Migraine ICYMI

Key clinical point: Consistent with the overall study population results, eptinezumab therapy demonstrated favorable efficacy and safety in patients with episodic migraine (EM) or chronic migraine (CM) and self-reported aura from the PROMISE studies.

Major finding: Over weeks 1-12, monthly migraine days decreased with 100 mg and 300 mg eptinezumab vs. placebo in patients with EM (100 mg, −3.9 days; 300 mg, −4.2 days vs. −3.3 days) and CM (100 mg, −7.1 days; 300 mg, −7.6 days vs. −5.9 days) with aura. Treatment-emergent adverse event rates were similar across treatment groups.

Study details: Of 1741 patients with EM/CM from the PROMISE-1 and PROMISE-2 trials, this post hoc analysis included 877 patients who self-reported migraine with aura at screening and received eptinezumab (n = 583) or placebo (n = 294).

Disclosures: Lundbeck Seattle BioPharmaceuticals, Inc., USA, funded the study. Some authors declared serving as consultants, speakers, advisors, or as a primary trial investigator for and receiving personal fees and research support from various sources, including Lundbeck. Some authors are current or former employees of Lundbeck or its subsidiary company.

Source: Ashina M et al. Efficacy and safety of eptinezumab in patients with migraine and self-reported aura: Post hoc analysis of PROMISE-1 and PROMISE-2. Cephalalgia. 2022 (Mar 18). Doi: 10.1177/03331024221077646

Key clinical point: Consistent with the overall study population results, eptinezumab therapy demonstrated favorable efficacy and safety in patients with episodic migraine (EM) or chronic migraine (CM) and self-reported aura from the PROMISE studies.

Major finding: Over weeks 1-12, monthly migraine days decreased with 100 mg and 300 mg eptinezumab vs. placebo in patients with EM (100 mg, −3.9 days; 300 mg, −4.2 days vs. −3.3 days) and CM (100 mg, −7.1 days; 300 mg, −7.6 days vs. −5.9 days) with aura. Treatment-emergent adverse event rates were similar across treatment groups.

Study details: Of 1741 patients with EM/CM from the PROMISE-1 and PROMISE-2 trials, this post hoc analysis included 877 patients who self-reported migraine with aura at screening and received eptinezumab (n = 583) or placebo (n = 294).

Disclosures: Lundbeck Seattle BioPharmaceuticals, Inc., USA, funded the study. Some authors declared serving as consultants, speakers, advisors, or as a primary trial investigator for and receiving personal fees and research support from various sources, including Lundbeck. Some authors are current or former employees of Lundbeck or its subsidiary company.

Source: Ashina M et al. Efficacy and safety of eptinezumab in patients with migraine and self-reported aura: Post hoc analysis of PROMISE-1 and PROMISE-2. Cephalalgia. 2022 (Mar 18). Doi: 10.1177/03331024221077646

Key clinical point: Consistent with the overall study population results, eptinezumab therapy demonstrated favorable efficacy and safety in patients with episodic migraine (EM) or chronic migraine (CM) and self-reported aura from the PROMISE studies.

Major finding: Over weeks 1-12, monthly migraine days decreased with 100 mg and 300 mg eptinezumab vs. placebo in patients with EM (100 mg, −3.9 days; 300 mg, −4.2 days vs. −3.3 days) and CM (100 mg, −7.1 days; 300 mg, −7.6 days vs. −5.9 days) with aura. Treatment-emergent adverse event rates were similar across treatment groups.

Study details: Of 1741 patients with EM/CM from the PROMISE-1 and PROMISE-2 trials, this post hoc analysis included 877 patients who self-reported migraine with aura at screening and received eptinezumab (n = 583) or placebo (n = 294).

Disclosures: Lundbeck Seattle BioPharmaceuticals, Inc., USA, funded the study. Some authors declared serving as consultants, speakers, advisors, or as a primary trial investigator for and receiving personal fees and research support from various sources, including Lundbeck. Some authors are current or former employees of Lundbeck or its subsidiary company.

Source: Ashina M et al. Efficacy and safety of eptinezumab in patients with migraine and self-reported aura: Post hoc analysis of PROMISE-1 and PROMISE-2. Cephalalgia. 2022 (Mar 18). Doi: 10.1177/03331024221077646

Key clinical point: Galcanezumab is an effective and safe long-term treatment option for chronic migraine.

Major finding: At month 12, patients in the placebo, 120 mg galcanezumab, and 240 mg galcanezumab groups showed a mean change of −8.5, −9.0, and −8.0 days in monthly migraine days from the beginning of the double-blind period, respectively (all within-group P < .001). No new safety concerns emerged with extended treatment.

Study details: Findings are from the 9-month open-label extension of the REGAIN trial including 1022 patients with chronic migraine who completed the preceding 3-month double-blind treatment (501, 259, and 262 patients assigned to the placebo, 120 mg galcanezumab, and 240 mg galcanezumab groups, respectively) and received a 240-mg galcanezumab loading dose, followed by 120 mg in the next month and flexible dosing thereafter.

Disclosures: This study was sponsored by Eli Lilly and Company. Some authors declared receiving speaker, consultant, or advisory board member honoraria from various sources, including Eli Lilly. Two authors reported being full-time employees and minor stockholders of Eli Lilly.

Source: Pozo-Rosich P et al. Long-term treatment with galcanezumab in patients with chronic migraine: results from the open-label extension of the REGAIN study. Curr Med Res Opin. 2022 (Apr 8). Doi:   10.1080/03007995.2022.2059975

Key clinical point: Galcanezumab is an effective and safe long-term treatment option for chronic migraine.

Major finding: At month 12, patients in the placebo, 120 mg galcanezumab, and 240 mg galcanezumab groups showed a mean change of −8.5, −9.0, and −8.0 days in monthly migraine days from the beginning of the double-blind period, respectively (all within-group P < .001). No new safety concerns emerged with extended treatment.

Study details: Findings are from the 9-month open-label extension of the REGAIN trial including 1022 patients with chronic migraine who completed the preceding 3-month double-blind treatment (501, 259, and 262 patients assigned to the placebo, 120 mg galcanezumab, and 240 mg galcanezumab groups, respectively) and received a 240-mg galcanezumab loading dose, followed by 120 mg in the next month and flexible dosing thereafter.

Disclosures: This study was sponsored by Eli Lilly and Company. Some authors declared receiving speaker, consultant, or advisory board member honoraria from various sources, including Eli Lilly. Two authors reported being full-time employees and minor stockholders of Eli Lilly.

Source: Pozo-Rosich P et al. Long-term treatment with galcanezumab in patients with chronic migraine: results from the open-label extension of the REGAIN study. Curr Med Res Opin. 2022 (Apr 8). Doi:   10.1080/03007995.2022.2059975

Key clinical point: Galcanezumab is an effective and safe long-term treatment option for chronic migraine.

Major finding: At month 12, patients in the placebo, 120 mg galcanezumab, and 240 mg galcanezumab groups showed a mean change of −8.5, −9.0, and −8.0 days in monthly migraine days from the beginning of the double-blind period, respectively (all within-group P < .001). No new safety concerns emerged with extended treatment.

Study details: Findings are from the 9-month open-label extension of the REGAIN trial including 1022 patients with chronic migraine who completed the preceding 3-month double-blind treatment (501, 259, and 262 patients assigned to the placebo, 120 mg galcanezumab, and 240 mg galcanezumab groups, respectively) and received a 240-mg galcanezumab loading dose, followed by 120 mg in the next month and flexible dosing thereafter.

Disclosures: This study was sponsored by Eli Lilly and Company. Some authors declared receiving speaker, consultant, or advisory board member honoraria from various sources, including Eli Lilly. Two authors reported being full-time employees and minor stockholders of Eli Lilly.

Source: Pozo-Rosich P et al. Long-term treatment with galcanezumab in patients with chronic migraine: results from the open-label extension of the REGAIN study. Curr Med Res Opin. 2022 (Apr 8). Doi:   10.1080/03007995.2022.2059975

Pregnant women with a history of migraine are at elevated risk for gestational hypertension and preeclampsia, and of delivering their baby preterm, new research suggests. In a large prospective study, researchers also found a link between migraine with aura and increased preeclampsia risk.

Overall, the findings suggest women with a history of migraine may benefit from enhanced monitoring during pregnancy, said coinvestigator Alexandra Purdue-Smithe, PhD, associate epidemiologist at Brigham and Women’s Hospital and instructor of medicine at Harvard Medical School, Boston. “Our results suggest that migraine history may be an important consideration in  obstetric risk assessment,” Dr. Purdue-Smithe added.

The findings will be presented at the 2022 annual meeting of the American Academy of Neurology.
 

Common neurovascular disorder

Migraine is a common neurovascular disorder, affecting about 15% of adults. The condition carries “a pretty remarkable sex bias” as it affects up to three times more women than men, and about a quarter of women in the reproductive age bracket of 18-44 years, Dr. Purdue-Smithe noted.

Despite this, relatively little is known about migraine and pregnancy risks, she said.

What is known is that women with migraine have a higher burden of cardiovascular risk factors such as obesity and chronic hypertension, and these factors can also increase risk for pregnancy complications, she added.

In the study, researchers analyzed data on 30,555 pregnancies in about 19,000 women without a history of cardiovascular disease, type 2 diabetes, or cancer during a 20-year period ending in 2009.

The data came from the Nurses’ Health Study II, a large prospective cohort study established in 1989 when it enrolled women aged 25-42 years. Participants in the ongoing study complete questionnaires every 2 years, reporting information on various health conditions as well as pregnancy and reproductive events.

The investigators estimated associations of physician-diagnosed prepregnancy migraine with preterm delivery, gestational diabetes, gestational hypertension, preeclampsia, and low birth weight (<2,500 grams [5.5 lb]).

About 11% of the women in the study had migraine diagnosed by a physician before pregnancy.

Researchers adjusted for age at pregnancy, race/ethnicity, age at menarche, and prepregnancy chronic hypertension, body mass index, physical activity, smoking status, alcohol intake, history of infertility, parity, oral contraceptive use, and analgesic use.
 

‘A bit surprising’

Results showed that compared with women without a history of migraine, those with such a history had higher risk for preterm delivery (relative risk [RR], 1.17; 95% confidence interval [CI], 1.05-1.30), gestational hypertension (RR, 1.28; 95% CI, 1.11-1.48), and preeclampsia (RR, 1.40; 95% CI, 1.19-1.65).

Prepregnancy migraine was not associated with low birth weight (RR, 0.99; 95% CI, 0.85-1.16) or gestational diabetes (RR, 1.05; 95% CI, .91-1.22).

It was a “bit surprising” that women with migraine had a higher risk for preterm delivery but their babies were not necessarily underweight – although some prior literature had similar findings, said Dr. Purdue-Smithe.

She noted that in her study the association was limited to moderate preterm delivery (gestational age, 32-37 weeks) and not with very preterm births (before 32 weeks).

Researchers also assessed adverse pregnancy outcomes by aura phenotype. “Women with migraine with aura have a higher risk of cardiovascular disease later in life, so we hypothesized that aura might be more strongly associated with adverse pregnancy outcomes with underlying vascular pathology,” Dr. Purdue-Smithe said.

Women with and without aura had elevated risks for preterm delivery and gestational hypertension. Those with aura had a slightly higher risk for preeclampsia (RR, 1.51; 95% CI, 1.22-1.88) than those without aura (RR, 1.29; 95% CI, 1.04-1.61).

As the association between migraine and adverse pregnancy outcomes persisted after adjustment for established cardiovascular and obstetric risk factors, “this suggests there may be subclinical factors that are contributing to elevated risks of these outcomes in women with migraine,” said Dr. Purdue-Smithe.

Such factors could include platelet activation, chronic inflammation, and endothelial dysfunction, she added.

While findings of some previous case-control and retrospective studies suggested a possible link between migraine and adverse pregnancy outcomes, until now few large prospective studies have examined the association.

“Strengths of our study include its prospective design, very large sample size, and more complete adjustment for potential prepregnancy confounders,” Dr. Purdue-Smithe said.
 

Independent risk factor?

In the past, it has been somewhat unclear whether migraine is an independent risk factor for these complications or whether women with migraine just have greater risk factors for adverse pregnancy outcomes.

“Our preliminary findings suggest that migraine is independently associated with these adverse pregnancy outcomes, or at least that’s what it seems,” said Dr. Purdue-Smithe.

The new results could be used by clinicians to “flag” women who may be at risk for complications, she added. “These women may benefit from closer monitoring in pregnancy so that if issues arise, physicians can act quickly.”

She noted that preeclampsia “can come on suddenly and escalate rapidly,” and there are few interventions to treat it besides delivery.

However, low-dose aspirin may be worth investigating. Various health care groups and the U.S. Preventive Services Task Force recommend pregnant women at high risk for preeclampsia take low-dose aspirin (81 mg/d) after 12 weeks’ gestation.

“It would be interesting to see if women with migraine who take aspirin in pregnancy can reduce their risk of preeclampsia, and future research should address this question,” said Dr. Purdue-Smithe.

Additional testing showed that associations with preeclampsia and gestational hypertension did not vary according to age and other obstetrical risks.

The Nurses’ Health Study II did not have information on number and severity of migraine attacks, so the researchers were unable to determine if these factors affect pregnancy outcomes.

“Understanding whether specific migraine features, such as attack frequency, are associated with adverse pregnancy outcomes will be an important area for future research,” said Dr. Purdue-Smithe. She noted prior studies showed the frequency of migraine attacks is related to ischemic stroke and other cardiovascular outcomes.

The authors acknowledged a limitation for the current study: Although migraine history was reported prior to pregnancy, information on migraine aura was collected after most of the pregnancies in the cohort were over. So the findings for migraine aura may have been influenced by participants’ ability to accurately remember their experiences.
 

Collaboration is key

Commenting on the research, Nina Riggins, MD, PhD, director of the Headache and Traumatic Brain Injury Center in the department of neurosciences at the University of California, San Diego, said the study “stands out” because it distinguishes pregnancy complications between those with and without aura among women with migraine. 

Dr. Riggins noted the investigators found the risk of preeclampsia, which on average occurs in about 3%-5% of pregnancies, is higher among women with migraine with aura.  

“The good news is that treatments are available,” she said. “Preconception planning should include this discussion for patients living with migraine.”

However, the study did not compare risks for patients who have frequent migraine attacks versus episodic migraine, Dr. Riggins noted. “We need to learn more about whether any treatments can be safe and effective to decrease risks of complications during pregnancy in this population,” she said.

“I believe, ultimately, what this study reveals is that collaboration among primary care, ob.gyn., maternal-fetal medicine specialists, and neurologists will likely benefit pregnant patients with migraine,” Dr. Riggins said.

The study received funding from the National Institutes of Health. Dr. Purdue-Smithe has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Pregnant women with a history of migraine are at elevated risk for gestational hypertension and preeclampsia, and of delivering their baby preterm, new research suggests. In a large prospective study, researchers also found a link between migraine with aura and increased preeclampsia risk.

Overall, the findings suggest women with a history of migraine may benefit from enhanced monitoring during pregnancy, said coinvestigator Alexandra Purdue-Smithe, PhD, associate epidemiologist at Brigham and Women’s Hospital and instructor of medicine at Harvard Medical School, Boston. “Our results suggest that migraine history may be an important consideration in  obstetric risk assessment,” Dr. Purdue-Smithe added.

The findings will be presented at the 2022 annual meeting of the American Academy of Neurology.
 

Common neurovascular disorder

Migraine is a common neurovascular disorder, affecting about 15% of adults. The condition carries “a pretty remarkable sex bias” as it affects up to three times more women than men, and about a quarter of women in the reproductive age bracket of 18-44 years, Dr. Purdue-Smithe noted.

Despite this, relatively little is known about migraine and pregnancy risks, she said.

What is known is that women with migraine have a higher burden of cardiovascular risk factors such as obesity and chronic hypertension, and these factors can also increase risk for pregnancy complications, she added.

In the study, researchers analyzed data on 30,555 pregnancies in about 19,000 women without a history of cardiovascular disease, type 2 diabetes, or cancer during a 20-year period ending in 2009.

The data came from the Nurses’ Health Study II, a large prospective cohort study established in 1989 when it enrolled women aged 25-42 years. Participants in the ongoing study complete questionnaires every 2 years, reporting information on various health conditions as well as pregnancy and reproductive events.

The investigators estimated associations of physician-diagnosed prepregnancy migraine with preterm delivery, gestational diabetes, gestational hypertension, preeclampsia, and low birth weight (<2,500 grams [5.5 lb]).

About 11% of the women in the study had migraine diagnosed by a physician before pregnancy.

Researchers adjusted for age at pregnancy, race/ethnicity, age at menarche, and prepregnancy chronic hypertension, body mass index, physical activity, smoking status, alcohol intake, history of infertility, parity, oral contraceptive use, and analgesic use.
 

‘A bit surprising’

Results showed that compared with women without a history of migraine, those with such a history had higher risk for preterm delivery (relative risk [RR], 1.17; 95% confidence interval [CI], 1.05-1.30), gestational hypertension (RR, 1.28; 95% CI, 1.11-1.48), and preeclampsia (RR, 1.40; 95% CI, 1.19-1.65).

Prepregnancy migraine was not associated with low birth weight (RR, 0.99; 95% CI, 0.85-1.16) or gestational diabetes (RR, 1.05; 95% CI, .91-1.22).

It was a “bit surprising” that women with migraine had a higher risk for preterm delivery but their babies were not necessarily underweight – although some prior literature had similar findings, said Dr. Purdue-Smithe.

She noted that in her study the association was limited to moderate preterm delivery (gestational age, 32-37 weeks) and not with very preterm births (before 32 weeks).

Researchers also assessed adverse pregnancy outcomes by aura phenotype. “Women with migraine with aura have a higher risk of cardiovascular disease later in life, so we hypothesized that aura might be more strongly associated with adverse pregnancy outcomes with underlying vascular pathology,” Dr. Purdue-Smithe said.

Women with and without aura had elevated risks for preterm delivery and gestational hypertension. Those with aura had a slightly higher risk for preeclampsia (RR, 1.51; 95% CI, 1.22-1.88) than those without aura (RR, 1.29; 95% CI, 1.04-1.61).

As the association between migraine and adverse pregnancy outcomes persisted after adjustment for established cardiovascular and obstetric risk factors, “this suggests there may be subclinical factors that are contributing to elevated risks of these outcomes in women with migraine,” said Dr. Purdue-Smithe.

Such factors could include platelet activation, chronic inflammation, and endothelial dysfunction, she added.

While findings of some previous case-control and retrospective studies suggested a possible link between migraine and adverse pregnancy outcomes, until now few large prospective studies have examined the association.

“Strengths of our study include its prospective design, very large sample size, and more complete adjustment for potential prepregnancy confounders,” Dr. Purdue-Smithe said.
 

Independent risk factor?

In the past, it has been somewhat unclear whether migraine is an independent risk factor for these complications or whether women with migraine just have greater risk factors for adverse pregnancy outcomes.

“Our preliminary findings suggest that migraine is independently associated with these adverse pregnancy outcomes, or at least that’s what it seems,” said Dr. Purdue-Smithe.

The new results could be used by clinicians to “flag” women who may be at risk for complications, she added. “These women may benefit from closer monitoring in pregnancy so that if issues arise, physicians can act quickly.”

She noted that preeclampsia “can come on suddenly and escalate rapidly,” and there are few interventions to treat it besides delivery.

However, low-dose aspirin may be worth investigating. Various health care groups and the U.S. Preventive Services Task Force recommend pregnant women at high risk for preeclampsia take low-dose aspirin (81 mg/d) after 12 weeks’ gestation.

“It would be interesting to see if women with migraine who take aspirin in pregnancy can reduce their risk of preeclampsia, and future research should address this question,” said Dr. Purdue-Smithe.

Additional testing showed that associations with preeclampsia and gestational hypertension did not vary according to age and other obstetrical risks.

The Nurses’ Health Study II did not have information on number and severity of migraine attacks, so the researchers were unable to determine if these factors affect pregnancy outcomes.

“Understanding whether specific migraine features, such as attack frequency, are associated with adverse pregnancy outcomes will be an important area for future research,” said Dr. Purdue-Smithe. She noted prior studies showed the frequency of migraine attacks is related to ischemic stroke and other cardiovascular outcomes.

The authors acknowledged a limitation for the current study: Although migraine history was reported prior to pregnancy, information on migraine aura was collected after most of the pregnancies in the cohort were over. So the findings for migraine aura may have been influenced by participants’ ability to accurately remember their experiences.
 

Collaboration is key

Commenting on the research, Nina Riggins, MD, PhD, director of the Headache and Traumatic Brain Injury Center in the department of neurosciences at the University of California, San Diego, said the study “stands out” because it distinguishes pregnancy complications between those with and without aura among women with migraine. 

Dr. Riggins noted the investigators found the risk of preeclampsia, which on average occurs in about 3%-5% of pregnancies, is higher among women with migraine with aura.  

“The good news is that treatments are available,” she said. “Preconception planning should include this discussion for patients living with migraine.”

However, the study did not compare risks for patients who have frequent migraine attacks versus episodic migraine, Dr. Riggins noted. “We need to learn more about whether any treatments can be safe and effective to decrease risks of complications during pregnancy in this population,” she said.

“I believe, ultimately, what this study reveals is that collaboration among primary care, ob.gyn., maternal-fetal medicine specialists, and neurologists will likely benefit pregnant patients with migraine,” Dr. Riggins said.

The study received funding from the National Institutes of Health. Dr. Purdue-Smithe has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Pregnant women with a history of migraine are at elevated risk for gestational hypertension and preeclampsia, and of delivering their baby preterm, new research suggests. In a large prospective study, researchers also found a link between migraine with aura and increased preeclampsia risk.

Overall, the findings suggest women with a history of migraine may benefit from enhanced monitoring during pregnancy, said coinvestigator Alexandra Purdue-Smithe, PhD, associate epidemiologist at Brigham and Women’s Hospital and instructor of medicine at Harvard Medical School, Boston. “Our results suggest that migraine history may be an important consideration in  obstetric risk assessment,” Dr. Purdue-Smithe added.

The findings will be presented at the 2022 annual meeting of the American Academy of Neurology.
 

Common neurovascular disorder

Migraine is a common neurovascular disorder, affecting about 15% of adults. The condition carries “a pretty remarkable sex bias” as it affects up to three times more women than men, and about a quarter of women in the reproductive age bracket of 18-44 years, Dr. Purdue-Smithe noted.

Despite this, relatively little is known about migraine and pregnancy risks, she said.

What is known is that women with migraine have a higher burden of cardiovascular risk factors such as obesity and chronic hypertension, and these factors can also increase risk for pregnancy complications, she added.

In the study, researchers analyzed data on 30,555 pregnancies in about 19,000 women without a history of cardiovascular disease, type 2 diabetes, or cancer during a 20-year period ending in 2009.

The data came from the Nurses’ Health Study II, a large prospective cohort study established in 1989 when it enrolled women aged 25-42 years. Participants in the ongoing study complete questionnaires every 2 years, reporting information on various health conditions as well as pregnancy and reproductive events.

The investigators estimated associations of physician-diagnosed prepregnancy migraine with preterm delivery, gestational diabetes, gestational hypertension, preeclampsia, and low birth weight (<2,500 grams [5.5 lb]).

About 11% of the women in the study had migraine diagnosed by a physician before pregnancy.

Researchers adjusted for age at pregnancy, race/ethnicity, age at menarche, and prepregnancy chronic hypertension, body mass index, physical activity, smoking status, alcohol intake, history of infertility, parity, oral contraceptive use, and analgesic use.
 

‘A bit surprising’

Results showed that compared with women without a history of migraine, those with such a history had higher risk for preterm delivery (relative risk [RR], 1.17; 95% confidence interval [CI], 1.05-1.30), gestational hypertension (RR, 1.28; 95% CI, 1.11-1.48), and preeclampsia (RR, 1.40; 95% CI, 1.19-1.65).

Prepregnancy migraine was not associated with low birth weight (RR, 0.99; 95% CI, 0.85-1.16) or gestational diabetes (RR, 1.05; 95% CI, .91-1.22).

It was a “bit surprising” that women with migraine had a higher risk for preterm delivery but their babies were not necessarily underweight – although some prior literature had similar findings, said Dr. Purdue-Smithe.

She noted that in her study the association was limited to moderate preterm delivery (gestational age, 32-37 weeks) and not with very preterm births (before 32 weeks).

Researchers also assessed adverse pregnancy outcomes by aura phenotype. “Women with migraine with aura have a higher risk of cardiovascular disease later in life, so we hypothesized that aura might be more strongly associated with adverse pregnancy outcomes with underlying vascular pathology,” Dr. Purdue-Smithe said.

Women with and without aura had elevated risks for preterm delivery and gestational hypertension. Those with aura had a slightly higher risk for preeclampsia (RR, 1.51; 95% CI, 1.22-1.88) than those without aura (RR, 1.29; 95% CI, 1.04-1.61).

As the association between migraine and adverse pregnancy outcomes persisted after adjustment for established cardiovascular and obstetric risk factors, “this suggests there may be subclinical factors that are contributing to elevated risks of these outcomes in women with migraine,” said Dr. Purdue-Smithe.

Such factors could include platelet activation, chronic inflammation, and endothelial dysfunction, she added.

While findings of some previous case-control and retrospective studies suggested a possible link between migraine and adverse pregnancy outcomes, until now few large prospective studies have examined the association.

“Strengths of our study include its prospective design, very large sample size, and more complete adjustment for potential prepregnancy confounders,” Dr. Purdue-Smithe said.
 

Independent risk factor?

In the past, it has been somewhat unclear whether migraine is an independent risk factor for these complications or whether women with migraine just have greater risk factors for adverse pregnancy outcomes.

“Our preliminary findings suggest that migraine is independently associated with these adverse pregnancy outcomes, or at least that’s what it seems,” said Dr. Purdue-Smithe.

The new results could be used by clinicians to “flag” women who may be at risk for complications, she added. “These women may benefit from closer monitoring in pregnancy so that if issues arise, physicians can act quickly.”

She noted that preeclampsia “can come on suddenly and escalate rapidly,” and there are few interventions to treat it besides delivery.

However, low-dose aspirin may be worth investigating. Various health care groups and the U.S. Preventive Services Task Force recommend pregnant women at high risk for preeclampsia take low-dose aspirin (81 mg/d) after 12 weeks’ gestation.

“It would be interesting to see if women with migraine who take aspirin in pregnancy can reduce their risk of preeclampsia, and future research should address this question,” said Dr. Purdue-Smithe.

Additional testing showed that associations with preeclampsia and gestational hypertension did not vary according to age and other obstetrical risks.

The Nurses’ Health Study II did not have information on number and severity of migraine attacks, so the researchers were unable to determine if these factors affect pregnancy outcomes.

“Understanding whether specific migraine features, such as attack frequency, are associated with adverse pregnancy outcomes will be an important area for future research,” said Dr. Purdue-Smithe. She noted prior studies showed the frequency of migraine attacks is related to ischemic stroke and other cardiovascular outcomes.

The authors acknowledged a limitation for the current study: Although migraine history was reported prior to pregnancy, information on migraine aura was collected after most of the pregnancies in the cohort were over. So the findings for migraine aura may have been influenced by participants’ ability to accurately remember their experiences.
 

Collaboration is key

Commenting on the research, Nina Riggins, MD, PhD, director of the Headache and Traumatic Brain Injury Center in the department of neurosciences at the University of California, San Diego, said the study “stands out” because it distinguishes pregnancy complications between those with and without aura among women with migraine. 

Dr. Riggins noted the investigators found the risk of preeclampsia, which on average occurs in about 3%-5% of pregnancies, is higher among women with migraine with aura.  

“The good news is that treatments are available,” she said. “Preconception planning should include this discussion for patients living with migraine.”

However, the study did not compare risks for patients who have frequent migraine attacks versus episodic migraine, Dr. Riggins noted. “We need to learn more about whether any treatments can be safe and effective to decrease risks of complications during pregnancy in this population,” she said.

“I believe, ultimately, what this study reveals is that collaboration among primary care, ob.gyn., maternal-fetal medicine specialists, and neurologists will likely benefit pregnant patients with migraine,” Dr. Riggins said.

The study received funding from the National Institutes of Health. Dr. Purdue-Smithe has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Neuromodulation is an up-and-coming subtype of treatments for migraine. These treatments vary significantly from transcutaneous electrical nerve stimulation (TENS)–like devices to transcranial magnetic stimulation to remote electrical stimulation of nociceptors in the arm or the vagus nerve. Some of these devices are primarily preventive in nature, whereas others are primarily for the acute treatment of migraine. Transcranial direct-current stimulation (TDCS) has recently been investigated in a number of other neurologic conditions, including multiple sclerosis and stroke, specifically for its ability to reverse manifestations of specific pathologic changes. With migraine, the question remains of whether central sensitization can similarly be reversed.

Prior studies looking at TDCS in the context of episodic migraine were mostly inconclusive. These were looking primarily at acute treatment rather than prevention. In a recent study, Hodai and colleagues took a small group of patients with treatment-refractory chronic migraine and randomly assigned them to TDCS or sham stimulation over a course of 2 months. The stimulations that the patients received were similar to protocols that have been investigated in multiple sclerosis and stroke, specifically anodal TDCS, which is thought to reverse gamma-aminobutyric acid (GABA)-ergic and glutamatergic dysregulations when the right or left cortex was stimulated.

The primary outcome of this study was decrease in baseline migraine attack frequency per month; secondary endpoints were improvement in the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) scores, the Short-Form Survey (SF-12) quality of life assessment, the Hospital Anxiety and Depression Scale (HADS) assessment, and a Clinical Global Impression (CGI) scale.

A total of 36 patients were randomly assigned to a sham or TDCS intervention. A larger reduction of migraine days per month was seen by the intervention group. The interventions were also well tolerated, and no serious adverse events were reported. None of the secondary outcomes, however, showed significance. Further analysis of responder rates showed a 50% responder rate of 36% in the intervention group vs. 14% in the sham group.

This is the first sham-controlled study investigating the use of this neuromodulation therapy for the prevention of migraine. TDCS appears to show promise even when selected for some of the most refractory situations. The question will become how this can be more practical for patient use in the future.

Prognosticating treatment effects in chronic migraine is extremely difficult to do. Most specialists have an extensive discussion with their patients that includes the likelihood of improvement in addition to the risks and benefits of the medications they are considering starting. There has been background discussion in the headache community over whether improvement with one calcitonin gene–related peptide (CGRP) antagonist medication is predictive of benefit with other medications in the class or with long-term improvement in migraine. Buse and colleagues present findings from a post hoc analysis of the PROMISE-2 study of eptinezumab for the prevention of chronic migraine.

Eptinezumab is an intravenously administered CGRP monoclonal antibody, given at either 100 mg or 300 mg every 3 months. PROMISE-2 was a randomized controlled trial that led to US Food and Drug Administration approval of eptinezumab for the prevention of chronic migraine. The authors here reviewed the data between the two intervention groups and the placebo group and then regrouped these patients according to response at month 1, defined by whether the patient was in a response group of 25%, 50%, or 75% response after 1 month of treatment. This was then compared with the patient global impact of change (PGIC) score at month 6.

This post hoc analysis did not include patients that had no response at all to either intervention or placebo at month 6. A total of 1072 patients were included in this analysis; the 100-mg, 300-mg, and placebo groups had approximately one third of patients in each.

The majority of patients in the 75% responder group continued to improve; more than half of those patients maintained the 75% response rate at month 6. More than two thirds of the 50% responders remained at a 50% response at 6 months as well. Those who responded at < 25% at month 1 were much less likely to achieve 50% response at month 6; however, the patients in the active groups were more likely to achieve a response compared with those in the placebo group.

The PGIC scores also showed significant improvement when comparing among the groups. Those who were "very much improved" at month 1 were significantly more likely to remain that way at the conclusion of the study.

Although prognosticating among different subtypes of CGRP antagonists is not yet possible, the authors here do show the ability to better inform and educate our patients when considering eptinezumab therapy for chronic migraine.

There is an age-old debate among headache specialists about overused medications: to wean or not to wean. The overuse of acute medications has long been shown to contribute to a higher frequency of migraine attacks over time, initially being called "transformed migraine" and subsequently being understood either as a subtype of chronic migraine or a separate headache disorder completely. Medication overuse headache (MOH) is something screened for by all headache providers when evaluating patients for worsening headaches. The addition of a preventive medication is the mainstay of treatment of any instance of higher frequency migraine; when MOH is a contributing factor, many practitioners will recommend complete discontinuation of the overused medications, whereas others will recommend waiting for the preventive medication to offer benefit first. As yet, there have not been any head-to-head trials investigating discontinuation vs. non-discontinuation of overused medications in this population.

Schwedt and colleagues designed a multisite trial prospectively enrolling patients with an International Classification of Headache Disorders (ICHD-3) diagnosis of both chronic migraine and MOH. Participants were told not to change their preventive medications for 4 weeks prior to enrollment. A total of 720 participants were enrolled through 14 clinics. Any patients already on preventive therapy were optimized to the best dose of that therapy or switched to other medications on the basis of the clinical investigator's judgement; all participants were randomly assigned to either discontinuation of the overused medication and given a novel acute therapy or were told to remain on their current acute therapy. No bridging therapies were recommended when switching or discontinuing acute therapies.

Of the 720 participants enrolled, 42% were already on preventive medicine. The overused medications ranged from simple analgesics for 64% of the study population to triptans, combination analgesics, and even opiates in 4% of the population. Butalbital use was included in the combination analgesic group. The primary outcome was reduction in moderate to severe migraine days, and secondary outcomes were scores for disability, depression, and quality of life (based on questionnaires).

There appeared to be no significant difference between the discontinuation and non-discontinuation groups. The authors describe this as noninferiority between the groups. To answer the age-old question of to wean or not to wean — there probably is not an answer that fits every patient. Patient adherence determines the effectiveness of anything we recommend. When evaluating patients with MOH, we have to consider whether discontinuing a medication that the patient has been depending on for months or longer will make it more or less likely for them to adhere to the other recommendations that we are making. Some patients will be very agreeable to try another acute option and stop overusing altogether. Others will be very apprehensive, and a slower, steadier approach that includes using the overused medication may be necessary. We aim always to individualize our recommendations for patients, and this should be no different.

Neuromodulation is an up-and-coming subtype of treatments for migraine. These treatments vary significantly from transcutaneous electrical nerve stimulation (TENS)–like devices to transcranial magnetic stimulation to remote electrical stimulation of nociceptors in the arm or the vagus nerve. Some of these devices are primarily preventive in nature, whereas others are primarily for the acute treatment of migraine. Transcranial direct-current stimulation (TDCS) has recently been investigated in a number of other neurologic conditions, including multiple sclerosis and stroke, specifically for its ability to reverse manifestations of specific pathologic changes. With migraine, the question remains of whether central sensitization can similarly be reversed.

Prior studies looking at TDCS in the context of episodic migraine were mostly inconclusive. These were looking primarily at acute treatment rather than prevention. In a recent study, Hodai and colleagues took a small group of patients with treatment-refractory chronic migraine and randomly assigned them to TDCS or sham stimulation over a course of 2 months. The stimulations that the patients received were similar to protocols that have been investigated in multiple sclerosis and stroke, specifically anodal TDCS, which is thought to reverse gamma-aminobutyric acid (GABA)-ergic and glutamatergic dysregulations when the right or left cortex was stimulated.

The primary outcome of this study was decrease in baseline migraine attack frequency per month; secondary endpoints were improvement in the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) scores, the Short-Form Survey (SF-12) quality of life assessment, the Hospital Anxiety and Depression Scale (HADS) assessment, and a Clinical Global Impression (CGI) scale.

A total of 36 patients were randomly assigned to a sham or TDCS intervention. A larger reduction of migraine days per month was seen by the intervention group. The interventions were also well tolerated, and no serious adverse events were reported. None of the secondary outcomes, however, showed significance. Further analysis of responder rates showed a 50% responder rate of 36% in the intervention group vs. 14% in the sham group.

This is the first sham-controlled study investigating the use of this neuromodulation therapy for the prevention of migraine. TDCS appears to show promise even when selected for some of the most refractory situations. The question will become how this can be more practical for patient use in the future.

Prognosticating treatment effects in chronic migraine is extremely difficult to do. Most specialists have an extensive discussion with their patients that includes the likelihood of improvement in addition to the risks and benefits of the medications they are considering starting. There has been background discussion in the headache community over whether improvement with one calcitonin gene–related peptide (CGRP) antagonist medication is predictive of benefit with other medications in the class or with long-term improvement in migraine. Buse and colleagues present findings from a post hoc analysis of the PROMISE-2 study of eptinezumab for the prevention of chronic migraine.

Eptinezumab is an intravenously administered CGRP monoclonal antibody, given at either 100 mg or 300 mg every 3 months. PROMISE-2 was a randomized controlled trial that led to US Food and Drug Administration approval of eptinezumab for the prevention of chronic migraine. The authors here reviewed the data between the two intervention groups and the placebo group and then regrouped these patients according to response at month 1, defined by whether the patient was in a response group of 25%, 50%, or 75% response after 1 month of treatment. This was then compared with the patient global impact of change (PGIC) score at month 6.

This post hoc analysis did not include patients that had no response at all to either intervention or placebo at month 6. A total of 1072 patients were included in this analysis; the 100-mg, 300-mg, and placebo groups had approximately one third of patients in each.

The majority of patients in the 75% responder group continued to improve; more than half of those patients maintained the 75% response rate at month 6. More than two thirds of the 50% responders remained at a 50% response at 6 months as well. Those who responded at < 25% at month 1 were much less likely to achieve 50% response at month 6; however, the patients in the active groups were more likely to achieve a response compared with those in the placebo group.

The PGIC scores also showed significant improvement when comparing among the groups. Those who were "very much improved" at month 1 were significantly more likely to remain that way at the conclusion of the study.

Although prognosticating among different subtypes of CGRP antagonists is not yet possible, the authors here do show the ability to better inform and educate our patients when considering eptinezumab therapy for chronic migraine.

There is an age-old debate among headache specialists about overused medications: to wean or not to wean. The overuse of acute medications has long been shown to contribute to a higher frequency of migraine attacks over time, initially being called "transformed migraine" and subsequently being understood either as a subtype of chronic migraine or a separate headache disorder completely. Medication overuse headache (MOH) is something screened for by all headache providers when evaluating patients for worsening headaches. The addition of a preventive medication is the mainstay of treatment of any instance of higher frequency migraine; when MOH is a contributing factor, many practitioners will recommend complete discontinuation of the overused medications, whereas others will recommend waiting for the preventive medication to offer benefit first. As yet, there have not been any head-to-head trials investigating discontinuation vs. non-discontinuation of overused medications in this population.

Schwedt and colleagues designed a multisite trial prospectively enrolling patients with an International Classification of Headache Disorders (ICHD-3) diagnosis of both chronic migraine and MOH. Participants were told not to change their preventive medications for 4 weeks prior to enrollment. A total of 720 participants were enrolled through 14 clinics. Any patients already on preventive therapy were optimized to the best dose of that therapy or switched to other medications on the basis of the clinical investigator's judgement; all participants were randomly assigned to either discontinuation of the overused medication and given a novel acute therapy or were told to remain on their current acute therapy. No bridging therapies were recommended when switching or discontinuing acute therapies.

Of the 720 participants enrolled, 42% were already on preventive medicine. The overused medications ranged from simple analgesics for 64% of the study population to triptans, combination analgesics, and even opiates in 4% of the population. Butalbital use was included in the combination analgesic group. The primary outcome was reduction in moderate to severe migraine days, and secondary outcomes were scores for disability, depression, and quality of life (based on questionnaires).

There appeared to be no significant difference between the discontinuation and non-discontinuation groups. The authors describe this as noninferiority between the groups. To answer the age-old question of to wean or not to wean — there probably is not an answer that fits every patient. Patient adherence determines the effectiveness of anything we recommend. When evaluating patients with MOH, we have to consider whether discontinuing a medication that the patient has been depending on for months or longer will make it more or less likely for them to adhere to the other recommendations that we are making. Some patients will be very agreeable to try another acute option and stop overusing altogether. Others will be very apprehensive, and a slower, steadier approach that includes using the overused medication may be necessary. We aim always to individualize our recommendations for patients, and this should be no different.

Neuromodulation is an up-and-coming subtype of treatments for migraine. These treatments vary significantly from transcutaneous electrical nerve stimulation (TENS)–like devices to transcranial magnetic stimulation to remote electrical stimulation of nociceptors in the arm or the vagus nerve. Some of these devices are primarily preventive in nature, whereas others are primarily for the acute treatment of migraine. Transcranial direct-current stimulation (TDCS) has recently been investigated in a number of other neurologic conditions, including multiple sclerosis and stroke, specifically for its ability to reverse manifestations of specific pathologic changes. With migraine, the question remains of whether central sensitization can similarly be reversed.

Prior studies looking at TDCS in the context of episodic migraine were mostly inconclusive. These were looking primarily at acute treatment rather than prevention. In a recent study, Hodai and colleagues took a small group of patients with treatment-refractory chronic migraine and randomly assigned them to TDCS or sham stimulation over a course of 2 months. The stimulations that the patients received were similar to protocols that have been investigated in multiple sclerosis and stroke, specifically anodal TDCS, which is thought to reverse gamma-aminobutyric acid (GABA)-ergic and glutamatergic dysregulations when the right or left cortex was stimulated.

The primary outcome of this study was decrease in baseline migraine attack frequency per month; secondary endpoints were improvement in the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) scores, the Short-Form Survey (SF-12) quality of life assessment, the Hospital Anxiety and Depression Scale (HADS) assessment, and a Clinical Global Impression (CGI) scale.

A total of 36 patients were randomly assigned to a sham or TDCS intervention. A larger reduction of migraine days per month was seen by the intervention group. The interventions were also well tolerated, and no serious adverse events were reported. None of the secondary outcomes, however, showed significance. Further analysis of responder rates showed a 50% responder rate of 36% in the intervention group vs. 14% in the sham group.

This is the first sham-controlled study investigating the use of this neuromodulation therapy for the prevention of migraine. TDCS appears to show promise even when selected for some of the most refractory situations. The question will become how this can be more practical for patient use in the future.

Prognosticating treatment effects in chronic migraine is extremely difficult to do. Most specialists have an extensive discussion with their patients that includes the likelihood of improvement in addition to the risks and benefits of the medications they are considering starting. There has been background discussion in the headache community over whether improvement with one calcitonin gene–related peptide (CGRP) antagonist medication is predictive of benefit with other medications in the class or with long-term improvement in migraine. Buse and colleagues present findings from a post hoc analysis of the PROMISE-2 study of eptinezumab for the prevention of chronic migraine.

Eptinezumab is an intravenously administered CGRP monoclonal antibody, given at either 100 mg or 300 mg every 3 months. PROMISE-2 was a randomized controlled trial that led to US Food and Drug Administration approval of eptinezumab for the prevention of chronic migraine. The authors here reviewed the data between the two intervention groups and the placebo group and then regrouped these patients according to response at month 1, defined by whether the patient was in a response group of 25%, 50%, or 75% response after 1 month of treatment. This was then compared with the patient global impact of change (PGIC) score at month 6.

This post hoc analysis did not include patients that had no response at all to either intervention or placebo at month 6. A total of 1072 patients were included in this analysis; the 100-mg, 300-mg, and placebo groups had approximately one third of patients in each.

The majority of patients in the 75% responder group continued to improve; more than half of those patients maintained the 75% response rate at month 6. More than two thirds of the 50% responders remained at a 50% response at 6 months as well. Those who responded at < 25% at month 1 were much less likely to achieve 50% response at month 6; however, the patients in the active groups were more likely to achieve a response compared with those in the placebo group.

The PGIC scores also showed significant improvement when comparing among the groups. Those who were "very much improved" at month 1 were significantly more likely to remain that way at the conclusion of the study.

Although prognosticating among different subtypes of CGRP antagonists is not yet possible, the authors here do show the ability to better inform and educate our patients when considering eptinezumab therapy for chronic migraine.

There is an age-old debate among headache specialists about overused medications: to wean or not to wean. The overuse of acute medications has long been shown to contribute to a higher frequency of migraine attacks over time, initially being called "transformed migraine" and subsequently being understood either as a subtype of chronic migraine or a separate headache disorder completely. Medication overuse headache (MOH) is something screened for by all headache providers when evaluating patients for worsening headaches. The addition of a preventive medication is the mainstay of treatment of any instance of higher frequency migraine; when MOH is a contributing factor, many practitioners will recommend complete discontinuation of the overused medications, whereas others will recommend waiting for the preventive medication to offer benefit first. As yet, there have not been any head-to-head trials investigating discontinuation vs. non-discontinuation of overused medications in this population.

Schwedt and colleagues designed a multisite trial prospectively enrolling patients with an International Classification of Headache Disorders (ICHD-3) diagnosis of both chronic migraine and MOH. Participants were told not to change their preventive medications for 4 weeks prior to enrollment. A total of 720 participants were enrolled through 14 clinics. Any patients already on preventive therapy were optimized to the best dose of that therapy or switched to other medications on the basis of the clinical investigator's judgement; all participants were randomly assigned to either discontinuation of the overused medication and given a novel acute therapy or were told to remain on their current acute therapy. No bridging therapies were recommended when switching or discontinuing acute therapies.

Of the 720 participants enrolled, 42% were already on preventive medicine. The overused medications ranged from simple analgesics for 64% of the study population to triptans, combination analgesics, and even opiates in 4% of the population. Butalbital use was included in the combination analgesic group. The primary outcome was reduction in moderate to severe migraine days, and secondary outcomes were scores for disability, depression, and quality of life (based on questionnaires).

There appeared to be no significant difference between the discontinuation and non-discontinuation groups. The authors describe this as noninferiority between the groups. To answer the age-old question of to wean or not to wean — there probably is not an answer that fits every patient. Patient adherence determines the effectiveness of anything we recommend. When evaluating patients with MOH, we have to consider whether discontinuing a medication that the patient has been depending on for months or longer will make it more or less likely for them to adhere to the other recommendations that we are making. Some patients will be very agreeable to try another acute option and stop overusing altogether. Others will be very apprehensive, and a slower, steadier approach that includes using the overused medication may be necessary. We aim always to individualize our recommendations for patients, and this should be no different.

The endocannabinoid system is a promising therapeutic target for the treatment of migraine, according to Italian researchers at the University of Pavia, and the C. Mondino National Institute of Neurology Foundation. “The complexity of the endocannabinoid system calls for accurate biochemical and pharmacological characterization of any new compounds undergoing testing and development,” noted Rosaria Greco, PhD. She and her colleagues authored a review on the topic that was published online Feb. 18, 2022, in Headache.

Although cannabis has been investigated for both the treatment and prevention of migraine, evidence for its benefit is weak because of lack of controlled studies, they explained. Archival data from a large database “showed greater improvements in men than in women and suggested that concentrated preparations were more effective than flower consumption.” In addition, a small single-center study linked nabilone, a synthetic cannabinoid, to reductions in pain duration, intensity, and daily intake of analgesics among patients with medication overuse headache. Finally, a pilot study reported a reduction in pain intensity among patients with chronic migraine treated with a combination of tested a combination of delta-9-tetrahydrocannabinol and cannabidiol. “Methodologically sound studies are now needed to investigate the possible effects of cannabis in migraine treatment and to define strains, formulations, and dosage,” they noted.
 

Not just cannabis

In addition to exogenous cannabis, there are now preclinical studies suggesting other compounds that interact with the endocannabinoid system “are also able to modulate the pathways involved in migraine-related pain,” the study authors wrote. “But the road ahead is still long. Multiple molecules linked to the endocannabinoid system have emerged as potential therapeutic targets.

The complexity of the system demands caution and precise biochemical and pharmacological characterization of the new compounds to be tested and developed.”

Among these compounds are endogenous ligands such as N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol that specifically target CB1 and CB2 receptors. Additionally, there are endocannabinoid-based drugs that also target the CB1/CB2 receptors, as well as other substances, such as lipids (palmitoylethanolamide [PEA]) and enzymes, that do not bind to the CB1/CB2 receptors but are responsible for endocannabinoid biosynthesis.

There is some evidence that the endocannabinoid system may be dysfunctional in patients with migraine, and the authors noted their work has shown that PEA plasma levels are increased during experimentally triggered migraine-like attacks. Thus, some preclinical and preliminary evidence suggests that administration of PEA or anandamide may have analgesic and anti-inflammatory effects in migraine.

Another approach is the inhibition of endocannabinoid catabolic enzymes, which could circumvent the adverse effects associated with direct activation of CB receptors. “Endocannabinoid tone enhancement has been proposed as an alternative modality of activation of CB receptors and is possibly devoid of the psychotropic effects reported with CB receptor agonists,” noted the authors, who have shown in animal and preclinical studies that inhibition of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase can modulate migraine pain.

Yet another way of indirectly impacting CB receptors is through their allosteric ligands, an approach that “deserves further investigation”, and “might provide interesting leads for clinical development, given that it may have a favorable side-effect profile with limited psychomimetic and depressant effects,” wrote the authors. And finally, inhibition of N-acylethanolamine acid amide hydrolase, the enzyme that preferentially hydrolyzes PEA, might be a promising approach.

“The multiplicity of options and the wealth of data already obtained in animal models underscore the importance of further advancing research in this area,” the authors concluded.
 

Patients are taking cannabinoids; physicians should learn about them

Commenting on the paper, Alan Rapaport, MD, clinical professor of neurology at the University of California, Los Angeles, said “this well-done paper points out the complexity of the endocannabinoid system and the multiple ways of getting it to work for certain patients. It details some of the studies that show beneficial results in migraine, medication overuse headache, chronic migraine, and pain. Patients with headache, other types of pain, anxiety, nausea, sleep issues, and other symptoms are already taking cannabinoids, usually derived from the marijuana plant, that are not well regulated. A few are prescribed drugs which target CB1 and CB2 receptors. Patients often get relief of some of their symptoms, sometimes getting high and many times not.

“The paper makes the point that previous studies are often small, not carefully controlled, or well documented. We do need to start doing larger, properly designed studies and getting them into the literature. Doctors need to learn more about these treatments. The next step will be to get [Food and Drug Administration]–approved treatments, so physicians and nurses will know exactly what we are giving, the beneficial effects to expect in a certain percentage of patients, and the adverse events to warn our patients about. Cannabinoids have been tried by a large percentage of patients with headache and pain. Now we need to standardize the various treatments that are sure to be suggested in the future.”

The study was funded by the Migraine Research Foundation, and the Italian Ministry of Health. The study authors declared no conflicts of interest.

The endocannabinoid system is a promising therapeutic target for the treatment of migraine, according to Italian researchers at the University of Pavia, and the C. Mondino National Institute of Neurology Foundation. “The complexity of the endocannabinoid system calls for accurate biochemical and pharmacological characterization of any new compounds undergoing testing and development,” noted Rosaria Greco, PhD. She and her colleagues authored a review on the topic that was published online Feb. 18, 2022, in Headache.

Although cannabis has been investigated for both the treatment and prevention of migraine, evidence for its benefit is weak because of lack of controlled studies, they explained. Archival data from a large database “showed greater improvements in men than in women and suggested that concentrated preparations were more effective than flower consumption.” In addition, a small single-center study linked nabilone, a synthetic cannabinoid, to reductions in pain duration, intensity, and daily intake of analgesics among patients with medication overuse headache. Finally, a pilot study reported a reduction in pain intensity among patients with chronic migraine treated with a combination of tested a combination of delta-9-tetrahydrocannabinol and cannabidiol. “Methodologically sound studies are now needed to investigate the possible effects of cannabis in migraine treatment and to define strains, formulations, and dosage,” they noted.
 

Not just cannabis

In addition to exogenous cannabis, there are now preclinical studies suggesting other compounds that interact with the endocannabinoid system “are also able to modulate the pathways involved in migraine-related pain,” the study authors wrote. “But the road ahead is still long. Multiple molecules linked to the endocannabinoid system have emerged as potential therapeutic targets.

The complexity of the system demands caution and precise biochemical and pharmacological characterization of the new compounds to be tested and developed.”

Among these compounds are endogenous ligands such as N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol that specifically target CB1 and CB2 receptors. Additionally, there are endocannabinoid-based drugs that also target the CB1/CB2 receptors, as well as other substances, such as lipids (palmitoylethanolamide [PEA]) and enzymes, that do not bind to the CB1/CB2 receptors but are responsible for endocannabinoid biosynthesis.

There is some evidence that the endocannabinoid system may be dysfunctional in patients with migraine, and the authors noted their work has shown that PEA plasma levels are increased during experimentally triggered migraine-like attacks. Thus, some preclinical and preliminary evidence suggests that administration of PEA or anandamide may have analgesic and anti-inflammatory effects in migraine.

Another approach is the inhibition of endocannabinoid catabolic enzymes, which could circumvent the adverse effects associated with direct activation of CB receptors. “Endocannabinoid tone enhancement has been proposed as an alternative modality of activation of CB receptors and is possibly devoid of the psychotropic effects reported with CB receptor agonists,” noted the authors, who have shown in animal and preclinical studies that inhibition of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase can modulate migraine pain.

Yet another way of indirectly impacting CB receptors is through their allosteric ligands, an approach that “deserves further investigation”, and “might provide interesting leads for clinical development, given that it may have a favorable side-effect profile with limited psychomimetic and depressant effects,” wrote the authors. And finally, inhibition of N-acylethanolamine acid amide hydrolase, the enzyme that preferentially hydrolyzes PEA, might be a promising approach.

“The multiplicity of options and the wealth of data already obtained in animal models underscore the importance of further advancing research in this area,” the authors concluded.
 

Patients are taking cannabinoids; physicians should learn about them

Commenting on the paper, Alan Rapaport, MD, clinical professor of neurology at the University of California, Los Angeles, said “this well-done paper points out the complexity of the endocannabinoid system and the multiple ways of getting it to work for certain patients. It details some of the studies that show beneficial results in migraine, medication overuse headache, chronic migraine, and pain. Patients with headache, other types of pain, anxiety, nausea, sleep issues, and other symptoms are already taking cannabinoids, usually derived from the marijuana plant, that are not well regulated. A few are prescribed drugs which target CB1 and CB2 receptors. Patients often get relief of some of their symptoms, sometimes getting high and many times not.

“The paper makes the point that previous studies are often small, not carefully controlled, or well documented. We do need to start doing larger, properly designed studies and getting them into the literature. Doctors need to learn more about these treatments. The next step will be to get [Food and Drug Administration]–approved treatments, so physicians and nurses will know exactly what we are giving, the beneficial effects to expect in a certain percentage of patients, and the adverse events to warn our patients about. Cannabinoids have been tried by a large percentage of patients with headache and pain. Now we need to standardize the various treatments that are sure to be suggested in the future.”

The study was funded by the Migraine Research Foundation, and the Italian Ministry of Health. The study authors declared no conflicts of interest.

The endocannabinoid system is a promising therapeutic target for the treatment of migraine, according to Italian researchers at the University of Pavia, and the C. Mondino National Institute of Neurology Foundation. “The complexity of the endocannabinoid system calls for accurate biochemical and pharmacological characterization of any new compounds undergoing testing and development,” noted Rosaria Greco, PhD. She and her colleagues authored a review on the topic that was published online Feb. 18, 2022, in Headache.

Although cannabis has been investigated for both the treatment and prevention of migraine, evidence for its benefit is weak because of lack of controlled studies, they explained. Archival data from a large database “showed greater improvements in men than in women and suggested that concentrated preparations were more effective than flower consumption.” In addition, a small single-center study linked nabilone, a synthetic cannabinoid, to reductions in pain duration, intensity, and daily intake of analgesics among patients with medication overuse headache. Finally, a pilot study reported a reduction in pain intensity among patients with chronic migraine treated with a combination of tested a combination of delta-9-tetrahydrocannabinol and cannabidiol. “Methodologically sound studies are now needed to investigate the possible effects of cannabis in migraine treatment and to define strains, formulations, and dosage,” they noted.
 

Not just cannabis

In addition to exogenous cannabis, there are now preclinical studies suggesting other compounds that interact with the endocannabinoid system “are also able to modulate the pathways involved in migraine-related pain,” the study authors wrote. “But the road ahead is still long. Multiple molecules linked to the endocannabinoid system have emerged as potential therapeutic targets.

The complexity of the system demands caution and precise biochemical and pharmacological characterization of the new compounds to be tested and developed.”

Among these compounds are endogenous ligands such as N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol that specifically target CB1 and CB2 receptors. Additionally, there are endocannabinoid-based drugs that also target the CB1/CB2 receptors, as well as other substances, such as lipids (palmitoylethanolamide [PEA]) and enzymes, that do not bind to the CB1/CB2 receptors but are responsible for endocannabinoid biosynthesis.

There is some evidence that the endocannabinoid system may be dysfunctional in patients with migraine, and the authors noted their work has shown that PEA plasma levels are increased during experimentally triggered migraine-like attacks. Thus, some preclinical and preliminary evidence suggests that administration of PEA or anandamide may have analgesic and anti-inflammatory effects in migraine.

Another approach is the inhibition of endocannabinoid catabolic enzymes, which could circumvent the adverse effects associated with direct activation of CB receptors. “Endocannabinoid tone enhancement has been proposed as an alternative modality of activation of CB receptors and is possibly devoid of the psychotropic effects reported with CB receptor agonists,” noted the authors, who have shown in animal and preclinical studies that inhibition of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase can modulate migraine pain.

Yet another way of indirectly impacting CB receptors is through their allosteric ligands, an approach that “deserves further investigation”, and “might provide interesting leads for clinical development, given that it may have a favorable side-effect profile with limited psychomimetic and depressant effects,” wrote the authors. And finally, inhibition of N-acylethanolamine acid amide hydrolase, the enzyme that preferentially hydrolyzes PEA, might be a promising approach.

“The multiplicity of options and the wealth of data already obtained in animal models underscore the importance of further advancing research in this area,” the authors concluded.
 

Patients are taking cannabinoids; physicians should learn about them

Commenting on the paper, Alan Rapaport, MD, clinical professor of neurology at the University of California, Los Angeles, said “this well-done paper points out the complexity of the endocannabinoid system and the multiple ways of getting it to work for certain patients. It details some of the studies that show beneficial results in migraine, medication overuse headache, chronic migraine, and pain. Patients with headache, other types of pain, anxiety, nausea, sleep issues, and other symptoms are already taking cannabinoids, usually derived from the marijuana plant, that are not well regulated. A few are prescribed drugs which target CB1 and CB2 receptors. Patients often get relief of some of their symptoms, sometimes getting high and many times not.

“The paper makes the point that previous studies are often small, not carefully controlled, or well documented. We do need to start doing larger, properly designed studies and getting them into the literature. Doctors need to learn more about these treatments. The next step will be to get [Food and Drug Administration]–approved treatments, so physicians and nurses will know exactly what we are giving, the beneficial effects to expect in a certain percentage of patients, and the adverse events to warn our patients about. Cannabinoids have been tried by a large percentage of patients with headache and pain. Now we need to standardize the various treatments that are sure to be suggested in the future.”

The study was funded by the Migraine Research Foundation, and the Italian Ministry of Health. The study authors declared no conflicts of interest.

Neurology, once considered a “diagnose and adios” specialty, is gaining newfound, scientific respect. Our vastly improved understanding of neurologic pathophysiology has led to many Food and Drug Administration–approved medications that can specifically enhance treatment outcomes. Medications for migraine, multiple sclerosis, epilepsy, and other chronic neurological diseases have been extended and modernized; for millions of patients, these medicines fulfill their long-awaited needs.

What would Dr Osler have said if he witnessed today’s definition of the practice of medicine? As singular as our patients and their disorders are, the delivery of care is anything but. The processes in the delivery of this care have created many unforeseen twists and turns, thanks to the electronic health record (EHR), the resource-based relative value scale (RBRVS), evaluation and management (E&M) coding, and private health insurance (PHI).

From a neurologist’s perspective, I will elaborate upon these changes that have affected our day-to-day neurology practices. I have practiced general neurology and headache medicine both in private and academic practices, evaluating and treating thousands of inpatients and outpatients in urban and rural healthcare facilities since 1986.

The EHR

Despite herculean, lofty, and sustained efforts by the medical business world to promote EHR adoption worldwide, goals remain unmet. Intended to improve the quality of care and patient outcomes, reduce medical errors, and crystalize communications among providers and with patients, it is instead associated with physician burnout (B), lack of usability (U) and interoperability (I), has likability (L) issues, and provides no productive physician direction (D) – there is an enormous need to BUILD it better.

In my own practice, it is inevitable that I will use my EHR laptop with an unknowing patient. If so, I try to make her feel comfortable in its presence as I strive to stay intent on our discussion. Yet I invariably split my concentration between machine and patient. The machine often gets my full attention, with its confusing and unnecessary medical record notes, tech glitches and screen interruptions, let alone its complicated web of tabs, buttons, links, and obscure prompts. As for fulfilling CMS’ meaningful use criteria to reap financial benefits, I long ago abandoned that effort if earning benefits and reaching the desired patient outcome weren’t on the same path.

We are required to read numerous EHR windows, deal with misused, template-based medical records and the usually faulty copy-and-paste function, which results in flagrant errors. A common example is templating or copy-and-pasting normal examination findings such as “pupils equal, round, and reactive to light and accommodation (PERRLA),” without making modifications for a patient who has obvious abnormal pupillary findings.  It is the EHR that often induces these types of documentation errors.

The EHR, as it exists now, intrudes into our time with patients. But for the past 30 years, the RBRVs have defined how we are compensated for our services. This compensation scale was created to provide a standard system of paying physicians’ services based on resource costs associated with patient care. The resource components are physician work, practice expense, and professional liability insurance. These components make our compensation based on effort rather than effect.

Payments are calculated into relative value units (RVUs), which are often structured into physician employment contracts.¹ There are many RVU calculations and formulas that determine physician reimbursement and compensation; these are not entirely straightforward and too often lack transparency. Despite Dr Osler’s plea in Aequanimitas for physicians to maintain imperturbability and equanimity, that plea goes to the wayside when debating the value of the RBRVS. This system dilutes the complexities of the physician visit, especially for patients with comorbidities, polypharmacy, and cognitive and social concerns.²

Another frustrating, time-absorbing business requirement is E&M coding; the codes came about around the same time as RBRVs. Congress established E&M in the mid-1990s to facilitate medical billing by translating physician-patient encounters into 5-digit codes. In a neurology office, this authentication takes considerable effort, detracts from the patient’s visit, and adds to the documentation requirement to receive insured patient payments.

Years ago, I reviewed neurology insurance claims for a global health service company. I remember the considerable discussion over subjective documentation technicalities, attempting to justify the submitted E&M code. The onerous administrative burden E&M has created continues to evolve, with no end in sight.

Private insurance

When was the last time that you did not have to submit a prior authorization (PA) request to a payer in a week’s worth of days?

PA requests impede timely, efficient, and much-needed vital care while usurping a physician’s decision-making process. In 2020, the American Medical Association released the responses of 1000 physicians who were asked about making PA requests.³ Physicians said that the time delays affected their patients’ health and created adverse events, including hospitalizations. PAs are not only requested for new drugs; physicians report that the increase in the volume of PAs includes requests for existing drugs and services.

It takes staff days to make the requests; most medical practices interact with dozens of different health plans, all with different requirements related to PAs. Insurers often follow the lead of Medicare, and Medicare does not cover most self-injectable medications.⁴

I can report the same experiences. Ten years ago, private insurers rejected ~20% of my practice’s PA requests. Today, more than half of my patients need a PA from their insurer—often for 2 or 3 prescriptions each—and at least half of the requests are rejected. And, unlike 10 years ago, most of my requests are still denied after an appeal.

My patients are mostly migraine patients. When appropriate, I discuss with them the new acute and preventive anti–calcitonin gene-related peptides (anti-CGRPs), which, for the chronic migraine patient, can be a small slice of heaven. Reality strikes, however, when we discuss the likely PA process. This shift no longer focuses on getting likely migraine relief, but instead on the insurance company or companies approving the PA.

Sometimes the PA approval process is only accomplished by patients fighting the PA battle for themselves. One patient recently had to convince her PA oversight insurance representative that, if her PA was denied, her suicide would follow.

And what do patients do if the PA has been denied? Sometimes I must treat a patient with something else, which is often less appropriate for that patient. I have had many patients who have given up during the process.

Industry sees PAs in a different light. A survey⁵ of 44 payers conducted in 2019 found that PAs save money, improve evidence-based care, and so on. Physicians asking for the PAs were singled out as the reasons PAs were denied, as these physicians did not follow proper protocols.

Despite government and PHI policies that are supposed to enhance healthcare delivery and stabilize costs, US healthcare costs stand at $3.6 trillion.^6,7 These medical practice transitions have increased administrative burden, accounting for 34% of US total healthcare expenditures vs 17% in Canada.^8,9

In neurology, successful outcomes are predicated on recognizing the singularity of each patient. The current health system’s need for homogenization is making such recognition difficult. I invite you to read my commentary entitled The Practice of Medicine - Hazy or Invisible Lines, which discusses the unintended consequences of these well-intentioned medical practice adjustments. 

Comments from Alan Rapoport, MD

Editor in Chief, Neurology Reviews

Professor Landy’s article excellently details just some of the roadblocks all neurologists face in providing patient-centric care. Prescribing medication or devices alone does not provide such care, but that is what many doctors must do because of limited time with the patient. Dr Osler was correct; we have to treat the patient who has the disease, not the disease the patient has. Taking an adequate history, conducting a full neurologic examination, documenting both, reviewing outside records, discussing the diagnosis and plan with the patient, ordering appropriate testing, and dictating all of the above in 20 or 30 minutes is impossible to do well. Going forward, we can expect computers and some form of artificial intelligence will help us to be more efficient, but we must keep the patient in the center. No wonder patients are not as happy with the healthcare system and their doctors as they used to be.

Alan Rapoport, MD

Clinical Professor of Neurology

The David Geffen School of Medicine at UCLA, Los Angeles, California

Past President

The International Headache Society (IHS)

Neurology, once considered a “diagnose and adios” specialty, is gaining newfound, scientific respect. Our vastly improved understanding of neurologic pathophysiology has led to many Food and Drug Administration–approved medications that can specifically enhance treatment outcomes. Medications for migraine, multiple sclerosis, epilepsy, and other chronic neurological diseases have been extended and modernized; for millions of patients, these medicines fulfill their long-awaited needs.

What would Dr Osler have said if he witnessed today’s definition of the practice of medicine? As singular as our patients and their disorders are, the delivery of care is anything but. The processes in the delivery of this care have created many unforeseen twists and turns, thanks to the electronic health record (EHR), the resource-based relative value scale (RBRVS), evaluation and management (E&M) coding, and private health insurance (PHI).

From a neurologist’s perspective, I will elaborate upon these changes that have affected our day-to-day neurology practices. I have practiced general neurology and headache medicine both in private and academic practices, evaluating and treating thousands of inpatients and outpatients in urban and rural healthcare facilities since 1986.

The EHR

Despite herculean, lofty, and sustained efforts by the medical business world to promote EHR adoption worldwide, goals remain unmet. Intended to improve the quality of care and patient outcomes, reduce medical errors, and crystalize communications among providers and with patients, it is instead associated with physician burnout (B), lack of usability (U) and interoperability (I), has likability (L) issues, and provides no productive physician direction (D) – there is an enormous need to BUILD it better.

In my own practice, it is inevitable that I will use my EHR laptop with an unknowing patient. If so, I try to make her feel comfortable in its presence as I strive to stay intent on our discussion. Yet I invariably split my concentration between machine and patient. The machine often gets my full attention, with its confusing and unnecessary medical record notes, tech glitches and screen interruptions, let alone its complicated web of tabs, buttons, links, and obscure prompts. As for fulfilling CMS’ meaningful use criteria to reap financial benefits, I long ago abandoned that effort if earning benefits and reaching the desired patient outcome weren’t on the same path.

We are required to read numerous EHR windows, deal with misused, template-based medical records and the usually faulty copy-and-paste function, which results in flagrant errors. A common example is templating or copy-and-pasting normal examination findings such as “pupils equal, round, and reactive to light and accommodation (PERRLA),” without making modifications for a patient who has obvious abnormal pupillary findings.  It is the EHR that often induces these types of documentation errors.

The EHR, as it exists now, intrudes into our time with patients. But for the past 30 years, the RBRVs have defined how we are compensated for our services. This compensation scale was created to provide a standard system of paying physicians’ services based on resource costs associated with patient care. The resource components are physician work, practice expense, and professional liability insurance. These components make our compensation based on effort rather than effect.

Payments are calculated into relative value units (RVUs), which are often structured into physician employment contracts.¹ There are many RVU calculations and formulas that determine physician reimbursement and compensation; these are not entirely straightforward and too often lack transparency. Despite Dr Osler’s plea in Aequanimitas for physicians to maintain imperturbability and equanimity, that plea goes to the wayside when debating the value of the RBRVS. This system dilutes the complexities of the physician visit, especially for patients with comorbidities, polypharmacy, and cognitive and social concerns.²

Another frustrating, time-absorbing business requirement is E&M coding; the codes came about around the same time as RBRVs. Congress established E&M in the mid-1990s to facilitate medical billing by translating physician-patient encounters into 5-digit codes. In a neurology office, this authentication takes considerable effort, detracts from the patient’s visit, and adds to the documentation requirement to receive insured patient payments.

Years ago, I reviewed neurology insurance claims for a global health service company. I remember the considerable discussion over subjective documentation technicalities, attempting to justify the submitted E&M code. The onerous administrative burden E&M has created continues to evolve, with no end in sight.

Private insurance

When was the last time that you did not have to submit a prior authorization (PA) request to a payer in a week’s worth of days?

PA requests impede timely, efficient, and much-needed vital care while usurping a physician’s decision-making process. In 2020, the American Medical Association released the responses of 1000 physicians who were asked about making PA requests.³ Physicians said that the time delays affected their patients’ health and created adverse events, including hospitalizations. PAs are not only requested for new drugs; physicians report that the increase in the volume of PAs includes requests for existing drugs and services.

It takes staff days to make the requests; most medical practices interact with dozens of different health plans, all with different requirements related to PAs. Insurers often follow the lead of Medicare, and Medicare does not cover most self-injectable medications.⁴

I can report the same experiences. Ten years ago, private insurers rejected ~20% of my practice’s PA requests. Today, more than half of my patients need a PA from their insurer—often for 2 or 3 prescriptions each—and at least half of the requests are rejected. And, unlike 10 years ago, most of my requests are still denied after an appeal.

My patients are mostly migraine patients. When appropriate, I discuss with them the new acute and preventive anti–calcitonin gene-related peptides (anti-CGRPs), which, for the chronic migraine patient, can be a small slice of heaven. Reality strikes, however, when we discuss the likely PA process. This shift no longer focuses on getting likely migraine relief, but instead on the insurance company or companies approving the PA.

Sometimes the PA approval process is only accomplished by patients fighting the PA battle for themselves. One patient recently had to convince her PA oversight insurance representative that, if her PA was denied, her suicide would follow.

And what do patients do if the PA has been denied? Sometimes I must treat a patient with something else, which is often less appropriate for that patient. I have had many patients who have given up during the process.

Industry sees PAs in a different light. A survey⁵ of 44 payers conducted in 2019 found that PAs save money, improve evidence-based care, and so on. Physicians asking for the PAs were singled out as the reasons PAs were denied, as these physicians did not follow proper protocols.

Despite government and PHI policies that are supposed to enhance healthcare delivery and stabilize costs, US healthcare costs stand at $3.6 trillion.^6,7 These medical practice transitions have increased administrative burden, accounting for 34% of US total healthcare expenditures vs 17% in Canada.^8,9

In neurology, successful outcomes are predicated on recognizing the singularity of each patient. The current health system’s need for homogenization is making such recognition difficult. I invite you to read my commentary entitled The Practice of Medicine - Hazy or Invisible Lines, which discusses the unintended consequences of these well-intentioned medical practice adjustments. 

Comments from Alan Rapoport, MD

Editor in Chief, Neurology Reviews

Professor Landy’s article excellently details just some of the roadblocks all neurologists face in providing patient-centric care. Prescribing medication or devices alone does not provide such care, but that is what many doctors must do because of limited time with the patient. Dr Osler was correct; we have to treat the patient who has the disease, not the disease the patient has. Taking an adequate history, conducting a full neurologic examination, documenting both, reviewing outside records, discussing the diagnosis and plan with the patient, ordering appropriate testing, and dictating all of the above in 20 or 30 minutes is impossible to do well. Going forward, we can expect computers and some form of artificial intelligence will help us to be more efficient, but we must keep the patient in the center. No wonder patients are not as happy with the healthcare system and their doctors as they used to be.

Alan Rapoport, MD

Clinical Professor of Neurology

The David Geffen School of Medicine at UCLA, Los Angeles, California

Past President

The International Headache Society (IHS)

Neurology, once considered a “diagnose and adios” specialty, is gaining newfound, scientific respect. Our vastly improved understanding of neurologic pathophysiology has led to many Food and Drug Administration–approved medications that can specifically enhance treatment outcomes. Medications for migraine, multiple sclerosis, epilepsy, and other chronic neurological diseases have been extended and modernized; for millions of patients, these medicines fulfill their long-awaited needs.

What would Dr Osler have said if he witnessed today’s definition of the practice of medicine? As singular as our patients and their disorders are, the delivery of care is anything but. The processes in the delivery of this care have created many unforeseen twists and turns, thanks to the electronic health record (EHR), the resource-based relative value scale (RBRVS), evaluation and management (E&M) coding, and private health insurance (PHI).

From a neurologist’s perspective, I will elaborate upon these changes that have affected our day-to-day neurology practices. I have practiced general neurology and headache medicine both in private and academic practices, evaluating and treating thousands of inpatients and outpatients in urban and rural healthcare facilities since 1986.

The EHR

Despite herculean, lofty, and sustained efforts by the medical business world to promote EHR adoption worldwide, goals remain unmet. Intended to improve the quality of care and patient outcomes, reduce medical errors, and crystalize communications among providers and with patients, it is instead associated with physician burnout (B), lack of usability (U) and interoperability (I), has likability (L) issues, and provides no productive physician direction (D) – there is an enormous need to BUILD it better.

In my own practice, it is inevitable that I will use my EHR laptop with an unknowing patient. If so, I try to make her feel comfortable in its presence as I strive to stay intent on our discussion. Yet I invariably split my concentration between machine and patient. The machine often gets my full attention, with its confusing and unnecessary medical record notes, tech glitches and screen interruptions, let alone its complicated web of tabs, buttons, links, and obscure prompts. As for fulfilling CMS’ meaningful use criteria to reap financial benefits, I long ago abandoned that effort if earning benefits and reaching the desired patient outcome weren’t on the same path.

We are required to read numerous EHR windows, deal with misused, template-based medical records and the usually faulty copy-and-paste function, which results in flagrant errors. A common example is templating or copy-and-pasting normal examination findings such as “pupils equal, round, and reactive to light and accommodation (PERRLA),” without making modifications for a patient who has obvious abnormal pupillary findings.  It is the EHR that often induces these types of documentation errors.

The EHR, as it exists now, intrudes into our time with patients. But for the past 30 years, the RBRVs have defined how we are compensated for our services. This compensation scale was created to provide a standard system of paying physicians’ services based on resource costs associated with patient care. The resource components are physician work, practice expense, and professional liability insurance. These components make our compensation based on effort rather than effect.

Payments are calculated into relative value units (RVUs), which are often structured into physician employment contracts.¹ There are many RVU calculations and formulas that determine physician reimbursement and compensation; these are not entirely straightforward and too often lack transparency. Despite Dr Osler’s plea in Aequanimitas for physicians to maintain imperturbability and equanimity, that plea goes to the wayside when debating the value of the RBRVS. This system dilutes the complexities of the physician visit, especially for patients with comorbidities, polypharmacy, and cognitive and social concerns.²

Another frustrating, time-absorbing business requirement is E&M coding; the codes came about around the same time as RBRVs. Congress established E&M in the mid-1990s to facilitate medical billing by translating physician-patient encounters into 5-digit codes. In a neurology office, this authentication takes considerable effort, detracts from the patient’s visit, and adds to the documentation requirement to receive insured patient payments.

Years ago, I reviewed neurology insurance claims for a global health service company. I remember the considerable discussion over subjective documentation technicalities, attempting to justify the submitted E&M code. The onerous administrative burden E&M has created continues to evolve, with no end in sight.

Private insurance

When was the last time that you did not have to submit a prior authorization (PA) request to a payer in a week’s worth of days?

PA requests impede timely, efficient, and much-needed vital care while usurping a physician’s decision-making process. In 2020, the American Medical Association released the responses of 1000 physicians who were asked about making PA requests.³ Physicians said that the time delays affected their patients’ health and created adverse events, including hospitalizations. PAs are not only requested for new drugs; physicians report that the increase in the volume of PAs includes requests for existing drugs and services.

It takes staff days to make the requests; most medical practices interact with dozens of different health plans, all with different requirements related to PAs. Insurers often follow the lead of Medicare, and Medicare does not cover most self-injectable medications.⁴

I can report the same experiences. Ten years ago, private insurers rejected ~20% of my practice’s PA requests. Today, more than half of my patients need a PA from their insurer—often for 2 or 3 prescriptions each—and at least half of the requests are rejected. And, unlike 10 years ago, most of my requests are still denied after an appeal.

My patients are mostly migraine patients. When appropriate, I discuss with them the new acute and preventive anti–calcitonin gene-related peptides (anti-CGRPs), which, for the chronic migraine patient, can be a small slice of heaven. Reality strikes, however, when we discuss the likely PA process. This shift no longer focuses on getting likely migraine relief, but instead on the insurance company or companies approving the PA.

Sometimes the PA approval process is only accomplished by patients fighting the PA battle for themselves. One patient recently had to convince her PA oversight insurance representative that, if her PA was denied, her suicide would follow.

And what do patients do if the PA has been denied? Sometimes I must treat a patient with something else, which is often less appropriate for that patient. I have had many patients who have given up during the process.

Industry sees PAs in a different light. A survey⁵ of 44 payers conducted in 2019 found that PAs save money, improve evidence-based care, and so on. Physicians asking for the PAs were singled out as the reasons PAs were denied, as these physicians did not follow proper protocols.

Despite government and PHI policies that are supposed to enhance healthcare delivery and stabilize costs, US healthcare costs stand at $3.6 trillion.^6,7 These medical practice transitions have increased administrative burden, accounting for 34% of US total healthcare expenditures vs 17% in Canada.^8,9

In neurology, successful outcomes are predicated on recognizing the singularity of each patient. The current health system’s need for homogenization is making such recognition difficult. I invite you to read my commentary entitled The Practice of Medicine - Hazy or Invisible Lines, which discusses the unintended consequences of these well-intentioned medical practice adjustments. 

Comments from Alan Rapoport, MD

Editor in Chief, Neurology Reviews

Professor Landy’s article excellently details just some of the roadblocks all neurologists face in providing patient-centric care. Prescribing medication or devices alone does not provide such care, but that is what many doctors must do because of limited time with the patient. Dr Osler was correct; we have to treat the patient who has the disease, not the disease the patient has. Taking an adequate history, conducting a full neurologic examination, documenting both, reviewing outside records, discussing the diagnosis and plan with the patient, ordering appropriate testing, and dictating all of the above in 20 or 30 minutes is impossible to do well. Going forward, we can expect computers and some form of artificial intelligence will help us to be more efficient, but we must keep the patient in the center. No wonder patients are not as happy with the healthcare system and their doctors as they used to be.

Alan Rapoport, MD

Clinical Professor of Neurology

The David Geffen School of Medicine at UCLA, Los Angeles, California

Past President

The International Headache Society (IHS)

The theme of the articles this month is migraine and blood vessels. Migraine is a known risk factor for vascular events, it is a known vasodilatory phenomenon, and it is commonly treated with vasoconstrictive medications. Genetic studies are further elucidating the connection between migraine and vascular risk factors. The following studies take this vascular connection to clinical relevance in different ways.

Previous studies have investigated the combination of simvastatin and vitamin D for migraine prevention. Statins have anti-inflammatory properties and migraine can partially be understood as an inflammatory vascular phenomenon. Vitamin D and simvastatin were previously shown to be effective in a randomized trial; this study¹ investigated the combination of atorvastatin with nortriptyline for migraine prevention. Patients were excluded if they had a vitamin D deficiency.

This was a triple-blinded study with one control group, one placebo plus notriptyline group, and one atorvastatin plus nortiptyline group. The nortiptyline dosage was 25mg nightly, and the interventions were given for 24 weeks. The primary outcome was decrease in headache day frequency; secondary outcomes were severity and quality of life as measured by the Migraine-Specific Quality of Life Questionnaire (MSQ).

Migraine frequency was seen to be significantly improved after 24 weeks in the statin group; however severity was not significantly affected. Adverse effects were mild and overall no subjects discontinued due to the intervention. Quality of life was also seen to be better in the combination statin/nortriptyline group.

The results of this study are compelling enough to consider the addition of a tricyclic antidepressant (TCA) for a patient already on a statin or to start a statin (in the appropriate clinical setting) on a patient already on a TCA. The main limiting factor may be the hesitation to use a TCA medication in an older patient, where the anticholinergic effects may be less predictable.

Caffeine has a controversial place in the headache world. Many patients either use caffeine as a way to treat their migraine attacks, or avoid it completely as they are told it is a migraine trigger. Most headache specialists recommend the avoidance of excessive caffeine use (typically considered >150 mg daily) and tell their patients to be consistent about when they consume caffeine. The effect of caffeine on migraine likely is due to its vasoactive property, specifically that it is vasoconstrictive in nature. These vasoactive properties may also be why many studies investigating cerebrovascular reactivity have been inconclusive in the past.

The authors in this study² recruited patients with episodic migraine and divided them based on caffeine use. All subjects underwent transcranial Doppler testing at baseline and after 3 months, caffeine users were instructed to discontinue caffeine in the interim. Doppler testing looked for differences in BHI (breath holding index) of the bilateral posterior cerebral arteries (PCA), which is a standard at their institution. Subjects were only investigated if they were headache-free and had not used a migraine abortive medication in the previous 48 hours. Preventive medications were not controlled for.

Although the investigators recommended discontinuation of caffeine for the caffeine users, only 28% of that subgroup did discontinue. They then subdivided the group of caffeine users into those whose caffeine intake increased, decreased, or stayed the same. Transcranial Doppler testing was performed in all subgroups.

The investigators found a lower BHI-PCA, or decrease in vasodilatory function, in the subgroups that remained on caffeine. Those who stopped caffeine had improvement in this metric, showing the possible reversibility that discontinuation of caffeine can have. It remains unclear precisely how caffeine is vasoactive, and the effects may be via adenosine receptors, endothelial function, neurotransmitter production, or regulation of the autonomic nervous system. The long-term vascular effects of caffeine are unknown, but they do appear to be reversible after a 3 month period.

Migraine, and especially migraine with aura, is well known as a vascular risk factor. The presence of migraine increases the odds ratio of stroke, myocardial ischemia, deep vein thrombosis and other vascular events significantly. The American College of Obstetrics and Gynecology recommends avoiding the use of any estrogen containing medication in the presence of migraine, due to estrogen itself being a pro-thrombotic hormone.  The precise mechanism that leads to this increased risk is unknown.

This study investigated the connection between migraine and large artery atherosclerosis (LAA). This group observed 415 consecutive patients aged 18-54 who presented for a first time ischemic stroke (other neurovascular events, such as cerebral venous sinus thrombosis, subarachnoid hemorrhage with secondary ischemia and transient ischemic attacks, were excluded). Data regarding these patient’s risks factors was collected and analyzed including elevated body mass index (BMI), hypertension, diabetes, tobacco use, and hyperlipidemia.

All patients underwent magnetic resonance imaging (MRI), as well as either magnetic resonance angiography (MRA) or computed tomography angiography (CTA), and duplex ultrasound confirmed the images. Atherosclerosis was classified using a standardized system (ASCOD: atherosclerosis, small-vessel disease, cardiac pathology, other causes, and dissection) that grades atheroslerotic lesions on a 0-3 scale.

The results may be considered counterintuitive. The presence of migraine was negatively associated with the presence of LAA: a history of migraine did not increase the risk of atherosclerosis. This was even the case when controlling for the traditional vascular risk factors. The authors theorize that likely the association between migraine and stroke and other vascular events is not related to atherosclerosis and may be due to other causes.

A genome-wide association study recently identified a specific polymorphism that was shared by migraine and coronary artery disease. But just like this study, the people with migraine had a negative association with coronary artery disease. If people with migraine do develop stroke or other vascular phenomena they typically present younger and healthier, and this may be why this negative correlation exists.

References

1. Sherafat M et al. The preventive effect of the combination of atorvastatin and nortriptyline in migraine-type headache: a randomized, triple-blind, placebo-controlled trial. Neurol Res. 2022 (Jan 17).
2. Gil Y-E et al. Effect of caffeine and caffeine cessation on cerebrovascular reactivity in patients with migraine. Headache. 2022;62(2):169-75 (Feb 3).
3. Gollion C et al. Migraine and large artery atherosclerosis in young adults with ischemic stroke. Headache. 2022;62(2):191-7 (Feb 5).

The theme of the articles this month is migraine and blood vessels. Migraine is a known risk factor for vascular events, it is a known vasodilatory phenomenon, and it is commonly treated with vasoconstrictive medications. Genetic studies are further elucidating the connection between migraine and vascular risk factors. The following studies take this vascular connection to clinical relevance in different ways.

Previous studies have investigated the combination of simvastatin and vitamin D for migraine prevention. Statins have anti-inflammatory properties and migraine can partially be understood as an inflammatory vascular phenomenon. Vitamin D and simvastatin were previously shown to be effective in a randomized trial; this study¹ investigated the combination of atorvastatin with nortriptyline for migraine prevention. Patients were excluded if they had a vitamin D deficiency.

This was a triple-blinded study with one control group, one placebo plus notriptyline group, and one atorvastatin plus nortiptyline group. The nortiptyline dosage was 25mg nightly, and the interventions were given for 24 weeks. The primary outcome was decrease in headache day frequency; secondary outcomes were severity and quality of life as measured by the Migraine-Specific Quality of Life Questionnaire (MSQ).

Migraine frequency was seen to be significantly improved after 24 weeks in the statin group; however severity was not significantly affected. Adverse effects were mild and overall no subjects discontinued due to the intervention. Quality of life was also seen to be better in the combination statin/nortriptyline group.

The results of this study are compelling enough to consider the addition of a tricyclic antidepressant (TCA) for a patient already on a statin or to start a statin (in the appropriate clinical setting) on a patient already on a TCA. The main limiting factor may be the hesitation to use a TCA medication in an older patient, where the anticholinergic effects may be less predictable.

Caffeine has a controversial place in the headache world. Many patients either use caffeine as a way to treat their migraine attacks, or avoid it completely as they are told it is a migraine trigger. Most headache specialists recommend the avoidance of excessive caffeine use (typically considered >150 mg daily) and tell their patients to be consistent about when they consume caffeine. The effect of caffeine on migraine likely is due to its vasoactive property, specifically that it is vasoconstrictive in nature. These vasoactive properties may also be why many studies investigating cerebrovascular reactivity have been inconclusive in the past.

The authors in this study² recruited patients with episodic migraine and divided them based on caffeine use. All subjects underwent transcranial Doppler testing at baseline and after 3 months, caffeine users were instructed to discontinue caffeine in the interim. Doppler testing looked for differences in BHI (breath holding index) of the bilateral posterior cerebral arteries (PCA), which is a standard at their institution. Subjects were only investigated if they were headache-free and had not used a migraine abortive medication in the previous 48 hours. Preventive medications were not controlled for.

Although the investigators recommended discontinuation of caffeine for the caffeine users, only 28% of that subgroup did discontinue. They then subdivided the group of caffeine users into those whose caffeine intake increased, decreased, or stayed the same. Transcranial Doppler testing was performed in all subgroups.

The investigators found a lower BHI-PCA, or decrease in vasodilatory function, in the subgroups that remained on caffeine. Those who stopped caffeine had improvement in this metric, showing the possible reversibility that discontinuation of caffeine can have. It remains unclear precisely how caffeine is vasoactive, and the effects may be via adenosine receptors, endothelial function, neurotransmitter production, or regulation of the autonomic nervous system. The long-term vascular effects of caffeine are unknown, but they do appear to be reversible after a 3 month period.

Migraine, and especially migraine with aura, is well known as a vascular risk factor. The presence of migraine increases the odds ratio of stroke, myocardial ischemia, deep vein thrombosis and other vascular events significantly. The American College of Obstetrics and Gynecology recommends avoiding the use of any estrogen containing medication in the presence of migraine, due to estrogen itself being a pro-thrombotic hormone.  The precise mechanism that leads to this increased risk is unknown.

This study investigated the connection between migraine and large artery atherosclerosis (LAA). This group observed 415 consecutive patients aged 18-54 who presented for a first time ischemic stroke (other neurovascular events, such as cerebral venous sinus thrombosis, subarachnoid hemorrhage with secondary ischemia and transient ischemic attacks, were excluded). Data regarding these patient’s risks factors was collected and analyzed including elevated body mass index (BMI), hypertension, diabetes, tobacco use, and hyperlipidemia.

All patients underwent magnetic resonance imaging (MRI), as well as either magnetic resonance angiography (MRA) or computed tomography angiography (CTA), and duplex ultrasound confirmed the images. Atherosclerosis was classified using a standardized system (ASCOD: atherosclerosis, small-vessel disease, cardiac pathology, other causes, and dissection) that grades atheroslerotic lesions on a 0-3 scale.

The results may be considered counterintuitive. The presence of migraine was negatively associated with the presence of LAA: a history of migraine did not increase the risk of atherosclerosis. This was even the case when controlling for the traditional vascular risk factors. The authors theorize that likely the association between migraine and stroke and other vascular events is not related to atherosclerosis and may be due to other causes.

A genome-wide association study recently identified a specific polymorphism that was shared by migraine and coronary artery disease. But just like this study, the people with migraine had a negative association with coronary artery disease. If people with migraine do develop stroke or other vascular phenomena they typically present younger and healthier, and this may be why this negative correlation exists.

References

1. Sherafat M et al. The preventive effect of the combination of atorvastatin and nortriptyline in migraine-type headache: a randomized, triple-blind, placebo-controlled trial. Neurol Res. 2022 (Jan 17).
2. Gil Y-E et al. Effect of caffeine and caffeine cessation on cerebrovascular reactivity in patients with migraine. Headache. 2022;62(2):169-75 (Feb 3).
3. Gollion C et al. Migraine and large artery atherosclerosis in young adults with ischemic stroke. Headache. 2022;62(2):191-7 (Feb 5).

The theme of the articles this month is migraine and blood vessels. Migraine is a known risk factor for vascular events, it is a known vasodilatory phenomenon, and it is commonly treated with vasoconstrictive medications. Genetic studies are further elucidating the connection between migraine and vascular risk factors. The following studies take this vascular connection to clinical relevance in different ways.

Previous studies have investigated the combination of simvastatin and vitamin D for migraine prevention. Statins have anti-inflammatory properties and migraine can partially be understood as an inflammatory vascular phenomenon. Vitamin D and simvastatin were previously shown to be effective in a randomized trial; this study¹ investigated the combination of atorvastatin with nortriptyline for migraine prevention. Patients were excluded if they had a vitamin D deficiency.

This was a triple-blinded study with one control group, one placebo plus notriptyline group, and one atorvastatin plus nortiptyline group. The nortiptyline dosage was 25mg nightly, and the interventions were given for 24 weeks. The primary outcome was decrease in headache day frequency; secondary outcomes were severity and quality of life as measured by the Migraine-Specific Quality of Life Questionnaire (MSQ).

Migraine frequency was seen to be significantly improved after 24 weeks in the statin group; however severity was not significantly affected. Adverse effects were mild and overall no subjects discontinued due to the intervention. Quality of life was also seen to be better in the combination statin/nortriptyline group.

The results of this study are compelling enough to consider the addition of a tricyclic antidepressant (TCA) for a patient already on a statin or to start a statin (in the appropriate clinical setting) on a patient already on a TCA. The main limiting factor may be the hesitation to use a TCA medication in an older patient, where the anticholinergic effects may be less predictable.

Caffeine has a controversial place in the headache world. Many patients either use caffeine as a way to treat their migraine attacks, or avoid it completely as they are told it is a migraine trigger. Most headache specialists recommend the avoidance of excessive caffeine use (typically considered >150 mg daily) and tell their patients to be consistent about when they consume caffeine. The effect of caffeine on migraine likely is due to its vasoactive property, specifically that it is vasoconstrictive in nature. These vasoactive properties may also be why many studies investigating cerebrovascular reactivity have been inconclusive in the past.

The authors in this study² recruited patients with episodic migraine and divided them based on caffeine use. All subjects underwent transcranial Doppler testing at baseline and after 3 months, caffeine users were instructed to discontinue caffeine in the interim. Doppler testing looked for differences in BHI (breath holding index) of the bilateral posterior cerebral arteries (PCA), which is a standard at their institution. Subjects were only investigated if they were headache-free and had not used a migraine abortive medication in the previous 48 hours. Preventive medications were not controlled for.

Although the investigators recommended discontinuation of caffeine for the caffeine users, only 28% of that subgroup did discontinue. They then subdivided the group of caffeine users into those whose caffeine intake increased, decreased, or stayed the same. Transcranial Doppler testing was performed in all subgroups.

The investigators found a lower BHI-PCA, or decrease in vasodilatory function, in the subgroups that remained on caffeine. Those who stopped caffeine had improvement in this metric, showing the possible reversibility that discontinuation of caffeine can have. It remains unclear precisely how caffeine is vasoactive, and the effects may be via adenosine receptors, endothelial function, neurotransmitter production, or regulation of the autonomic nervous system. The long-term vascular effects of caffeine are unknown, but they do appear to be reversible after a 3 month period.

Migraine, and especially migraine with aura, is well known as a vascular risk factor. The presence of migraine increases the odds ratio of stroke, myocardial ischemia, deep vein thrombosis and other vascular events significantly. The American College of Obstetrics and Gynecology recommends avoiding the use of any estrogen containing medication in the presence of migraine, due to estrogen itself being a pro-thrombotic hormone.  The precise mechanism that leads to this increased risk is unknown.

This study investigated the connection between migraine and large artery atherosclerosis (LAA). This group observed 415 consecutive patients aged 18-54 who presented for a first time ischemic stroke (other neurovascular events, such as cerebral venous sinus thrombosis, subarachnoid hemorrhage with secondary ischemia and transient ischemic attacks, were excluded). Data regarding these patient’s risks factors was collected and analyzed including elevated body mass index (BMI), hypertension, diabetes, tobacco use, and hyperlipidemia.

All patients underwent magnetic resonance imaging (MRI), as well as either magnetic resonance angiography (MRA) or computed tomography angiography (CTA), and duplex ultrasound confirmed the images. Atherosclerosis was classified using a standardized system (ASCOD: atherosclerosis, small-vessel disease, cardiac pathology, other causes, and dissection) that grades atheroslerotic lesions on a 0-3 scale.

The results may be considered counterintuitive. The presence of migraine was negatively associated with the presence of LAA: a history of migraine did not increase the risk of atherosclerosis. This was even the case when controlling for the traditional vascular risk factors. The authors theorize that likely the association between migraine and stroke and other vascular events is not related to atherosclerosis and may be due to other causes.

A genome-wide association study recently identified a specific polymorphism that was shared by migraine and coronary artery disease. But just like this study, the people with migraine had a negative association with coronary artery disease. If people with migraine do develop stroke or other vascular phenomena they typically present younger and healthier, and this may be why this negative correlation exists.

References

1. Sherafat M et al. The preventive effect of the combination of atorvastatin and nortriptyline in migraine-type headache: a randomized, triple-blind, placebo-controlled trial. Neurol Res. 2022 (Jan 17).
2. Gil Y-E et al. Effect of caffeine and caffeine cessation on cerebrovascular reactivity in patients with migraine. Headache. 2022;62(2):169-75 (Feb 3).
3. Gollion C et al. Migraine and large artery atherosclerosis in young adults with ischemic stroke. Headache. 2022;62(2):191-7 (Feb 5).

Anti–calcitonin gene-related peptide (anti-CGRP) monoclonal antibodies are effective for patients with chronic migraine and medication overuse headache regardless of detoxification strategy, according to investigators.

Abruptly discontinuing overused analgesics with health care provider oversight – a frequently resource-intensive and challenging process – is no more effective for controlling medication overuse headache than simply advising patients to stop, reported lead author Umberto Pensato, MD, of the University of Bologna, Italy, and colleagues.

“[C]urrently, the abrupt discontinuation of the overused painkiller(s), accompanied by the start of a pharmacological preventive therapy, is the most recommended strategy [for medication overuse headache],” the investigators wrote in Cephalalgia. “While painkiller(s) withdrawal could be accomplished on an outpatient basis in most cases, an in-hospital setting may be required to achieve successful discontinuation in a subgroup of patients with medication overuse headache, further weighing on individual and hospital costs. Additionally hampering this approach, the abrupt discontinuation of the overused painkiller(s) invariably results in disabling withdrawal symptoms for up to 2 weeks, including a transitory worsening of headache, the so-called ‘rebound headache.’ ”
 

Inpatient or outpatient: Does it matter?

According to Dr. Pensato and colleagues, early evidence suggests that previous painkiller withdrawal does not impact the efficacy of anti-CGRPs for medication overuse headache, yet relevant data remain scarce. To address this knowledge gap, they conducted a prospective, real-world study exploring the relationship between detoxification and outcomes after starting anti-CGRP therapy.

Out of 401 patients enrolled based on initiation of erenumab or galcanezumab, 111 satisfied inclusion criteria, including diagnosis of chronic migraine and medication overuse headache, at least 28 days of analgesic usage and headache days per month in the preceding 3 months, and other factors. Of these 111 patients, 83 underwent in-hospital detox, while the remaining 28 patients, who declined detox based on personal reasons or COVID-19–related bed shortage, were advised to discontinue overused medication on an outpatient basis (without oversight).

The primary endpoint was medication overuse headache responder rate after 3 months, as defined by ICHD-3 diagnostic criteria. Secondary endpoints included 6-item headache impact test (HIT-6), monthly headache days (MHD), migraine disability assessment score (MIDAS), mean pain intensity (MPI), monthly pain medication intake (MPMI), baseline predictors of response/refractoriness, and safety.

Three months after starting anti-CGRP therapy, 59% of patients had resolution of medication overuse headache, including 57% in the inpatient detox group and 64% in the outpatient group, a difference that was not statistically significant (P = .4788). Approximately half of the patients (51%) had at least 50% reduction in monthly headache days; although the rate was numerically lower in the inpatient group compared with the outpatient group, the difference was again not significant (51% vs. 54%; P = .8393).

“Our results support the emerging evidence that anti-CGRP drugs may be effective in these patients irrespective of the detoxification program,” the investigators concluded. “Further studies are needed to definitively confirm these results, potentially leading to a paradigm shift in the management of medication overuse headache.”
 

Abrupt or gradual detox?

According to Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews, the study was hampered by two major design limitations.

“The biggest problem I see is that the two groups were treated very differently for their detoxification,” Dr. Rapoport said. “One group was detoxified abruptly in the hospital, so the authors were sure that the patients were off acute-care medication before they started their preventives. The other group was advised to stop their medication on an outpatient basis. The issue is that we have no follow-up as to whether the outpatients did or did not abruptly detoxify. A bigger issue was that the two groups were not randomized so there are many other variables that may have come into consideration.”

Still, Dr. Rapoport, a past president of the International Headache Society (IHS), noted that the findings strengthen a growing body of evidence supporting the efficacy of monoclonal antibodies for medication overuse headache regardless of detoxification strategy. He cited a 2020 study by Carlsen and colleagues conducted at the Danish Headache Center in Copenhagen, which reported similar medication overuse headache outcomes across three randomized cohorts whether they received preventive therapy with detoxification, preventive therapy without detoxification, or detoxification followed 2 months later by preventive therapy.

“What I have noticed since we have had monoclonal antibodies in our armamentarium is that these drugs work very well even when the patient has not fully detoxified,” Dr. Rapoport said. “What I do with my patients is not teach them how to detoxify now, but simply educate them to take fewer acute care medications as their headaches get better from the monoclonal antibodies; they should try to take fewer acute care medications for milder, shorter headaches, and just let them go away on their own. Previous research suggests that even when a patient is not educated at all about medication overuse headache and the reason for detoxification, monoclonal antibodies still work in the presence of medication overuse headache, and improve it.”

The investigators disclosed relationships with Allergan, Novartis, Teva, and others. Dr. Rapoport is on the speakers bureau for AbbVie.

Anti–calcitonin gene-related peptide (anti-CGRP) monoclonal antibodies are effective for patients with chronic migraine and medication overuse headache regardless of detoxification strategy, according to investigators.

Abruptly discontinuing overused analgesics with health care provider oversight – a frequently resource-intensive and challenging process – is no more effective for controlling medication overuse headache than simply advising patients to stop, reported lead author Umberto Pensato, MD, of the University of Bologna, Italy, and colleagues.

“[C]urrently, the abrupt discontinuation of the overused painkiller(s), accompanied by the start of a pharmacological preventive therapy, is the most recommended strategy [for medication overuse headache],” the investigators wrote in Cephalalgia. “While painkiller(s) withdrawal could be accomplished on an outpatient basis in most cases, an in-hospital setting may be required to achieve successful discontinuation in a subgroup of patients with medication overuse headache, further weighing on individual and hospital costs. Additionally hampering this approach, the abrupt discontinuation of the overused painkiller(s) invariably results in disabling withdrawal symptoms for up to 2 weeks, including a transitory worsening of headache, the so-called ‘rebound headache.’ ”
 

Inpatient or outpatient: Does it matter?

According to Dr. Pensato and colleagues, early evidence suggests that previous painkiller withdrawal does not impact the efficacy of anti-CGRPs for medication overuse headache, yet relevant data remain scarce. To address this knowledge gap, they conducted a prospective, real-world study exploring the relationship between detoxification and outcomes after starting anti-CGRP therapy.

Out of 401 patients enrolled based on initiation of erenumab or galcanezumab, 111 satisfied inclusion criteria, including diagnosis of chronic migraine and medication overuse headache, at least 28 days of analgesic usage and headache days per month in the preceding 3 months, and other factors. Of these 111 patients, 83 underwent in-hospital detox, while the remaining 28 patients, who declined detox based on personal reasons or COVID-19–related bed shortage, were advised to discontinue overused medication on an outpatient basis (without oversight).

The primary endpoint was medication overuse headache responder rate after 3 months, as defined by ICHD-3 diagnostic criteria. Secondary endpoints included 6-item headache impact test (HIT-6), monthly headache days (MHD), migraine disability assessment score (MIDAS), mean pain intensity (MPI), monthly pain medication intake (MPMI), baseline predictors of response/refractoriness, and safety.

Three months after starting anti-CGRP therapy, 59% of patients had resolution of medication overuse headache, including 57% in the inpatient detox group and 64% in the outpatient group, a difference that was not statistically significant (P = .4788). Approximately half of the patients (51%) had at least 50% reduction in monthly headache days; although the rate was numerically lower in the inpatient group compared with the outpatient group, the difference was again not significant (51% vs. 54%; P = .8393).

“Our results support the emerging evidence that anti-CGRP drugs may be effective in these patients irrespective of the detoxification program,” the investigators concluded. “Further studies are needed to definitively confirm these results, potentially leading to a paradigm shift in the management of medication overuse headache.”
 

Abrupt or gradual detox?

According to Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews, the study was hampered by two major design limitations.

“The biggest problem I see is that the two groups were treated very differently for their detoxification,” Dr. Rapoport said. “One group was detoxified abruptly in the hospital, so the authors were sure that the patients were off acute-care medication before they started their preventives. The other group was advised to stop their medication on an outpatient basis. The issue is that we have no follow-up as to whether the outpatients did or did not abruptly detoxify. A bigger issue was that the two groups were not randomized so there are many other variables that may have come into consideration.”

Still, Dr. Rapoport, a past president of the International Headache Society (IHS), noted that the findings strengthen a growing body of evidence supporting the efficacy of monoclonal antibodies for medication overuse headache regardless of detoxification strategy. He cited a 2020 study by Carlsen and colleagues conducted at the Danish Headache Center in Copenhagen, which reported similar medication overuse headache outcomes across three randomized cohorts whether they received preventive therapy with detoxification, preventive therapy without detoxification, or detoxification followed 2 months later by preventive therapy.

“What I have noticed since we have had monoclonal antibodies in our armamentarium is that these drugs work very well even when the patient has not fully detoxified,” Dr. Rapoport said. “What I do with my patients is not teach them how to detoxify now, but simply educate them to take fewer acute care medications as their headaches get better from the monoclonal antibodies; they should try to take fewer acute care medications for milder, shorter headaches, and just let them go away on their own. Previous research suggests that even when a patient is not educated at all about medication overuse headache and the reason for detoxification, monoclonal antibodies still work in the presence of medication overuse headache, and improve it.”

The investigators disclosed relationships with Allergan, Novartis, Teva, and others. Dr. Rapoport is on the speakers bureau for AbbVie.

Anti–calcitonin gene-related peptide (anti-CGRP) monoclonal antibodies are effective for patients with chronic migraine and medication overuse headache regardless of detoxification strategy, according to investigators.

Abruptly discontinuing overused analgesics with health care provider oversight – a frequently resource-intensive and challenging process – is no more effective for controlling medication overuse headache than simply advising patients to stop, reported lead author Umberto Pensato, MD, of the University of Bologna, Italy, and colleagues.

“[C]urrently, the abrupt discontinuation of the overused painkiller(s), accompanied by the start of a pharmacological preventive therapy, is the most recommended strategy [for medication overuse headache],” the investigators wrote in Cephalalgia. “While painkiller(s) withdrawal could be accomplished on an outpatient basis in most cases, an in-hospital setting may be required to achieve successful discontinuation in a subgroup of patients with medication overuse headache, further weighing on individual and hospital costs. Additionally hampering this approach, the abrupt discontinuation of the overused painkiller(s) invariably results in disabling withdrawal symptoms for up to 2 weeks, including a transitory worsening of headache, the so-called ‘rebound headache.’ ”
 

Inpatient or outpatient: Does it matter?

According to Dr. Pensato and colleagues, early evidence suggests that previous painkiller withdrawal does not impact the efficacy of anti-CGRPs for medication overuse headache, yet relevant data remain scarce. To address this knowledge gap, they conducted a prospective, real-world study exploring the relationship between detoxification and outcomes after starting anti-CGRP therapy.

Out of 401 patients enrolled based on initiation of erenumab or galcanezumab, 111 satisfied inclusion criteria, including diagnosis of chronic migraine and medication overuse headache, at least 28 days of analgesic usage and headache days per month in the preceding 3 months, and other factors. Of these 111 patients, 83 underwent in-hospital detox, while the remaining 28 patients, who declined detox based on personal reasons or COVID-19–related bed shortage, were advised to discontinue overused medication on an outpatient basis (without oversight).

The primary endpoint was medication overuse headache responder rate after 3 months, as defined by ICHD-3 diagnostic criteria. Secondary endpoints included 6-item headache impact test (HIT-6), monthly headache days (MHD), migraine disability assessment score (MIDAS), mean pain intensity (MPI), monthly pain medication intake (MPMI), baseline predictors of response/refractoriness, and safety.

Three months after starting anti-CGRP therapy, 59% of patients had resolution of medication overuse headache, including 57% in the inpatient detox group and 64% in the outpatient group, a difference that was not statistically significant (P = .4788). Approximately half of the patients (51%) had at least 50% reduction in monthly headache days; although the rate was numerically lower in the inpatient group compared with the outpatient group, the difference was again not significant (51% vs. 54%; P = .8393).

“Our results support the emerging evidence that anti-CGRP drugs may be effective in these patients irrespective of the detoxification program,” the investigators concluded. “Further studies are needed to definitively confirm these results, potentially leading to a paradigm shift in the management of medication overuse headache.”
 

Abrupt or gradual detox?

According to Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, and editor-in-chief of Neurology Reviews, the study was hampered by two major design limitations.

“The biggest problem I see is that the two groups were treated very differently for their detoxification,” Dr. Rapoport said. “One group was detoxified abruptly in the hospital, so the authors were sure that the patients were off acute-care medication before they started their preventives. The other group was advised to stop their medication on an outpatient basis. The issue is that we have no follow-up as to whether the outpatients did or did not abruptly detoxify. A bigger issue was that the two groups were not randomized so there are many other variables that may have come into consideration.”

Still, Dr. Rapoport, a past president of the International Headache Society (IHS), noted that the findings strengthen a growing body of evidence supporting the efficacy of monoclonal antibodies for medication overuse headache regardless of detoxification strategy. He cited a 2020 study by Carlsen and colleagues conducted at the Danish Headache Center in Copenhagen, which reported similar medication overuse headache outcomes across three randomized cohorts whether they received preventive therapy with detoxification, preventive therapy without detoxification, or detoxification followed 2 months later by preventive therapy.

“What I have noticed since we have had monoclonal antibodies in our armamentarium is that these drugs work very well even when the patient has not fully detoxified,” Dr. Rapoport said. “What I do with my patients is not teach them how to detoxify now, but simply educate them to take fewer acute care medications as their headaches get better from the monoclonal antibodies; they should try to take fewer acute care medications for milder, shorter headaches, and just let them go away on their own. Previous research suggests that even when a patient is not educated at all about medication overuse headache and the reason for detoxification, monoclonal antibodies still work in the presence of medication overuse headache, and improve it.”

The investigators disclosed relationships with Allergan, Novartis, Teva, and others. Dr. Rapoport is on the speakers bureau for AbbVie.

Key clinical point: Atogepant shows a favorable safety and efficacy profile in the prophylactic treatment of episodic migraine.

Major finding: Atogepant (10 mg, 30 mg, and 60 mg) vs. placebo caused a significant reduction in mean monthly migraine (P < .00001, P < .00001, and P = .007; respectively), headache (P < .00001, P < .00001, and P = .001; respectively), and medication use (all P < .00001) days; an increase in the ≥50% responder rate (P = .0008, P = .02, and P = .04; respectively); and a nonsignificant difference in the outcomes of adverse events (P = .57, P = .64, and P = .68; respectively).

Study details: Findings are from a meta-analysis of 3 randomized controlled trials including 2,466 adult patients with episodic migraine who received atogepant (10 mg, 30 mg, or 60 mg once daily) or placebo.

Disclosures: The study was supported by the Suzhou Health Talents Training Project. None of the authors declared any conflicts of interest.

Source: Tao X et al. J Headache Pain. 2022;23:19 (Jan 29). Doi: 10.1186/s10194-022-01391-2

Key clinical point: Atogepant shows a favorable safety and efficacy profile in the prophylactic treatment of episodic migraine.

Major finding: Atogepant (10 mg, 30 mg, and 60 mg) vs. placebo caused a significant reduction in mean monthly migraine (P < .00001, P < .00001, and P = .007; respectively), headache (P < .00001, P < .00001, and P = .001; respectively), and medication use (all P < .00001) days; an increase in the ≥50% responder rate (P = .0008, P = .02, and P = .04; respectively); and a nonsignificant difference in the outcomes of adverse events (P = .57, P = .64, and P = .68; respectively).

Study details: Findings are from a meta-analysis of 3 randomized controlled trials including 2,466 adult patients with episodic migraine who received atogepant (10 mg, 30 mg, or 60 mg once daily) or placebo.

Disclosures: The study was supported by the Suzhou Health Talents Training Project. None of the authors declared any conflicts of interest.

Source: Tao X et al. J Headache Pain. 2022;23:19 (Jan 29). Doi: 10.1186/s10194-022-01391-2

Key clinical point: Atogepant shows a favorable safety and efficacy profile in the prophylactic treatment of episodic migraine.

Major finding: Atogepant (10 mg, 30 mg, and 60 mg) vs. placebo caused a significant reduction in mean monthly migraine (P < .00001, P < .00001, and P = .007; respectively), headache (P < .00001, P < .00001, and P = .001; respectively), and medication use (all P < .00001) days; an increase in the ≥50% responder rate (P = .0008, P = .02, and P = .04; respectively); and a nonsignificant difference in the outcomes of adverse events (P = .57, P = .64, and P = .68; respectively).

Study details: Findings are from a meta-analysis of 3 randomized controlled trials including 2,466 adult patients with episodic migraine who received atogepant (10 mg, 30 mg, or 60 mg once daily) or placebo.

Disclosures: The study was supported by the Suzhou Health Talents Training Project. None of the authors declared any conflicts of interest.

Source: Tao X et al. J Headache Pain. 2022;23:19 (Jan 29). Doi: 10.1186/s10194-022-01391-2

Key clinical point: Discontinuation of anticalcitonin gene-related protein (CGRP) monoclonal antibodies (mAb) leads to a progressive increase in monthly migraine days (MMD) and analgesic use from the first month, which, on reinitiation, revert to values comparable with those in the last month of treatment.

Main finding: At months 2 and 3 after discontinuation, a significant increase in MMD (P = .003 and P < .001, respectively) and analgesic use (both P < .001) was observed compared with month 12 of treatment. In the reinitiation month, the MMD (P = .40), days with ≥1 analgesic used (P = .83), and number of analgesics used (P = .74) were similar to the treatment month 12 values.

Study details: Findings are from a single-center, prospective, observational study involving 44 patients >18 years of age with treatment-resistant chronic migraine who received erenumab or galcanezumab for 12 months before a 3-month treatment discontinuation phase and 1 month of reinitiation.

Disclosures: The study received no specific funding. Some authors reported receiving personal fees or grants from various sources.

Source: Iannone LF et al. Eur J Neurol. 2022 (Jan 31). Doi: 10.1111/ene.15260

Key clinical point: Discontinuation of anticalcitonin gene-related protein (CGRP) monoclonal antibodies (mAb) leads to a progressive increase in monthly migraine days (MMD) and analgesic use from the first month, which, on reinitiation, revert to values comparable with those in the last month of treatment.

Main finding: At months 2 and 3 after discontinuation, a significant increase in MMD (P = .003 and P < .001, respectively) and analgesic use (both P < .001) was observed compared with month 12 of treatment. In the reinitiation month, the MMD (P = .40), days with ≥1 analgesic used (P = .83), and number of analgesics used (P = .74) were similar to the treatment month 12 values.

Study details: Findings are from a single-center, prospective, observational study involving 44 patients >18 years of age with treatment-resistant chronic migraine who received erenumab or galcanezumab for 12 months before a 3-month treatment discontinuation phase and 1 month of reinitiation.

Disclosures: The study received no specific funding. Some authors reported receiving personal fees or grants from various sources.

Source: Iannone LF et al. Eur J Neurol. 2022 (Jan 31). Doi: 10.1111/ene.15260

Key clinical point: Discontinuation of anticalcitonin gene-related protein (CGRP) monoclonal antibodies (mAb) leads to a progressive increase in monthly migraine days (MMD) and analgesic use from the first month, which, on reinitiation, revert to values comparable with those in the last month of treatment.

Main finding: At months 2 and 3 after discontinuation, a significant increase in MMD (P = .003 and P < .001, respectively) and analgesic use (both P < .001) was observed compared with month 12 of treatment. In the reinitiation month, the MMD (P = .40), days with ≥1 analgesic used (P = .83), and number of analgesics used (P = .74) were similar to the treatment month 12 values.

Study details: Findings are from a single-center, prospective, observational study involving 44 patients >18 years of age with treatment-resistant chronic migraine who received erenumab or galcanezumab for 12 months before a 3-month treatment discontinuation phase and 1 month of reinitiation.

Disclosures: The study received no specific funding. Some authors reported receiving personal fees or grants from various sources.

Source: Iannone LF et al. Eur J Neurol. 2022 (Jan 31). Doi: 10.1111/ene.15260