User login
Opioids for headache?
Some believe that the medications, though risky, can be a useful tool in the neurologist’s treatment arsenal, while others argue that opioids are just too risky when there are other, safer alternatives available.
Those were the cruxes of arguments put forward by Paul Rizzoli, MD, and Christopher H. Gottschalk, MD, who conducted individual talks at the 2021 Scottsdale Headache Symposium. Dr. Rizzoli, associate professor of neurology at Harvard Medical School, Boston, argued in favor of the use of opioids and butalbital-containing medications. Dr. Gottschalk, assistant professor of neurology at Yale University, New Haven, Conn., argued against their use.
In certain situations opioids are worth the risk
Whether or not to use opioids in the treatment of headache is “a reasonable question, because these medications can clearly be seen as having risk. So perhaps another way to frame this question is as a risk-benefit issue. Are these medications worth the risk? How useful is the benefit of opioids, if the consequence is dependence or addiction?” Dr. Rizzoli began.
Although reviews show effectiveness of opioids in treating migraine, a three-part review in 2012 found greater efficacy of dihydroergotamine (DHE), ketorolac, and chlorpromazine. That’s not surprising, said Dr. Rizzoli, since those competing drugs are migraine-specific.
Dr. Rizzoli quoted a 2014 review indicating that there were incomplete data on the relative efficacy of opioids versus other analgesics, and for some patients opioids would likely be the optimal treatment, such as those who have contraindications to ergot-type medications or neuroleptic medications, pregnant women, or patients who don’t respond to other medications.
Dr. Rizzoli noted that The International Association for the Study of Pain has concluded that no other oral medications provide immediate and effective pain relief, and that short-term use rarely leads to addiction.
“So, to me, the answer is not to avoid opioids or outlaw them but instead to use them judiciously and infrequently, and in a short term or rescue fashion,” said Dr. Rizzoli.
He pointed out that physicians accept risks of other medications, and act to mitigate those risks. He said that risk mitigation with opioids can take the form of avoiding prescriptions in some situations, like when patients have a personal or family history of substance abuse, or in cases of some behavioral or emotional disorders.
Dr. Rizzoli went on to discuss the use of butalbital, which acts as a CNS depressant and has a variety of effects, including sedation, anxiolytic, hypnotic, and antiepileptic effects, but it is only a weak analgesic, but it nevertheless works in headache, said Dr. Rizzoli, citing patient reports and personal experience.
“It’s difficult to appreciate this theme of efficacy behind all the hype in the literature and in the press against butalbital, and the fact that it has not been adequately studied. But I would submit that the fact that we are even having this discussion is support enough for the use of butalbital. If butalbital either didn’t work or was simply a drug of abuse, it would likely have faded away by now,” said Dr. Rizzoli. He conceded that butalbital can be overused and may lead episodic headache to become chronic daily headache, but he noted that Seymour Solomon, MD, professor emeritus at Albert Einstein College of Medicine, New York, has estimated that removal of butalbital from the market would reduce chronic headache in the general population by only a small fraction of one percent.
Butalbital also has another interesting effect, which is that patients may quickly return to normal functioning after the headache resolves. “Maybe this is all due to management of anxiety, the presumed mechanism of action of barbiturates. So, instead of lobbying for its removal, I would propose that we should take a closer look at what’s going on here, and what the mechanism of action of this fairly interesting compound might be,” said Dr. Rizzoli.
Dr. Rizzoli also said there is some evidence that migraine-specific drugs also affect the tolerance to opioid drugs. “Somehow, they seem to interact with the opioid pain system. If that’s true, the implication is that you probably cannot escape the opioid receptors in the management of migraine,” said Dr. Rizzoli.
Ultimately, he supports the judicious use of opioids and butalbital containing-medications for headache relief. “My argument is that it is just too simplistic to cease use of these meds. Yes, they should be used in a restricted and careful way, but not abandoned,” said Dr. Rizzoli.
Opiates should be avoided
Following Dr. Rizzoli’s presentation, Dr. Gottschalk presented an argument against the use of opioids in the treatment of headache.
He began by quoting the ABIM Choosing Wisely Campaign of 2012, which concluded that fioricet and narcotics should be avoided in headache unless the patient is desperate. “As a headache specialist, I can tell you that I have not faced situations sufficiently desperate to use any of these. The American Headache Society in a series of evidence assessments has concluded similarly, that they are of no use,” said Dr. Gottschalk.
Opiates and barbiturates may also increase risk of migraine chronification. One study found that triptans are associated with low rates of chronification, at just a few percent when used fewer than 4 days a month, and about 20% per year when used 10-14 days per month. Opiate use showed a broadly similar pattern, while barbiturates showed a particularly alarming pattern: “Every level of use was associated with astronomically high rates and measurably higher at the highest level of use. For opiates, the odds ratio was about 2 – statistically significant. For barbiturates it was clearly greater than 2, whereas with triptans, the odds ratio showed a nonsignificant, slight increase in risk. And for NSAIDs, the odds ratio was, if anything, less than 1,” said Dr. Gottschalk.
He also discussed aspects of behavioral pharmacology, in which positive reinforcement associated with decreased headache may encourage repeated use of the drug. “Given these, it should be no surprise to anyone that emergency room treatment with opiates for acute migraine is clearly associated with increased recidivism for patients given those drugs,” said Dr. Gottschalk.
Opiate use is associated with increased pain sensitivity, and in the case of migraine, it may interfere with the activity of other treatments.
As for butalbital-containing compounds, they are positive-reinforcing drugs, and they are not indicated for migraine, only tension headache. There is no evidence of benefit in migraine, but butalbital is anxiolytic, which could lead an individual to increase its use.
A recent meta-analysis of therapies for episodic migraine found that hydromorphone and meperidine are less effective than standard therapies such as prochlorperazine or metoclopramide. Another study suggested that opioid use may interfere with the efficacy of NSAIDs in the emergency room environment, while a post hoc analysis of rizatriptan clinical trials found that recent opiate use was associated with a lower response rate, and the effect was more pronounced in women.
Among patients with chronic migraine, a 2004 study found that opiates were the most commonly used medication, and other studies found that chronic migraine does not arise in nonmigraine patients treated with opiates, “suggesting that migraine is specifically prone to opiate-induced hyperalgesia of migraine itself,” said Dr. Gottschalk.
Even under careful monitoring, misuse occurs in more than 50% of patients, “suggesting that even under the best circumstances, it is difficult to use this class of drugs safely in long term,” said Dr. Gottschalk.
He pointed out that the risk of drug addiction rises with various clinical and socioeconomic factors, including living in impoverished environments, adverse childhood experiences, low socioeconomic status, exposure to pollutants, and stressors. “In other words, all features associated with systemic racism are clearly associated with an increased risk of addiction,” said Dr. Gottschalk. Other factors include availability of the drug, such as whether or not a physician prescribes it, and repeated use.
These concerns, combined with positive-reinforcing properties of opiates and association with migraine progression and refractoriness, and the lack of progression risk found with use of NSAIDs and triptans, and the fact that effective acute therapy is associated with a lower risk of progression, argue against the use of opiates, said Dr. Gottschalk.
There is even a potential risk that the experience of migraine and its relief due to self-administration may become a rewarding experience that propagates the problem. It’s possible that anticipatory anxiety related to fear stressors could lead to migraine, or to physical sensations interpreted as migraine prodrome. “[It] raises the question of whether or not positive reinforcement by drugs makes migraine itself a rewarding experience and therefore more likely to occur as a cue for drug self-administration. The question I pose is: Is there any reason to test this theory in drugs of no proven benefit in the treatment of migraine? I would say very clearly, No,” said Dr. Gottschalk.
Clarifying the finer points of the debate
In the Q&A session after the talk, Dr. Rizzoli said that he doesn’t advocate for long-term use of opiates, except in rare cases where the diagnosis gets changed to a chronic pain syndrome. “We’re talking about intermittent use for treatment of an acute event. Do we put limits on them? I think the answer is clearly Yes, and the limits are more strict than those for triptans. My own sense as a clinician is I want all of the available tools. From a clinical perspective, there are a large number of people who do just fine with intermittent use of these medicines, and so I wouldn’t restrict them,” said Dr. Rizzoli.
Dr. Gottschalk agreed that opiates may make sense for some patients, but expressed concerns about any and all physicians prescribing them. “The part about the tools is partly a question of: Who gets to use them? In the hands of a headache specialist in those isolated cases with careful restrictions, sure. But what I’m making is a slippery slope argument: What we know is that in emergency rooms, these are used routinely, and that [those] patients are precisely the ones who are at higher risk of addiction. So in some sense, I’m just saying I think we need to have much clearer boundaries,” he said.
Dr. Rizzoli has no relevant financial disclosures. Dr. Gottschalk has been on the advisory boards of Alder, AbbVie, Amgen/Novartis, Biohaven, Theranica, Upsher-Smith, Axsome, Vorso, Currax, and Impel. He has been a consultant for Alder, Alexion, and Spherix Global Insights. He has received research support from Relivion.
Some believe that the medications, though risky, can be a useful tool in the neurologist’s treatment arsenal, while others argue that opioids are just too risky when there are other, safer alternatives available.
Those were the cruxes of arguments put forward by Paul Rizzoli, MD, and Christopher H. Gottschalk, MD, who conducted individual talks at the 2021 Scottsdale Headache Symposium. Dr. Rizzoli, associate professor of neurology at Harvard Medical School, Boston, argued in favor of the use of opioids and butalbital-containing medications. Dr. Gottschalk, assistant professor of neurology at Yale University, New Haven, Conn., argued against their use.
In certain situations opioids are worth the risk
Whether or not to use opioids in the treatment of headache is “a reasonable question, because these medications can clearly be seen as having risk. So perhaps another way to frame this question is as a risk-benefit issue. Are these medications worth the risk? How useful is the benefit of opioids, if the consequence is dependence or addiction?” Dr. Rizzoli began.
Although reviews show effectiveness of opioids in treating migraine, a three-part review in 2012 found greater efficacy of dihydroergotamine (DHE), ketorolac, and chlorpromazine. That’s not surprising, said Dr. Rizzoli, since those competing drugs are migraine-specific.
Dr. Rizzoli quoted a 2014 review indicating that there were incomplete data on the relative efficacy of opioids versus other analgesics, and for some patients opioids would likely be the optimal treatment, such as those who have contraindications to ergot-type medications or neuroleptic medications, pregnant women, or patients who don’t respond to other medications.
Dr. Rizzoli noted that The International Association for the Study of Pain has concluded that no other oral medications provide immediate and effective pain relief, and that short-term use rarely leads to addiction.
“So, to me, the answer is not to avoid opioids or outlaw them but instead to use them judiciously and infrequently, and in a short term or rescue fashion,” said Dr. Rizzoli.
He pointed out that physicians accept risks of other medications, and act to mitigate those risks. He said that risk mitigation with opioids can take the form of avoiding prescriptions in some situations, like when patients have a personal or family history of substance abuse, or in cases of some behavioral or emotional disorders.
Dr. Rizzoli went on to discuss the use of butalbital, which acts as a CNS depressant and has a variety of effects, including sedation, anxiolytic, hypnotic, and antiepileptic effects, but it is only a weak analgesic, but it nevertheless works in headache, said Dr. Rizzoli, citing patient reports and personal experience.
“It’s difficult to appreciate this theme of efficacy behind all the hype in the literature and in the press against butalbital, and the fact that it has not been adequately studied. But I would submit that the fact that we are even having this discussion is support enough for the use of butalbital. If butalbital either didn’t work or was simply a drug of abuse, it would likely have faded away by now,” said Dr. Rizzoli. He conceded that butalbital can be overused and may lead episodic headache to become chronic daily headache, but he noted that Seymour Solomon, MD, professor emeritus at Albert Einstein College of Medicine, New York, has estimated that removal of butalbital from the market would reduce chronic headache in the general population by only a small fraction of one percent.
Butalbital also has another interesting effect, which is that patients may quickly return to normal functioning after the headache resolves. “Maybe this is all due to management of anxiety, the presumed mechanism of action of barbiturates. So, instead of lobbying for its removal, I would propose that we should take a closer look at what’s going on here, and what the mechanism of action of this fairly interesting compound might be,” said Dr. Rizzoli.
Dr. Rizzoli also said there is some evidence that migraine-specific drugs also affect the tolerance to opioid drugs. “Somehow, they seem to interact with the opioid pain system. If that’s true, the implication is that you probably cannot escape the opioid receptors in the management of migraine,” said Dr. Rizzoli.
Ultimately, he supports the judicious use of opioids and butalbital containing-medications for headache relief. “My argument is that it is just too simplistic to cease use of these meds. Yes, they should be used in a restricted and careful way, but not abandoned,” said Dr. Rizzoli.
Opiates should be avoided
Following Dr. Rizzoli’s presentation, Dr. Gottschalk presented an argument against the use of opioids in the treatment of headache.
He began by quoting the ABIM Choosing Wisely Campaign of 2012, which concluded that fioricet and narcotics should be avoided in headache unless the patient is desperate. “As a headache specialist, I can tell you that I have not faced situations sufficiently desperate to use any of these. The American Headache Society in a series of evidence assessments has concluded similarly, that they are of no use,” said Dr. Gottschalk.
Opiates and barbiturates may also increase risk of migraine chronification. One study found that triptans are associated with low rates of chronification, at just a few percent when used fewer than 4 days a month, and about 20% per year when used 10-14 days per month. Opiate use showed a broadly similar pattern, while barbiturates showed a particularly alarming pattern: “Every level of use was associated with astronomically high rates and measurably higher at the highest level of use. For opiates, the odds ratio was about 2 – statistically significant. For barbiturates it was clearly greater than 2, whereas with triptans, the odds ratio showed a nonsignificant, slight increase in risk. And for NSAIDs, the odds ratio was, if anything, less than 1,” said Dr. Gottschalk.
He also discussed aspects of behavioral pharmacology, in which positive reinforcement associated with decreased headache may encourage repeated use of the drug. “Given these, it should be no surprise to anyone that emergency room treatment with opiates for acute migraine is clearly associated with increased recidivism for patients given those drugs,” said Dr. Gottschalk.
Opiate use is associated with increased pain sensitivity, and in the case of migraine, it may interfere with the activity of other treatments.
As for butalbital-containing compounds, they are positive-reinforcing drugs, and they are not indicated for migraine, only tension headache. There is no evidence of benefit in migraine, but butalbital is anxiolytic, which could lead an individual to increase its use.
A recent meta-analysis of therapies for episodic migraine found that hydromorphone and meperidine are less effective than standard therapies such as prochlorperazine or metoclopramide. Another study suggested that opioid use may interfere with the efficacy of NSAIDs in the emergency room environment, while a post hoc analysis of rizatriptan clinical trials found that recent opiate use was associated with a lower response rate, and the effect was more pronounced in women.
Among patients with chronic migraine, a 2004 study found that opiates were the most commonly used medication, and other studies found that chronic migraine does not arise in nonmigraine patients treated with opiates, “suggesting that migraine is specifically prone to opiate-induced hyperalgesia of migraine itself,” said Dr. Gottschalk.
Even under careful monitoring, misuse occurs in more than 50% of patients, “suggesting that even under the best circumstances, it is difficult to use this class of drugs safely in long term,” said Dr. Gottschalk.
He pointed out that the risk of drug addiction rises with various clinical and socioeconomic factors, including living in impoverished environments, adverse childhood experiences, low socioeconomic status, exposure to pollutants, and stressors. “In other words, all features associated with systemic racism are clearly associated with an increased risk of addiction,” said Dr. Gottschalk. Other factors include availability of the drug, such as whether or not a physician prescribes it, and repeated use.
These concerns, combined with positive-reinforcing properties of opiates and association with migraine progression and refractoriness, and the lack of progression risk found with use of NSAIDs and triptans, and the fact that effective acute therapy is associated with a lower risk of progression, argue against the use of opiates, said Dr. Gottschalk.
There is even a potential risk that the experience of migraine and its relief due to self-administration may become a rewarding experience that propagates the problem. It’s possible that anticipatory anxiety related to fear stressors could lead to migraine, or to physical sensations interpreted as migraine prodrome. “[It] raises the question of whether or not positive reinforcement by drugs makes migraine itself a rewarding experience and therefore more likely to occur as a cue for drug self-administration. The question I pose is: Is there any reason to test this theory in drugs of no proven benefit in the treatment of migraine? I would say very clearly, No,” said Dr. Gottschalk.
Clarifying the finer points of the debate
In the Q&A session after the talk, Dr. Rizzoli said that he doesn’t advocate for long-term use of opiates, except in rare cases where the diagnosis gets changed to a chronic pain syndrome. “We’re talking about intermittent use for treatment of an acute event. Do we put limits on them? I think the answer is clearly Yes, and the limits are more strict than those for triptans. My own sense as a clinician is I want all of the available tools. From a clinical perspective, there are a large number of people who do just fine with intermittent use of these medicines, and so I wouldn’t restrict them,” said Dr. Rizzoli.
Dr. Gottschalk agreed that opiates may make sense for some patients, but expressed concerns about any and all physicians prescribing them. “The part about the tools is partly a question of: Who gets to use them? In the hands of a headache specialist in those isolated cases with careful restrictions, sure. But what I’m making is a slippery slope argument: What we know is that in emergency rooms, these are used routinely, and that [those] patients are precisely the ones who are at higher risk of addiction. So in some sense, I’m just saying I think we need to have much clearer boundaries,” he said.
Dr. Rizzoli has no relevant financial disclosures. Dr. Gottschalk has been on the advisory boards of Alder, AbbVie, Amgen/Novartis, Biohaven, Theranica, Upsher-Smith, Axsome, Vorso, Currax, and Impel. He has been a consultant for Alder, Alexion, and Spherix Global Insights. He has received research support from Relivion.
Some believe that the medications, though risky, can be a useful tool in the neurologist’s treatment arsenal, while others argue that opioids are just too risky when there are other, safer alternatives available.
Those were the cruxes of arguments put forward by Paul Rizzoli, MD, and Christopher H. Gottschalk, MD, who conducted individual talks at the 2021 Scottsdale Headache Symposium. Dr. Rizzoli, associate professor of neurology at Harvard Medical School, Boston, argued in favor of the use of opioids and butalbital-containing medications. Dr. Gottschalk, assistant professor of neurology at Yale University, New Haven, Conn., argued against their use.
In certain situations opioids are worth the risk
Whether or not to use opioids in the treatment of headache is “a reasonable question, because these medications can clearly be seen as having risk. So perhaps another way to frame this question is as a risk-benefit issue. Are these medications worth the risk? How useful is the benefit of opioids, if the consequence is dependence or addiction?” Dr. Rizzoli began.
Although reviews show effectiveness of opioids in treating migraine, a three-part review in 2012 found greater efficacy of dihydroergotamine (DHE), ketorolac, and chlorpromazine. That’s not surprising, said Dr. Rizzoli, since those competing drugs are migraine-specific.
Dr. Rizzoli quoted a 2014 review indicating that there were incomplete data on the relative efficacy of opioids versus other analgesics, and for some patients opioids would likely be the optimal treatment, such as those who have contraindications to ergot-type medications or neuroleptic medications, pregnant women, or patients who don’t respond to other medications.
Dr. Rizzoli noted that The International Association for the Study of Pain has concluded that no other oral medications provide immediate and effective pain relief, and that short-term use rarely leads to addiction.
“So, to me, the answer is not to avoid opioids or outlaw them but instead to use them judiciously and infrequently, and in a short term or rescue fashion,” said Dr. Rizzoli.
He pointed out that physicians accept risks of other medications, and act to mitigate those risks. He said that risk mitigation with opioids can take the form of avoiding prescriptions in some situations, like when patients have a personal or family history of substance abuse, or in cases of some behavioral or emotional disorders.
Dr. Rizzoli went on to discuss the use of butalbital, which acts as a CNS depressant and has a variety of effects, including sedation, anxiolytic, hypnotic, and antiepileptic effects, but it is only a weak analgesic, but it nevertheless works in headache, said Dr. Rizzoli, citing patient reports and personal experience.
“It’s difficult to appreciate this theme of efficacy behind all the hype in the literature and in the press against butalbital, and the fact that it has not been adequately studied. But I would submit that the fact that we are even having this discussion is support enough for the use of butalbital. If butalbital either didn’t work or was simply a drug of abuse, it would likely have faded away by now,” said Dr. Rizzoli. He conceded that butalbital can be overused and may lead episodic headache to become chronic daily headache, but he noted that Seymour Solomon, MD, professor emeritus at Albert Einstein College of Medicine, New York, has estimated that removal of butalbital from the market would reduce chronic headache in the general population by only a small fraction of one percent.
Butalbital also has another interesting effect, which is that patients may quickly return to normal functioning after the headache resolves. “Maybe this is all due to management of anxiety, the presumed mechanism of action of barbiturates. So, instead of lobbying for its removal, I would propose that we should take a closer look at what’s going on here, and what the mechanism of action of this fairly interesting compound might be,” said Dr. Rizzoli.
Dr. Rizzoli also said there is some evidence that migraine-specific drugs also affect the tolerance to opioid drugs. “Somehow, they seem to interact with the opioid pain system. If that’s true, the implication is that you probably cannot escape the opioid receptors in the management of migraine,” said Dr. Rizzoli.
Ultimately, he supports the judicious use of opioids and butalbital containing-medications for headache relief. “My argument is that it is just too simplistic to cease use of these meds. Yes, they should be used in a restricted and careful way, but not abandoned,” said Dr. Rizzoli.
Opiates should be avoided
Following Dr. Rizzoli’s presentation, Dr. Gottschalk presented an argument against the use of opioids in the treatment of headache.
He began by quoting the ABIM Choosing Wisely Campaign of 2012, which concluded that fioricet and narcotics should be avoided in headache unless the patient is desperate. “As a headache specialist, I can tell you that I have not faced situations sufficiently desperate to use any of these. The American Headache Society in a series of evidence assessments has concluded similarly, that they are of no use,” said Dr. Gottschalk.
Opiates and barbiturates may also increase risk of migraine chronification. One study found that triptans are associated with low rates of chronification, at just a few percent when used fewer than 4 days a month, and about 20% per year when used 10-14 days per month. Opiate use showed a broadly similar pattern, while barbiturates showed a particularly alarming pattern: “Every level of use was associated with astronomically high rates and measurably higher at the highest level of use. For opiates, the odds ratio was about 2 – statistically significant. For barbiturates it was clearly greater than 2, whereas with triptans, the odds ratio showed a nonsignificant, slight increase in risk. And for NSAIDs, the odds ratio was, if anything, less than 1,” said Dr. Gottschalk.
He also discussed aspects of behavioral pharmacology, in which positive reinforcement associated with decreased headache may encourage repeated use of the drug. “Given these, it should be no surprise to anyone that emergency room treatment with opiates for acute migraine is clearly associated with increased recidivism for patients given those drugs,” said Dr. Gottschalk.
Opiate use is associated with increased pain sensitivity, and in the case of migraine, it may interfere with the activity of other treatments.
As for butalbital-containing compounds, they are positive-reinforcing drugs, and they are not indicated for migraine, only tension headache. There is no evidence of benefit in migraine, but butalbital is anxiolytic, which could lead an individual to increase its use.
A recent meta-analysis of therapies for episodic migraine found that hydromorphone and meperidine are less effective than standard therapies such as prochlorperazine or metoclopramide. Another study suggested that opioid use may interfere with the efficacy of NSAIDs in the emergency room environment, while a post hoc analysis of rizatriptan clinical trials found that recent opiate use was associated with a lower response rate, and the effect was more pronounced in women.
Among patients with chronic migraine, a 2004 study found that opiates were the most commonly used medication, and other studies found that chronic migraine does not arise in nonmigraine patients treated with opiates, “suggesting that migraine is specifically prone to opiate-induced hyperalgesia of migraine itself,” said Dr. Gottschalk.
Even under careful monitoring, misuse occurs in more than 50% of patients, “suggesting that even under the best circumstances, it is difficult to use this class of drugs safely in long term,” said Dr. Gottschalk.
He pointed out that the risk of drug addiction rises with various clinical and socioeconomic factors, including living in impoverished environments, adverse childhood experiences, low socioeconomic status, exposure to pollutants, and stressors. “In other words, all features associated with systemic racism are clearly associated with an increased risk of addiction,” said Dr. Gottschalk. Other factors include availability of the drug, such as whether or not a physician prescribes it, and repeated use.
These concerns, combined with positive-reinforcing properties of opiates and association with migraine progression and refractoriness, and the lack of progression risk found with use of NSAIDs and triptans, and the fact that effective acute therapy is associated with a lower risk of progression, argue against the use of opiates, said Dr. Gottschalk.
There is even a potential risk that the experience of migraine and its relief due to self-administration may become a rewarding experience that propagates the problem. It’s possible that anticipatory anxiety related to fear stressors could lead to migraine, or to physical sensations interpreted as migraine prodrome. “[It] raises the question of whether or not positive reinforcement by drugs makes migraine itself a rewarding experience and therefore more likely to occur as a cue for drug self-administration. The question I pose is: Is there any reason to test this theory in drugs of no proven benefit in the treatment of migraine? I would say very clearly, No,” said Dr. Gottschalk.
Clarifying the finer points of the debate
In the Q&A session after the talk, Dr. Rizzoli said that he doesn’t advocate for long-term use of opiates, except in rare cases where the diagnosis gets changed to a chronic pain syndrome. “We’re talking about intermittent use for treatment of an acute event. Do we put limits on them? I think the answer is clearly Yes, and the limits are more strict than those for triptans. My own sense as a clinician is I want all of the available tools. From a clinical perspective, there are a large number of people who do just fine with intermittent use of these medicines, and so I wouldn’t restrict them,” said Dr. Rizzoli.
Dr. Gottschalk agreed that opiates may make sense for some patients, but expressed concerns about any and all physicians prescribing them. “The part about the tools is partly a question of: Who gets to use them? In the hands of a headache specialist in those isolated cases with careful restrictions, sure. But what I’m making is a slippery slope argument: What we know is that in emergency rooms, these are used routinely, and that [those] patients are precisely the ones who are at higher risk of addiction. So in some sense, I’m just saying I think we need to have much clearer boundaries,” he said.
Dr. Rizzoli has no relevant financial disclosures. Dr. Gottschalk has been on the advisory boards of Alder, AbbVie, Amgen/Novartis, Biohaven, Theranica, Upsher-Smith, Axsome, Vorso, Currax, and Impel. He has been a consultant for Alder, Alexion, and Spherix Global Insights. He has received research support from Relivion.
FROM 2021 SCOTTSDALE HEADACHE SYMPOSIUM
Visual snow: Alarming and not uncommon
“This is a symptom of vision where patients describe numerous flickering dots throughout their vision. Sometimes they’ll use the term grainy or pixelated vision. Many times there’s a dynamic moving component to this. Many patients will describe this as like a TV static overlay on their vision,” Carrie Robertson, MD, said during a presentation on the topic at the 2021 Scottsdale Headache Symposium. Dr. Robertson is a neurologist at the Mayo Clinic in Rochester, Minn.
“It turns out that a little over 3% of us probably see this in our vision. So even if you haven’t seen this in the clinic yet, it’s likely that you will in the future,” said Dr. Robertson.
The first report describing visual snow appeared in 1995, among migraine patients. As of 2014 there were only 10 cases described in the literature. Although the condition was initially thought of as an unusual feature of migraine, a 2014 combined chart review and survey found that 15 of 22 patients had additional visual symptoms, such as photophobia or difficulty with night vision. Twenty of the 22 patients had comorbid migraine. Other symptoms include visual ghosts that persist after looking away from an object, as well as a higher frequency of experiencing floaters.
Symptoms aren’t restricted to the visual domain. Migraine, tinnitus, dizziness, and impaired concentration also occur.
The condition is more common than many suspect. “We used to think it was very rare. Now we assume that this was just under recognized,” said Dr. Robertson. One survey in the United Kingdom found that 3.7% of respondents reported visual snow, and 2.2% met the criteria for the syndrome.
A common and typically benign problem
It is a common clinical problem, according to Andrew Charles, MD, professor of neurology at the University of California, Los Angeles, and director of the UCLA Goldberg Migraine Program. “Almost every week I personally see somebody and then in our group, we have a whole host of them,” he said.
“When you see these patients in clinic, it’s important to remember that this is a heterogeneous disorder,” said Dr. Robertson. “Some patients will say, ‘Oh yeah, I’ve seen visual snow for as long as I can remember, I didn’t even know it was abnormal.’ Some will describe a family history of visual snow. Others will show up in clinic panicked because their visual snow just started or sometimes it’ll start after a triggering events like a head injury or hallucinogen use, and they’re worried that they’re going to go blind.”
It’s important to rule out other potential causes. Dr. Robertson’s group examined 248 cases of visual snow and found that 89 had a comorbidity that explained the condition. Issues within the retina, cornea, and the optical nerve can cause visual snow, which makes it critical that patients be seen by an ophthalmologist.
Some patients reported improvement when they stopped a new medication. “I always ask if there was a specific medicine that they started at the onset of their symptoms,” said Dr. Robertson. Other rare conditions associated with visual snow include idiopathic intracranial hypertension, posterior cortical atrophy, and even the Heidenhain variant of Creutzfeldt-Jakob disease.
In the absence of a secondary cause, and the if condition doesn’t worsen, physicians should reassure patients that the condition is typically benign. “Many of these patients are panicked that they’re going to lose their vision, and that’s what brings them to your office. It’s important to stress that visual snow is real, that you believe them, that they’re seeing what they say that they’re seeing. It’s not a migraine aura, but it’s typically benign. I like to give the analogy that it’s similar to tinnitus because I think that that’s helpful for patients to put it in that category of benign but very annoying,” said Dr. Robertson.
Limited treatment options
Unfortunately, there is little evidence on medications to treat the problem. According to Dr. Robertson, the best available evidence – from case reports – is for lamotrigine. Nearly 20% of patients achieve a partial response, and complete responses are rare.
Clinical trials are a possibility, but patients should be made aware that medications have the potential to worsen visual snow.
Nonpharmaceutical approaches include visual and mental distraction, along with manipulation of lighting at work and at home. Stress reduction may help, and Dr. Robertson may send patients with dizziness for visual vestibular therapy to work on visual motion desensitization exercises.
There are visual snow relief videos available on YouTube, which may provide temporary relief. “It’s probably similar to white noise therapy for tinnitus,” said Dr. Robertson.
Colored glass lenses may be helpful. “I’m having the best success at this point with FL-41 lenses. Some prefer amber, and others prefer the rose-tinted, just like migraine. I usually start with that,” said Dr. Robertson. Yellow lenses may help with nyctalopia.
She recommends that patients avoid consuming too much caffeine, and that they avoid stimulants, especially attention-deficit disorder (ADD) medications. “I’ve had a lot of patients worsen with ADD medication,” said Dr. Robertson. She also warns patients away from marijuana and hallucinogens.
There is a large community available for patients with visual snow, including more than 60 Facebook groups, and many YouTube videos of patients describing their experiences. There is even a visual snow simulator that neurologists can show patients to confirm what they are seeing. “It’s very validating for the patient,” said Dr. Robertson.
Dr. Charles noted the relatively few treatment options and poor understanding of the mechanisms behind the condition. “It’s incredibly frustrating that we have to tell them that we have so little understanding of basic mechanisms, and no really clear therapeutic strategy that we can apply across all patients and expect results,” said Dr. Charles.
The heightened interest in the condition does represent some hope. “It’s very much reassuring to people that, number one, we’re starting to understand it – but number two, that they’re not crazy. It’s very much validating to hear that it’s now a topic of much more rigorous investigation,” said Dr. Charles.
Dr. Robertson and Dr. Charles have no relevant financial disclosures.
“This is a symptom of vision where patients describe numerous flickering dots throughout their vision. Sometimes they’ll use the term grainy or pixelated vision. Many times there’s a dynamic moving component to this. Many patients will describe this as like a TV static overlay on their vision,” Carrie Robertson, MD, said during a presentation on the topic at the 2021 Scottsdale Headache Symposium. Dr. Robertson is a neurologist at the Mayo Clinic in Rochester, Minn.
“It turns out that a little over 3% of us probably see this in our vision. So even if you haven’t seen this in the clinic yet, it’s likely that you will in the future,” said Dr. Robertson.
The first report describing visual snow appeared in 1995, among migraine patients. As of 2014 there were only 10 cases described in the literature. Although the condition was initially thought of as an unusual feature of migraine, a 2014 combined chart review and survey found that 15 of 22 patients had additional visual symptoms, such as photophobia or difficulty with night vision. Twenty of the 22 patients had comorbid migraine. Other symptoms include visual ghosts that persist after looking away from an object, as well as a higher frequency of experiencing floaters.
Symptoms aren’t restricted to the visual domain. Migraine, tinnitus, dizziness, and impaired concentration also occur.
The condition is more common than many suspect. “We used to think it was very rare. Now we assume that this was just under recognized,” said Dr. Robertson. One survey in the United Kingdom found that 3.7% of respondents reported visual snow, and 2.2% met the criteria for the syndrome.
A common and typically benign problem
It is a common clinical problem, according to Andrew Charles, MD, professor of neurology at the University of California, Los Angeles, and director of the UCLA Goldberg Migraine Program. “Almost every week I personally see somebody and then in our group, we have a whole host of them,” he said.
“When you see these patients in clinic, it’s important to remember that this is a heterogeneous disorder,” said Dr. Robertson. “Some patients will say, ‘Oh yeah, I’ve seen visual snow for as long as I can remember, I didn’t even know it was abnormal.’ Some will describe a family history of visual snow. Others will show up in clinic panicked because their visual snow just started or sometimes it’ll start after a triggering events like a head injury or hallucinogen use, and they’re worried that they’re going to go blind.”
It’s important to rule out other potential causes. Dr. Robertson’s group examined 248 cases of visual snow and found that 89 had a comorbidity that explained the condition. Issues within the retina, cornea, and the optical nerve can cause visual snow, which makes it critical that patients be seen by an ophthalmologist.
Some patients reported improvement when they stopped a new medication. “I always ask if there was a specific medicine that they started at the onset of their symptoms,” said Dr. Robertson. Other rare conditions associated with visual snow include idiopathic intracranial hypertension, posterior cortical atrophy, and even the Heidenhain variant of Creutzfeldt-Jakob disease.
In the absence of a secondary cause, and the if condition doesn’t worsen, physicians should reassure patients that the condition is typically benign. “Many of these patients are panicked that they’re going to lose their vision, and that’s what brings them to your office. It’s important to stress that visual snow is real, that you believe them, that they’re seeing what they say that they’re seeing. It’s not a migraine aura, but it’s typically benign. I like to give the analogy that it’s similar to tinnitus because I think that that’s helpful for patients to put it in that category of benign but very annoying,” said Dr. Robertson.
Limited treatment options
Unfortunately, there is little evidence on medications to treat the problem. According to Dr. Robertson, the best available evidence – from case reports – is for lamotrigine. Nearly 20% of patients achieve a partial response, and complete responses are rare.
Clinical trials are a possibility, but patients should be made aware that medications have the potential to worsen visual snow.
Nonpharmaceutical approaches include visual and mental distraction, along with manipulation of lighting at work and at home. Stress reduction may help, and Dr. Robertson may send patients with dizziness for visual vestibular therapy to work on visual motion desensitization exercises.
There are visual snow relief videos available on YouTube, which may provide temporary relief. “It’s probably similar to white noise therapy for tinnitus,” said Dr. Robertson.
Colored glass lenses may be helpful. “I’m having the best success at this point with FL-41 lenses. Some prefer amber, and others prefer the rose-tinted, just like migraine. I usually start with that,” said Dr. Robertson. Yellow lenses may help with nyctalopia.
She recommends that patients avoid consuming too much caffeine, and that they avoid stimulants, especially attention-deficit disorder (ADD) medications. “I’ve had a lot of patients worsen with ADD medication,” said Dr. Robertson. She also warns patients away from marijuana and hallucinogens.
There is a large community available for patients with visual snow, including more than 60 Facebook groups, and many YouTube videos of patients describing their experiences. There is even a visual snow simulator that neurologists can show patients to confirm what they are seeing. “It’s very validating for the patient,” said Dr. Robertson.
Dr. Charles noted the relatively few treatment options and poor understanding of the mechanisms behind the condition. “It’s incredibly frustrating that we have to tell them that we have so little understanding of basic mechanisms, and no really clear therapeutic strategy that we can apply across all patients and expect results,” said Dr. Charles.
The heightened interest in the condition does represent some hope. “It’s very much reassuring to people that, number one, we’re starting to understand it – but number two, that they’re not crazy. It’s very much validating to hear that it’s now a topic of much more rigorous investigation,” said Dr. Charles.
Dr. Robertson and Dr. Charles have no relevant financial disclosures.
“This is a symptom of vision where patients describe numerous flickering dots throughout their vision. Sometimes they’ll use the term grainy or pixelated vision. Many times there’s a dynamic moving component to this. Many patients will describe this as like a TV static overlay on their vision,” Carrie Robertson, MD, said during a presentation on the topic at the 2021 Scottsdale Headache Symposium. Dr. Robertson is a neurologist at the Mayo Clinic in Rochester, Minn.
“It turns out that a little over 3% of us probably see this in our vision. So even if you haven’t seen this in the clinic yet, it’s likely that you will in the future,” said Dr. Robertson.
The first report describing visual snow appeared in 1995, among migraine patients. As of 2014 there were only 10 cases described in the literature. Although the condition was initially thought of as an unusual feature of migraine, a 2014 combined chart review and survey found that 15 of 22 patients had additional visual symptoms, such as photophobia or difficulty with night vision. Twenty of the 22 patients had comorbid migraine. Other symptoms include visual ghosts that persist after looking away from an object, as well as a higher frequency of experiencing floaters.
Symptoms aren’t restricted to the visual domain. Migraine, tinnitus, dizziness, and impaired concentration also occur.
The condition is more common than many suspect. “We used to think it was very rare. Now we assume that this was just under recognized,” said Dr. Robertson. One survey in the United Kingdom found that 3.7% of respondents reported visual snow, and 2.2% met the criteria for the syndrome.
A common and typically benign problem
It is a common clinical problem, according to Andrew Charles, MD, professor of neurology at the University of California, Los Angeles, and director of the UCLA Goldberg Migraine Program. “Almost every week I personally see somebody and then in our group, we have a whole host of them,” he said.
“When you see these patients in clinic, it’s important to remember that this is a heterogeneous disorder,” said Dr. Robertson. “Some patients will say, ‘Oh yeah, I’ve seen visual snow for as long as I can remember, I didn’t even know it was abnormal.’ Some will describe a family history of visual snow. Others will show up in clinic panicked because their visual snow just started or sometimes it’ll start after a triggering events like a head injury or hallucinogen use, and they’re worried that they’re going to go blind.”
It’s important to rule out other potential causes. Dr. Robertson’s group examined 248 cases of visual snow and found that 89 had a comorbidity that explained the condition. Issues within the retina, cornea, and the optical nerve can cause visual snow, which makes it critical that patients be seen by an ophthalmologist.
Some patients reported improvement when they stopped a new medication. “I always ask if there was a specific medicine that they started at the onset of their symptoms,” said Dr. Robertson. Other rare conditions associated with visual snow include idiopathic intracranial hypertension, posterior cortical atrophy, and even the Heidenhain variant of Creutzfeldt-Jakob disease.
In the absence of a secondary cause, and the if condition doesn’t worsen, physicians should reassure patients that the condition is typically benign. “Many of these patients are panicked that they’re going to lose their vision, and that’s what brings them to your office. It’s important to stress that visual snow is real, that you believe them, that they’re seeing what they say that they’re seeing. It’s not a migraine aura, but it’s typically benign. I like to give the analogy that it’s similar to tinnitus because I think that that’s helpful for patients to put it in that category of benign but very annoying,” said Dr. Robertson.
Limited treatment options
Unfortunately, there is little evidence on medications to treat the problem. According to Dr. Robertson, the best available evidence – from case reports – is for lamotrigine. Nearly 20% of patients achieve a partial response, and complete responses are rare.
Clinical trials are a possibility, but patients should be made aware that medications have the potential to worsen visual snow.
Nonpharmaceutical approaches include visual and mental distraction, along with manipulation of lighting at work and at home. Stress reduction may help, and Dr. Robertson may send patients with dizziness for visual vestibular therapy to work on visual motion desensitization exercises.
There are visual snow relief videos available on YouTube, which may provide temporary relief. “It’s probably similar to white noise therapy for tinnitus,” said Dr. Robertson.
Colored glass lenses may be helpful. “I’m having the best success at this point with FL-41 lenses. Some prefer amber, and others prefer the rose-tinted, just like migraine. I usually start with that,” said Dr. Robertson. Yellow lenses may help with nyctalopia.
She recommends that patients avoid consuming too much caffeine, and that they avoid stimulants, especially attention-deficit disorder (ADD) medications. “I’ve had a lot of patients worsen with ADD medication,” said Dr. Robertson. She also warns patients away from marijuana and hallucinogens.
There is a large community available for patients with visual snow, including more than 60 Facebook groups, and many YouTube videos of patients describing their experiences. There is even a visual snow simulator that neurologists can show patients to confirm what they are seeing. “It’s very validating for the patient,” said Dr. Robertson.
Dr. Charles noted the relatively few treatment options and poor understanding of the mechanisms behind the condition. “It’s incredibly frustrating that we have to tell them that we have so little understanding of basic mechanisms, and no really clear therapeutic strategy that we can apply across all patients and expect results,” said Dr. Charles.
The heightened interest in the condition does represent some hope. “It’s very much reassuring to people that, number one, we’re starting to understand it – but number two, that they’re not crazy. It’s very much validating to hear that it’s now a topic of much more rigorous investigation,” said Dr. Charles.
Dr. Robertson and Dr. Charles have no relevant financial disclosures.
FROM 2021 SCOTTSDALE HEADACHE SYMPOSIUM
Headache is a common post–COVID-19 complaint
The Centers for Disease Control and Prevention has identified it as a sentinel symptom of COVID-19 disease. “A lot of the recommendations surrounding post-COVID headache is that if you identify a patient who has headaches associated with fever, and myalgia, and other systemic symptoms, the specificity of a COVID-19 diagnosis goes up. So [COVID-19] is a really important feature to look out for in patients with headache,” Deena Kuruvilla, MD, said during a presentation on post–COVID-19 headache at the 2021 Scottsdale Headache Symposium.
Estimates of the prevalence of headache in COVID-19 range widely, from 6.5% to 71%, but Dr. Kuruvilla has plenty of personal experience with it. “During my stint on the inpatient neurology service during the peak of COVID, I saw patients with headache being one of the most frequent complaints, [along with] dizziness, stroke, and seizure among many other neurological manifestations,” said Dr. Kuruvilla, director of the Westport (Conn.) Headache Institute.
One meta-analysis showed that 47% of patients with COVID-19 complain of headache within 30 days of diagnosis, and this drops to around 10% at 60-90 days, and around 8% at 180 days.
A survey of 3,458 patients, published in the Journal of Headache Pain, found that migraine is the most common type of post–COVID-19 headache phenotype, and patients reporting anosmia-ageusia were more likely to have post–COVID-19 headache (odds ratio [OR], 5.39; 95% confidence interval, 1.66-17.45).
A case-control study of post–COVID-19 headache patients with and without a history of migraine found that those with a history of migraine were more likely to have post–COVID-19 symptoms (OR, 1.70; P < .001) and fatigue (OR, 2.89; P = .008). “Interestingly, they found no difference in headache as post-COVID symptoms in people who had a history of migraine compared with people without a history of migraine,” said Dr. Kuruvilla.
Headache and COVID-19: What is the connection?
Several mechanisms have been proposed for direct invasion of the central nervous system, either via infection through the angiotensin-converting enzyme 2 (ACE-2) receptor, which is expressed in brain regions including the motor cortex, the posterior cingulate cortex, and the olfactory bulb, among other locations. Another potential mechanism is direct entry through the olfactory nerve and the associated olfactory epithelium. There are various potential mechanisms for spread among the peripheral nervous system, and the blood-brain barrier can be compromised by infection of vascular endothelial cells. According to the literature, neuronal damage seems to occur directly from viral damage rather than from the immune response, said Dr. Kuruvilla.
The virus may also gain entry to the CNS indirectly, as a result of hypoxia and metabolic disturbances, as well as dehydration and systematic inflammation. The cytokine storm associated with COVID-19 infection can activate C-reactive protein and calcitonin gene-related peptide (CGRP), which plays a key role in migraine pathology. The CGRP receptor antagonist vazegepant is being studied in a phase 2 clinical trial for the treatment of COVID-19–related lung inflammation.
Testing and treatment
“If I see patients with new headache, worsening headache from their baseline, or headache with systemic symptoms, I often consider screening them for COVID. If that screening is positive, I proceed with PCR testing. I also consider an MRI of the brain with and without gadolinium just to rule out any secondary causes for headache,” said Dr. Kuruvilla, noting that she has diagnosed patients with venous sinus thrombosis, ischemic stroke, and meningitis following COVID-19.
The existing literature suggests that lumbar puncture in patients with SARS-CoV-2 typically returns normal results, but Dr. Kuruvilla proceeds with it anyway with viral, bacterial, fungal, and autoimmune studies to rule out potential secondary causes for headache.
There are few studies on how to treat post–COVID-19 headache, and the general recommendation is that headache phenotype should drive treatment decisions.
In a case series, three patients with persistent headache following mild COVID-19 infection were treated with onabotulinumtoxinA and amitriptyline. They had daily headaches, along with post–COVID-19 symptoms including fatigue and insomnia. After treatment, each patient converted to episodic headaches.
One retrospective study of 37 patients found that a 5-day course of indomethacin 50 mg twice per day and pantoprazole 40 mg once per day was associated with a 50% or greater improvement in headache on the third day in 36 of the 37 patients. Five patients were free of pain by day 5.
A common problem
Neurologists have been involved in the treatment of COVID-19 since the beginning, and post–COVID-19 headache has added another layer. “It’s been a remarkably common clinical problem. And the fact that it’s actually reached the level of headache specialist actually shows that in some cases, it’s really quite a significant problem, in both its severity and persistence. So I think it’s a very, very significant issue,” said Andrew Charles, MD, professor of neurology at the University of California, Los Angeles, and director of the UCLA Goldberg Migraine Program.
Dr. Kuruvilla also discussed the question of whether neurological damage is due to direct damage from the virus, or indirect damage from an immune response. This was debated during the Q&A session following Dr. Kuruvilla’s talk, and it was pointed out that headache is a frequent side effect of the Pfizer and Moderna vaccines.
“It’s a huge open question about how much is direct invasion or damage or not even damage, but just change in function with the viral infection, as opposed to inflammation. The fact that very often the response to the vaccine is similar to what you see with COVID suggests that at least some component of it is inflammation. I wouldn’t commit to one mechanism or the other, but I’d say that it’s possible that it’s really both,” said Dr. Charles.
Dr. Kuruvilla has consulted for Cefaly, Neurolief, Theranica, Now What Media, and KX advisors. She has been on the speakers bureau for Abbvie/Allergan, Amgen/Novartis, and Lilly. She has been on advisory boards for Abbvie/Allergan, Lilly, Theranica, and Amgen/Novartis. Dr. Charles has no relevant financial disclosures.
The Centers for Disease Control and Prevention has identified it as a sentinel symptom of COVID-19 disease. “A lot of the recommendations surrounding post-COVID headache is that if you identify a patient who has headaches associated with fever, and myalgia, and other systemic symptoms, the specificity of a COVID-19 diagnosis goes up. So [COVID-19] is a really important feature to look out for in patients with headache,” Deena Kuruvilla, MD, said during a presentation on post–COVID-19 headache at the 2021 Scottsdale Headache Symposium.
Estimates of the prevalence of headache in COVID-19 range widely, from 6.5% to 71%, but Dr. Kuruvilla has plenty of personal experience with it. “During my stint on the inpatient neurology service during the peak of COVID, I saw patients with headache being one of the most frequent complaints, [along with] dizziness, stroke, and seizure among many other neurological manifestations,” said Dr. Kuruvilla, director of the Westport (Conn.) Headache Institute.
One meta-analysis showed that 47% of patients with COVID-19 complain of headache within 30 days of diagnosis, and this drops to around 10% at 60-90 days, and around 8% at 180 days.
A survey of 3,458 patients, published in the Journal of Headache Pain, found that migraine is the most common type of post–COVID-19 headache phenotype, and patients reporting anosmia-ageusia were more likely to have post–COVID-19 headache (odds ratio [OR], 5.39; 95% confidence interval, 1.66-17.45).
A case-control study of post–COVID-19 headache patients with and without a history of migraine found that those with a history of migraine were more likely to have post–COVID-19 symptoms (OR, 1.70; P < .001) and fatigue (OR, 2.89; P = .008). “Interestingly, they found no difference in headache as post-COVID symptoms in people who had a history of migraine compared with people without a history of migraine,” said Dr. Kuruvilla.
Headache and COVID-19: What is the connection?
Several mechanisms have been proposed for direct invasion of the central nervous system, either via infection through the angiotensin-converting enzyme 2 (ACE-2) receptor, which is expressed in brain regions including the motor cortex, the posterior cingulate cortex, and the olfactory bulb, among other locations. Another potential mechanism is direct entry through the olfactory nerve and the associated olfactory epithelium. There are various potential mechanisms for spread among the peripheral nervous system, and the blood-brain barrier can be compromised by infection of vascular endothelial cells. According to the literature, neuronal damage seems to occur directly from viral damage rather than from the immune response, said Dr. Kuruvilla.
The virus may also gain entry to the CNS indirectly, as a result of hypoxia and metabolic disturbances, as well as dehydration and systematic inflammation. The cytokine storm associated with COVID-19 infection can activate C-reactive protein and calcitonin gene-related peptide (CGRP), which plays a key role in migraine pathology. The CGRP receptor antagonist vazegepant is being studied in a phase 2 clinical trial for the treatment of COVID-19–related lung inflammation.
Testing and treatment
“If I see patients with new headache, worsening headache from their baseline, or headache with systemic symptoms, I often consider screening them for COVID. If that screening is positive, I proceed with PCR testing. I also consider an MRI of the brain with and without gadolinium just to rule out any secondary causes for headache,” said Dr. Kuruvilla, noting that she has diagnosed patients with venous sinus thrombosis, ischemic stroke, and meningitis following COVID-19.
The existing literature suggests that lumbar puncture in patients with SARS-CoV-2 typically returns normal results, but Dr. Kuruvilla proceeds with it anyway with viral, bacterial, fungal, and autoimmune studies to rule out potential secondary causes for headache.
There are few studies on how to treat post–COVID-19 headache, and the general recommendation is that headache phenotype should drive treatment decisions.
In a case series, three patients with persistent headache following mild COVID-19 infection were treated with onabotulinumtoxinA and amitriptyline. They had daily headaches, along with post–COVID-19 symptoms including fatigue and insomnia. After treatment, each patient converted to episodic headaches.
One retrospective study of 37 patients found that a 5-day course of indomethacin 50 mg twice per day and pantoprazole 40 mg once per day was associated with a 50% or greater improvement in headache on the third day in 36 of the 37 patients. Five patients were free of pain by day 5.
A common problem
Neurologists have been involved in the treatment of COVID-19 since the beginning, and post–COVID-19 headache has added another layer. “It’s been a remarkably common clinical problem. And the fact that it’s actually reached the level of headache specialist actually shows that in some cases, it’s really quite a significant problem, in both its severity and persistence. So I think it’s a very, very significant issue,” said Andrew Charles, MD, professor of neurology at the University of California, Los Angeles, and director of the UCLA Goldberg Migraine Program.
Dr. Kuruvilla also discussed the question of whether neurological damage is due to direct damage from the virus, or indirect damage from an immune response. This was debated during the Q&A session following Dr. Kuruvilla’s talk, and it was pointed out that headache is a frequent side effect of the Pfizer and Moderna vaccines.
“It’s a huge open question about how much is direct invasion or damage or not even damage, but just change in function with the viral infection, as opposed to inflammation. The fact that very often the response to the vaccine is similar to what you see with COVID suggests that at least some component of it is inflammation. I wouldn’t commit to one mechanism or the other, but I’d say that it’s possible that it’s really both,” said Dr. Charles.
Dr. Kuruvilla has consulted for Cefaly, Neurolief, Theranica, Now What Media, and KX advisors. She has been on the speakers bureau for Abbvie/Allergan, Amgen/Novartis, and Lilly. She has been on advisory boards for Abbvie/Allergan, Lilly, Theranica, and Amgen/Novartis. Dr. Charles has no relevant financial disclosures.
The Centers for Disease Control and Prevention has identified it as a sentinel symptom of COVID-19 disease. “A lot of the recommendations surrounding post-COVID headache is that if you identify a patient who has headaches associated with fever, and myalgia, and other systemic symptoms, the specificity of a COVID-19 diagnosis goes up. So [COVID-19] is a really important feature to look out for in patients with headache,” Deena Kuruvilla, MD, said during a presentation on post–COVID-19 headache at the 2021 Scottsdale Headache Symposium.
Estimates of the prevalence of headache in COVID-19 range widely, from 6.5% to 71%, but Dr. Kuruvilla has plenty of personal experience with it. “During my stint on the inpatient neurology service during the peak of COVID, I saw patients with headache being one of the most frequent complaints, [along with] dizziness, stroke, and seizure among many other neurological manifestations,” said Dr. Kuruvilla, director of the Westport (Conn.) Headache Institute.
One meta-analysis showed that 47% of patients with COVID-19 complain of headache within 30 days of diagnosis, and this drops to around 10% at 60-90 days, and around 8% at 180 days.
A survey of 3,458 patients, published in the Journal of Headache Pain, found that migraine is the most common type of post–COVID-19 headache phenotype, and patients reporting anosmia-ageusia were more likely to have post–COVID-19 headache (odds ratio [OR], 5.39; 95% confidence interval, 1.66-17.45).
A case-control study of post–COVID-19 headache patients with and without a history of migraine found that those with a history of migraine were more likely to have post–COVID-19 symptoms (OR, 1.70; P < .001) and fatigue (OR, 2.89; P = .008). “Interestingly, they found no difference in headache as post-COVID symptoms in people who had a history of migraine compared with people without a history of migraine,” said Dr. Kuruvilla.
Headache and COVID-19: What is the connection?
Several mechanisms have been proposed for direct invasion of the central nervous system, either via infection through the angiotensin-converting enzyme 2 (ACE-2) receptor, which is expressed in brain regions including the motor cortex, the posterior cingulate cortex, and the olfactory bulb, among other locations. Another potential mechanism is direct entry through the olfactory nerve and the associated olfactory epithelium. There are various potential mechanisms for spread among the peripheral nervous system, and the blood-brain barrier can be compromised by infection of vascular endothelial cells. According to the literature, neuronal damage seems to occur directly from viral damage rather than from the immune response, said Dr. Kuruvilla.
The virus may also gain entry to the CNS indirectly, as a result of hypoxia and metabolic disturbances, as well as dehydration and systematic inflammation. The cytokine storm associated with COVID-19 infection can activate C-reactive protein and calcitonin gene-related peptide (CGRP), which plays a key role in migraine pathology. The CGRP receptor antagonist vazegepant is being studied in a phase 2 clinical trial for the treatment of COVID-19–related lung inflammation.
Testing and treatment
“If I see patients with new headache, worsening headache from their baseline, or headache with systemic symptoms, I often consider screening them for COVID. If that screening is positive, I proceed with PCR testing. I also consider an MRI of the brain with and without gadolinium just to rule out any secondary causes for headache,” said Dr. Kuruvilla, noting that she has diagnosed patients with venous sinus thrombosis, ischemic stroke, and meningitis following COVID-19.
The existing literature suggests that lumbar puncture in patients with SARS-CoV-2 typically returns normal results, but Dr. Kuruvilla proceeds with it anyway with viral, bacterial, fungal, and autoimmune studies to rule out potential secondary causes for headache.
There are few studies on how to treat post–COVID-19 headache, and the general recommendation is that headache phenotype should drive treatment decisions.
In a case series, three patients with persistent headache following mild COVID-19 infection were treated with onabotulinumtoxinA and amitriptyline. They had daily headaches, along with post–COVID-19 symptoms including fatigue and insomnia. After treatment, each patient converted to episodic headaches.
One retrospective study of 37 patients found that a 5-day course of indomethacin 50 mg twice per day and pantoprazole 40 mg once per day was associated with a 50% or greater improvement in headache on the third day in 36 of the 37 patients. Five patients were free of pain by day 5.
A common problem
Neurologists have been involved in the treatment of COVID-19 since the beginning, and post–COVID-19 headache has added another layer. “It’s been a remarkably common clinical problem. And the fact that it’s actually reached the level of headache specialist actually shows that in some cases, it’s really quite a significant problem, in both its severity and persistence. So I think it’s a very, very significant issue,” said Andrew Charles, MD, professor of neurology at the University of California, Los Angeles, and director of the UCLA Goldberg Migraine Program.
Dr. Kuruvilla also discussed the question of whether neurological damage is due to direct damage from the virus, or indirect damage from an immune response. This was debated during the Q&A session following Dr. Kuruvilla’s talk, and it was pointed out that headache is a frequent side effect of the Pfizer and Moderna vaccines.
“It’s a huge open question about how much is direct invasion or damage or not even damage, but just change in function with the viral infection, as opposed to inflammation. The fact that very often the response to the vaccine is similar to what you see with COVID suggests that at least some component of it is inflammation. I wouldn’t commit to one mechanism or the other, but I’d say that it’s possible that it’s really both,” said Dr. Charles.
Dr. Kuruvilla has consulted for Cefaly, Neurolief, Theranica, Now What Media, and KX advisors. She has been on the speakers bureau for Abbvie/Allergan, Amgen/Novartis, and Lilly. She has been on advisory boards for Abbvie/Allergan, Lilly, Theranica, and Amgen/Novartis. Dr. Charles has no relevant financial disclosures.
FROM 2021 SCOTTSDALE HEADACHE SYMPOSIUM