headache with her period. “You may not want to use the word ‘migraine,’ because many women have been taught that headache is part of PMS,” said Dr. Hutchinson. Asking a woman how pregnancy, delivery, and breastfeeding affected her headaches can add further detail to her history and provide insight about the effects of hormonal changes. Asking what type of birth control the woman is taking can influence the choice of treatment, since some therapies are not appropriate during pregnancy.
Available treatments
NSAIDs are among the treatments that neurologists should consider for the short-term prevention of menstrually related migraine, said Dr. Hutchinson. A study of 35 patients by Sances et al. compared placebo with 550 mg of naproxen sodium given twice daily. Treatment began at 7 days before bleeding onset and continued until the 6th day of menses. Patients underwent treatment for three menstrual cycles. Naproxen sodium significantly reduced headache intensity, headache duration, and the number of headache days, compared with baseline. Treatment was superior to placebo at 3 months. Approximately 33% of patients in the active group were headache free, but no controls were.
Magnesium is another potentially effective option. Facchinetti et al. compared placebo with 360 mg/day of magnesium in a study of 20 patients. Treatment, which was given for two cycles, began at 15 days before menses and ended at the start of menses. Compared with placebo, magnesium reduced the number of headache days and the total pain index. Magnesium is inexpensive, but it causes diarrhea in some patients. “Some women choose to take magnesium all month long, other women start at around ovulation,” said Dr. Hutchinson.
Hormonal treatments are another possible option for the short-term prevention of menstrually related migraine. For women who do not plan to become pregnant, oral contraceptive pills can keep estrogen levels high enough to prevent menstrually related migraine. Gynecologists may suggest that a woman take the pill continuously, skipping the placebo, for an entire year, but Dr. Hutchinson recommends that a woman stop taking the pill for 4 days approximately every 3 months. This discontinuation allows for withdrawal bleeding, but is not likely to cause a prolonged enough decrease in estrogen to provoke migraine, she said. The continuous contraceptive ring, which is inserted vaginally, is an alternative to the pill.
For women who do not want or need contraception, an estrogen patch or gel may be appropriate. Two studies in the 1980s found that a gel containing 1.5 mg of estradiol per 2.5 g reduced migraine frequency, duration, and severity. These studies did not gather long-term safety data, however. A 2006 study by MacGregor et al. found that percutaneous estradiol was associated with a 22% reduction in the number of migraine days, as well as with decreases in headache severity and associated nausea. But the risk of migraine during the 5 days following treatment cessation was increased by 40%. This finding suggests that the treatment period should be extended, said Dr. Hutchinson.
In addition to the timing, the dose of treatment affects the outcome. Smite et al. found no benefit of a 50-mcg dose of estradiol, compared with placebo. Pradalier and colleagues found that a 100-mcg dose was associated with decreased use of rescue medication, compared with a 25-mcg dose. These studies did not gather long-term safety data.
Oral contraceptives and the risk of stroke
Combined oral contraceptives, however, are associated with increased risk of stroke in women with migraine with aura. The dose of estrogen in the contraceptive affects the level of risk, said Dr. Hutchinson. A systematic review by Sheikh et al. found that high-dose ethinyl estradiol (i.e., greater than 50 mcg) was associated with a higher risk of ischemic and hemorrhagic stroke than low-dose ethinyl estradiol (i.e., less than 50 mcg) was. A 20-mcg dose was associated with an odds ratio of stroke of 1.7. Furthermore, among women using combined hormonal contraception, the risk of stroke was higher in women with aura than in women without aura.
“I like to look at the big picture,” said Dr. Hutchinson. “There’s a big difference between a woman who has one or two auras a year that last for 10 minutes and a woman who has complicated aura. I’m going to approach [the latter] woman differently.”
No consensus guidelines for prescribing combined oral contraceptives to women with migraine and aura have been developed. The International Headache Society says that physicians may prescribe low-dose estrogen to women with simple visual aura. The American College of Obstetricians and Gynecologists recommends progestin-only intrauterine or barrier contraception for this population. The World Health Organization holds that estrogen-containing contraception is contraindicated in all women who have migraine with aura.
“If you have women who have migraine without aura, low–estrogen dose combined hormonal contraceptives can be quite appropriate,” said Dr. Hutchinson. “I would tend to go with a 10- or 20-mcg low dose. It could be an option for women with migraine with aura, but only if the benefits outweigh the risks.” In a study by Calhoun et al., the vaginal ring was associated with reduced aura frequency in women with migraine and aura.
Choosing preventive and rescue medications
Although no triptan has FDA approval for the short-term prevention of menstrual migraine, studies have suggested that they are effective. In a study by Sances and colleagues, a twice-daily 1-mg dose of naratriptan taken 6 days perimenstrually reduced the frequency of menstrual-related migraine. At least 50% of treated patients in the study had no menstrual-related migraine. Silberstein and colleagues found that 59% of women who took 2.5 mg of frovatriptan twice daily had no menstrual-related migraine during the 6-day perimenstrual period, compared with 33% of women who received placebo.
Patients with menstrual migraine sometimes need rescue medication. Sumatriptan, either as an injection or an inhaled therapy, is one option. Another injectable option is a 60-mg intramuscular dose of ketorolac. Finally, occipital or sphenopalatine nerve block may be effective as well.
Dr. Hutchinson reported consulting for or serving on the advisory board of Alder, Allergan, Amgen, Biohaven, electroCore, Lilly, Novartis, Supernus, Teva, Theranica, and Upsher-Smith. She has served on speakers bureaus for Allergan, Amgen, electroCore, Lilly, Novartis, Supernus, and Teva.
STOWE, VT. – , said Susan Hutchinson, MD, director of the Orange County Migraine and Headache Center in Irvine, Calif. Compared with headaches associated with nonmenstrual migraine, headaches resulting from menstrual migraine last longer and are more difficult to treat. They tend to be associated with morning awakening and with nausea and vomiting. But in younger women with regular menses, menstrual migraine is predictable. The disorder offers “an incredible chance to be preemptive and think about short-term preventive strategies,” Dr. Hutchinson said at the annual meeting of the Headache Cooperative of New England.
What is menstrual migraine?
Menstrual migraine occurs during the perimenstrual window, which begins at 2 days before onset of bleeding and ends at 3 days of menses. Migraine that occurs during this window at least two-thirds of the time satisfies the criteria for menstrual migraine. A prospective headache diary is recommended, but not required, for making the diagnosis, said Dr. Hutchinson.
Most women with migraine have perimenstrual exacerbation of their headaches, as well as headaches at other times of the month. This phenotype is called menstrually related migraine. Pure menstrual migraine is migraine associated exclusively with menses. The International Classification of Headache Disorders-3 recognizes that menstrual migraine can be with or without aura. A headache diary can help distinguish between menstrual migraine and menstrually related migraine.
For pure menstrual migraine, it is appropriate to treat during the perimenstrual window. Preventive treatment may not be necessary throughout the month, said Dr. Hutchinson. Furthermore, hormonal treatment is the type of therapy most likely to be effective, she added. Menstrually related migraine requires a broader approach.
Gathering information during the visit
A 1972 study by Somerville and colleagues indicated that a decrease in estrogen is a powerful trigger of migraine. The investigators administered estrogen (i.e., intramuscular estradiol) or progesterone during the late luteal phase to women with menstrual migraine. Among women who received estrogen, migraine onset was postponed until the estrogen level decreased. The administration of progesterone postponed bleeding, but did not affect migraine. Progesterone treatment prevents migraine effectively on occasion, but estrogen treatment is much more likely to be a successful strategy, said Dr. Hutchinson.
Neurologists should ask certain questions of women with migraine, whether the patients are new or not, to gather information needed to make treatment decisions. For example, it is advisable to ask a woman whether she often has a headache with her period. “You may not want to use the word ‘migraine,’ because many women have been taught that headache is part of PMS,” said Dr. Hutchinson. Asking a woman how pregnancy, delivery, and breastfeeding affected her headaches can add further detail to her history and provide insight about the effects of hormonal changes. Asking what type of birth control the woman is taking can influence the choice of treatment, since some therapies are not appropriate during pregnancy.
Available treatments
NSAIDs are among the treatments that neurologists should consider for the short-term prevention of menstrually related migraine, said Dr. Hutchinson. A study of 35 patients by Sances et al. compared placebo with 550 mg of naproxen sodium given twice daily. Treatment began at 7 days before bleeding onset and continued until the 6th day of menses. Patients underwent treatment for three menstrual cycles. Naproxen sodium significantly reduced headache intensity, headache duration, and the number of headache days, compared with baseline. Treatment was superior to placebo at 3 months. Approximately 33% of patients in the active group were headache free, but no controls were.
Magnesium is another potentially effective option. Facchinetti et al. compared placebo with 360 mg/day of magnesium in a study of 20 patients. Treatment, which was given for two cycles, began at 15 days before menses and ended at the start of menses. Compared with placebo, magnesium reduced the number of headache days and the total pain index. Magnesium is inexpensive, but it causes diarrhea in some patients. “Some women choose to take magnesium all month long, other women start at around ovulation,” said Dr. Hutchinson.
Hormonal treatments are another possible option for the short-term prevention of menstrually related migraine. For women who do not plan to become pregnant, oral contraceptive pills can keep estrogen levels high enough to prevent menstrually related migraine. Gynecologists may suggest that a woman take the pill continuously, skipping the placebo, for an entire year, but Dr. Hutchinson recommends that a woman stop taking the pill for 4 days approximately every 3 months. This discontinuation allows for withdrawal bleeding, but is not likely to cause a prolonged enough decrease in estrogen to provoke migraine, she said. The continuous contraceptive ring, which is inserted vaginally, is an alternative to the pill.
For women who do not want or need contraception, an estrogen patch or gel may be appropriate. Two studies in the 1980s found that a gel containing 1.5 mg of estradiol per 2.5 g reduced migraine frequency, duration, and severity. These studies did not gather long-term safety data, however. A 2006 study by MacGregor et al. found that percutaneous estradiol was associated with a 22% reduction in the number of migraine days, as well as with decreases in headache severity and associated nausea. But the risk of migraine during the 5 days following treatment cessation was increased by 40%. This finding suggests that the treatment period should be extended, said Dr. Hutchinson.
In addition to the timing, the dose of treatment affects the outcome. Smite et al. found no benefit of a 50-mcg dose of estradiol, compared with placebo. Pradalier and colleagues found that a 100-mcg dose was associated with decreased use of rescue medication, compared with a 25-mcg dose. These studies did not gather long-term safety data.
Oral contraceptives and the risk of stroke
Combined oral contraceptives, however, are associated with increased risk of stroke in women with migraine with aura. The dose of estrogen in the contraceptive affects the level of risk, said Dr. Hutchinson. A systematic review by Sheikh et al. found that high-dose ethinyl estradiol (i.e., greater than 50 mcg) was associated with a higher risk of ischemic and hemorrhagic stroke than low-dose ethinyl estradiol (i.e., less than 50 mcg) was. A 20-mcg dose was associated with an odds ratio of stroke of 1.7. Furthermore, among women using combined hormonal contraception, the risk of stroke was higher in women with aura than in women without aura.
“I like to look at the big picture,” said Dr. Hutchinson. “There’s a big difference between a woman who has one or two auras a year that last for 10 minutes and a woman who has complicated aura. I’m going to approach [the latter] woman differently.”
No consensus guidelines for prescribing combined oral contraceptives to women with migraine and aura have been developed. The International Headache Society says that physicians may prescribe low-dose estrogen to women with simple visual aura. The American College of Obstetricians and Gynecologists recommends progestin-only intrauterine or barrier contraception for this population. The World Health Organization holds that estrogen-containing contraception is contraindicated in all women who have migraine with aura.
“If you have women who have migraine without aura, low–estrogen dose combined hormonal contraceptives can be quite appropriate,” said Dr. Hutchinson. “I would tend to go with a 10- or 20-mcg low dose. It could be an option for women with migraine with aura, but only if the benefits outweigh the risks.” In a study by Calhoun et al., the vaginal ring was associated with reduced aura frequency in women with migraine and aura.
Choosing preventive and rescue medications
Although no triptan has FDA approval for the short-term prevention of menstrual migraine, studies have suggested that they are effective. In a study by Sances and colleagues, a twice-daily 1-mg dose of naratriptan taken 6 days perimenstrually reduced the frequency of menstrual-related migraine. At least 50% of treated patients in the study had no menstrual-related migraine. Silberstein and colleagues found that 59% of women who took 2.5 mg of frovatriptan twice daily had no menstrual-related migraine during the 6-day perimenstrual period, compared with 33% of women who received placebo.
Patients with menstrual migraine sometimes need rescue medication. Sumatriptan, either as an injection or an inhaled therapy, is one option. Another injectable option is a 60-mg intramuscular dose of ketorolac. Finally, occipital or sphenopalatine nerve block may be effective as well.
Dr. Hutchinson reported consulting for or serving on the advisory board of Alder, Allergan, Amgen, Biohaven, electroCore, Lilly, Novartis, Supernus, Teva, Theranica, and Upsher-Smith. She has served on speakers bureaus for Allergan, Amgen, electroCore, Lilly, Novartis, Supernus, and Teva.
STOWE, VT. – , said Susan Hutchinson, MD, director of the Orange County Migraine and Headache Center in Irvine, Calif. Compared with headaches associated with nonmenstrual migraine, headaches resulting from menstrual migraine last longer and are more difficult to treat. They tend to be associated with morning awakening and with nausea and vomiting. But in younger women with regular menses, menstrual migraine is predictable. The disorder offers “an incredible chance to be preemptive and think about short-term preventive strategies,” Dr. Hutchinson said at the annual meeting of the Headache Cooperative of New England.
What is menstrual migraine?
Menstrual migraine occurs during the perimenstrual window, which begins at 2 days before onset of bleeding and ends at 3 days of menses. Migraine that occurs during this window at least two-thirds of the time satisfies the criteria for menstrual migraine. A prospective headache diary is recommended, but not required, for making the diagnosis, said Dr. Hutchinson.
Most women with migraine have perimenstrual exacerbation of their headaches, as well as headaches at other times of the month. This phenotype is called menstrually related migraine. Pure menstrual migraine is migraine associated exclusively with menses. The International Classification of Headache Disorders-3 recognizes that menstrual migraine can be with or without aura. A headache diary can help distinguish between menstrual migraine and menstrually related migraine.
For pure menstrual migraine, it is appropriate to treat during the perimenstrual window. Preventive treatment may not be necessary throughout the month, said Dr. Hutchinson. Furthermore, hormonal treatment is the type of therapy most likely to be effective, she added. Menstrually related migraine requires a broader approach.
Gathering information during the visit
A 1972 study by Somerville and colleagues indicated that a decrease in estrogen is a powerful trigger of migraine. The investigators administered estrogen (i.e., intramuscular estradiol) or progesterone during the late luteal phase to women with menstrual migraine. Among women who received estrogen, migraine onset was postponed until the estrogen level decreased. The administration of progesterone postponed bleeding, but did not affect migraine. Progesterone treatment prevents migraine effectively on occasion, but estrogen treatment is much more likely to be a successful strategy, said Dr. Hutchinson.
Neurologists should ask certain questions of women with migraine, whether the patients are new or not, to gather information needed to make treatment decisions. For example, it is advisable to ask a woman whether she often has a headache with her period. “You may not want to use the word ‘migraine,’ because many women have been taught that headache is part of PMS,” said Dr. Hutchinson. Asking a woman how pregnancy, delivery, and breastfeeding affected her headaches can add further detail to her history and provide insight about the effects of hormonal changes. Asking what type of birth control the woman is taking can influence the choice of treatment, since some therapies are not appropriate during pregnancy.
Available treatments
NSAIDs are among the treatments that neurologists should consider for the short-term prevention of menstrually related migraine, said Dr. Hutchinson. A study of 35 patients by Sances et al. compared placebo with 550 mg of naproxen sodium given twice daily. Treatment began at 7 days before bleeding onset and continued until the 6th day of menses. Patients underwent treatment for three menstrual cycles. Naproxen sodium significantly reduced headache intensity, headache duration, and the number of headache days, compared with baseline. Treatment was superior to placebo at 3 months. Approximately 33% of patients in the active group were headache free, but no controls were.
Magnesium is another potentially effective option. Facchinetti et al. compared placebo with 360 mg/day of magnesium in a study of 20 patients. Treatment, which was given for two cycles, began at 15 days before menses and ended at the start of menses. Compared with placebo, magnesium reduced the number of headache days and the total pain index. Magnesium is inexpensive, but it causes diarrhea in some patients. “Some women choose to take magnesium all month long, other women start at around ovulation,” said Dr. Hutchinson.
Hormonal treatments are another possible option for the short-term prevention of menstrually related migraine. For women who do not plan to become pregnant, oral contraceptive pills can keep estrogen levels high enough to prevent menstrually related migraine. Gynecologists may suggest that a woman take the pill continuously, skipping the placebo, for an entire year, but Dr. Hutchinson recommends that a woman stop taking the pill for 4 days approximately every 3 months. This discontinuation allows for withdrawal bleeding, but is not likely to cause a prolonged enough decrease in estrogen to provoke migraine, she said. The continuous contraceptive ring, which is inserted vaginally, is an alternative to the pill.
For women who do not want or need contraception, an estrogen patch or gel may be appropriate. Two studies in the 1980s found that a gel containing 1.5 mg of estradiol per 2.5 g reduced migraine frequency, duration, and severity. These studies did not gather long-term safety data, however. A 2006 study by MacGregor et al. found that percutaneous estradiol was associated with a 22% reduction in the number of migraine days, as well as with decreases in headache severity and associated nausea. But the risk of migraine during the 5 days following treatment cessation was increased by 40%. This finding suggests that the treatment period should be extended, said Dr. Hutchinson.
In addition to the timing, the dose of treatment affects the outcome. Smite et al. found no benefit of a 50-mcg dose of estradiol, compared with placebo. Pradalier and colleagues found that a 100-mcg dose was associated with decreased use of rescue medication, compared with a 25-mcg dose. These studies did not gather long-term safety data.
Oral contraceptives and the risk of stroke
Combined oral contraceptives, however, are associated with increased risk of stroke in women with migraine with aura. The dose of estrogen in the contraceptive affects the level of risk, said Dr. Hutchinson. A systematic review by Sheikh et al. found that high-dose ethinyl estradiol (i.e., greater than 50 mcg) was associated with a higher risk of ischemic and hemorrhagic stroke than low-dose ethinyl estradiol (i.e., less than 50 mcg) was. A 20-mcg dose was associated with an odds ratio of stroke of 1.7. Furthermore, among women using combined hormonal contraception, the risk of stroke was higher in women with aura than in women without aura.
“I like to look at the big picture,” said Dr. Hutchinson. “There’s a big difference between a woman who has one or two auras a year that last for 10 minutes and a woman who has complicated aura. I’m going to approach [the latter] woman differently.”
No consensus guidelines for prescribing combined oral contraceptives to women with migraine and aura have been developed. The International Headache Society says that physicians may prescribe low-dose estrogen to women with simple visual aura. The American College of Obstetricians and Gynecologists recommends progestin-only intrauterine or barrier contraception for this population. The World Health Organization holds that estrogen-containing contraception is contraindicated in all women who have migraine with aura.
“If you have women who have migraine without aura, low–estrogen dose combined hormonal contraceptives can be quite appropriate,” said Dr. Hutchinson. “I would tend to go with a 10- or 20-mcg low dose. It could be an option for women with migraine with aura, but only if the benefits outweigh the risks.” In a study by Calhoun et al., the vaginal ring was associated with reduced aura frequency in women with migraine and aura.
Choosing preventive and rescue medications
Although no triptan has FDA approval for the short-term prevention of menstrual migraine, studies have suggested that they are effective. In a study by Sances and colleagues, a twice-daily 1-mg dose of naratriptan taken 6 days perimenstrually reduced the frequency of menstrual-related migraine. At least 50% of treated patients in the study had no menstrual-related migraine. Silberstein and colleagues found that 59% of women who took 2.5 mg of frovatriptan twice daily had no menstrual-related migraine during the 6-day perimenstrual period, compared with 33% of women who received placebo.
Patients with menstrual migraine sometimes need rescue medication. Sumatriptan, either as an injection or an inhaled therapy, is one option. Another injectable option is a 60-mg intramuscular dose of ketorolac. Finally, occipital or sphenopalatine nerve block may be effective as well.
Dr. Hutchinson reported consulting for or serving on the advisory board of Alder, Allergan, Amgen, Biohaven, electroCore, Lilly, Novartis, Supernus, Teva, Theranica, and Upsher-Smith. She has served on speakers bureaus for Allergan, Amgen, electroCore, Lilly, Novartis, Supernus, and Teva.
REPORTING FROM HCNE Stowe 2020
Migraine tied to risk of comorbidities
Key clinical point: Patients with migraine have an increased risk for comorbidities, and the risk is influenced by headache pain intensity and monthly headache days.
Major finding: Patients with migraine vs those without had an increased risk for insomnia, depression, anxiety, gastric ulcers/gastrointestinal bleeding, peripheral artery disease, angina, epilepsy, asthma, arthritis, stroke or transient ischemic attack, rheumatoid arthritis, allergies/hay fever, and vitamin D deficiency (P less than. 001). Increasing headache pain intensity was associated with an increased risk for inflammatory comorbidities, and monthly headache day frequency with risk for nearly all conditions.
Study details: The data come from the Migraine in America Symptoms and Treatment Study, which included 15,133 patients with migraine and 77,453 control individuals without migraine.
Disclosures: This study was funded and sponsored by Dr. Reddy’s Laboratories group of companies, Princeton, NJ. Sagar Munjal and Preeti Singh are employees of Dr. Reddy’s Laboratories. Richard B. Lipton, Dawn C. Buse, Michael L. Reed, Todd J. Schwedt, and David W. Dodick reported paid consultancy for Dr. Reddy’s Laboratories. The authors also reported ties with one or more pharmaceutical companies.
Citation: Buse DC et al. J Headache Pain. 2020 Mar 2. doi: 10.1186/s10194-020-1084-y.
Key clinical point: Patients with migraine have an increased risk for comorbidities, and the risk is influenced by headache pain intensity and monthly headache days.
Major finding: Patients with migraine vs those without had an increased risk for insomnia, depression, anxiety, gastric ulcers/gastrointestinal bleeding, peripheral artery disease, angina, epilepsy, asthma, arthritis, stroke or transient ischemic attack, rheumatoid arthritis, allergies/hay fever, and vitamin D deficiency (P less than. 001). Increasing headache pain intensity was associated with an increased risk for inflammatory comorbidities, and monthly headache day frequency with risk for nearly all conditions.
Study details: The data come from the Migraine in America Symptoms and Treatment Study, which included 15,133 patients with migraine and 77,453 control individuals without migraine.
Disclosures: This study was funded and sponsored by Dr. Reddy’s Laboratories group of companies, Princeton, NJ. Sagar Munjal and Preeti Singh are employees of Dr. Reddy’s Laboratories. Richard B. Lipton, Dawn C. Buse, Michael L. Reed, Todd J. Schwedt, and David W. Dodick reported paid consultancy for Dr. Reddy’s Laboratories. The authors also reported ties with one or more pharmaceutical companies.
Citation: Buse DC et al. J Headache Pain. 2020 Mar 2. doi: 10.1186/s10194-020-1084-y.
Key clinical point: Patients with migraine have an increased risk for comorbidities, and the risk is influenced by headache pain intensity and monthly headache days.
Major finding: Patients with migraine vs those without had an increased risk for insomnia, depression, anxiety, gastric ulcers/gastrointestinal bleeding, peripheral artery disease, angina, epilepsy, asthma, arthritis, stroke or transient ischemic attack, rheumatoid arthritis, allergies/hay fever, and vitamin D deficiency (P less than. 001). Increasing headache pain intensity was associated with an increased risk for inflammatory comorbidities, and monthly headache day frequency with risk for nearly all conditions.
Study details: The data come from the Migraine in America Symptoms and Treatment Study, which included 15,133 patients with migraine and 77,453 control individuals without migraine.
Disclosures: This study was funded and sponsored by Dr. Reddy’s Laboratories group of companies, Princeton, NJ. Sagar Munjal and Preeti Singh are employees of Dr. Reddy’s Laboratories. Richard B. Lipton, Dawn C. Buse, Michael L. Reed, Todd J. Schwedt, and David W. Dodick reported paid consultancy for Dr. Reddy’s Laboratories. The authors also reported ties with one or more pharmaceutical companies.
Citation: Buse DC et al. J Headache Pain. 2020 Mar 2. doi: 10.1186/s10194-020-1084-y.
Topical basil essential oil reduces severity and frequency of migraine attacks
Key clinical point: Topical basil essential oil at higher doses can effectively reduce the severity of pain intensity and frequency of migraine attacks.
Major Finding: The interaction between dose and time factors was significantly associated with both pain intensity and frequency of attack (P less than .001 for both). The odds of higher pain intensity and rates of higher frequency of migraine attacks in the basil essential oil vs placebo group decreased over time.
Study details: In a triple-blind study, 144 patients with migraine were randomly assigned to basil essential oil 2%, 4%, 6%, and placebo groups (1:1:1:1) by a stratified method.
Disclosures: This study was supported by the Lorestan University of Medical Sciences, Khorramabad, Iran. The authors declared no conflicts of interest.
Citation: Ahmadifard M et al. Complement Med Res. 2020 Mar 10. doi: 10.1159/000506349.
Key clinical point: Topical basil essential oil at higher doses can effectively reduce the severity of pain intensity and frequency of migraine attacks.
Major Finding: The interaction between dose and time factors was significantly associated with both pain intensity and frequency of attack (P less than .001 for both). The odds of higher pain intensity and rates of higher frequency of migraine attacks in the basil essential oil vs placebo group decreased over time.
Study details: In a triple-blind study, 144 patients with migraine were randomly assigned to basil essential oil 2%, 4%, 6%, and placebo groups (1:1:1:1) by a stratified method.
Disclosures: This study was supported by the Lorestan University of Medical Sciences, Khorramabad, Iran. The authors declared no conflicts of interest.
Citation: Ahmadifard M et al. Complement Med Res. 2020 Mar 10. doi: 10.1159/000506349.
Key clinical point: Topical basil essential oil at higher doses can effectively reduce the severity of pain intensity and frequency of migraine attacks.
Major Finding: The interaction between dose and time factors was significantly associated with both pain intensity and frequency of attack (P less than .001 for both). The odds of higher pain intensity and rates of higher frequency of migraine attacks in the basil essential oil vs placebo group decreased over time.
Study details: In a triple-blind study, 144 patients with migraine were randomly assigned to basil essential oil 2%, 4%, 6%, and placebo groups (1:1:1:1) by a stratified method.
Disclosures: This study was supported by the Lorestan University of Medical Sciences, Khorramabad, Iran. The authors declared no conflicts of interest.
Citation: Ahmadifard M et al. Complement Med Res. 2020 Mar 10. doi: 10.1159/000506349.
Cervical nVNS is safe and effective for acute pain relief in migraine and cluster headaches
Key clinical point: Cervical noninvasive vagus nerve stimulation (nVNS) is a safe and effective technique for relieving acute pain in migraine and cluster headaches.
Major finding: The nVNS vs. sham-device treatment was effective in attaining a pain-free status within 30 minutes (P = .02), pain-relief status within 30 minutes (P = .007), pain-relief status at 60 minutes (P = .006), pain-free status in ≥50% of treated attacks (P = .005) and reduced use of abortive medication (P = .02). No significant differences were observed in decreased headache days (P = .117), adverse events (P = .81), and satisfaction (P = .07) between the nVNS and sham-device groups.
Study details: A systematic review and meta-analysis of 6 randomized controlled trials of nVNS for treating headaches (n = 983).
Disclosures: The authors declared no conflicts of interest.
Citation: Lai YH et al. Neuromodulation. 2020 Mar 12. doi: 10.1111/ner.13122.
Key clinical point: Cervical noninvasive vagus nerve stimulation (nVNS) is a safe and effective technique for relieving acute pain in migraine and cluster headaches.
Major finding: The nVNS vs. sham-device treatment was effective in attaining a pain-free status within 30 minutes (P = .02), pain-relief status within 30 minutes (P = .007), pain-relief status at 60 minutes (P = .006), pain-free status in ≥50% of treated attacks (P = .005) and reduced use of abortive medication (P = .02). No significant differences were observed in decreased headache days (P = .117), adverse events (P = .81), and satisfaction (P = .07) between the nVNS and sham-device groups.
Study details: A systematic review and meta-analysis of 6 randomized controlled trials of nVNS for treating headaches (n = 983).
Disclosures: The authors declared no conflicts of interest.
Citation: Lai YH et al. Neuromodulation. 2020 Mar 12. doi: 10.1111/ner.13122.
Key clinical point: Cervical noninvasive vagus nerve stimulation (nVNS) is a safe and effective technique for relieving acute pain in migraine and cluster headaches.
Major finding: The nVNS vs. sham-device treatment was effective in attaining a pain-free status within 30 minutes (P = .02), pain-relief status within 30 minutes (P = .007), pain-relief status at 60 minutes (P = .006), pain-free status in ≥50% of treated attacks (P = .005) and reduced use of abortive medication (P = .02). No significant differences were observed in decreased headache days (P = .117), adverse events (P = .81), and satisfaction (P = .07) between the nVNS and sham-device groups.
Study details: A systematic review and meta-analysis of 6 randomized controlled trials of nVNS for treating headaches (n = 983).
Disclosures: The authors declared no conflicts of interest.
Citation: Lai YH et al. Neuromodulation. 2020 Mar 12. doi: 10.1111/ner.13122.
Pediatric migraine: Topiramate reduces monthly headache days and disability
Key clinical point: Topiramate can reduce the number of headache days in a month and disability levels in children with migraine.
Major finding: Topiramate vs. placebo significantly reduced the number of migraine days in a month (P = .0008) and migraine-related disability in pediatric patients (P = .04), but showed no significant difference in the proportion of patients experiencing a ≥50% reduction in monthly headache days (P = .11). Topiramate was associated with higher rates of side effects, including weight loss and paresthesia (P less than .01 for both).
Study details: A meta-analysis of 5 randomized controlled trials, including 531 children with migraine aged 6-17 years.
Disclosures: The authors declared no conflicts of interest.
Citation: Wu X et al. Front Pediatr. 2020 Feb 27. doi: 10.3389/fped.2020.00028.
Key clinical point: Topiramate can reduce the number of headache days in a month and disability levels in children with migraine.
Major finding: Topiramate vs. placebo significantly reduced the number of migraine days in a month (P = .0008) and migraine-related disability in pediatric patients (P = .04), but showed no significant difference in the proportion of patients experiencing a ≥50% reduction in monthly headache days (P = .11). Topiramate was associated with higher rates of side effects, including weight loss and paresthesia (P less than .01 for both).
Study details: A meta-analysis of 5 randomized controlled trials, including 531 children with migraine aged 6-17 years.
Disclosures: The authors declared no conflicts of interest.
Citation: Wu X et al. Front Pediatr. 2020 Feb 27. doi: 10.3389/fped.2020.00028.
Key clinical point: Topiramate can reduce the number of headache days in a month and disability levels in children with migraine.
Major finding: Topiramate vs. placebo significantly reduced the number of migraine days in a month (P = .0008) and migraine-related disability in pediatric patients (P = .04), but showed no significant difference in the proportion of patients experiencing a ≥50% reduction in monthly headache days (P = .11). Topiramate was associated with higher rates of side effects, including weight loss and paresthesia (P less than .01 for both).
Study details: A meta-analysis of 5 randomized controlled trials, including 531 children with migraine aged 6-17 years.
Disclosures: The authors declared no conflicts of interest.
Citation: Wu X et al. Front Pediatr. 2020 Feb 27. doi: 10.3389/fped.2020.00028.