User login
Chronic daily migraine from medication overuse: How worried should you be?
. Physicians worry about episodic migraine converting to chronic daily headache, but this worry can also lead to under-treatment and even stigmatization of patients who aggressively treat their symptoms.
These concerns and others were a topic of a debate at the Headache Cooperative of New England’s 20th Annual HCNE Boston Fall Headache Symposium, which was conducted virtually.
The International Classification of Headache-3 (ICHD-3) defines medication overuse headache as a headache that occurs on 15 or more days per month in a patient with pre-existing primary headache, and that develops because of regular overuse of acute or symptomatic headache medication. The ICHD-3 also says that headache usually resolves when overuse is stopped, though not always.
Paul Rizzoli, MD, took issue with that definition. “If you have a lot of headaches and you take medication for them, then you likely have medication overuse headache. They say the most common cause of symptoms suggestive of chronic migraine is medication overuse. That’s like saying, if you have a rash on your arm, then it is an allergic sun exposure rash. No need to characterize the rash,” said Dr. Rizzoli, who is clinical director of the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital in Boston, during the session.
Is medication overuse really the culprit?
Dr. Rizzoli began by emphasizing that taking a lot of medication is always a concern. “Significant hepatic and renal and GI toxicities can result from taking and overusing medication of all sorts. What (I am) questioning is whether or not this rather strange, arbitrary, fluidly-defined concept of abortive migraine medicine overuse is truly responsible for causing all of the ills of which it is accused – and just as importantly, if the proposed solution for it, which is to just stop the overused medication and all will be better – if that solution is the right or wrong advice to give to a patient,” he said.
Much of Dr. Rizzoli’s criticism rested on the definition of medication overuse syndrome. He believes that many concerns about medication overuse can be traced to the use of opiates or barbiturate-containing medications, which have known propensities to lead to headaches. Other cases are less well defined, and “it’s not quite clear what the pathophysiology of the condition is – whether or not it’s the same as rebound or withdrawal headache, or if it is the same as a pronociceptive effect of analgesics, also called medicine-induced headache. Both are well documented and accepted, and the idea of opioid-induced analgesia tolerance is well documented and has several plausible mechanisms attributed to it,” said Dr. Rizzoli.
He said that changes in structural imaging in the brain suggest there at least two subgroups of patients that are both labeled as having medication overuse headache, one from medication overuse and one from progression of migraine disease. “Based on physiology, medication overuse headache cannot be clearly seen as a unitary condition,” he said.
Dr. Rizzoli cited other research on triptans, opioids, and barbiturates that showed an overall conversion from episodic migraine to chronic migraine, with the lowest frequency occurring in patients taking acetaminophen, aspirin, and caffeine (2%), followed by NSAIDs (4%), triptans (4%), opioids (5%), and barbiturates (6%). A total of 52 patients who became chronic were taking triptans, on average 7 days per month. The 1,370 triptan-using patients who remained episodic took triptans on average 5 days per month. “Does this seem like a huge difference between these two groups? The transformation rate in just this triptan subgroup was about 3%-4%, suggesting that, compared with the overall transformation rate of 3%, use of triptans did not exert much force overall on the baseline rate,” he said. Similar patterns were visible with use of other classes of drugs.
Meanwhile, the higher rates of conversion seen with opioids and barbiturates suggests an effect from these drugs. “Perhaps this data suggests the previously known effect is at play here and argues against the need for a separate diagnosis of medication overuse headache,” Dr. Rizzoli said.
“The evidence that simple analgesics can cause medication overuse headache is especially weak, and the evidence that NSAIDs do is conflicting, with some evidence suggesting they’re protective at some doses.” Other population studies suggested most patients with daily headache do not overuse medications, and studies in India, where analgesics are rarely used, still showed a similar rate of conversion to daily headache. Other studies failed to show evidence that withdrawal of overused medication leads to improvement. “Studies of populations after aggressive management of medicine overuse headache indicate that, for the majority of the headaches, for the most part did not clear after treatment, except maybe for a short time,” said Dr. Rizzoli.
A systematic review of 18 population studies showed the prevalence of medical overuse headache ranged from 11% to 68%. “That indicates substantial uncertainty about the magnitude of the problem,” said Dr. Rizzoli.
He also noted potential harms to patients. Many patients come in experience between 10 and 20 headaches per month. “To see them out of medical overuse would have us advising not to treat half of their headaches monthly in order to avoid this evil. Many patients who have read or heard about this condition are themselves restricting treatment so as to avoid medication overuse headache. The harms of such undertreatment have not been fully investigated.”
To get at the issue, he recommended adapting the traditional number-needed-to-treat calculation. “You could calculate a number needed to overtreat. If medication use is assumed to be the sole cause of headache chronification, the calculations could suggest you would need to restrict therapy for about 4 people for each person you protect from going chronic. That’s a lot of undertreatment,” said Dr. Rizzoli.
He summed up by saying that some patients may have a progressive disorder with structure and physiological changes in the brain that result in chronic pain, and such patients should be identified and studied. In others with frequent headache, high medication use may simply be associated with the condition becoming chronic, but not causative. “These diagnostic groups may be mixed and may be difficult to untangle,” said Dr. Rizzoli.
Medication overuse is to blame
Dr. Rizzoli’s debate lecture was followed by Barbara Nye, MD, who argued that concerns over medication overuse headache are valid. She noted a more unifying definition in ICHD-3, which requires regular medication overuse for at least 3 months, along with primary headache disorder.
Dr. Nye, who is codirector of the Headache Clinic at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., related her experience that medication overuse headache often occurs more quickly than the 3-month time frame contained in ICHD-3, especially in patients who were given pain medications after undergoing surgery. She echoed Dr. Rizzoli’s concerns about opiates and barbiturates. “Medicine overuse headache should be something we focus on, and we should be warning providers both in neurology and primary care about the frequent use of opiate and butalbital-containing medications, and frequent over-the-counter medicine use in high-frequency headache disorders,” Dr. Nye said during her talk.
She cited research showing risk factors for conversion from episodic to chronic daily headache. As well as medication overuse, these include White race, lower education status, previous marriage, obesity, diabetes, arthritis, top-quartile caffeine use, stressful life events, and higher headache frequency.
Risks vary by medication class. Opiates and narcotics used more than 2 or 3 times per week are of particular concern, as are short-acting over-the-counter medicines used more than three times per week or 10-15 days per month. She agreed that NSAIDs may have a protective effect, but only at much lower doses and when used about five (or fewer) times per month. One study showed a possible protection effect of NSAIDs, though when used more than 10 days/month, they were associated with medication overuse headache.
Fioricet and Fiorinal, used more than 1 day/week, have an early and robust medicine overuse effect. “Limiting that use is very important,” said Dr. Nye. Other medicines and doses of concern include Tramadol/Ultram used at a higher than 50 mg/day dose, which has a metabolite that causes headache, and triptans used more than 10 days/month.
These concerns came about after analysis of large trials in patients with other conditions who also suffer from episodic migraines. A study of patients with irritable bowel syndrome and migraine showed a risk of conversion with opioid treatment. Another study of patients with arthritis and episodic migraine showed an association between conversion and NSAIDs alone, NSAIDs combined with Tylenol, and NSAIDs combined with opioids.
Risks of medication overuse also included collateral damage to the gastrointestinal and kidney systems, development of dependence, exacerbation of depression, and opioid-induced hyperalgesia, according to Dr. Nye. The overused medication may also interfere with the use of preventive medication. Those concerns drive the conventional wisdom of weaning patients off the overused medication, Dr. Nye said.
Dr. Nye discussed some of the observations of structural changes in the brain found in episodic migraine and chronic migraine associated with medication overuse. Functional MRI showed changes in grey matter, both as a result of medication overuse headache and further changes after medication withdrawal. “A lot of neuroplasticity and neuroadaptation occurs, and these effects seem to be sustained anywhere from 4-6 months after (medicine) discontinuation,” said Dr. Nye.
Common ground
Dr. Nye emphasized the need to be aware of the dangers of medication overuse headache, but noted that clinicians should address the problem to ensure that patients are empowered, potentially providing preventive medications and encouraging more effective use of daily abortive medications.
In response, Dr. Rizzoli suggested that the two agreed on many issues. For her part, Dr. Nye agreed that medication overuse headache is a muddy concept that needs more research to understand the relationship between opiate use and chronic migraine, “but I do think there have been some good studies of fMRI evaluating the difference between those with medication overuse headache and seeing how they convert back to a different underlying network (following medication withdrawal). I do agree that there is probably a subpopulation that is not affected by medication overuse headache,” Dr. Nye said.
In the end, both expressed concerns for the patient. “I share Barbara’s concern that we need to be mindful and protect our patients from medication use, but on the other hand I think we also need to protect our patients from the complications of having a diagnosis of medical overuse and the stigmatization that goes with that. That particular issue goes both ways,” said Dr. Rizzoli.
“I absolutely agree with that,” responded Dr. Nye.
Dr. Nye is on the advisory boards for Biohaven, Upsher Smith, and Impel. She is a trial site principal investigator for Allergan, Amgen, and Satsuma. Dr. Rizzoli has been a consultant for Nestle and served on the scientific advisory or data safety monitoring board for Biohaven and Xoc Pharma. He has also received research support from Allergan.
. Physicians worry about episodic migraine converting to chronic daily headache, but this worry can also lead to under-treatment and even stigmatization of patients who aggressively treat their symptoms.
These concerns and others were a topic of a debate at the Headache Cooperative of New England’s 20th Annual HCNE Boston Fall Headache Symposium, which was conducted virtually.
The International Classification of Headache-3 (ICHD-3) defines medication overuse headache as a headache that occurs on 15 or more days per month in a patient with pre-existing primary headache, and that develops because of regular overuse of acute or symptomatic headache medication. The ICHD-3 also says that headache usually resolves when overuse is stopped, though not always.
Paul Rizzoli, MD, took issue with that definition. “If you have a lot of headaches and you take medication for them, then you likely have medication overuse headache. They say the most common cause of symptoms suggestive of chronic migraine is medication overuse. That’s like saying, if you have a rash on your arm, then it is an allergic sun exposure rash. No need to characterize the rash,” said Dr. Rizzoli, who is clinical director of the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital in Boston, during the session.
Is medication overuse really the culprit?
Dr. Rizzoli began by emphasizing that taking a lot of medication is always a concern. “Significant hepatic and renal and GI toxicities can result from taking and overusing medication of all sorts. What (I am) questioning is whether or not this rather strange, arbitrary, fluidly-defined concept of abortive migraine medicine overuse is truly responsible for causing all of the ills of which it is accused – and just as importantly, if the proposed solution for it, which is to just stop the overused medication and all will be better – if that solution is the right or wrong advice to give to a patient,” he said.
Much of Dr. Rizzoli’s criticism rested on the definition of medication overuse syndrome. He believes that many concerns about medication overuse can be traced to the use of opiates or barbiturate-containing medications, which have known propensities to lead to headaches. Other cases are less well defined, and “it’s not quite clear what the pathophysiology of the condition is – whether or not it’s the same as rebound or withdrawal headache, or if it is the same as a pronociceptive effect of analgesics, also called medicine-induced headache. Both are well documented and accepted, and the idea of opioid-induced analgesia tolerance is well documented and has several plausible mechanisms attributed to it,” said Dr. Rizzoli.
He said that changes in structural imaging in the brain suggest there at least two subgroups of patients that are both labeled as having medication overuse headache, one from medication overuse and one from progression of migraine disease. “Based on physiology, medication overuse headache cannot be clearly seen as a unitary condition,” he said.
Dr. Rizzoli cited other research on triptans, opioids, and barbiturates that showed an overall conversion from episodic migraine to chronic migraine, with the lowest frequency occurring in patients taking acetaminophen, aspirin, and caffeine (2%), followed by NSAIDs (4%), triptans (4%), opioids (5%), and barbiturates (6%). A total of 52 patients who became chronic were taking triptans, on average 7 days per month. The 1,370 triptan-using patients who remained episodic took triptans on average 5 days per month. “Does this seem like a huge difference between these two groups? The transformation rate in just this triptan subgroup was about 3%-4%, suggesting that, compared with the overall transformation rate of 3%, use of triptans did not exert much force overall on the baseline rate,” he said. Similar patterns were visible with use of other classes of drugs.
Meanwhile, the higher rates of conversion seen with opioids and barbiturates suggests an effect from these drugs. “Perhaps this data suggests the previously known effect is at play here and argues against the need for a separate diagnosis of medication overuse headache,” Dr. Rizzoli said.
“The evidence that simple analgesics can cause medication overuse headache is especially weak, and the evidence that NSAIDs do is conflicting, with some evidence suggesting they’re protective at some doses.” Other population studies suggested most patients with daily headache do not overuse medications, and studies in India, where analgesics are rarely used, still showed a similar rate of conversion to daily headache. Other studies failed to show evidence that withdrawal of overused medication leads to improvement. “Studies of populations after aggressive management of medicine overuse headache indicate that, for the majority of the headaches, for the most part did not clear after treatment, except maybe for a short time,” said Dr. Rizzoli.
A systematic review of 18 population studies showed the prevalence of medical overuse headache ranged from 11% to 68%. “That indicates substantial uncertainty about the magnitude of the problem,” said Dr. Rizzoli.
He also noted potential harms to patients. Many patients come in experience between 10 and 20 headaches per month. “To see them out of medical overuse would have us advising not to treat half of their headaches monthly in order to avoid this evil. Many patients who have read or heard about this condition are themselves restricting treatment so as to avoid medication overuse headache. The harms of such undertreatment have not been fully investigated.”
To get at the issue, he recommended adapting the traditional number-needed-to-treat calculation. “You could calculate a number needed to overtreat. If medication use is assumed to be the sole cause of headache chronification, the calculations could suggest you would need to restrict therapy for about 4 people for each person you protect from going chronic. That’s a lot of undertreatment,” said Dr. Rizzoli.
He summed up by saying that some patients may have a progressive disorder with structure and physiological changes in the brain that result in chronic pain, and such patients should be identified and studied. In others with frequent headache, high medication use may simply be associated with the condition becoming chronic, but not causative. “These diagnostic groups may be mixed and may be difficult to untangle,” said Dr. Rizzoli.
Medication overuse is to blame
Dr. Rizzoli’s debate lecture was followed by Barbara Nye, MD, who argued that concerns over medication overuse headache are valid. She noted a more unifying definition in ICHD-3, which requires regular medication overuse for at least 3 months, along with primary headache disorder.
Dr. Nye, who is codirector of the Headache Clinic at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., related her experience that medication overuse headache often occurs more quickly than the 3-month time frame contained in ICHD-3, especially in patients who were given pain medications after undergoing surgery. She echoed Dr. Rizzoli’s concerns about opiates and barbiturates. “Medicine overuse headache should be something we focus on, and we should be warning providers both in neurology and primary care about the frequent use of opiate and butalbital-containing medications, and frequent over-the-counter medicine use in high-frequency headache disorders,” Dr. Nye said during her talk.
She cited research showing risk factors for conversion from episodic to chronic daily headache. As well as medication overuse, these include White race, lower education status, previous marriage, obesity, diabetes, arthritis, top-quartile caffeine use, stressful life events, and higher headache frequency.
Risks vary by medication class. Opiates and narcotics used more than 2 or 3 times per week are of particular concern, as are short-acting over-the-counter medicines used more than three times per week or 10-15 days per month. She agreed that NSAIDs may have a protective effect, but only at much lower doses and when used about five (or fewer) times per month. One study showed a possible protection effect of NSAIDs, though when used more than 10 days/month, they were associated with medication overuse headache.
Fioricet and Fiorinal, used more than 1 day/week, have an early and robust medicine overuse effect. “Limiting that use is very important,” said Dr. Nye. Other medicines and doses of concern include Tramadol/Ultram used at a higher than 50 mg/day dose, which has a metabolite that causes headache, and triptans used more than 10 days/month.
These concerns came about after analysis of large trials in patients with other conditions who also suffer from episodic migraines. A study of patients with irritable bowel syndrome and migraine showed a risk of conversion with opioid treatment. Another study of patients with arthritis and episodic migraine showed an association between conversion and NSAIDs alone, NSAIDs combined with Tylenol, and NSAIDs combined with opioids.
Risks of medication overuse also included collateral damage to the gastrointestinal and kidney systems, development of dependence, exacerbation of depression, and opioid-induced hyperalgesia, according to Dr. Nye. The overused medication may also interfere with the use of preventive medication. Those concerns drive the conventional wisdom of weaning patients off the overused medication, Dr. Nye said.
Dr. Nye discussed some of the observations of structural changes in the brain found in episodic migraine and chronic migraine associated with medication overuse. Functional MRI showed changes in grey matter, both as a result of medication overuse headache and further changes after medication withdrawal. “A lot of neuroplasticity and neuroadaptation occurs, and these effects seem to be sustained anywhere from 4-6 months after (medicine) discontinuation,” said Dr. Nye.
Common ground
Dr. Nye emphasized the need to be aware of the dangers of medication overuse headache, but noted that clinicians should address the problem to ensure that patients are empowered, potentially providing preventive medications and encouraging more effective use of daily abortive medications.
In response, Dr. Rizzoli suggested that the two agreed on many issues. For her part, Dr. Nye agreed that medication overuse headache is a muddy concept that needs more research to understand the relationship between opiate use and chronic migraine, “but I do think there have been some good studies of fMRI evaluating the difference between those with medication overuse headache and seeing how they convert back to a different underlying network (following medication withdrawal). I do agree that there is probably a subpopulation that is not affected by medication overuse headache,” Dr. Nye said.
In the end, both expressed concerns for the patient. “I share Barbara’s concern that we need to be mindful and protect our patients from medication use, but on the other hand I think we also need to protect our patients from the complications of having a diagnosis of medical overuse and the stigmatization that goes with that. That particular issue goes both ways,” said Dr. Rizzoli.
“I absolutely agree with that,” responded Dr. Nye.
Dr. Nye is on the advisory boards for Biohaven, Upsher Smith, and Impel. She is a trial site principal investigator for Allergan, Amgen, and Satsuma. Dr. Rizzoli has been a consultant for Nestle and served on the scientific advisory or data safety monitoring board for Biohaven and Xoc Pharma. He has also received research support from Allergan.
. Physicians worry about episodic migraine converting to chronic daily headache, but this worry can also lead to under-treatment and even stigmatization of patients who aggressively treat their symptoms.
These concerns and others were a topic of a debate at the Headache Cooperative of New England’s 20th Annual HCNE Boston Fall Headache Symposium, which was conducted virtually.
The International Classification of Headache-3 (ICHD-3) defines medication overuse headache as a headache that occurs on 15 or more days per month in a patient with pre-existing primary headache, and that develops because of regular overuse of acute or symptomatic headache medication. The ICHD-3 also says that headache usually resolves when overuse is stopped, though not always.
Paul Rizzoli, MD, took issue with that definition. “If you have a lot of headaches and you take medication for them, then you likely have medication overuse headache. They say the most common cause of symptoms suggestive of chronic migraine is medication overuse. That’s like saying, if you have a rash on your arm, then it is an allergic sun exposure rash. No need to characterize the rash,” said Dr. Rizzoli, who is clinical director of the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital in Boston, during the session.
Is medication overuse really the culprit?
Dr. Rizzoli began by emphasizing that taking a lot of medication is always a concern. “Significant hepatic and renal and GI toxicities can result from taking and overusing medication of all sorts. What (I am) questioning is whether or not this rather strange, arbitrary, fluidly-defined concept of abortive migraine medicine overuse is truly responsible for causing all of the ills of which it is accused – and just as importantly, if the proposed solution for it, which is to just stop the overused medication and all will be better – if that solution is the right or wrong advice to give to a patient,” he said.
Much of Dr. Rizzoli’s criticism rested on the definition of medication overuse syndrome. He believes that many concerns about medication overuse can be traced to the use of opiates or barbiturate-containing medications, which have known propensities to lead to headaches. Other cases are less well defined, and “it’s not quite clear what the pathophysiology of the condition is – whether or not it’s the same as rebound or withdrawal headache, or if it is the same as a pronociceptive effect of analgesics, also called medicine-induced headache. Both are well documented and accepted, and the idea of opioid-induced analgesia tolerance is well documented and has several plausible mechanisms attributed to it,” said Dr. Rizzoli.
He said that changes in structural imaging in the brain suggest there at least two subgroups of patients that are both labeled as having medication overuse headache, one from medication overuse and one from progression of migraine disease. “Based on physiology, medication overuse headache cannot be clearly seen as a unitary condition,” he said.
Dr. Rizzoli cited other research on triptans, opioids, and barbiturates that showed an overall conversion from episodic migraine to chronic migraine, with the lowest frequency occurring in patients taking acetaminophen, aspirin, and caffeine (2%), followed by NSAIDs (4%), triptans (4%), opioids (5%), and barbiturates (6%). A total of 52 patients who became chronic were taking triptans, on average 7 days per month. The 1,370 triptan-using patients who remained episodic took triptans on average 5 days per month. “Does this seem like a huge difference between these two groups? The transformation rate in just this triptan subgroup was about 3%-4%, suggesting that, compared with the overall transformation rate of 3%, use of triptans did not exert much force overall on the baseline rate,” he said. Similar patterns were visible with use of other classes of drugs.
Meanwhile, the higher rates of conversion seen with opioids and barbiturates suggests an effect from these drugs. “Perhaps this data suggests the previously known effect is at play here and argues against the need for a separate diagnosis of medication overuse headache,” Dr. Rizzoli said.
“The evidence that simple analgesics can cause medication overuse headache is especially weak, and the evidence that NSAIDs do is conflicting, with some evidence suggesting they’re protective at some doses.” Other population studies suggested most patients with daily headache do not overuse medications, and studies in India, where analgesics are rarely used, still showed a similar rate of conversion to daily headache. Other studies failed to show evidence that withdrawal of overused medication leads to improvement. “Studies of populations after aggressive management of medicine overuse headache indicate that, for the majority of the headaches, for the most part did not clear after treatment, except maybe for a short time,” said Dr. Rizzoli.
A systematic review of 18 population studies showed the prevalence of medical overuse headache ranged from 11% to 68%. “That indicates substantial uncertainty about the magnitude of the problem,” said Dr. Rizzoli.
He also noted potential harms to patients. Many patients come in experience between 10 and 20 headaches per month. “To see them out of medical overuse would have us advising not to treat half of their headaches monthly in order to avoid this evil. Many patients who have read or heard about this condition are themselves restricting treatment so as to avoid medication overuse headache. The harms of such undertreatment have not been fully investigated.”
To get at the issue, he recommended adapting the traditional number-needed-to-treat calculation. “You could calculate a number needed to overtreat. If medication use is assumed to be the sole cause of headache chronification, the calculations could suggest you would need to restrict therapy for about 4 people for each person you protect from going chronic. That’s a lot of undertreatment,” said Dr. Rizzoli.
He summed up by saying that some patients may have a progressive disorder with structure and physiological changes in the brain that result in chronic pain, and such patients should be identified and studied. In others with frequent headache, high medication use may simply be associated with the condition becoming chronic, but not causative. “These diagnostic groups may be mixed and may be difficult to untangle,” said Dr. Rizzoli.
Medication overuse is to blame
Dr. Rizzoli’s debate lecture was followed by Barbara Nye, MD, who argued that concerns over medication overuse headache are valid. She noted a more unifying definition in ICHD-3, which requires regular medication overuse for at least 3 months, along with primary headache disorder.
Dr. Nye, who is codirector of the Headache Clinic at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., related her experience that medication overuse headache often occurs more quickly than the 3-month time frame contained in ICHD-3, especially in patients who were given pain medications after undergoing surgery. She echoed Dr. Rizzoli’s concerns about opiates and barbiturates. “Medicine overuse headache should be something we focus on, and we should be warning providers both in neurology and primary care about the frequent use of opiate and butalbital-containing medications, and frequent over-the-counter medicine use in high-frequency headache disorders,” Dr. Nye said during her talk.
She cited research showing risk factors for conversion from episodic to chronic daily headache. As well as medication overuse, these include White race, lower education status, previous marriage, obesity, diabetes, arthritis, top-quartile caffeine use, stressful life events, and higher headache frequency.
Risks vary by medication class. Opiates and narcotics used more than 2 or 3 times per week are of particular concern, as are short-acting over-the-counter medicines used more than three times per week or 10-15 days per month. She agreed that NSAIDs may have a protective effect, but only at much lower doses and when used about five (or fewer) times per month. One study showed a possible protection effect of NSAIDs, though when used more than 10 days/month, they were associated with medication overuse headache.
Fioricet and Fiorinal, used more than 1 day/week, have an early and robust medicine overuse effect. “Limiting that use is very important,” said Dr. Nye. Other medicines and doses of concern include Tramadol/Ultram used at a higher than 50 mg/day dose, which has a metabolite that causes headache, and triptans used more than 10 days/month.
These concerns came about after analysis of large trials in patients with other conditions who also suffer from episodic migraines. A study of patients with irritable bowel syndrome and migraine showed a risk of conversion with opioid treatment. Another study of patients with arthritis and episodic migraine showed an association between conversion and NSAIDs alone, NSAIDs combined with Tylenol, and NSAIDs combined with opioids.
Risks of medication overuse also included collateral damage to the gastrointestinal and kidney systems, development of dependence, exacerbation of depression, and opioid-induced hyperalgesia, according to Dr. Nye. The overused medication may also interfere with the use of preventive medication. Those concerns drive the conventional wisdom of weaning patients off the overused medication, Dr. Nye said.
Dr. Nye discussed some of the observations of structural changes in the brain found in episodic migraine and chronic migraine associated with medication overuse. Functional MRI showed changes in grey matter, both as a result of medication overuse headache and further changes after medication withdrawal. “A lot of neuroplasticity and neuroadaptation occurs, and these effects seem to be sustained anywhere from 4-6 months after (medicine) discontinuation,” said Dr. Nye.
Common ground
Dr. Nye emphasized the need to be aware of the dangers of medication overuse headache, but noted that clinicians should address the problem to ensure that patients are empowered, potentially providing preventive medications and encouraging more effective use of daily abortive medications.
In response, Dr. Rizzoli suggested that the two agreed on many issues. For her part, Dr. Nye agreed that medication overuse headache is a muddy concept that needs more research to understand the relationship between opiate use and chronic migraine, “but I do think there have been some good studies of fMRI evaluating the difference between those with medication overuse headache and seeing how they convert back to a different underlying network (following medication withdrawal). I do agree that there is probably a subpopulation that is not affected by medication overuse headache,” Dr. Nye said.
In the end, both expressed concerns for the patient. “I share Barbara’s concern that we need to be mindful and protect our patients from medication use, but on the other hand I think we also need to protect our patients from the complications of having a diagnosis of medical overuse and the stigmatization that goes with that. That particular issue goes both ways,” said Dr. Rizzoli.
“I absolutely agree with that,” responded Dr. Nye.
Dr. Nye is on the advisory boards for Biohaven, Upsher Smith, and Impel. She is a trial site principal investigator for Allergan, Amgen, and Satsuma. Dr. Rizzoli has been a consultant for Nestle and served on the scientific advisory or data safety monitoring board for Biohaven and Xoc Pharma. He has also received research support from Allergan.
FROM HCNE’S 20TH ANNUAL BOSTON FALL HEADACHE SYMPOSIUM
A closer look at migraine aura
Migraine aura sometimes accompanies or precedes migraine pain, but the phenomenon is difficult to treat and poorly understood. However, some evidence points to potential neurological mechanisms, and migraine aura is associated with cardiovascular disease risk.
Andrea Harriott, MD, PhD, said at the Stowe Headache Symposium sponsored by the Headache Cooperative of New England, which was conducted virtually. Dr. Harriott is assistant professor of neurology at Massachusetts General Hospital in Boston.
Somewhere between 20% and 40% of patients with migraine experience aura. It is most often visual, though it can also include sensory, aphasic, and motor symptoms. Visual aura usually begins as a flickering zigzag pattern in the central visual field that moves slowly toward the periphery and often leaves a scotoma. Typical duration is 15-30 minutes. Aura symptoms are more common in females.
Research in the 1940s conducted by the Brazilian researcher Aristides de Azevedo Pacheco Leão, PhD, then at Harvard Medical School, Boston, showed evidence of CSD in rabbits after electrical or mechanical stimulation. He observed a wave of vasodilation and increased blood flow over the cortex that spread over nearly the entire dorsolateral cortex within 3-6 minutes.
In the 1940s and 1950s, researchers sketched on paper the visual disturbance over 10 minutes, tracking the expanding spectrum across the visual field, from the center toward the periphery. The resulting scotoma advanced across the visual cortex at a rate very similar to that of the cortical spreading observed by Dr. Leão, “potentially linking this electrical event that was described with the aura event of migraine,” said Dr. Harriott. Those researchers hypothesized that the aura was produced by a strong excitation phase, followed by a wave of total inhibition.
More recent functional magnetic resonance imaging studies have also shown that CSD-like disturbances occur when patients experience migraine aura. In one study, researchers observed an initial increase and then a decrease in the blood oxygenation level dependent (BOLD) signal, which spread slowly across the visual cortex and correlated with the aura event. “This study was really important in confirming that a CSD-like phenomenon was likely the underlying perturbation that produced the visual aura of migraine,” said Dr. Harriott.
Despite the evidence that CSD causes migraine aura, its connection to migraine pain hasn’t been firmly established. But Dr. Harriott presented some evidence linking the two. Migraine aura is usually followed by pain, and aura precedes migraine attacks 78%-93% of the time. Cephalic allodynia occurs in migraine about 70% to 80% of the time, and migraine with aura is more often associated with severe cutaneous allodynia than is migraine without aura. Finally, migraine patients with comorbidities have more severe disability, and more frequent cutaneous allodynia and aura than does the general migraine population (40% vs. 29%).
All of that suggests that activation of trigeminal nociceptors is involved with migraine aura, according to Dr. Harriott. Preclinical studies have also suggested links between CSD and activation of trigeminal nociceptors, with both immunohistochemical and electrophysiological lines of evidence. “These data suggest that spreading depression actually activates trigeminal nociceptors that we know are involved in signal pain in the head and neck, and that we know are involved in cephalic allodynia as well,” Dr. Harriott said.
The evidence impressed Allan Purdy, MD, professor of medicine at Dalhousie University, Halifax, N.S., who was the discussant for the presentation. “It’s an excellent case that CSD is a remarkably good correlate for aura,” he said during the session.
Along with potential impacts on migraine pain, aura is also associated with cardiovascular risk. “This is really important to know about in our clinical population,” said Dr. Harriott.
Meta-analyses of case control and cohort studies have shown associations between migraine aura and vascular disorders such as ischemic stroke. One meta-analysis showed about a twofold increased risk associated with migraine compared with the nonmigraine population. This difference was driven by migraine with aura (relative risk [RR], 2.25; 95% confidence interval [CI], 1.53-3.33) rather than migraine without aura (RR, 1.24; 95% CI, 0.86-1.79). Migraine generally is associated with greater risk of myocardial infarction (adjusted hazard ratio, 1.33; 95% CI, 1.08-1.64), and that association may be stronger in the aura phenotype.
There doesn’t appear to be evidence that traditional risk factors for heart disease – such as hypertension, diabetes, or high cholesterol – play a role in the association between aura and heart disease. One possibility is that variables like platelet activation, hypercoagulable state, or genetic susceptibility could be responsible.
The risks associated with migraine aura should be noted, but with a caveat, according to Dr. Purdy. “Even though the relative risk is high, the absolute risk is still relatively low, and patients with migraine with aura, who smoke or are female and over 45, those are the cases where the worry comes in.”
Dr. Harriott and Dr. Purdy have nothing to disclose.
Migraine aura sometimes accompanies or precedes migraine pain, but the phenomenon is difficult to treat and poorly understood. However, some evidence points to potential neurological mechanisms, and migraine aura is associated with cardiovascular disease risk.
Andrea Harriott, MD, PhD, said at the Stowe Headache Symposium sponsored by the Headache Cooperative of New England, which was conducted virtually. Dr. Harriott is assistant professor of neurology at Massachusetts General Hospital in Boston.
Somewhere between 20% and 40% of patients with migraine experience aura. It is most often visual, though it can also include sensory, aphasic, and motor symptoms. Visual aura usually begins as a flickering zigzag pattern in the central visual field that moves slowly toward the periphery and often leaves a scotoma. Typical duration is 15-30 minutes. Aura symptoms are more common in females.
Research in the 1940s conducted by the Brazilian researcher Aristides de Azevedo Pacheco Leão, PhD, then at Harvard Medical School, Boston, showed evidence of CSD in rabbits after electrical or mechanical stimulation. He observed a wave of vasodilation and increased blood flow over the cortex that spread over nearly the entire dorsolateral cortex within 3-6 minutes.
In the 1940s and 1950s, researchers sketched on paper the visual disturbance over 10 minutes, tracking the expanding spectrum across the visual field, from the center toward the periphery. The resulting scotoma advanced across the visual cortex at a rate very similar to that of the cortical spreading observed by Dr. Leão, “potentially linking this electrical event that was described with the aura event of migraine,” said Dr. Harriott. Those researchers hypothesized that the aura was produced by a strong excitation phase, followed by a wave of total inhibition.
More recent functional magnetic resonance imaging studies have also shown that CSD-like disturbances occur when patients experience migraine aura. In one study, researchers observed an initial increase and then a decrease in the blood oxygenation level dependent (BOLD) signal, which spread slowly across the visual cortex and correlated with the aura event. “This study was really important in confirming that a CSD-like phenomenon was likely the underlying perturbation that produced the visual aura of migraine,” said Dr. Harriott.
Despite the evidence that CSD causes migraine aura, its connection to migraine pain hasn’t been firmly established. But Dr. Harriott presented some evidence linking the two. Migraine aura is usually followed by pain, and aura precedes migraine attacks 78%-93% of the time. Cephalic allodynia occurs in migraine about 70% to 80% of the time, and migraine with aura is more often associated with severe cutaneous allodynia than is migraine without aura. Finally, migraine patients with comorbidities have more severe disability, and more frequent cutaneous allodynia and aura than does the general migraine population (40% vs. 29%).
All of that suggests that activation of trigeminal nociceptors is involved with migraine aura, according to Dr. Harriott. Preclinical studies have also suggested links between CSD and activation of trigeminal nociceptors, with both immunohistochemical and electrophysiological lines of evidence. “These data suggest that spreading depression actually activates trigeminal nociceptors that we know are involved in signal pain in the head and neck, and that we know are involved in cephalic allodynia as well,” Dr. Harriott said.
The evidence impressed Allan Purdy, MD, professor of medicine at Dalhousie University, Halifax, N.S., who was the discussant for the presentation. “It’s an excellent case that CSD is a remarkably good correlate for aura,” he said during the session.
Along with potential impacts on migraine pain, aura is also associated with cardiovascular risk. “This is really important to know about in our clinical population,” said Dr. Harriott.
Meta-analyses of case control and cohort studies have shown associations between migraine aura and vascular disorders such as ischemic stroke. One meta-analysis showed about a twofold increased risk associated with migraine compared with the nonmigraine population. This difference was driven by migraine with aura (relative risk [RR], 2.25; 95% confidence interval [CI], 1.53-3.33) rather than migraine without aura (RR, 1.24; 95% CI, 0.86-1.79). Migraine generally is associated with greater risk of myocardial infarction (adjusted hazard ratio, 1.33; 95% CI, 1.08-1.64), and that association may be stronger in the aura phenotype.
There doesn’t appear to be evidence that traditional risk factors for heart disease – such as hypertension, diabetes, or high cholesterol – play a role in the association between aura and heart disease. One possibility is that variables like platelet activation, hypercoagulable state, or genetic susceptibility could be responsible.
The risks associated with migraine aura should be noted, but with a caveat, according to Dr. Purdy. “Even though the relative risk is high, the absolute risk is still relatively low, and patients with migraine with aura, who smoke or are female and over 45, those are the cases where the worry comes in.”
Dr. Harriott and Dr. Purdy have nothing to disclose.
Migraine aura sometimes accompanies or precedes migraine pain, but the phenomenon is difficult to treat and poorly understood. However, some evidence points to potential neurological mechanisms, and migraine aura is associated with cardiovascular disease risk.
Andrea Harriott, MD, PhD, said at the Stowe Headache Symposium sponsored by the Headache Cooperative of New England, which was conducted virtually. Dr. Harriott is assistant professor of neurology at Massachusetts General Hospital in Boston.
Somewhere between 20% and 40% of patients with migraine experience aura. It is most often visual, though it can also include sensory, aphasic, and motor symptoms. Visual aura usually begins as a flickering zigzag pattern in the central visual field that moves slowly toward the periphery and often leaves a scotoma. Typical duration is 15-30 minutes. Aura symptoms are more common in females.
Research in the 1940s conducted by the Brazilian researcher Aristides de Azevedo Pacheco Leão, PhD, then at Harvard Medical School, Boston, showed evidence of CSD in rabbits after electrical or mechanical stimulation. He observed a wave of vasodilation and increased blood flow over the cortex that spread over nearly the entire dorsolateral cortex within 3-6 minutes.
In the 1940s and 1950s, researchers sketched on paper the visual disturbance over 10 minutes, tracking the expanding spectrum across the visual field, from the center toward the periphery. The resulting scotoma advanced across the visual cortex at a rate very similar to that of the cortical spreading observed by Dr. Leão, “potentially linking this electrical event that was described with the aura event of migraine,” said Dr. Harriott. Those researchers hypothesized that the aura was produced by a strong excitation phase, followed by a wave of total inhibition.
More recent functional magnetic resonance imaging studies have also shown that CSD-like disturbances occur when patients experience migraine aura. In one study, researchers observed an initial increase and then a decrease in the blood oxygenation level dependent (BOLD) signal, which spread slowly across the visual cortex and correlated with the aura event. “This study was really important in confirming that a CSD-like phenomenon was likely the underlying perturbation that produced the visual aura of migraine,” said Dr. Harriott.
Despite the evidence that CSD causes migraine aura, its connection to migraine pain hasn’t been firmly established. But Dr. Harriott presented some evidence linking the two. Migraine aura is usually followed by pain, and aura precedes migraine attacks 78%-93% of the time. Cephalic allodynia occurs in migraine about 70% to 80% of the time, and migraine with aura is more often associated with severe cutaneous allodynia than is migraine without aura. Finally, migraine patients with comorbidities have more severe disability, and more frequent cutaneous allodynia and aura than does the general migraine population (40% vs. 29%).
All of that suggests that activation of trigeminal nociceptors is involved with migraine aura, according to Dr. Harriott. Preclinical studies have also suggested links between CSD and activation of trigeminal nociceptors, with both immunohistochemical and electrophysiological lines of evidence. “These data suggest that spreading depression actually activates trigeminal nociceptors that we know are involved in signal pain in the head and neck, and that we know are involved in cephalic allodynia as well,” Dr. Harriott said.
The evidence impressed Allan Purdy, MD, professor of medicine at Dalhousie University, Halifax, N.S., who was the discussant for the presentation. “It’s an excellent case that CSD is a remarkably good correlate for aura,” he said during the session.
Along with potential impacts on migraine pain, aura is also associated with cardiovascular risk. “This is really important to know about in our clinical population,” said Dr. Harriott.
Meta-analyses of case control and cohort studies have shown associations between migraine aura and vascular disorders such as ischemic stroke. One meta-analysis showed about a twofold increased risk associated with migraine compared with the nonmigraine population. This difference was driven by migraine with aura (relative risk [RR], 2.25; 95% confidence interval [CI], 1.53-3.33) rather than migraine without aura (RR, 1.24; 95% CI, 0.86-1.79). Migraine generally is associated with greater risk of myocardial infarction (adjusted hazard ratio, 1.33; 95% CI, 1.08-1.64), and that association may be stronger in the aura phenotype.
There doesn’t appear to be evidence that traditional risk factors for heart disease – such as hypertension, diabetes, or high cholesterol – play a role in the association between aura and heart disease. One possibility is that variables like platelet activation, hypercoagulable state, or genetic susceptibility could be responsible.
The risks associated with migraine aura should be noted, but with a caveat, according to Dr. Purdy. “Even though the relative risk is high, the absolute risk is still relatively low, and patients with migraine with aura, who smoke or are female and over 45, those are the cases where the worry comes in.”
Dr. Harriott and Dr. Purdy have nothing to disclose.
FROM HCNE STOWE 2020
Drug-drug interactions to avoid in patients with GI cancer
warned a leading expert in the field.
Rachel P. Riechelmann, MD, AC Camargo Cancer Center, São Paulo, Brazil, was delivering a keynote speech during the ESMO 22nd World Congress on Gastrointestinal Cancer Virtual Experience on July 4.
One of the drug-drug interactions that can have a deleterious effect on patients with GI cancers is that occurring between proton pump inhibitors (PPIs), such as omeprazole, and chemotherapy regimens containing capecitabine, she said.
She cited clinical trial data showing that the use of PPIs can increase the risk for progression in colorectal cancer patients being treated with adjuvant CapeOx (capecitabine with oxaliplatin) or FOLFOX (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin). Further clinical trial data from the LOGIC trial show that PPIs have a significant effect on both progression-free and overall survival in HER2+ gastric cancer patients being treated with CapOx with or without lapatinib.
Commenting on the presentation on Twitter, Jose Fernando Moura, MD, PhD, Medical Oncology, Real Hospital Português, Recife, Brazil, agreed that it is better to avoid PPIs during chemotherapy for colorectal and gastrointestinal tumors.
Benedikt Westphalen, MD, PhD, coordinator, molecular oncology, University of Munich Comprehensive Cancer Center, Munich, Germany, replied that the data presented by Dr. Riechelmann are “clearly interesting.”
He added his own checklist of things to consider in regard to drug-drug interactions, including changes in drug levels, the effect on the microbiome, and gender differences.
Previous studies, including many from Dr. Riechelmann’s group, have indicated that potential drug-drug interactions occur in about two thirds of inpatients and in approximately one third of outpatients.
The frequency of clinically relevant drug interactions in oncology patients enrolled in clinical trials is “not that high,” however, at between 3% and 17%, depending on the mechanism of interaction, she commented.
“But it should be zero, because all clinical trials have a list of combinations that should not be prescribed and drugs that should be avoided,” she added.
There have been very few studies on the occurrence of drug-drug interactions in oncology patients in the real world, Dr. Riechelmann commented.
One study suggested that 4% of oncology deaths in hospitals were due to adverse drug reactions or interactions. Another study, conducted by Dr. Riechelmann’s team, suggested that 2% of nonelective hospitalizations among oncology patients were for drug-drug interactions.
She said that common potential drug interactions in oncology involve the use of aspirin, warfarin, beta blockers, and corticosteroids.
She also singled out olaparib (Lynparza, AstraZeneca) as an interesting case. Coadministration of drugs that act as CYP3A4 inhibitors or inducers can effect exposure to this drug; itraconazole significantly increases exposure, and rifampin significantly reduces exposure.
Avoiding interactions
In conclusion, Dr. Riechelmann made a series of recommendations for avoiding dangerous drug-drug interactions in cancer patients, the first of which is to avoid polypharmacy in the first place.
She also suggested that high-risk patients, such as those taking many drugs and who have comorbid illness, should be screened for potential drug interactions, and attention should be paid to “dangerous” combinations.
Combinations to avoid include those of two drugs that each prolong the QT interval. These include quinolones, azithromycin, and clarithromycin.
“I think every one of us has to develop our own list of dangerous combinations” that should be avoided if possible, she said. If their use is necessary, patients should be informed of the potential risk and should be monitored closely for adverse events.
No funding for the study has been reported. The investigators have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
warned a leading expert in the field.
Rachel P. Riechelmann, MD, AC Camargo Cancer Center, São Paulo, Brazil, was delivering a keynote speech during the ESMO 22nd World Congress on Gastrointestinal Cancer Virtual Experience on July 4.
One of the drug-drug interactions that can have a deleterious effect on patients with GI cancers is that occurring between proton pump inhibitors (PPIs), such as omeprazole, and chemotherapy regimens containing capecitabine, she said.
She cited clinical trial data showing that the use of PPIs can increase the risk for progression in colorectal cancer patients being treated with adjuvant CapeOx (capecitabine with oxaliplatin) or FOLFOX (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin). Further clinical trial data from the LOGIC trial show that PPIs have a significant effect on both progression-free and overall survival in HER2+ gastric cancer patients being treated with CapOx with or without lapatinib.
Commenting on the presentation on Twitter, Jose Fernando Moura, MD, PhD, Medical Oncology, Real Hospital Português, Recife, Brazil, agreed that it is better to avoid PPIs during chemotherapy for colorectal and gastrointestinal tumors.
Benedikt Westphalen, MD, PhD, coordinator, molecular oncology, University of Munich Comprehensive Cancer Center, Munich, Germany, replied that the data presented by Dr. Riechelmann are “clearly interesting.”
He added his own checklist of things to consider in regard to drug-drug interactions, including changes in drug levels, the effect on the microbiome, and gender differences.
Previous studies, including many from Dr. Riechelmann’s group, have indicated that potential drug-drug interactions occur in about two thirds of inpatients and in approximately one third of outpatients.
The frequency of clinically relevant drug interactions in oncology patients enrolled in clinical trials is “not that high,” however, at between 3% and 17%, depending on the mechanism of interaction, she commented.
“But it should be zero, because all clinical trials have a list of combinations that should not be prescribed and drugs that should be avoided,” she added.
There have been very few studies on the occurrence of drug-drug interactions in oncology patients in the real world, Dr. Riechelmann commented.
One study suggested that 4% of oncology deaths in hospitals were due to adverse drug reactions or interactions. Another study, conducted by Dr. Riechelmann’s team, suggested that 2% of nonelective hospitalizations among oncology patients were for drug-drug interactions.
She said that common potential drug interactions in oncology involve the use of aspirin, warfarin, beta blockers, and corticosteroids.
She also singled out olaparib (Lynparza, AstraZeneca) as an interesting case. Coadministration of drugs that act as CYP3A4 inhibitors or inducers can effect exposure to this drug; itraconazole significantly increases exposure, and rifampin significantly reduces exposure.
Avoiding interactions
In conclusion, Dr. Riechelmann made a series of recommendations for avoiding dangerous drug-drug interactions in cancer patients, the first of which is to avoid polypharmacy in the first place.
She also suggested that high-risk patients, such as those taking many drugs and who have comorbid illness, should be screened for potential drug interactions, and attention should be paid to “dangerous” combinations.
Combinations to avoid include those of two drugs that each prolong the QT interval. These include quinolones, azithromycin, and clarithromycin.
“I think every one of us has to develop our own list of dangerous combinations” that should be avoided if possible, she said. If their use is necessary, patients should be informed of the potential risk and should be monitored closely for adverse events.
No funding for the study has been reported. The investigators have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
warned a leading expert in the field.
Rachel P. Riechelmann, MD, AC Camargo Cancer Center, São Paulo, Brazil, was delivering a keynote speech during the ESMO 22nd World Congress on Gastrointestinal Cancer Virtual Experience on July 4.
One of the drug-drug interactions that can have a deleterious effect on patients with GI cancers is that occurring between proton pump inhibitors (PPIs), such as omeprazole, and chemotherapy regimens containing capecitabine, she said.
She cited clinical trial data showing that the use of PPIs can increase the risk for progression in colorectal cancer patients being treated with adjuvant CapeOx (capecitabine with oxaliplatin) or FOLFOX (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin). Further clinical trial data from the LOGIC trial show that PPIs have a significant effect on both progression-free and overall survival in HER2+ gastric cancer patients being treated with CapOx with or without lapatinib.
Commenting on the presentation on Twitter, Jose Fernando Moura, MD, PhD, Medical Oncology, Real Hospital Português, Recife, Brazil, agreed that it is better to avoid PPIs during chemotherapy for colorectal and gastrointestinal tumors.
Benedikt Westphalen, MD, PhD, coordinator, molecular oncology, University of Munich Comprehensive Cancer Center, Munich, Germany, replied that the data presented by Dr. Riechelmann are “clearly interesting.”
He added his own checklist of things to consider in regard to drug-drug interactions, including changes in drug levels, the effect on the microbiome, and gender differences.
Previous studies, including many from Dr. Riechelmann’s group, have indicated that potential drug-drug interactions occur in about two thirds of inpatients and in approximately one third of outpatients.
The frequency of clinically relevant drug interactions in oncology patients enrolled in clinical trials is “not that high,” however, at between 3% and 17%, depending on the mechanism of interaction, she commented.
“But it should be zero, because all clinical trials have a list of combinations that should not be prescribed and drugs that should be avoided,” she added.
There have been very few studies on the occurrence of drug-drug interactions in oncology patients in the real world, Dr. Riechelmann commented.
One study suggested that 4% of oncology deaths in hospitals were due to adverse drug reactions or interactions. Another study, conducted by Dr. Riechelmann’s team, suggested that 2% of nonelective hospitalizations among oncology patients were for drug-drug interactions.
She said that common potential drug interactions in oncology involve the use of aspirin, warfarin, beta blockers, and corticosteroids.
She also singled out olaparib (Lynparza, AstraZeneca) as an interesting case. Coadministration of drugs that act as CYP3A4 inhibitors or inducers can effect exposure to this drug; itraconazole significantly increases exposure, and rifampin significantly reduces exposure.
Avoiding interactions
In conclusion, Dr. Riechelmann made a series of recommendations for avoiding dangerous drug-drug interactions in cancer patients, the first of which is to avoid polypharmacy in the first place.
She also suggested that high-risk patients, such as those taking many drugs and who have comorbid illness, should be screened for potential drug interactions, and attention should be paid to “dangerous” combinations.
Combinations to avoid include those of two drugs that each prolong the QT interval. These include quinolones, azithromycin, and clarithromycin.
“I think every one of us has to develop our own list of dangerous combinations” that should be avoided if possible, she said. If their use is necessary, patients should be informed of the potential risk and should be monitored closely for adverse events.
No funding for the study has been reported. The investigators have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Entrectinib results emphasize need for NTRK detection
Although fusions in the neurotrophic receptor tyrosine kinase (NTRK) gene are rare in gastrointestinal carcinomas (found in fewer than 5% of cases), they should be looked for, inasmuch as treatment with the TRK inhibitor entrectinib (Rozlytrek, Genentech/Roche) can achieve robust and durable responses, say researchers.
This point was made during several presentations at the virtual World Conference on Gastrointestinal Cancer (WCGC) 2020 on July 1.
Entrectinib and similar agents that act on NTRK fusion genes are described as tumor agnostic, in that they are biomarkers that define the cancer rather than the organ of origin.
The Food and Drug Administration last year granted accelerated approval of entrectinib for patients with locally advanced or metastatic NTRK-expressing solid tumors that have progressed following prior therapies. The drug can also be used as a first-line treatment when there are no effective therapies.
At the meeting, Manish R. Patel, MD, Department of Medicine, University of Minnesota, Minneapolis, and colleagues presented combined results from the ALKA-372-001, STARTRK-1, and STARTRK-2 studies of entrectinib.
They identified 12 gastrointestinal carcinoma patients among 74 adults with locally advanced/metastatic NTRK fusion positive, TRK inhibitor-naive solid tumors who had undergone at least 6 months of follow-up.
Many of these 12 patients had colorectal cancer (58%) or pancreatic cancer (24%).
Treatment with entrectinib elicited an overall response rate of 50%, which consisted entirely of partial responses.
The median duration of response was 12.9 months, which was largely driven by a median duration of response of 15.1 months among colorectal cancer patients, vs 10.0 months among pancreatic cancer patients and 9.3 months in the patient with cholangiocarcinoma.
The median progression-free survival was 7.1 months across the whole cohort. It was 8.0 months for pancreatic cancer patients and 12.0 months for the patient with cholangiocarcinoma.
The median overall survival was 16 months.
Dr. Patel said that this “demonstrates that entrectinib induces durable and clinically meaningful systemic responses in patients with gastrointestinal carcinomas harboring NTRK fusions.”
He noted that entrectinib is “overall very well tolerated, with very few dose interruptions or reductions, and the discontinuation rate was very low.” The majority of adverse events were of grade 1/2. The most common event was change in taste, which occurred in 37.3% of patients. There were no treatment-related deaths.
“The main take-away point from this abstract is that, though they are rare, if we identify patients with NTRK fusions during the course of the disease, we can offer them benefit from entrectinib, and I would argue that ... we should be screening patients for NTRK fusions much more frequently,” Dr. Patel added.
In the second study, a Belgian team performed immunohistochemistry (IHC) analysis followed by next-generation sequencing on archived samples of biliopancreatic cancers to determine the prevalence of NTRK fusions.
They found just one fusion among almost 150 biliary tract cancers and none in nearly 300 pancreatic adenocarcinomas.
Lead author Anne Demols, MD, PhD, Department of Gastroenterology and Gastrointestinal Oncology, CUB Hôpital Erasme, Brussels, Belgium, said the results show that, “consistent” with their low frequency in solid tumors, NTRK gene fusions are “also rare” in biliopancreatic cancers.
“Given this low frequency, testing and identification are of high clinical importance, due to possible treatment with pan-TRK inhibitors,” she said.
She added that a two-step diagnosis is recommended, in that it is both “time saving” and economical, and that next-generation sequencing is “mandatory” to confirm a positive result on IHC.
For discussant Juan W. Valle, MD, professor of medical oncology at the University of Manchester, United Kingdom, the results of the second study reinforce the take-home message of the first.
He said that “two-step diagnosis can preselect patients suitable for next-generation sequencing assay, and what we saw from the previous [study] is that the therapeutic implications make this an important diagnosis.”
Valle noted that there is an “immortal time bias” in the trial analysis, because patients had to be well enough to undergo at least 6 months of follow-up, and that “future work will focus on the best platform to use for known, as well as the identification of new, fusion partners.”
He highlighted the “improved response rate and progression-free survival” achieved with entrectinib among patients with gastrointestinal cancers harboring NTRK fusions, which will benefit patient outcomes.
Pashtoon Kasi, MD, a gastrointestinal oncologist at the University of Iowa Holden Comprehensive Cancer Center, Iowa City, commented on Twitter that, for him, the results were more than just about the impressive response rate but how “brisk, robust, and durable these tend to be.”
In his experience, even patients with stage IV disease who have responded to entrectinib have been able to undergo “secondary ‘curative’ resections.”
The ALKA-372-001, STARTRK-1 and STARTRK-2 studies were sponsored by F. Hoffmann-La Roche. The study by Demols and colleagues was funded by a research grant from Bayer Health. Dr. Patel reports relationships with Nektar Therapeutic, MSD, and Fate Therapeutics. Demols reports relationships with Bayer, Ipsen, Vifor, Servier and Roche. Dr. Valle reports relationships with numerous companies.
This article first appeared on Medscape.com.
Although fusions in the neurotrophic receptor tyrosine kinase (NTRK) gene are rare in gastrointestinal carcinomas (found in fewer than 5% of cases), they should be looked for, inasmuch as treatment with the TRK inhibitor entrectinib (Rozlytrek, Genentech/Roche) can achieve robust and durable responses, say researchers.
This point was made during several presentations at the virtual World Conference on Gastrointestinal Cancer (WCGC) 2020 on July 1.
Entrectinib and similar agents that act on NTRK fusion genes are described as tumor agnostic, in that they are biomarkers that define the cancer rather than the organ of origin.
The Food and Drug Administration last year granted accelerated approval of entrectinib for patients with locally advanced or metastatic NTRK-expressing solid tumors that have progressed following prior therapies. The drug can also be used as a first-line treatment when there are no effective therapies.
At the meeting, Manish R. Patel, MD, Department of Medicine, University of Minnesota, Minneapolis, and colleagues presented combined results from the ALKA-372-001, STARTRK-1, and STARTRK-2 studies of entrectinib.
They identified 12 gastrointestinal carcinoma patients among 74 adults with locally advanced/metastatic NTRK fusion positive, TRK inhibitor-naive solid tumors who had undergone at least 6 months of follow-up.
Many of these 12 patients had colorectal cancer (58%) or pancreatic cancer (24%).
Treatment with entrectinib elicited an overall response rate of 50%, which consisted entirely of partial responses.
The median duration of response was 12.9 months, which was largely driven by a median duration of response of 15.1 months among colorectal cancer patients, vs 10.0 months among pancreatic cancer patients and 9.3 months in the patient with cholangiocarcinoma.
The median progression-free survival was 7.1 months across the whole cohort. It was 8.0 months for pancreatic cancer patients and 12.0 months for the patient with cholangiocarcinoma.
The median overall survival was 16 months.
Dr. Patel said that this “demonstrates that entrectinib induces durable and clinically meaningful systemic responses in patients with gastrointestinal carcinomas harboring NTRK fusions.”
He noted that entrectinib is “overall very well tolerated, with very few dose interruptions or reductions, and the discontinuation rate was very low.” The majority of adverse events were of grade 1/2. The most common event was change in taste, which occurred in 37.3% of patients. There were no treatment-related deaths.
“The main take-away point from this abstract is that, though they are rare, if we identify patients with NTRK fusions during the course of the disease, we can offer them benefit from entrectinib, and I would argue that ... we should be screening patients for NTRK fusions much more frequently,” Dr. Patel added.
In the second study, a Belgian team performed immunohistochemistry (IHC) analysis followed by next-generation sequencing on archived samples of biliopancreatic cancers to determine the prevalence of NTRK fusions.
They found just one fusion among almost 150 biliary tract cancers and none in nearly 300 pancreatic adenocarcinomas.
Lead author Anne Demols, MD, PhD, Department of Gastroenterology and Gastrointestinal Oncology, CUB Hôpital Erasme, Brussels, Belgium, said the results show that, “consistent” with their low frequency in solid tumors, NTRK gene fusions are “also rare” in biliopancreatic cancers.
“Given this low frequency, testing and identification are of high clinical importance, due to possible treatment with pan-TRK inhibitors,” she said.
She added that a two-step diagnosis is recommended, in that it is both “time saving” and economical, and that next-generation sequencing is “mandatory” to confirm a positive result on IHC.
For discussant Juan W. Valle, MD, professor of medical oncology at the University of Manchester, United Kingdom, the results of the second study reinforce the take-home message of the first.
He said that “two-step diagnosis can preselect patients suitable for next-generation sequencing assay, and what we saw from the previous [study] is that the therapeutic implications make this an important diagnosis.”
Valle noted that there is an “immortal time bias” in the trial analysis, because patients had to be well enough to undergo at least 6 months of follow-up, and that “future work will focus on the best platform to use for known, as well as the identification of new, fusion partners.”
He highlighted the “improved response rate and progression-free survival” achieved with entrectinib among patients with gastrointestinal cancers harboring NTRK fusions, which will benefit patient outcomes.
Pashtoon Kasi, MD, a gastrointestinal oncologist at the University of Iowa Holden Comprehensive Cancer Center, Iowa City, commented on Twitter that, for him, the results were more than just about the impressive response rate but how “brisk, robust, and durable these tend to be.”
In his experience, even patients with stage IV disease who have responded to entrectinib have been able to undergo “secondary ‘curative’ resections.”
The ALKA-372-001, STARTRK-1 and STARTRK-2 studies were sponsored by F. Hoffmann-La Roche. The study by Demols and colleagues was funded by a research grant from Bayer Health. Dr. Patel reports relationships with Nektar Therapeutic, MSD, and Fate Therapeutics. Demols reports relationships with Bayer, Ipsen, Vifor, Servier and Roche. Dr. Valle reports relationships with numerous companies.
This article first appeared on Medscape.com.
Although fusions in the neurotrophic receptor tyrosine kinase (NTRK) gene are rare in gastrointestinal carcinomas (found in fewer than 5% of cases), they should be looked for, inasmuch as treatment with the TRK inhibitor entrectinib (Rozlytrek, Genentech/Roche) can achieve robust and durable responses, say researchers.
This point was made during several presentations at the virtual World Conference on Gastrointestinal Cancer (WCGC) 2020 on July 1.
Entrectinib and similar agents that act on NTRK fusion genes are described as tumor agnostic, in that they are biomarkers that define the cancer rather than the organ of origin.
The Food and Drug Administration last year granted accelerated approval of entrectinib for patients with locally advanced or metastatic NTRK-expressing solid tumors that have progressed following prior therapies. The drug can also be used as a first-line treatment when there are no effective therapies.
At the meeting, Manish R. Patel, MD, Department of Medicine, University of Minnesota, Minneapolis, and colleagues presented combined results from the ALKA-372-001, STARTRK-1, and STARTRK-2 studies of entrectinib.
They identified 12 gastrointestinal carcinoma patients among 74 adults with locally advanced/metastatic NTRK fusion positive, TRK inhibitor-naive solid tumors who had undergone at least 6 months of follow-up.
Many of these 12 patients had colorectal cancer (58%) or pancreatic cancer (24%).
Treatment with entrectinib elicited an overall response rate of 50%, which consisted entirely of partial responses.
The median duration of response was 12.9 months, which was largely driven by a median duration of response of 15.1 months among colorectal cancer patients, vs 10.0 months among pancreatic cancer patients and 9.3 months in the patient with cholangiocarcinoma.
The median progression-free survival was 7.1 months across the whole cohort. It was 8.0 months for pancreatic cancer patients and 12.0 months for the patient with cholangiocarcinoma.
The median overall survival was 16 months.
Dr. Patel said that this “demonstrates that entrectinib induces durable and clinically meaningful systemic responses in patients with gastrointestinal carcinomas harboring NTRK fusions.”
He noted that entrectinib is “overall very well tolerated, with very few dose interruptions or reductions, and the discontinuation rate was very low.” The majority of adverse events were of grade 1/2. The most common event was change in taste, which occurred in 37.3% of patients. There were no treatment-related deaths.
“The main take-away point from this abstract is that, though they are rare, if we identify patients with NTRK fusions during the course of the disease, we can offer them benefit from entrectinib, and I would argue that ... we should be screening patients for NTRK fusions much more frequently,” Dr. Patel added.
In the second study, a Belgian team performed immunohistochemistry (IHC) analysis followed by next-generation sequencing on archived samples of biliopancreatic cancers to determine the prevalence of NTRK fusions.
They found just one fusion among almost 150 biliary tract cancers and none in nearly 300 pancreatic adenocarcinomas.
Lead author Anne Demols, MD, PhD, Department of Gastroenterology and Gastrointestinal Oncology, CUB Hôpital Erasme, Brussels, Belgium, said the results show that, “consistent” with their low frequency in solid tumors, NTRK gene fusions are “also rare” in biliopancreatic cancers.
“Given this low frequency, testing and identification are of high clinical importance, due to possible treatment with pan-TRK inhibitors,” she said.
She added that a two-step diagnosis is recommended, in that it is both “time saving” and economical, and that next-generation sequencing is “mandatory” to confirm a positive result on IHC.
For discussant Juan W. Valle, MD, professor of medical oncology at the University of Manchester, United Kingdom, the results of the second study reinforce the take-home message of the first.
He said that “two-step diagnosis can preselect patients suitable for next-generation sequencing assay, and what we saw from the previous [study] is that the therapeutic implications make this an important diagnosis.”
Valle noted that there is an “immortal time bias” in the trial analysis, because patients had to be well enough to undergo at least 6 months of follow-up, and that “future work will focus on the best platform to use for known, as well as the identification of new, fusion partners.”
He highlighted the “improved response rate and progression-free survival” achieved with entrectinib among patients with gastrointestinal cancers harboring NTRK fusions, which will benefit patient outcomes.
Pashtoon Kasi, MD, a gastrointestinal oncologist at the University of Iowa Holden Comprehensive Cancer Center, Iowa City, commented on Twitter that, for him, the results were more than just about the impressive response rate but how “brisk, robust, and durable these tend to be.”
In his experience, even patients with stage IV disease who have responded to entrectinib have been able to undergo “secondary ‘curative’ resections.”
The ALKA-372-001, STARTRK-1 and STARTRK-2 studies were sponsored by F. Hoffmann-La Roche. The study by Demols and colleagues was funded by a research grant from Bayer Health. Dr. Patel reports relationships with Nektar Therapeutic, MSD, and Fate Therapeutics. Demols reports relationships with Bayer, Ipsen, Vifor, Servier and Roche. Dr. Valle reports relationships with numerous companies.
This article first appeared on Medscape.com.
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.
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
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