Headache & Migraine

Typical aura without headache, a rare subtype of migraine, occurs exclusively in 4% patients with migraine, and may take place at some point in 38% of patients with migraine with aura, according to recent study. Furthermore, typical aura without headache, also known as migraine aura without headache or acephalgic migraine, commonly presents with visual aura without headache, brainstem aura without headache, and can also develop later in life, known as late-onset migraine accompaniment. Its pathophysiology is suggested to be similar to classic migraines, with cortical spreading depression leading to aura formation but without an associated headache. Presently, no clinical trials have been performed to evaluate treatment options, but case reports suggest that most patients will respond to the traditional treatments for migraine with aura.

Shah DR, Dilwali S, Friedman DI. Migraine aura without headache. Curr Pain Headache Rep. 2018;22:77. doi:10.1007/s11916-018-0725-1.

Typical aura without headache, a rare subtype of migraine, occurs exclusively in 4% patients with migraine, and may take place at some point in 38% of patients with migraine with aura, according to recent study. Furthermore, typical aura without headache, also known as migraine aura without headache or acephalgic migraine, commonly presents with visual aura without headache, brainstem aura without headache, and can also develop later in life, known as late-onset migraine accompaniment. Its pathophysiology is suggested to be similar to classic migraines, with cortical spreading depression leading to aura formation but without an associated headache. Presently, no clinical trials have been performed to evaluate treatment options, but case reports suggest that most patients will respond to the traditional treatments for migraine with aura.

Shah DR, Dilwali S, Friedman DI. Migraine aura without headache. Curr Pain Headache Rep. 2018;22:77. doi:10.1007/s11916-018-0725-1.

Typical aura without headache, a rare subtype of migraine, occurs exclusively in 4% patients with migraine, and may take place at some point in 38% of patients with migraine with aura, according to recent study. Furthermore, typical aura without headache, also known as migraine aura without headache or acephalgic migraine, commonly presents with visual aura without headache, brainstem aura without headache, and can also develop later in life, known as late-onset migraine accompaniment. Its pathophysiology is suggested to be similar to classic migraines, with cortical spreading depression leading to aura formation but without an associated headache. Presently, no clinical trials have been performed to evaluate treatment options, but case reports suggest that most patients will respond to the traditional treatments for migraine with aura.

Shah DR, Dilwali S, Friedman DI. Migraine aura without headache. Curr Pain Headache Rep. 2018;22:77. doi:10.1007/s11916-018-0725-1.

Patients with migraines and patients classified as Caucasian had higher odds of being diagnosed with transient global amnesia (TGA), according to a recent study. All minority populations, however, showed a lower rate of diagnosis that fell short of statistical significance.  Data were obtained from the Nationwide Inpatient Sample using ICD-9 and procedure codes. Descriptive and survey logistic regression analyses were conducted and adjusted for influence of comorbidities, demographic characteristics, and hospitalization-related factors. Researchers found:

• Patients with migraines were 5.98 times more likely to also have a diagnosis of TGA compared with patients without migraines.
• Similarly, patients with TGA were more likely to have hypertension, precerebral disease, and hyperlipidemia.
• The odds of being diagnosed with TGA was lower among African Americans and Hispanics as well as among patients classified as Asian/other, compared with Caucasians.
• TGA was associated with lower hospital charges ($14,242 vs $21,319), shorter hospital stays (mean days: 2.49 [SE=0.036] vs 4.72 [SE=0.025]), and routine hospital discharges (91.4% vs 74.5%).

Yi M, Sherzai AZ, Ani C, et al. Strong association between migraine and transient global amnesia: A National Inpatient Sample analysis. [Published online ahead of print October 11, 2018]. J Neuropsychiatry Clin Neurosci. doi:10.1176/appi.neuropsych.17120353.

Patients with migraines and patients classified as Caucasian had higher odds of being diagnosed with transient global amnesia (TGA), according to a recent study. All minority populations, however, showed a lower rate of diagnosis that fell short of statistical significance.  Data were obtained from the Nationwide Inpatient Sample using ICD-9 and procedure codes. Descriptive and survey logistic regression analyses were conducted and adjusted for influence of comorbidities, demographic characteristics, and hospitalization-related factors. Researchers found:

• Patients with migraines were 5.98 times more likely to also have a diagnosis of TGA compared with patients without migraines.
• Similarly, patients with TGA were more likely to have hypertension, precerebral disease, and hyperlipidemia.
• The odds of being diagnosed with TGA was lower among African Americans and Hispanics as well as among patients classified as Asian/other, compared with Caucasians.
• TGA was associated with lower hospital charges ($14,242 vs $21,319), shorter hospital stays (mean days: 2.49 [SE=0.036] vs 4.72 [SE=0.025]), and routine hospital discharges (91.4% vs 74.5%).

Yi M, Sherzai AZ, Ani C, et al. Strong association between migraine and transient global amnesia: A National Inpatient Sample analysis. [Published online ahead of print October 11, 2018]. J Neuropsychiatry Clin Neurosci. doi:10.1176/appi.neuropsych.17120353.

Patients with migraines and patients classified as Caucasian had higher odds of being diagnosed with transient global amnesia (TGA), according to a recent study. All minority populations, however, showed a lower rate of diagnosis that fell short of statistical significance.  Data were obtained from the Nationwide Inpatient Sample using ICD-9 and procedure codes. Descriptive and survey logistic regression analyses were conducted and adjusted for influence of comorbidities, demographic characteristics, and hospitalization-related factors. Researchers found:

• Patients with migraines were 5.98 times more likely to also have a diagnosis of TGA compared with patients without migraines.
• Similarly, patients with TGA were more likely to have hypertension, precerebral disease, and hyperlipidemia.
• The odds of being diagnosed with TGA was lower among African Americans and Hispanics as well as among patients classified as Asian/other, compared with Caucasians.
• TGA was associated with lower hospital charges ($14,242 vs $21,319), shorter hospital stays (mean days: 2.49 [SE=0.036] vs 4.72 [SE=0.025]), and routine hospital discharges (91.4% vs 74.5%).

Yi M, Sherzai AZ, Ani C, et al. Strong association between migraine and transient global amnesia: A National Inpatient Sample analysis. [Published online ahead of print October 11, 2018]. J Neuropsychiatry Clin Neurosci. doi:10.1176/appi.neuropsych.17120353.

CHICAGO—Among children with pediatric stroke, older age at stroke onset, unilateral infarct location, and stroke etiologies of arterio­pathy and chronic illness are associated with the development of poststroke headache, according to a retrospective study presented at the 47th Annual Meeting of the Child Neurology Society.

Poststroke headache is a common morbidity among patients with pediatric stroke, said Ana B. Chelse, MD, of Ann & Robert H. Lurie Children’s Hospital and Northwestern University Feinberg School of Medicine in Chicago, and colleagues. In addition, poststroke headache in children may increase health care utilization, including neuroimaging and hospital admission, the investigators said.

Research indicates that about 20% of children with stroke have headache one year after the stroke, but data about poststroke headache in children are limited.

To assess the prevalence of novel headache after pediatric stroke, the characteristics of patients with poststroke headache, and the association between poststroke headache and stroke recurrence, Dr. Chelse and colleagues conducted a single-center, retrospective study of children 30 days to 18 years old with stroke. The researchers used an internal database to identify patients with a radiographically confirmed stroke at Lurie Children’s Hospital between January 1, 2008, and December 31, 2016.

Patients with ischemic stroke with secondary hemorrhage were included in the study, but patients with primary intracerebral hemorrhage were not. The researchers obtained patients’ demographic characteristics, infarct location, headache history, emergency department visits, neuroimaging, hospital admissions, and headache treatment from medical records. They defined stroke recurrence as an acute neurologic deficit with evidence of new radiologically confirmed ischemia.

The investigators analyzed the data using chi-squared and Fisher’s exact tests. They also performed exploratory multiple logistic regression analyses that included predictors deemed significant in univariate analyses.

Of 183 patients, 45 (24.5%) had poststroke headache. Headache developed at an average of 11.7 months after stroke. In multiple logistic regression analysis, older age and unilateral infarct location were associated with poststroke headache, as were stroke etiologies of arteriopathy (odds ratio [OR], 7.28) or chronic illness (OR, 1.90). Twenty-one patients (11.4%) had a recurrent stroke during the study period. Poststroke headache was associated with stroke recurrence in a univariate analysis, but the association did not reach statistical significance after multiple logistic regression. This association is “uncertain but potentially important,” Dr. Chelse and colleagues said.

CHICAGO—Among children with pediatric stroke, older age at stroke onset, unilateral infarct location, and stroke etiologies of arterio­pathy and chronic illness are associated with the development of poststroke headache, according to a retrospective study presented at the 47th Annual Meeting of the Child Neurology Society.

Poststroke headache is a common morbidity among patients with pediatric stroke, said Ana B. Chelse, MD, of Ann & Robert H. Lurie Children’s Hospital and Northwestern University Feinberg School of Medicine in Chicago, and colleagues. In addition, poststroke headache in children may increase health care utilization, including neuroimaging and hospital admission, the investigators said.

Research indicates that about 20% of children with stroke have headache one year after the stroke, but data about poststroke headache in children are limited.

To assess the prevalence of novel headache after pediatric stroke, the characteristics of patients with poststroke headache, and the association between poststroke headache and stroke recurrence, Dr. Chelse and colleagues conducted a single-center, retrospective study of children 30 days to 18 years old with stroke. The researchers used an internal database to identify patients with a radiographically confirmed stroke at Lurie Children’s Hospital between January 1, 2008, and December 31, 2016.

Patients with ischemic stroke with secondary hemorrhage were included in the study, but patients with primary intracerebral hemorrhage were not. The researchers obtained patients’ demographic characteristics, infarct location, headache history, emergency department visits, neuroimaging, hospital admissions, and headache treatment from medical records. They defined stroke recurrence as an acute neurologic deficit with evidence of new radiologically confirmed ischemia.

The investigators analyzed the data using chi-squared and Fisher’s exact tests. They also performed exploratory multiple logistic regression analyses that included predictors deemed significant in univariate analyses.

Of 183 patients, 45 (24.5%) had poststroke headache. Headache developed at an average of 11.7 months after stroke. In multiple logistic regression analysis, older age and unilateral infarct location were associated with poststroke headache, as were stroke etiologies of arteriopathy (odds ratio [OR], 7.28) or chronic illness (OR, 1.90). Twenty-one patients (11.4%) had a recurrent stroke during the study period. Poststroke headache was associated with stroke recurrence in a univariate analysis, but the association did not reach statistical significance after multiple logistic regression. This association is “uncertain but potentially important,” Dr. Chelse and colleagues said.

CHICAGO—Among children with pediatric stroke, older age at stroke onset, unilateral infarct location, and stroke etiologies of arterio­pathy and chronic illness are associated with the development of poststroke headache, according to a retrospective study presented at the 47th Annual Meeting of the Child Neurology Society.

Poststroke headache is a common morbidity among patients with pediatric stroke, said Ana B. Chelse, MD, of Ann & Robert H. Lurie Children’s Hospital and Northwestern University Feinberg School of Medicine in Chicago, and colleagues. In addition, poststroke headache in children may increase health care utilization, including neuroimaging and hospital admission, the investigators said.

Research indicates that about 20% of children with stroke have headache one year after the stroke, but data about poststroke headache in children are limited.

To assess the prevalence of novel headache after pediatric stroke, the characteristics of patients with poststroke headache, and the association between poststroke headache and stroke recurrence, Dr. Chelse and colleagues conducted a single-center, retrospective study of children 30 days to 18 years old with stroke. The researchers used an internal database to identify patients with a radiographically confirmed stroke at Lurie Children’s Hospital between January 1, 2008, and December 31, 2016.

Patients with ischemic stroke with secondary hemorrhage were included in the study, but patients with primary intracerebral hemorrhage were not. The researchers obtained patients’ demographic characteristics, infarct location, headache history, emergency department visits, neuroimaging, hospital admissions, and headache treatment from medical records. They defined stroke recurrence as an acute neurologic deficit with evidence of new radiologically confirmed ischemia.

The investigators analyzed the data using chi-squared and Fisher’s exact tests. They also performed exploratory multiple logistic regression analyses that included predictors deemed significant in univariate analyses.

Of 183 patients, 45 (24.5%) had poststroke headache. Headache developed at an average of 11.7 months after stroke. In multiple logistic regression analysis, older age and unilateral infarct location were associated with poststroke headache, as were stroke etiologies of arteriopathy (odds ratio [OR], 7.28) or chronic illness (OR, 1.90). Twenty-one patients (11.4%) had a recurrent stroke during the study period. Poststroke headache was associated with stroke recurrence in a univariate analysis, but the association did not reach statistical significance after multiple logistic regression. This association is “uncertain but potentially important,” Dr. Chelse and colleagues said.

ASHEVILLE, NC—New daily persistent headache is rare and difficult to treat. Although neurologists may be tempted to try a series of treatments until the patient improves, therapeutic success is more likely if the neurologist can identify a triggering event, said Todd Rozen, MD, a neurologist at Mayo Clinic in Jacksonville, Florida. Elements of the patient’s history or clinical examination also can guide treatment, he added at the Eighth Annual Scientific Meeting of the Southern Headache Society.

Patients Remember the Onset

New daily persistent headache was first described in 1986, and few researchers have studied it. It is a persistent headache with a clearly remembered onset. “Most [patients] can name the date it began or at least the month,” said Dr. Rozen. The headache becomes unremitting within 24 hours and must be present for longer than three months, according to the current diagnostic criteria. Patients may have a remitting form, a relapsing-remitting form, or a refractory form of the headache. The age of onset “can be as early as in the mid to late teens or early 20s, especially in the female population,” said Dr. Rozen. Age of onset also depends on the triggering event.

The pain typically is bilateral and moderate to severe. Although many patients may present with a tension-type headache, more than 60% have migrainous symptoms such as nausea, photophobia, or phonophobia, said Dr. Rozen.

The disorder is more common among women than among men. Between 10% and 13% of patients who present to headache clinics have new daily persistent headache, said Dr. Rozen. “It is either becoming more prevalent in the office, or we are better at recognizing it.”

Comparing Effects on the Genders

For a study published in 2016, Dr. Rozen examined 97 patients (65 women) with new daily persistent headache. Approximately 53% of patients could not identify a triggering event for their headache, which makes treatment “much more difficult,” said Dr. Rozen. Although the mean age of onset was younger in women (32.4) than men (35.8), the age of onset was the same between genders when Dr. Rozen examined for individual triggers.

The frequency of individual triggering events also was the same between genders, and these results suggest that each trigger may be associated with a discrete pathogenesis. Triggers included infection or flulike illness (22%), stressful life event (9%), surgery (9%), and other (7%). All patients who had identified surgery as a trigger had been intubated, and Dr. Rozen hypothesized that their headaches were cervicogenic. The younger patients who had undergone surgery were hypermobile, and the older patients had neck arthritis as predisposing risk factors for neck irritation with intubation.

A Somatoform Disorder?

The stubbornly refractory nature of this disorder has aroused the suspicion that it may be somatoform. In 2017, Uniyal and colleagues found that somatization, generalized anxiety disorder, depression, and catastrophization were more common in patients with new daily persistent headache, compared with patients with chronic low back pain and healthy controls.

Interpreting these data is difficult, said Dr. Rozen. They may indicate that these psychiatric comorbidities are risk factors for new daily persistent headache. An equally plausible interpretation is that these patients have a different disorder (eg, Ehlers-Danlos syndrome) that encompasses these common traits. Finally, symptoms such as depression and catastrophization may be sequelae of, rather than risk factors for, new daily persistent headache.

Researchers have found imaging abnormalities to be rare in patients with new daily persistent headache. About two-thirds of patients in a 2002 study had normal MRI or CT results, and the rest had nonspecific findings unrelated to the headache. Dr. Rozen found that white matter lesions were uncommon in patients with this disorder, except for those with a history of migraine or cardiovascular or cerebrovascular risk factors. CSF likewise generally is normal in patients with new daily persistent headache.

Triggers Suggest Treatments

Goadsby proposed in 2011 that new daily persistent headache is a syndrome rather than a single disorder. “I’m completely in agreement,” said Dr. Rozen. “However, I do believe that individuals who have the same triggering event have the same pathogenesis.” Identifying the triggering event and understanding the temporal profile of the first headache can enable the choice of appropriate therapy, he added.

A patient whose persistent headache begins with a thunderclap onset likely has a prolonged cerebral artery vasospasm. Dr. Rozen treated a patient whose initial headache was a thunderclap; imaging ultimately revealed that she had a vasospasm. Her headache responded to nimodipine within days. Nimodipine generally provides relief within three to five days, said Dr. Rozen. If it worsens the headache, then the patient does not have vasospasm, he added.

Many patients with new daily persistent headache have a physical presentation that suggests Marfan syndrome. This observation led Dr. Rozen to hypothesize that cervical hypermobility is a risk factor for new daily persistent headache. Hypermobile patients may put significant stress on the C1, C2, and C3 joints, which are “where the trigeminal–cervical complex comes together,” said Dr. Rozen. A long plane ride or appointment with the dentist could trigger new daily persistent headache. Treatment with onabotulinumtoxinA often helps these patients. High cervical blocks also can bring relief, said Dr. Rozen.

He and his colleagues recently identified a new subset of patients with new daily persistent headache. They were older female patients with a mean age of 57 who suddenly developed the disorder. Most of them reported that the pain was worst before they got out of bed in the morning. Within seconds of assuming the Trendelenburg position, these patients had intensified pain and nausea, suggesting CSF hypertension. The patients all responded to acetazolamide or spironolactone, which lowered CSF pressure. “I think these individuals developed cerebral vein insufficiency because of estrogen withdrawal based on their age. Plus, the majority were overweight, which can also raise baseline CSF pressure.”

Examination Should Incorporate Imaging

All patients with new daily persistent headache should undergo imaging, including a brain MRI with and without gadolinium, plus an MR venogram, which can identify CSF leaks and a cerebral vein thrombosis, which are leading secondary causes of the disorder. Neurologists could examine patients’ viral titers in addition if the history suggests a post infectious trigger. A lumbar puncture and measurement of opening CSF pressure are appropriate for patients who have not responded to medication.

Evidence From the Literature

The literature possibly supports the efficacy of several treatments in new daily persistent headache, but includes no placebo-controlled trials for them. Dr. Rozen found doxycycline to be helpful for several patients with elevated CSF tumor necrosis factor alpha.

Marmura and colleagues found that mexiletine reduced the severity of pain in patients with refractory new daily persistent headache. The treatment did not reduce headache frequency, however, and side effects were common.

In a retrospective study, Prakash et al followed 63 patients with new daily persistent headache for five years. They found that patients who received IV methyl prednisolone and sodium valproate had a better response than patients who received other therapies. They called for prospective and controlled studies to confirm this observation.

In general, aggressive initial therapy is warranted, “especially if you meet an individual within one year of headache onset,” said Dr. Rozen. The likelihood of response to therapy appears to decline with the duration of the headache. “Infusion therapy or inpatient therapy with IV medications, even with standard migraine protocols, may help break the cycle,” Dr. Rozen concluded.

—Erik Greb

Suggested Reading

Goadsby PJ. New daily persistent headache: a syndrome, not a discrete disorder. Headache. 2011;51(4):650-653.

Marmura MJ, Passero FC Jr, Young WB. Mexiletine for refractory chronic daily headache: a report of nine cases. Headache. 2008;48(10):1506-1510.

Prakash S, Saini S, Rana KR, Mahato P. Refining clinical features and therapeutic options of new daily persistent headache: a retrospective study of 63 patients in India. J Headache Pain. 2012;13(6):477-485.

Rozen TD. A new subtype of chronic daily headache presenting in older women. J Womens Health (Larchmt). 2018;27(2):203-208.

Rozen TD. Triggering events and new daily persistent headache: age and gender differences and insights on pathogenesis-a clinic-based study. Headache. 2016;56(1):164-173.

Uniyal R, Paliwal VK, Tripathi A. Psychiatric comorbidity in new daily persistent headache: a cross-sectional study. Eur J Pain. 2017;21(6):1031-1038.

ASHEVILLE, NC—New daily persistent headache is rare and difficult to treat. Although neurologists may be tempted to try a series of treatments until the patient improves, therapeutic success is more likely if the neurologist can identify a triggering event, said Todd Rozen, MD, a neurologist at Mayo Clinic in Jacksonville, Florida. Elements of the patient’s history or clinical examination also can guide treatment, he added at the Eighth Annual Scientific Meeting of the Southern Headache Society.

Patients Remember the Onset

New daily persistent headache was first described in 1986, and few researchers have studied it. It is a persistent headache with a clearly remembered onset. “Most [patients] can name the date it began or at least the month,” said Dr. Rozen. The headache becomes unremitting within 24 hours and must be present for longer than three months, according to the current diagnostic criteria. Patients may have a remitting form, a relapsing-remitting form, or a refractory form of the headache. The age of onset “can be as early as in the mid to late teens or early 20s, especially in the female population,” said Dr. Rozen. Age of onset also depends on the triggering event.

The pain typically is bilateral and moderate to severe. Although many patients may present with a tension-type headache, more than 60% have migrainous symptoms such as nausea, photophobia, or phonophobia, said Dr. Rozen.

The disorder is more common among women than among men. Between 10% and 13% of patients who present to headache clinics have new daily persistent headache, said Dr. Rozen. “It is either becoming more prevalent in the office, or we are better at recognizing it.”

Comparing Effects on the Genders

For a study published in 2016, Dr. Rozen examined 97 patients (65 women) with new daily persistent headache. Approximately 53% of patients could not identify a triggering event for their headache, which makes treatment “much more difficult,” said Dr. Rozen. Although the mean age of onset was younger in women (32.4) than men (35.8), the age of onset was the same between genders when Dr. Rozen examined for individual triggers.

The frequency of individual triggering events also was the same between genders, and these results suggest that each trigger may be associated with a discrete pathogenesis. Triggers included infection or flulike illness (22%), stressful life event (9%), surgery (9%), and other (7%). All patients who had identified surgery as a trigger had been intubated, and Dr. Rozen hypothesized that their headaches were cervicogenic. The younger patients who had undergone surgery were hypermobile, and the older patients had neck arthritis as predisposing risk factors for neck irritation with intubation.

A Somatoform Disorder?

The stubbornly refractory nature of this disorder has aroused the suspicion that it may be somatoform. In 2017, Uniyal and colleagues found that somatization, generalized anxiety disorder, depression, and catastrophization were more common in patients with new daily persistent headache, compared with patients with chronic low back pain and healthy controls.

Interpreting these data is difficult, said Dr. Rozen. They may indicate that these psychiatric comorbidities are risk factors for new daily persistent headache. An equally plausible interpretation is that these patients have a different disorder (eg, Ehlers-Danlos syndrome) that encompasses these common traits. Finally, symptoms such as depression and catastrophization may be sequelae of, rather than risk factors for, new daily persistent headache.

Researchers have found imaging abnormalities to be rare in patients with new daily persistent headache. About two-thirds of patients in a 2002 study had normal MRI or CT results, and the rest had nonspecific findings unrelated to the headache. Dr. Rozen found that white matter lesions were uncommon in patients with this disorder, except for those with a history of migraine or cardiovascular or cerebrovascular risk factors. CSF likewise generally is normal in patients with new daily persistent headache.

Triggers Suggest Treatments

Goadsby proposed in 2011 that new daily persistent headache is a syndrome rather than a single disorder. “I’m completely in agreement,” said Dr. Rozen. “However, I do believe that individuals who have the same triggering event have the same pathogenesis.” Identifying the triggering event and understanding the temporal profile of the first headache can enable the choice of appropriate therapy, he added.

A patient whose persistent headache begins with a thunderclap onset likely has a prolonged cerebral artery vasospasm. Dr. Rozen treated a patient whose initial headache was a thunderclap; imaging ultimately revealed that she had a vasospasm. Her headache responded to nimodipine within days. Nimodipine generally provides relief within three to five days, said Dr. Rozen. If it worsens the headache, then the patient does not have vasospasm, he added.

Many patients with new daily persistent headache have a physical presentation that suggests Marfan syndrome. This observation led Dr. Rozen to hypothesize that cervical hypermobility is a risk factor for new daily persistent headache. Hypermobile patients may put significant stress on the C1, C2, and C3 joints, which are “where the trigeminal–cervical complex comes together,” said Dr. Rozen. A long plane ride or appointment with the dentist could trigger new daily persistent headache. Treatment with onabotulinumtoxinA often helps these patients. High cervical blocks also can bring relief, said Dr. Rozen.

He and his colleagues recently identified a new subset of patients with new daily persistent headache. They were older female patients with a mean age of 57 who suddenly developed the disorder. Most of them reported that the pain was worst before they got out of bed in the morning. Within seconds of assuming the Trendelenburg position, these patients had intensified pain and nausea, suggesting CSF hypertension. The patients all responded to acetazolamide or spironolactone, which lowered CSF pressure. “I think these individuals developed cerebral vein insufficiency because of estrogen withdrawal based on their age. Plus, the majority were overweight, which can also raise baseline CSF pressure.”

Examination Should Incorporate Imaging

All patients with new daily persistent headache should undergo imaging, including a brain MRI with and without gadolinium, plus an MR venogram, which can identify CSF leaks and a cerebral vein thrombosis, which are leading secondary causes of the disorder. Neurologists could examine patients’ viral titers in addition if the history suggests a post infectious trigger. A lumbar puncture and measurement of opening CSF pressure are appropriate for patients who have not responded to medication.

Evidence From the Literature

The literature possibly supports the efficacy of several treatments in new daily persistent headache, but includes no placebo-controlled trials for them. Dr. Rozen found doxycycline to be helpful for several patients with elevated CSF tumor necrosis factor alpha.

Marmura and colleagues found that mexiletine reduced the severity of pain in patients with refractory new daily persistent headache. The treatment did not reduce headache frequency, however, and side effects were common.

In a retrospective study, Prakash et al followed 63 patients with new daily persistent headache for five years. They found that patients who received IV methyl prednisolone and sodium valproate had a better response than patients who received other therapies. They called for prospective and controlled studies to confirm this observation.

In general, aggressive initial therapy is warranted, “especially if you meet an individual within one year of headache onset,” said Dr. Rozen. The likelihood of response to therapy appears to decline with the duration of the headache. “Infusion therapy or inpatient therapy with IV medications, even with standard migraine protocols, may help break the cycle,” Dr. Rozen concluded.

—Erik Greb

Suggested Reading

Goadsby PJ. New daily persistent headache: a syndrome, not a discrete disorder. Headache. 2011;51(4):650-653.

Marmura MJ, Passero FC Jr, Young WB. Mexiletine for refractory chronic daily headache: a report of nine cases. Headache. 2008;48(10):1506-1510.

Prakash S, Saini S, Rana KR, Mahato P. Refining clinical features and therapeutic options of new daily persistent headache: a retrospective study of 63 patients in India. J Headache Pain. 2012;13(6):477-485.

Rozen TD. A new subtype of chronic daily headache presenting in older women. J Womens Health (Larchmt). 2018;27(2):203-208.

Rozen TD. Triggering events and new daily persistent headache: age and gender differences and insights on pathogenesis-a clinic-based study. Headache. 2016;56(1):164-173.

Uniyal R, Paliwal VK, Tripathi A. Psychiatric comorbidity in new daily persistent headache: a cross-sectional study. Eur J Pain. 2017;21(6):1031-1038.

ASHEVILLE, NC—New daily persistent headache is rare and difficult to treat. Although neurologists may be tempted to try a series of treatments until the patient improves, therapeutic success is more likely if the neurologist can identify a triggering event, said Todd Rozen, MD, a neurologist at Mayo Clinic in Jacksonville, Florida. Elements of the patient’s history or clinical examination also can guide treatment, he added at the Eighth Annual Scientific Meeting of the Southern Headache Society.

Patients Remember the Onset

New daily persistent headache was first described in 1986, and few researchers have studied it. It is a persistent headache with a clearly remembered onset. “Most [patients] can name the date it began or at least the month,” said Dr. Rozen. The headache becomes unremitting within 24 hours and must be present for longer than three months, according to the current diagnostic criteria. Patients may have a remitting form, a relapsing-remitting form, or a refractory form of the headache. The age of onset “can be as early as in the mid to late teens or early 20s, especially in the female population,” said Dr. Rozen. Age of onset also depends on the triggering event.

The pain typically is bilateral and moderate to severe. Although many patients may present with a tension-type headache, more than 60% have migrainous symptoms such as nausea, photophobia, or phonophobia, said Dr. Rozen.

The disorder is more common among women than among men. Between 10% and 13% of patients who present to headache clinics have new daily persistent headache, said Dr. Rozen. “It is either becoming more prevalent in the office, or we are better at recognizing it.”

Comparing Effects on the Genders

For a study published in 2016, Dr. Rozen examined 97 patients (65 women) with new daily persistent headache. Approximately 53% of patients could not identify a triggering event for their headache, which makes treatment “much more difficult,” said Dr. Rozen. Although the mean age of onset was younger in women (32.4) than men (35.8), the age of onset was the same between genders when Dr. Rozen examined for individual triggers.

The frequency of individual triggering events also was the same between genders, and these results suggest that each trigger may be associated with a discrete pathogenesis. Triggers included infection or flulike illness (22%), stressful life event (9%), surgery (9%), and other (7%). All patients who had identified surgery as a trigger had been intubated, and Dr. Rozen hypothesized that their headaches were cervicogenic. The younger patients who had undergone surgery were hypermobile, and the older patients had neck arthritis as predisposing risk factors for neck irritation with intubation.

A Somatoform Disorder?

The stubbornly refractory nature of this disorder has aroused the suspicion that it may be somatoform. In 2017, Uniyal and colleagues found that somatization, generalized anxiety disorder, depression, and catastrophization were more common in patients with new daily persistent headache, compared with patients with chronic low back pain and healthy controls.

Interpreting these data is difficult, said Dr. Rozen. They may indicate that these psychiatric comorbidities are risk factors for new daily persistent headache. An equally plausible interpretation is that these patients have a different disorder (eg, Ehlers-Danlos syndrome) that encompasses these common traits. Finally, symptoms such as depression and catastrophization may be sequelae of, rather than risk factors for, new daily persistent headache.

Researchers have found imaging abnormalities to be rare in patients with new daily persistent headache. About two-thirds of patients in a 2002 study had normal MRI or CT results, and the rest had nonspecific findings unrelated to the headache. Dr. Rozen found that white matter lesions were uncommon in patients with this disorder, except for those with a history of migraine or cardiovascular or cerebrovascular risk factors. CSF likewise generally is normal in patients with new daily persistent headache.

Triggers Suggest Treatments

Goadsby proposed in 2011 that new daily persistent headache is a syndrome rather than a single disorder. “I’m completely in agreement,” said Dr. Rozen. “However, I do believe that individuals who have the same triggering event have the same pathogenesis.” Identifying the triggering event and understanding the temporal profile of the first headache can enable the choice of appropriate therapy, he added.

A patient whose persistent headache begins with a thunderclap onset likely has a prolonged cerebral artery vasospasm. Dr. Rozen treated a patient whose initial headache was a thunderclap; imaging ultimately revealed that she had a vasospasm. Her headache responded to nimodipine within days. Nimodipine generally provides relief within three to five days, said Dr. Rozen. If it worsens the headache, then the patient does not have vasospasm, he added.

Many patients with new daily persistent headache have a physical presentation that suggests Marfan syndrome. This observation led Dr. Rozen to hypothesize that cervical hypermobility is a risk factor for new daily persistent headache. Hypermobile patients may put significant stress on the C1, C2, and C3 joints, which are “where the trigeminal–cervical complex comes together,” said Dr. Rozen. A long plane ride or appointment with the dentist could trigger new daily persistent headache. Treatment with onabotulinumtoxinA often helps these patients. High cervical blocks also can bring relief, said Dr. Rozen.

He and his colleagues recently identified a new subset of patients with new daily persistent headache. They were older female patients with a mean age of 57 who suddenly developed the disorder. Most of them reported that the pain was worst before they got out of bed in the morning. Within seconds of assuming the Trendelenburg position, these patients had intensified pain and nausea, suggesting CSF hypertension. The patients all responded to acetazolamide or spironolactone, which lowered CSF pressure. “I think these individuals developed cerebral vein insufficiency because of estrogen withdrawal based on their age. Plus, the majority were overweight, which can also raise baseline CSF pressure.”

Examination Should Incorporate Imaging

All patients with new daily persistent headache should undergo imaging, including a brain MRI with and without gadolinium, plus an MR venogram, which can identify CSF leaks and a cerebral vein thrombosis, which are leading secondary causes of the disorder. Neurologists could examine patients’ viral titers in addition if the history suggests a post infectious trigger. A lumbar puncture and measurement of opening CSF pressure are appropriate for patients who have not responded to medication.

Evidence From the Literature

The literature possibly supports the efficacy of several treatments in new daily persistent headache, but includes no placebo-controlled trials for them. Dr. Rozen found doxycycline to be helpful for several patients with elevated CSF tumor necrosis factor alpha.

Marmura and colleagues found that mexiletine reduced the severity of pain in patients with refractory new daily persistent headache. The treatment did not reduce headache frequency, however, and side effects were common.

In a retrospective study, Prakash et al followed 63 patients with new daily persistent headache for five years. They found that patients who received IV methyl prednisolone and sodium valproate had a better response than patients who received other therapies. They called for prospective and controlled studies to confirm this observation.

In general, aggressive initial therapy is warranted, “especially if you meet an individual within one year of headache onset,” said Dr. Rozen. The likelihood of response to therapy appears to decline with the duration of the headache. “Infusion therapy or inpatient therapy with IV medications, even with standard migraine protocols, may help break the cycle,” Dr. Rozen concluded.

—Erik Greb

Suggested Reading

Goadsby PJ. New daily persistent headache: a syndrome, not a discrete disorder. Headache. 2011;51(4):650-653.

Marmura MJ, Passero FC Jr, Young WB. Mexiletine for refractory chronic daily headache: a report of nine cases. Headache. 2008;48(10):1506-1510.

Prakash S, Saini S, Rana KR, Mahato P. Refining clinical features and therapeutic options of new daily persistent headache: a retrospective study of 63 patients in India. J Headache Pain. 2012;13(6):477-485.

Rozen TD. A new subtype of chronic daily headache presenting in older women. J Womens Health (Larchmt). 2018;27(2):203-208.

Rozen TD. Triggering events and new daily persistent headache: age and gender differences and insights on pathogenesis-a clinic-based study. Headache. 2016;56(1):164-173.

Uniyal R, Paliwal VK, Tripathi A. Psychiatric comorbidity in new daily persistent headache: a cross-sectional study. Eur J Pain. 2017;21(6):1031-1038.

ASHEVILLE, NC—Menstrual-related migraine (MRM) can be particularly disabling and is difficult to treat using conventional migraine medications. To reduce the risk of MRM, a patient’s decrease in estrogen levels on the days around menses onset must be limited to 10 µg of ethinyl estradiol or less, said Anne H. Calhoun, MD, Professor of Anesthesiology and Psychiatry at the University of North Carolina and Partner and Cofounder of the Carolina Headache Institute in Durham, North Carolina.

“Most migraineurs by far are women, and as such, most migraineurs have MRM,” she said. “Nearly two-thirds of migraineurs have hormonal triggers, and it is our job to help our patients cope with them.”

Peak Times for Headache Occurrence

MRM occurrence correlates with days during a woman’s menstrual cycle, Dr. Calhoun said at the Eighth Annual Scientific Meeting of the Southern Headache Society. A study of diary data from 155 women found a 50% increased likelihood of migraine during the five days before menses, compared with all other times during the cycle.

“However, during the five days after the onset of bleeding, there was a 2.5 times increased risk of migraine,” Dr. Calhoun said. “Analysis of an even narrower time frame—two days before and after the onset of menses—shows a three to nearly five times increased migraine risk.” The pain was twice as likely to be considered severe two days before menses and more than three times as likely to be considered severe during the first three days of menstruation, she added.

Conventional migraine therapy may have limited efficacy for the treatment of MRM, Dr. Calhoun suggested. For example, one retrospective analysis examined data from two randomized trials of oral rizatriptan. In a subgroup of 335 women with MRM, 68% of women taking rizatriptan 10 mg and 70% of women taking rizatriptan 5 mg experienced pain relief, compared with 44% of women taking placebo. “However, for women who used the treatment on the day of bleeding, the response was about the same as placebo,” she said.

Hormonal Fluctuations Associated With Migraine

Fluctuations in estrogen levels are key to why migraine is more likely at certain times during a woman’s cycle, Dr. Calhoun said. She cited a study of 81 menstruating women with clinically diagnosed migraine that assessed their risk of tension-type headache and migraine with and without aura. There was a significantly elevated risk of tension-type headache and migraine without aura on the first two days of menses and a significantly higher risk of migraine without aura during the two days before menses onset. Furthermore, there was a significantly lower risk of all headache types around the time of ovulation.

“I looked at the data from this study and used the information differently,” Dr. Calhoun said. “In this same population of migraineurs, I added all their headaches together for each day and discovered that there was an increase in headache frequency when estrogen levels were low.”

When estrogen levels decrease, monoamine oxidase increases, serotonin and β-endorphin levels decrease, and serotonergic postsynaptic responsiveness and neurotransmitter uptake decrease. “In addition, there is an increase in calcitonin gene-related peptide concentrations,” Dr. Calhoun said. “This is why menstrual migraine is so much more intense than … non-MRM.”

Manipulation of Estrogen Levels

Corroborating evidence was found in a study that looked at hormone-related symptoms in 262 oral contraceptive users. Headache occurred significantly more frequently during the one-week hormone-free interval than during the three active-pill weeks, Dr. Calhoun noted. “Typical contraceptive treatment consists of a low-dose 20-µg ethinyl estradiol pill (combined with a progestin) for 21 days, followed by seven days of placebo,” she said. “A 20-µg drop in ethinyl estradiol (the estrogen in most oral contraceptives) is enough to cause a migraine, but if you limit that to a 10-µg drop, you can prevent migraine.”

Therefore, a patient on a 20-µg pill should be prescribed a 10-µg dose of ethinyl estradiol in the fourth week, Dr. Calhoun explained. If she is on a 30-µg pill, a 20-µg dose of ethinyl estradiol would be needed in the fourth week. “Continual hormonal combined contraceptives (with no placebo days) are also a good solution, so long as she does not have breakthrough bleeding,” she added.

Dr. Calhoun and colleagues examined the patient records of 229 consecutive women who were prescribed hormonal prophylaxis for MRM. Three hormonal preventive strategies were used: low-dose oral contraceptive with supplemental estrogen during the menstrual week; extended-cycle oral contraception with supplemental estrogen in the menstrual week; or a natural menstrual cycle with perimenstrual application of an estradiol patch two days beforethe expected onset of bleeding and continued for a week. In all, 168 women had resolution of MRM, 40 had persistence of MRM, and 21 refused or discontinued hormonal prophylaxis. Resolution of MRM was associated with a reversion to episodic migraine, resolution of medication overuse, and an overall decreased consumption of triptans, opioids, acute agents, and migraine preventive medication.

—Adriene Marshall

Suggested Reading

Calhoun A, Ford S. Elimination of menstrual-related migraine beneficially impacts chronification and medication overuse. Headache. 2008;48(8):1186-1193.

MacGregor EA, Hackshaw A. Prevalence of migraine on each day of the natural menstrual cycle. Neurology. 2004;63(2):351-353.

Silberstein SD, Massiou H, Le Jeunne C, et al. Rizatriptan in the treatment of menstrual migraine. Obstet Gynecol. 2000;96(2):237-242.Stewart WF, Lipton RB, Chee E, et al. Menstrual cycle and headache in a population sample of migraineurs. Neurology. 2000;55(10):1517-1523.

ASHEVILLE, NC—Menstrual-related migraine (MRM) can be particularly disabling and is difficult to treat using conventional migraine medications. To reduce the risk of MRM, a patient’s decrease in estrogen levels on the days around menses onset must be limited to 10 µg of ethinyl estradiol or less, said Anne H. Calhoun, MD, Professor of Anesthesiology and Psychiatry at the University of North Carolina and Partner and Cofounder of the Carolina Headache Institute in Durham, North Carolina.

“Most migraineurs by far are women, and as such, most migraineurs have MRM,” she said. “Nearly two-thirds of migraineurs have hormonal triggers, and it is our job to help our patients cope with them.”

Peak Times for Headache Occurrence

MRM occurrence correlates with days during a woman’s menstrual cycle, Dr. Calhoun said at the Eighth Annual Scientific Meeting of the Southern Headache Society. A study of diary data from 155 women found a 50% increased likelihood of migraine during the five days before menses, compared with all other times during the cycle.

“However, during the five days after the onset of bleeding, there was a 2.5 times increased risk of migraine,” Dr. Calhoun said. “Analysis of an even narrower time frame—two days before and after the onset of menses—shows a three to nearly five times increased migraine risk.” The pain was twice as likely to be considered severe two days before menses and more than three times as likely to be considered severe during the first three days of menstruation, she added.

Conventional migraine therapy may have limited efficacy for the treatment of MRM, Dr. Calhoun suggested. For example, one retrospective analysis examined data from two randomized trials of oral rizatriptan. In a subgroup of 335 women with MRM, 68% of women taking rizatriptan 10 mg and 70% of women taking rizatriptan 5 mg experienced pain relief, compared with 44% of women taking placebo. “However, for women who used the treatment on the day of bleeding, the response was about the same as placebo,” she said.

Hormonal Fluctuations Associated With Migraine

Fluctuations in estrogen levels are key to why migraine is more likely at certain times during a woman’s cycle, Dr. Calhoun said. She cited a study of 81 menstruating women with clinically diagnosed migraine that assessed their risk of tension-type headache and migraine with and without aura. There was a significantly elevated risk of tension-type headache and migraine without aura on the first two days of menses and a significantly higher risk of migraine without aura during the two days before menses onset. Furthermore, there was a significantly lower risk of all headache types around the time of ovulation.

“I looked at the data from this study and used the information differently,” Dr. Calhoun said. “In this same population of migraineurs, I added all their headaches together for each day and discovered that there was an increase in headache frequency when estrogen levels were low.”

When estrogen levels decrease, monoamine oxidase increases, serotonin and β-endorphin levels decrease, and serotonergic postsynaptic responsiveness and neurotransmitter uptake decrease. “In addition, there is an increase in calcitonin gene-related peptide concentrations,” Dr. Calhoun said. “This is why menstrual migraine is so much more intense than … non-MRM.”

Manipulation of Estrogen Levels

Corroborating evidence was found in a study that looked at hormone-related symptoms in 262 oral contraceptive users. Headache occurred significantly more frequently during the one-week hormone-free interval than during the three active-pill weeks, Dr. Calhoun noted. “Typical contraceptive treatment consists of a low-dose 20-µg ethinyl estradiol pill (combined with a progestin) for 21 days, followed by seven days of placebo,” she said. “A 20-µg drop in ethinyl estradiol (the estrogen in most oral contraceptives) is enough to cause a migraine, but if you limit that to a 10-µg drop, you can prevent migraine.”

Therefore, a patient on a 20-µg pill should be prescribed a 10-µg dose of ethinyl estradiol in the fourth week, Dr. Calhoun explained. If she is on a 30-µg pill, a 20-µg dose of ethinyl estradiol would be needed in the fourth week. “Continual hormonal combined contraceptives (with no placebo days) are also a good solution, so long as she does not have breakthrough bleeding,” she added.

Dr. Calhoun and colleagues examined the patient records of 229 consecutive women who were prescribed hormonal prophylaxis for MRM. Three hormonal preventive strategies were used: low-dose oral contraceptive with supplemental estrogen during the menstrual week; extended-cycle oral contraception with supplemental estrogen in the menstrual week; or a natural menstrual cycle with perimenstrual application of an estradiol patch two days beforethe expected onset of bleeding and continued for a week. In all, 168 women had resolution of MRM, 40 had persistence of MRM, and 21 refused or discontinued hormonal prophylaxis. Resolution of MRM was associated with a reversion to episodic migraine, resolution of medication overuse, and an overall decreased consumption of triptans, opioids, acute agents, and migraine preventive medication.

—Adriene Marshall

Suggested Reading

Calhoun A, Ford S. Elimination of menstrual-related migraine beneficially impacts chronification and medication overuse. Headache. 2008;48(8):1186-1193.

MacGregor EA, Hackshaw A. Prevalence of migraine on each day of the natural menstrual cycle. Neurology. 2004;63(2):351-353.

Silberstein SD, Massiou H, Le Jeunne C, et al. Rizatriptan in the treatment of menstrual migraine. Obstet Gynecol. 2000;96(2):237-242.Stewart WF, Lipton RB, Chee E, et al. Menstrual cycle and headache in a population sample of migraineurs. Neurology. 2000;55(10):1517-1523.

ASHEVILLE, NC—Menstrual-related migraine (MRM) can be particularly disabling and is difficult to treat using conventional migraine medications. To reduce the risk of MRM, a patient’s decrease in estrogen levels on the days around menses onset must be limited to 10 µg of ethinyl estradiol or less, said Anne H. Calhoun, MD, Professor of Anesthesiology and Psychiatry at the University of North Carolina and Partner and Cofounder of the Carolina Headache Institute in Durham, North Carolina.

“Most migraineurs by far are women, and as such, most migraineurs have MRM,” she said. “Nearly two-thirds of migraineurs have hormonal triggers, and it is our job to help our patients cope with them.”

Peak Times for Headache Occurrence

MRM occurrence correlates with days during a woman’s menstrual cycle, Dr. Calhoun said at the Eighth Annual Scientific Meeting of the Southern Headache Society. A study of diary data from 155 women found a 50% increased likelihood of migraine during the five days before menses, compared with all other times during the cycle.

“However, during the five days after the onset of bleeding, there was a 2.5 times increased risk of migraine,” Dr. Calhoun said. “Analysis of an even narrower time frame—two days before and after the onset of menses—shows a three to nearly five times increased migraine risk.” The pain was twice as likely to be considered severe two days before menses and more than three times as likely to be considered severe during the first three days of menstruation, she added.

Conventional migraine therapy may have limited efficacy for the treatment of MRM, Dr. Calhoun suggested. For example, one retrospective analysis examined data from two randomized trials of oral rizatriptan. In a subgroup of 335 women with MRM, 68% of women taking rizatriptan 10 mg and 70% of women taking rizatriptan 5 mg experienced pain relief, compared with 44% of women taking placebo. “However, for women who used the treatment on the day of bleeding, the response was about the same as placebo,” she said.

Hormonal Fluctuations Associated With Migraine

Fluctuations in estrogen levels are key to why migraine is more likely at certain times during a woman’s cycle, Dr. Calhoun said. She cited a study of 81 menstruating women with clinically diagnosed migraine that assessed their risk of tension-type headache and migraine with and without aura. There was a significantly elevated risk of tension-type headache and migraine without aura on the first two days of menses and a significantly higher risk of migraine without aura during the two days before menses onset. Furthermore, there was a significantly lower risk of all headache types around the time of ovulation.

“I looked at the data from this study and used the information differently,” Dr. Calhoun said. “In this same population of migraineurs, I added all their headaches together for each day and discovered that there was an increase in headache frequency when estrogen levels were low.”

When estrogen levels decrease, monoamine oxidase increases, serotonin and β-endorphin levels decrease, and serotonergic postsynaptic responsiveness and neurotransmitter uptake decrease. “In addition, there is an increase in calcitonin gene-related peptide concentrations,” Dr. Calhoun said. “This is why menstrual migraine is so much more intense than … non-MRM.”

Manipulation of Estrogen Levels

Corroborating evidence was found in a study that looked at hormone-related symptoms in 262 oral contraceptive users. Headache occurred significantly more frequently during the one-week hormone-free interval than during the three active-pill weeks, Dr. Calhoun noted. “Typical contraceptive treatment consists of a low-dose 20-µg ethinyl estradiol pill (combined with a progestin) for 21 days, followed by seven days of placebo,” she said. “A 20-µg drop in ethinyl estradiol (the estrogen in most oral contraceptives) is enough to cause a migraine, but if you limit that to a 10-µg drop, you can prevent migraine.”

Therefore, a patient on a 20-µg pill should be prescribed a 10-µg dose of ethinyl estradiol in the fourth week, Dr. Calhoun explained. If she is on a 30-µg pill, a 20-µg dose of ethinyl estradiol would be needed in the fourth week. “Continual hormonal combined contraceptives (with no placebo days) are also a good solution, so long as she does not have breakthrough bleeding,” she added.

Dr. Calhoun and colleagues examined the patient records of 229 consecutive women who were prescribed hormonal prophylaxis for MRM. Three hormonal preventive strategies were used: low-dose oral contraceptive with supplemental estrogen during the menstrual week; extended-cycle oral contraception with supplemental estrogen in the menstrual week; or a natural menstrual cycle with perimenstrual application of an estradiol patch two days beforethe expected onset of bleeding and continued for a week. In all, 168 women had resolution of MRM, 40 had persistence of MRM, and 21 refused or discontinued hormonal prophylaxis. Resolution of MRM was associated with a reversion to episodic migraine, resolution of medication overuse, and an overall decreased consumption of triptans, opioids, acute agents, and migraine preventive medication.

—Adriene Marshall

Suggested Reading

Calhoun A, Ford S. Elimination of menstrual-related migraine beneficially impacts chronification and medication overuse. Headache. 2008;48(8):1186-1193.

MacGregor EA, Hackshaw A. Prevalence of migraine on each day of the natural menstrual cycle. Neurology. 2004;63(2):351-353.

Silberstein SD, Massiou H, Le Jeunne C, et al. Rizatriptan in the treatment of menstrual migraine. Obstet Gynecol. 2000;96(2):237-242.Stewart WF, Lipton RB, Chee E, et al. Menstrual cycle and headache in a population sample of migraineurs. Neurology. 2000;55(10):1517-1523.

BERLIN—Gray matter–white matter (GM/WM) contrast ratio on T1 magnetization prepared rapid gradient echo (MPRAGE) is sensitive to multiple sclerosis (MS), but not to migraine pathology, according to research presented at ECTRIMS 2018. The diagnostic and prognostic value of this MRI marker could be subjects for future investigations, said the study authors.

Researchers have suggested that MRI brain T1 GM/WM contrast may be a marker of neurodegeneration in Alzheimer’s disease. Whether this contrast has diagnostic value in MS remains unknown, however. Tina Mitrovic, a research assistant at the University of Basel in Switzerland, and colleagues conducted a study to compare the T1 GM/WM contrast in patients with MS, migraineurs, and healthy controls. They also investigated whether the contrast was associated with disability outcomes in MS.

BERLIN—Gray matter–white matter (GM/WM) contrast ratio on T1 magnetization prepared rapid gradient echo (MPRAGE) is sensitive to multiple sclerosis (MS), but not to migraine pathology, according to research presented at ECTRIMS 2018. The diagnostic and prognostic value of this MRI marker could be subjects for future investigations, said the study authors.

Researchers have suggested that MRI brain T1 GM/WM contrast may be a marker of neurodegeneration in Alzheimer’s disease. Whether this contrast has diagnostic value in MS remains unknown, however. Tina Mitrovic, a research assistant at the University of Basel in Switzerland, and colleagues conducted a study to compare the T1 GM/WM contrast in patients with MS, migraineurs, and healthy controls. They also investigated whether the contrast was associated with disability outcomes in MS.

BERLIN—Gray matter–white matter (GM/WM) contrast ratio on T1 magnetization prepared rapid gradient echo (MPRAGE) is sensitive to multiple sclerosis (MS), but not to migraine pathology, according to research presented at ECTRIMS 2018. The diagnostic and prognostic value of this MRI marker could be subjects for future investigations, said the study authors.

Researchers have suggested that MRI brain T1 GM/WM contrast may be a marker of neurodegeneration in Alzheimer’s disease. Whether this contrast has diagnostic value in MS remains unknown, however. Tina Mitrovic, a research assistant at the University of Basel in Switzerland, and colleagues conducted a study to compare the T1 GM/WM contrast in patients with MS, migraineurs, and healthy controls. They also investigated whether the contrast was associated with disability outcomes in MS.

CHICAGO—Among pediatric patients who receive IV dihydroergotamine (DHE) for headache, chest pain is a common side effect and reason for early cessation of DHE, according to a study presented at the 47th Annual Meeting of the Child Neurology Society. Chest pain may not represent a serious cardiovascular problem, and patients who continue DHE despite chest pain have better chances of acute headache resolution, compared with patients who stop DHE, said Sara Fridinger, MD, a fellow with the Division of Neurology at Children’s Hospital of Philadelphia.

IV DHE is an effective headache treatment for children, but it has many side effects, including chest pain. Chest pain in pediatric patients who receive IV DHE may result from esophageal spasms, but it raises concerns about myocardial ischemia because of the drug’s vasospastic qualities, the researchers said.

To determine the incidence and significance of chest pain among pediatric patients who received IV DHE for headache, Dr. Fridinger and Christina Szperka, MD, Director of the Pediatric Headache Program at Children’s Hospital of Philadelphia, conducted a retrospective chart review. They examined data from pediatric patients at their hospital who received IV DHE between January 2014 and July 2016. They excluded patients who received DHE for secondary headache. Data from 183 patients (median age, 15.7; 81% female) were included in their analysis, including reports of chest pain and other side effects, EKG data, and cardiac enzymes.

Chest pain occurred in 27% (n = 49) of patients who received DHE. Chest pain occurred after the first dose in 33% of patients and after the second dose in 61%. All patients received premedication before the dose that caused chest pain, and metoclopramide was used as premedication in 80% of cases. No patients with chest pain had elevated troponin. Of the 31% of patients with chest pain who had EKG abnormalities, the abnormalities were either unchanged from baseline or deemed not clinically significant. Of patients with chest pain, 39% stopped DHE due to chest pain, whereas 61% continued with the DHE protocol.

Thirty-seven percent of patients who stopped DHE due to chest pain and 50% of those who continued DHE despite chest pain achieved resolution of the acute headache.

“It is reassuring that no patients were found to have elevated cardiac enzymes and no patients had frankly abnormal EKGs,” said Drs. Fridinger and Szperka.

CHICAGO—Among pediatric patients who receive IV dihydroergotamine (DHE) for headache, chest pain is a common side effect and reason for early cessation of DHE, according to a study presented at the 47th Annual Meeting of the Child Neurology Society. Chest pain may not represent a serious cardiovascular problem, and patients who continue DHE despite chest pain have better chances of acute headache resolution, compared with patients who stop DHE, said Sara Fridinger, MD, a fellow with the Division of Neurology at Children’s Hospital of Philadelphia.

IV DHE is an effective headache treatment for children, but it has many side effects, including chest pain. Chest pain in pediatric patients who receive IV DHE may result from esophageal spasms, but it raises concerns about myocardial ischemia because of the drug’s vasospastic qualities, the researchers said.

To determine the incidence and significance of chest pain among pediatric patients who received IV DHE for headache, Dr. Fridinger and Christina Szperka, MD, Director of the Pediatric Headache Program at Children’s Hospital of Philadelphia, conducted a retrospective chart review. They examined data from pediatric patients at their hospital who received IV DHE between January 2014 and July 2016. They excluded patients who received DHE for secondary headache. Data from 183 patients (median age, 15.7; 81% female) were included in their analysis, including reports of chest pain and other side effects, EKG data, and cardiac enzymes.

Chest pain occurred in 27% (n = 49) of patients who received DHE. Chest pain occurred after the first dose in 33% of patients and after the second dose in 61%. All patients received premedication before the dose that caused chest pain, and metoclopramide was used as premedication in 80% of cases. No patients with chest pain had elevated troponin. Of the 31% of patients with chest pain who had EKG abnormalities, the abnormalities were either unchanged from baseline or deemed not clinically significant. Of patients with chest pain, 39% stopped DHE due to chest pain, whereas 61% continued with the DHE protocol.

Thirty-seven percent of patients who stopped DHE due to chest pain and 50% of those who continued DHE despite chest pain achieved resolution of the acute headache.

“It is reassuring that no patients were found to have elevated cardiac enzymes and no patients had frankly abnormal EKGs,” said Drs. Fridinger and Szperka.

CHICAGO—Among pediatric patients who receive IV dihydroergotamine (DHE) for headache, chest pain is a common side effect and reason for early cessation of DHE, according to a study presented at the 47th Annual Meeting of the Child Neurology Society. Chest pain may not represent a serious cardiovascular problem, and patients who continue DHE despite chest pain have better chances of acute headache resolution, compared with patients who stop DHE, said Sara Fridinger, MD, a fellow with the Division of Neurology at Children’s Hospital of Philadelphia.

IV DHE is an effective headache treatment for children, but it has many side effects, including chest pain. Chest pain in pediatric patients who receive IV DHE may result from esophageal spasms, but it raises concerns about myocardial ischemia because of the drug’s vasospastic qualities, the researchers said.

To determine the incidence and significance of chest pain among pediatric patients who received IV DHE for headache, Dr. Fridinger and Christina Szperka, MD, Director of the Pediatric Headache Program at Children’s Hospital of Philadelphia, conducted a retrospective chart review. They examined data from pediatric patients at their hospital who received IV DHE between January 2014 and July 2016. They excluded patients who received DHE for secondary headache. Data from 183 patients (median age, 15.7; 81% female) were included in their analysis, including reports of chest pain and other side effects, EKG data, and cardiac enzymes.

Chest pain occurred in 27% (n = 49) of patients who received DHE. Chest pain occurred after the first dose in 33% of patients and after the second dose in 61%. All patients received premedication before the dose that caused chest pain, and metoclopramide was used as premedication in 80% of cases. No patients with chest pain had elevated troponin. Of the 31% of patients with chest pain who had EKG abnormalities, the abnormalities were either unchanged from baseline or deemed not clinically significant. Of patients with chest pain, 39% stopped DHE due to chest pain, whereas 61% continued with the DHE protocol.

Thirty-seven percent of patients who stopped DHE due to chest pain and 50% of those who continued DHE despite chest pain achieved resolution of the acute headache.

“It is reassuring that no patients were found to have elevated cardiac enzymes and no patients had frankly abnormal EKGs,” said Drs. Fridinger and Szperka.

In the largest analysis ever of cardiovascular risk associated with the initiation of nonsteroidal anti-inflammatory drugs (NSAIDs), diclofenac was associated with higher risk for adverse cardiovascular outcomes. The study findings were published online September 4 in BMJ.

Those beginning diclofenac had a 50% increased 30-day risk for a composite outcome of major adverse cardiovascular events (MACE), compared with individuals who did not initiate an NSAID or acetaminophen (95% confidence interval for incidence rate ratio, 1.4–1.7).

The risk was still significantly elevated when the study’s first author, Morten Schmidt, MD, PhD, of the Department of Clinical Epidemiology at Aarhus University in Denmark, and his colleagues compared diclofenac initiation with beginning other NSAIDs or acetaminophen. Compared with that associated with ibuprofen or acetaminophen, the MACE risk was elevated 20% in diclofenac initiators (95% CI, 1.1–1.3 for both). Initiating diclofenac was associated with 30% greater risk for MACE, compared with initiating naproxen (95% CI, 1.1–1.5).

Novel Methodology

The researchers used the longstanding and comprehensive Danish health registry system to their advantage in designing a cohort trial that was modeled to resemble a clinical trial. For each month, beginning in 1996 and continuing through 2016, Dr. Schmidt and his collaborators assembled propensity-matched cohorts of individuals to compare each study group. The study design achieved many of the aims of a clinical trial while working within the ethical constraints of studying medications known to elevate cardiovascular risk.

For each 30-day period, the investigators tracked and compared cardiovascular outcomes for each group. Each month, data for a new cohort were collected, beginning a new “clinical trial.” Individuals could be included in more than one month’s worth of “trial” data as long as they continued to meet inclusion criteria.

The completeness of Danish health data meant that the researchers were confident in data about comorbidities, other prescription medications, and outcomes.

Dr. Schmidt and his colleagues performed subgroup and sensitivity analyses to look at the extent to which preexisting risks for cardiovascular disease mediated MACE risk on diclofenac initiation. They found that diclofenac initiators in the highest risk group had as many as 40 excess cardiovascular events per year—about half of them fatal—that were attributable to starting the medication. Although that group had the highest absolute risk, “the relative risks were highest in those with the lowest baseline risk,” said the investigators.

Secondary outcomes for the study included the association between medication use or non-use and each component of the composite primary outcome. These components included first-time occurrences of the nonfatal end points of atrial fibrillation or flutter, ischemic stroke, heart failure, and myocardial infarction. Cardiac death included death from any cardiac cause.

“Supporting use of a combined end point, event rates consistently increased for all individual outcomes” for diclofenac initiators, compared with those who did not start an NSAID, said Dr. Schmidt and his colleagues.

Individuals were excluded if they had known cardiovascular, kidney, liver, or ulcer disease and if they had malignancy or serious mental health diagnoses such as dementia or schizophrenia. Participants, mean age 48 to 56, had to be at least 18 and could not have filled a prescription for an NSAID within the previous 12 months. Men made up 36.6% to 46.3% of the cohorts.

Dr. Schmidt and his collaborators said that in comparison with other NSAIDs, the short half-life of diclofenac means that a supratherapeutic plasma concentration of diclofenac soon after initiation achieves not just cyclooxygenase-2 (COX-2), but also COX-1 inhibition. However, after those high levels fall, patients taking diclofenac spend a substantial period of time with unopposed COX-2 inhibition, a prothrombotic state that also is associated with blood pressure elevation, atherogenesis, and worsening of heart failure.

Diclofenac and ibuprofen entailed similar gastrointestinal bleeding risks, and both medications were associated with a higher risk of bleeding than were ibuprofen, acetaminophen, and no medication.

Public Health Implications

“Comparing diclofenac initiation with no NSAID initiation, the consistency between our results and those of previous meta-analyses of both trial and observational data provides strong evidence to guide clinical decision making,” said Dr. Schmidt and his coauthors.

“Considering its cardiovascular and gastrointestinal risks, however, there is little justification to initiate diclofenac treatment before other traditional NSAIDs,” noted the investigators. “It is time to acknowledge the potential health risk of diclofenac and to reduce its use.”

The study was funded by the Department of Clinical Epidemiology Research Foundation, University of Aarhus, and by the Program for Clinical Research Infrastructure, funded by the Lundbeck Foundation, Novo Nordisk Foundation, and the Danish Research Council. The authors reported that they had no relevant conflicts of interest.

—Kari Oakes

Suggested Reading

Schmidt M, Sørensen HT, Pedersen L. Diclofenac use and cardiovascular risks: series of nationwide cohort studies. BMJ. 2018;362:k3426.

For expert commentary on this article, please visit our Migraine Resource Center online at https://www.mdedge.com/neurologyreviews/migraineresourcecenter/article/177937/headache-migraine/physician-commentary

In the largest analysis ever of cardiovascular risk associated with the initiation of nonsteroidal anti-inflammatory drugs (NSAIDs), diclofenac was associated with higher risk for adverse cardiovascular outcomes. The study findings were published online September 4 in BMJ.

Those beginning diclofenac had a 50% increased 30-day risk for a composite outcome of major adverse cardiovascular events (MACE), compared with individuals who did not initiate an NSAID or acetaminophen (95% confidence interval for incidence rate ratio, 1.4–1.7).

The risk was still significantly elevated when the study’s first author, Morten Schmidt, MD, PhD, of the Department of Clinical Epidemiology at Aarhus University in Denmark, and his colleagues compared diclofenac initiation with beginning other NSAIDs or acetaminophen. Compared with that associated with ibuprofen or acetaminophen, the MACE risk was elevated 20% in diclofenac initiators (95% CI, 1.1–1.3 for both). Initiating diclofenac was associated with 30% greater risk for MACE, compared with initiating naproxen (95% CI, 1.1–1.5).

Novel Methodology

The researchers used the longstanding and comprehensive Danish health registry system to their advantage in designing a cohort trial that was modeled to resemble a clinical trial. For each month, beginning in 1996 and continuing through 2016, Dr. Schmidt and his collaborators assembled propensity-matched cohorts of individuals to compare each study group. The study design achieved many of the aims of a clinical trial while working within the ethical constraints of studying medications known to elevate cardiovascular risk.

For each 30-day period, the investigators tracked and compared cardiovascular outcomes for each group. Each month, data for a new cohort were collected, beginning a new “clinical trial.” Individuals could be included in more than one month’s worth of “trial” data as long as they continued to meet inclusion criteria.

The completeness of Danish health data meant that the researchers were confident in data about comorbidities, other prescription medications, and outcomes.

Dr. Schmidt and his colleagues performed subgroup and sensitivity analyses to look at the extent to which preexisting risks for cardiovascular disease mediated MACE risk on diclofenac initiation. They found that diclofenac initiators in the highest risk group had as many as 40 excess cardiovascular events per year—about half of them fatal—that were attributable to starting the medication. Although that group had the highest absolute risk, “the relative risks were highest in those with the lowest baseline risk,” said the investigators.

Secondary outcomes for the study included the association between medication use or non-use and each component of the composite primary outcome. These components included first-time occurrences of the nonfatal end points of atrial fibrillation or flutter, ischemic stroke, heart failure, and myocardial infarction. Cardiac death included death from any cardiac cause.

“Supporting use of a combined end point, event rates consistently increased for all individual outcomes” for diclofenac initiators, compared with those who did not start an NSAID, said Dr. Schmidt and his colleagues.

Individuals were excluded if they had known cardiovascular, kidney, liver, or ulcer disease and if they had malignancy or serious mental health diagnoses such as dementia or schizophrenia. Participants, mean age 48 to 56, had to be at least 18 and could not have filled a prescription for an NSAID within the previous 12 months. Men made up 36.6% to 46.3% of the cohorts.

Dr. Schmidt and his collaborators said that in comparison with other NSAIDs, the short half-life of diclofenac means that a supratherapeutic plasma concentration of diclofenac soon after initiation achieves not just cyclooxygenase-2 (COX-2), but also COX-1 inhibition. However, after those high levels fall, patients taking diclofenac spend a substantial period of time with unopposed COX-2 inhibition, a prothrombotic state that also is associated with blood pressure elevation, atherogenesis, and worsening of heart failure.

Diclofenac and ibuprofen entailed similar gastrointestinal bleeding risks, and both medications were associated with a higher risk of bleeding than were ibuprofen, acetaminophen, and no medication.

Public Health Implications

“Comparing diclofenac initiation with no NSAID initiation, the consistency between our results and those of previous meta-analyses of both trial and observational data provides strong evidence to guide clinical decision making,” said Dr. Schmidt and his coauthors.

“Considering its cardiovascular and gastrointestinal risks, however, there is little justification to initiate diclofenac treatment before other traditional NSAIDs,” noted the investigators. “It is time to acknowledge the potential health risk of diclofenac and to reduce its use.”

The study was funded by the Department of Clinical Epidemiology Research Foundation, University of Aarhus, and by the Program for Clinical Research Infrastructure, funded by the Lundbeck Foundation, Novo Nordisk Foundation, and the Danish Research Council. The authors reported that they had no relevant conflicts of interest.

—Kari Oakes

Suggested Reading

Schmidt M, Sørensen HT, Pedersen L. Diclofenac use and cardiovascular risks: series of nationwide cohort studies. BMJ. 2018;362:k3426.

For expert commentary on this article, please visit our Migraine Resource Center online at https://www.mdedge.com/neurologyreviews/migraineresourcecenter/article/177937/headache-migraine/physician-commentary

In the largest analysis ever of cardiovascular risk associated with the initiation of nonsteroidal anti-inflammatory drugs (NSAIDs), diclofenac was associated with higher risk for adverse cardiovascular outcomes. The study findings were published online September 4 in BMJ.

Those beginning diclofenac had a 50% increased 30-day risk for a composite outcome of major adverse cardiovascular events (MACE), compared with individuals who did not initiate an NSAID or acetaminophen (95% confidence interval for incidence rate ratio, 1.4–1.7).

The risk was still significantly elevated when the study’s first author, Morten Schmidt, MD, PhD, of the Department of Clinical Epidemiology at Aarhus University in Denmark, and his colleagues compared diclofenac initiation with beginning other NSAIDs or acetaminophen. Compared with that associated with ibuprofen or acetaminophen, the MACE risk was elevated 20% in diclofenac initiators (95% CI, 1.1–1.3 for both). Initiating diclofenac was associated with 30% greater risk for MACE, compared with initiating naproxen (95% CI, 1.1–1.5).

Novel Methodology

The researchers used the longstanding and comprehensive Danish health registry system to their advantage in designing a cohort trial that was modeled to resemble a clinical trial. For each month, beginning in 1996 and continuing through 2016, Dr. Schmidt and his collaborators assembled propensity-matched cohorts of individuals to compare each study group. The study design achieved many of the aims of a clinical trial while working within the ethical constraints of studying medications known to elevate cardiovascular risk.

For each 30-day period, the investigators tracked and compared cardiovascular outcomes for each group. Each month, data for a new cohort were collected, beginning a new “clinical trial.” Individuals could be included in more than one month’s worth of “trial” data as long as they continued to meet inclusion criteria.

The completeness of Danish health data meant that the researchers were confident in data about comorbidities, other prescription medications, and outcomes.

Dr. Schmidt and his colleagues performed subgroup and sensitivity analyses to look at the extent to which preexisting risks for cardiovascular disease mediated MACE risk on diclofenac initiation. They found that diclofenac initiators in the highest risk group had as many as 40 excess cardiovascular events per year—about half of them fatal—that were attributable to starting the medication. Although that group had the highest absolute risk, “the relative risks were highest in those with the lowest baseline risk,” said the investigators.

Secondary outcomes for the study included the association between medication use or non-use and each component of the composite primary outcome. These components included first-time occurrences of the nonfatal end points of atrial fibrillation or flutter, ischemic stroke, heart failure, and myocardial infarction. Cardiac death included death from any cardiac cause.

“Supporting use of a combined end point, event rates consistently increased for all individual outcomes” for diclofenac initiators, compared with those who did not start an NSAID, said Dr. Schmidt and his colleagues.

Individuals were excluded if they had known cardiovascular, kidney, liver, or ulcer disease and if they had malignancy or serious mental health diagnoses such as dementia or schizophrenia. Participants, mean age 48 to 56, had to be at least 18 and could not have filled a prescription for an NSAID within the previous 12 months. Men made up 36.6% to 46.3% of the cohorts.

Dr. Schmidt and his collaborators said that in comparison with other NSAIDs, the short half-life of diclofenac means that a supratherapeutic plasma concentration of diclofenac soon after initiation achieves not just cyclooxygenase-2 (COX-2), but also COX-1 inhibition. However, after those high levels fall, patients taking diclofenac spend a substantial period of time with unopposed COX-2 inhibition, a prothrombotic state that also is associated with blood pressure elevation, atherogenesis, and worsening of heart failure.

Diclofenac and ibuprofen entailed similar gastrointestinal bleeding risks, and both medications were associated with a higher risk of bleeding than were ibuprofen, acetaminophen, and no medication.

Public Health Implications

“Comparing diclofenac initiation with no NSAID initiation, the consistency between our results and those of previous meta-analyses of both trial and observational data provides strong evidence to guide clinical decision making,” said Dr. Schmidt and his coauthors.

“Considering its cardiovascular and gastrointestinal risks, however, there is little justification to initiate diclofenac treatment before other traditional NSAIDs,” noted the investigators. “It is time to acknowledge the potential health risk of diclofenac and to reduce its use.”

The study was funded by the Department of Clinical Epidemiology Research Foundation, University of Aarhus, and by the Program for Clinical Research Infrastructure, funded by the Lundbeck Foundation, Novo Nordisk Foundation, and the Danish Research Council. The authors reported that they had no relevant conflicts of interest.

—Kari Oakes

Suggested Reading

Schmidt M, Sørensen HT, Pedersen L. Diclofenac use and cardiovascular risks: series of nationwide cohort studies. BMJ. 2018;362:k3426.

For expert commentary on this article, please visit our Migraine Resource Center online at https://www.mdedge.com/neurologyreviews/migraineresourcecenter/article/177937/headache-migraine/physician-commentary

Physicians continue to support advanced alternative payment models despite the fact that operational issues have not improved over the last 4 years and new ones have cropped up, according to a follow-up survey conducted by the RAND Corporation for the American Medical Association.

“All the things we heard in 2014 were still present in 2018. Both the challenges that practices had experienced back in 2014 having to do with data timeliness, data completeness and accuracy, payment model execution, all those challenges persisted,” Mark W. Friedberg, MD, senior physician policy researcher at RAND, said in an interview.

RAND surveyed 31 practices of varying practice size and specialty across six geographic regions, some of which participated in the 2014 survey. Supplemental information was provided by interviews with 32 market observers, 8 health plan leaders, 10 hospital and hospital system leaders, 10 state and local medical society leaders, and 4 chapter leaders with MGMA (formerly the Medical Group Management Association).

“We had thought we would hear that the problem had gotten a little bit better since there has been some investment in trying to tamp down the wide range of measures that are involved in these alternative payment models,” Dr. Friedberg said. “We did not see any evidence of that having any effect on the practices that participated in this study this time around.”

Indeed, concerns reported in 2014 were again reported in 2018, along with a new set of concerns, including the perceived pace of change in alternative payment models (APMs), the complexity of APMs, and physician concerns over two-sided risk models.

“Practices, especially those that participated both times, said in 2014 we had these challenges [of rapid changes in APM models] and since then, things have just gotten a lot faster,” he said, noting that doctors are complaining of models that are going through changes, sometimes without much warning. “They are changing quite rapidly from year to year. If you look at the MACRA QPP [Quality Payment Program] for example, that model changes every year to some extent and those things are hard for them to keep up with.”

Running hand in hand with the change is the complexity of the changes, a result of expanding performance measures and uncertainty with thresholds for penalties and rewards and in some ways has had little impact on improving care.

Dr. Friedberg noted that some practices are hiring people to examine APMs to devise strategic ways to choose and report data for maximum return.

“In a practice, for example, if their quality of care was already very good, what these folks ended up doing was help them choose measures and work the attribution algorithms in a strategic way to either guarantee a bonus or minimize the risk of incurring a penalty,” he said.

He also noted that practices appear to becoming more risk averse.

“We heard a lot more of the following thing, which is that if [practices] were in a two-sided risk model, several of them reported trying and succeeding in some cases offloading the downside risk to partners,” Dr. Friedberg reported. “And what this resulted in was that the practice, even though from the payer’s perspective they are in a two-sided model, the practice was actually in a one-sided model with a partner who is taking all of the downside risk and a portion of the upside risk, leaving a small upside risk proposition that remained for the practice.”

He said the range of partners that were absorbing the downside risk included hospitals, device manufacturers, consulting companies, or private equity firms.

Despite the concerns surrounding APMs, Dr. Friedberg said that “we did not hear practices broadly saying that they just weren’t interested in alternative payment models. In general, practices still remained pretty enthusiastic about these alternative payment models in theory. If they could be made simpler, if the pace of change weren’t quite so fast, that they would have a chance to really do some important care improvements in alternative payment models.”

He noted some of the surveyed practices were able to make investments in care as a direct result of participating in APMs, such as in behavioral health capabilities in primary care, for example, leading to quality of care improvements.

However, these issues could reveal a future unwillingness to participate in APMs, especially two-sided risk models, something at least the Centers for Medicare & Medicaid Services are pushing for as a stated goal of the QPP is to get practices to participate in APMs and take on more risk.

The growing aversion to taking on downside risk could lead practices to simply stay in fee for service and simply take the payment penalty because it is a fixed amount that can be planned for, as opposed to the fluctuations of bonuses and penalties that comes with a rapidly changing APM environment, Dr. Friedberg said.

Going forward, the report makes a number of recommendations to help create an environment that would potentially make APMs more successful, including simplifying the models; creating stable, predictable, and moderately paced pathways to APM participation; making data available in a more timely fashion; minimizing downside risk or helping practices better manage it; and designing APMs that will encourage clinical changes to help improve the effectiveness of care delivered.

[email protected]

Physicians continue to support advanced alternative payment models despite the fact that operational issues have not improved over the last 4 years and new ones have cropped up, according to a follow-up survey conducted by the RAND Corporation for the American Medical Association.

“All the things we heard in 2014 were still present in 2018. Both the challenges that practices had experienced back in 2014 having to do with data timeliness, data completeness and accuracy, payment model execution, all those challenges persisted,” Mark W. Friedberg, MD, senior physician policy researcher at RAND, said in an interview.

RAND surveyed 31 practices of varying practice size and specialty across six geographic regions, some of which participated in the 2014 survey. Supplemental information was provided by interviews with 32 market observers, 8 health plan leaders, 10 hospital and hospital system leaders, 10 state and local medical society leaders, and 4 chapter leaders with MGMA (formerly the Medical Group Management Association).

“We had thought we would hear that the problem had gotten a little bit better since there has been some investment in trying to tamp down the wide range of measures that are involved in these alternative payment models,” Dr. Friedberg said. “We did not see any evidence of that having any effect on the practices that participated in this study this time around.”

Indeed, concerns reported in 2014 were again reported in 2018, along with a new set of concerns, including the perceived pace of change in alternative payment models (APMs), the complexity of APMs, and physician concerns over two-sided risk models.

“Practices, especially those that participated both times, said in 2014 we had these challenges [of rapid changes in APM models] and since then, things have just gotten a lot faster,” he said, noting that doctors are complaining of models that are going through changes, sometimes without much warning. “They are changing quite rapidly from year to year. If you look at the MACRA QPP [Quality Payment Program] for example, that model changes every year to some extent and those things are hard for them to keep up with.”

Running hand in hand with the change is the complexity of the changes, a result of expanding performance measures and uncertainty with thresholds for penalties and rewards and in some ways has had little impact on improving care.

Dr. Friedberg noted that some practices are hiring people to examine APMs to devise strategic ways to choose and report data for maximum return.

“In a practice, for example, if their quality of care was already very good, what these folks ended up doing was help them choose measures and work the attribution algorithms in a strategic way to either guarantee a bonus or minimize the risk of incurring a penalty,” he said.

He also noted that practices appear to becoming more risk averse.

“We heard a lot more of the following thing, which is that if [practices] were in a two-sided risk model, several of them reported trying and succeeding in some cases offloading the downside risk to partners,” Dr. Friedberg reported. “And what this resulted in was that the practice, even though from the payer’s perspective they are in a two-sided model, the practice was actually in a one-sided model with a partner who is taking all of the downside risk and a portion of the upside risk, leaving a small upside risk proposition that remained for the practice.”

He said the range of partners that were absorbing the downside risk included hospitals, device manufacturers, consulting companies, or private equity firms.

Despite the concerns surrounding APMs, Dr. Friedberg said that “we did not hear practices broadly saying that they just weren’t interested in alternative payment models. In general, practices still remained pretty enthusiastic about these alternative payment models in theory. If they could be made simpler, if the pace of change weren’t quite so fast, that they would have a chance to really do some important care improvements in alternative payment models.”

He noted some of the surveyed practices were able to make investments in care as a direct result of participating in APMs, such as in behavioral health capabilities in primary care, for example, leading to quality of care improvements.

However, these issues could reveal a future unwillingness to participate in APMs, especially two-sided risk models, something at least the Centers for Medicare & Medicaid Services are pushing for as a stated goal of the QPP is to get practices to participate in APMs and take on more risk.

The growing aversion to taking on downside risk could lead practices to simply stay in fee for service and simply take the payment penalty because it is a fixed amount that can be planned for, as opposed to the fluctuations of bonuses and penalties that comes with a rapidly changing APM environment, Dr. Friedberg said.

Going forward, the report makes a number of recommendations to help create an environment that would potentially make APMs more successful, including simplifying the models; creating stable, predictable, and moderately paced pathways to APM participation; making data available in a more timely fashion; minimizing downside risk or helping practices better manage it; and designing APMs that will encourage clinical changes to help improve the effectiveness of care delivered.

[email protected]

Physicians continue to support advanced alternative payment models despite the fact that operational issues have not improved over the last 4 years and new ones have cropped up, according to a follow-up survey conducted by the RAND Corporation for the American Medical Association.

“All the things we heard in 2014 were still present in 2018. Both the challenges that practices had experienced back in 2014 having to do with data timeliness, data completeness and accuracy, payment model execution, all those challenges persisted,” Mark W. Friedberg, MD, senior physician policy researcher at RAND, said in an interview.

RAND surveyed 31 practices of varying practice size and specialty across six geographic regions, some of which participated in the 2014 survey. Supplemental information was provided by interviews with 32 market observers, 8 health plan leaders, 10 hospital and hospital system leaders, 10 state and local medical society leaders, and 4 chapter leaders with MGMA (formerly the Medical Group Management Association).

“We had thought we would hear that the problem had gotten a little bit better since there has been some investment in trying to tamp down the wide range of measures that are involved in these alternative payment models,” Dr. Friedberg said. “We did not see any evidence of that having any effect on the practices that participated in this study this time around.”

Indeed, concerns reported in 2014 were again reported in 2018, along with a new set of concerns, including the perceived pace of change in alternative payment models (APMs), the complexity of APMs, and physician concerns over two-sided risk models.

“Practices, especially those that participated both times, said in 2014 we had these challenges [of rapid changes in APM models] and since then, things have just gotten a lot faster,” he said, noting that doctors are complaining of models that are going through changes, sometimes without much warning. “They are changing quite rapidly from year to year. If you look at the MACRA QPP [Quality Payment Program] for example, that model changes every year to some extent and those things are hard for them to keep up with.”

Running hand in hand with the change is the complexity of the changes, a result of expanding performance measures and uncertainty with thresholds for penalties and rewards and in some ways has had little impact on improving care.

Dr. Friedberg noted that some practices are hiring people to examine APMs to devise strategic ways to choose and report data for maximum return.

“In a practice, for example, if their quality of care was already very good, what these folks ended up doing was help them choose measures and work the attribution algorithms in a strategic way to either guarantee a bonus or minimize the risk of incurring a penalty,” he said.

He also noted that practices appear to becoming more risk averse.

“We heard a lot more of the following thing, which is that if [practices] were in a two-sided risk model, several of them reported trying and succeeding in some cases offloading the downside risk to partners,” Dr. Friedberg reported. “And what this resulted in was that the practice, even though from the payer’s perspective they are in a two-sided model, the practice was actually in a one-sided model with a partner who is taking all of the downside risk and a portion of the upside risk, leaving a small upside risk proposition that remained for the practice.”

He said the range of partners that were absorbing the downside risk included hospitals, device manufacturers, consulting companies, or private equity firms.

Despite the concerns surrounding APMs, Dr. Friedberg said that “we did not hear practices broadly saying that they just weren’t interested in alternative payment models. In general, practices still remained pretty enthusiastic about these alternative payment models in theory. If they could be made simpler, if the pace of change weren’t quite so fast, that they would have a chance to really do some important care improvements in alternative payment models.”

He noted some of the surveyed practices were able to make investments in care as a direct result of participating in APMs, such as in behavioral health capabilities in primary care, for example, leading to quality of care improvements.

However, these issues could reveal a future unwillingness to participate in APMs, especially two-sided risk models, something at least the Centers for Medicare & Medicaid Services are pushing for as a stated goal of the QPP is to get practices to participate in APMs and take on more risk.

The growing aversion to taking on downside risk could lead practices to simply stay in fee for service and simply take the payment penalty because it is a fixed amount that can be planned for, as opposed to the fluctuations of bonuses and penalties that comes with a rapidly changing APM environment, Dr. Friedberg said.

Going forward, the report makes a number of recommendations to help create an environment that would potentially make APMs more successful, including simplifying the models; creating stable, predictable, and moderately paced pathways to APM participation; making data available in a more timely fashion; minimizing downside risk or helping practices better manage it; and designing APMs that will encourage clinical changes to help improve the effectiveness of care delivered.

[email protected]

In July 2018, The BMJ published a study examining the cardiovascular risks of diclofenac initiation compared with initiation of other traditional non-steroidal anti-inflammatory drugs, initiation of paracetamol, and no initiation. The results showed a 50% increase in adverse events among diclofenac initiators compared with non-initiators (as well as a 20% increase over paracetamol/ibuprofen initiators, and 30% increase over naproxen initiators). (Read the full study here). Here, I asked several of my colleagues to weigh in on the results of this study and its implications for our practices, and then I share my own thoughts on these findings:

Marcelo Bigal, MD, PhD
Chief Medical Officer, Purdue Pharma

It is well established that NSAIDs are associated with increased risk of poor cardiovascular outcomes. This study offers powerful evidence that the risk after frequent diclofenac use is disproportionally increased relative to other commonly used NSAIDs, such as ibuprofen or naproxen. It is relevant to discuss the implications of the findings for the treatment of migraine.

The acute treatment of migraine associated with attack-related disability should favor triptans as first line therapy, not NSAIDs. Because triptans are vasoconstrictive medications, unmet needs exist in patients at cardiovascular risk. Anti-CGRP acute migraine therapies, as well as “ditans” (5HT-1f antagonist) are under regulatory review and may address the needs of these patients. In the context of acute migraine therapy, diclofenac and NSAIDs are typically used instead of triptans, or with triptans when additional efficacy is needed. We certainly find that the use of diclofenac in these situations should be judicious, and reserved to those who clearly need it, have infrequent migraine attacks, and are otherwise healthy.

Diclofenac is also often used in the emergency department in many countries as a rescue therapy. In a series of clinical trials where we tested most commonly used drugs in this setting in Brazil, we found that efficacies were 83.6% for intravenous dipyrone, 66.7% for intramuscular diclofenac and 81.8% for intravenous chlorpromazine. We continue to believe that diclofenac is an important, non-sedative and non-opioid option for the management of headaches in the emergency department, assuming that at discharge, patients would receive proper guidance on the management of migraine without relying on frequent use of NSAIDs.

Jack Schim, MD
Co-Director, The Headache Center of Southern California

This article supports findings of prior epidemiologic studies correlating exposure to NSAIDs with increased cerebrovascular and cardiovascular risk. Prior studies have shown a dose-related response in risk associated with NSAID therapy, supporting a causal association. However, while relative risk is significantly higher in individuals with NSAID exposure, the absolute risk remains very low. The greater risk from NSAIDs continues to be to the kidneys, and to the stomach.  

As with all therapies, we need to weigh the advantages and disadvantages of NSAID therapy with our headache patients. All medications carry their own risks. For acute treatment of migraines, our primary tool, triptans, are contraindicated in a significant subset of individuals, including patients with ischemic coronary artery as well as those with history of stroke or transient ischemic attack (TIA). The alternatives, NSAIDs, dopamine blocking agents, have utility and risks.

Diclofenac powder to be dissolved in water is an effective abortive for migraine for many individuals. In general, our patients have intermittent exposure, preferably not more than 2 days per week. For the appropriate individual, NSAIDS, including diclofenac, remain an important tool in the acute care armamentarium.

Rob Cowan, MD, FAAN, FAHS
Higgins Professor of Neurology and Neurosciences
Chief, Division of Headache Medicine, Dept. of Neurology and Neurosciences
Director, Stanford University School of Medicine

These kinds of large, population-based studies must be interpreted with caution. While they may emulate the protocol of prospective studies, they lack proper inclusion/exclusion criteria, particularly with respect to indication. It may be reasonable to assume that the population of diclofenac users is "sicker" than the general population and the population that is using cheaper, more accessible NSAIDs or paracetamol. Without knowing the access and economic issues in Denmark, it is difficult to weigh these variables in the study. Thus, while it is certainly an important issue to explore (the relative risks and benefits of a given medication within a class), the absence of a well-designed, prospective study precludes any definitive conclusion regarding relative safety and risk profile for Diclofenac.

+++

These are great comments by my colleagues. My impression after seeing the data and reading my colleague’s comments, is that diclofenac may be riskier than other NSAIDs in this study; but when used properly in generally healthy migraineurs, it is probably more effective than dangerous when evaluating the risk/benefit ratio. When diclofenac is used as an oral solution (Cambia), 2 days per week or less, in a patient without serious gastrointestinal, renal, cardiac or hypertensive issues, it appears to pose little risk to the patient. When given to the wrong patient, or when taken too frequently, is could be dangerous. What I really like about this preparation is that it causes fewer adverse events compared to triptans and works very quickly. It can be used when triptans have been used enough that week or if they tend to cause significant adverse events when taken. We can use diclofenac for our headache patients, but we should remain vigilant to give it cautiously and only to patients who have no contraindication to its use.

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, M.D.
Editor-in-Chief
Migraine Resource Center

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

In July 2018, The BMJ published a study examining the cardiovascular risks of diclofenac initiation compared with initiation of other traditional non-steroidal anti-inflammatory drugs, initiation of paracetamol, and no initiation. The results showed a 50% increase in adverse events among diclofenac initiators compared with non-initiators (as well as a 20% increase over paracetamol/ibuprofen initiators, and 30% increase over naproxen initiators). (Read the full study here). Here, I asked several of my colleagues to weigh in on the results of this study and its implications for our practices, and then I share my own thoughts on these findings:

Marcelo Bigal, MD, PhD
Chief Medical Officer, Purdue Pharma

It is well established that NSAIDs are associated with increased risk of poor cardiovascular outcomes. This study offers powerful evidence that the risk after frequent diclofenac use is disproportionally increased relative to other commonly used NSAIDs, such as ibuprofen or naproxen. It is relevant to discuss the implications of the findings for the treatment of migraine.

The acute treatment of migraine associated with attack-related disability should favor triptans as first line therapy, not NSAIDs. Because triptans are vasoconstrictive medications, unmet needs exist in patients at cardiovascular risk. Anti-CGRP acute migraine therapies, as well as “ditans” (5HT-1f antagonist) are under regulatory review and may address the needs of these patients. In the context of acute migraine therapy, diclofenac and NSAIDs are typically used instead of triptans, or with triptans when additional efficacy is needed. We certainly find that the use of diclofenac in these situations should be judicious, and reserved to those who clearly need it, have infrequent migraine attacks, and are otherwise healthy.

Diclofenac is also often used in the emergency department in many countries as a rescue therapy. In a series of clinical trials where we tested most commonly used drugs in this setting in Brazil, we found that efficacies were 83.6% for intravenous dipyrone, 66.7% for intramuscular diclofenac and 81.8% for intravenous chlorpromazine. We continue to believe that diclofenac is an important, non-sedative and non-opioid option for the management of headaches in the emergency department, assuming that at discharge, patients would receive proper guidance on the management of migraine without relying on frequent use of NSAIDs.

Jack Schim, MD
Co-Director, The Headache Center of Southern California

This article supports findings of prior epidemiologic studies correlating exposure to NSAIDs with increased cerebrovascular and cardiovascular risk. Prior studies have shown a dose-related response in risk associated with NSAID therapy, supporting a causal association. However, while relative risk is significantly higher in individuals with NSAID exposure, the absolute risk remains very low. The greater risk from NSAIDs continues to be to the kidneys, and to the stomach.  

As with all therapies, we need to weigh the advantages and disadvantages of NSAID therapy with our headache patients. All medications carry their own risks. For acute treatment of migraines, our primary tool, triptans, are contraindicated in a significant subset of individuals, including patients with ischemic coronary artery as well as those with history of stroke or transient ischemic attack (TIA). The alternatives, NSAIDs, dopamine blocking agents, have utility and risks.

Diclofenac powder to be dissolved in water is an effective abortive for migraine for many individuals. In general, our patients have intermittent exposure, preferably not more than 2 days per week. For the appropriate individual, NSAIDS, including diclofenac, remain an important tool in the acute care armamentarium.

Rob Cowan, MD, FAAN, FAHS
Higgins Professor of Neurology and Neurosciences
Chief, Division of Headache Medicine, Dept. of Neurology and Neurosciences
Director, Stanford University School of Medicine

These kinds of large, population-based studies must be interpreted with caution. While they may emulate the protocol of prospective studies, they lack proper inclusion/exclusion criteria, particularly with respect to indication. It may be reasonable to assume that the population of diclofenac users is "sicker" than the general population and the population that is using cheaper, more accessible NSAIDs or paracetamol. Without knowing the access and economic issues in Denmark, it is difficult to weigh these variables in the study. Thus, while it is certainly an important issue to explore (the relative risks and benefits of a given medication within a class), the absence of a well-designed, prospective study precludes any definitive conclusion regarding relative safety and risk profile for Diclofenac.

+++

These are great comments by my colleagues. My impression after seeing the data and reading my colleague’s comments, is that diclofenac may be riskier than other NSAIDs in this study; but when used properly in generally healthy migraineurs, it is probably more effective than dangerous when evaluating the risk/benefit ratio. When diclofenac is used as an oral solution (Cambia), 2 days per week or less, in a patient without serious gastrointestinal, renal, cardiac or hypertensive issues, it appears to pose little risk to the patient. When given to the wrong patient, or when taken too frequently, is could be dangerous. What I really like about this preparation is that it causes fewer adverse events compared to triptans and works very quickly. It can be used when triptans have been used enough that week or if they tend to cause significant adverse events when taken. We can use diclofenac for our headache patients, but we should remain vigilant to give it cautiously and only to patients who have no contraindication to its use.

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, M.D.
Editor-in-Chief
Migraine Resource Center

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

In July 2018, The BMJ published a study examining the cardiovascular risks of diclofenac initiation compared with initiation of other traditional non-steroidal anti-inflammatory drugs, initiation of paracetamol, and no initiation. The results showed a 50% increase in adverse events among diclofenac initiators compared with non-initiators (as well as a 20% increase over paracetamol/ibuprofen initiators, and 30% increase over naproxen initiators). (Read the full study here). Here, I asked several of my colleagues to weigh in on the results of this study and its implications for our practices, and then I share my own thoughts on these findings:

Marcelo Bigal, MD, PhD
Chief Medical Officer, Purdue Pharma

It is well established that NSAIDs are associated with increased risk of poor cardiovascular outcomes. This study offers powerful evidence that the risk after frequent diclofenac use is disproportionally increased relative to other commonly used NSAIDs, such as ibuprofen or naproxen. It is relevant to discuss the implications of the findings for the treatment of migraine.

The acute treatment of migraine associated with attack-related disability should favor triptans as first line therapy, not NSAIDs. Because triptans are vasoconstrictive medications, unmet needs exist in patients at cardiovascular risk. Anti-CGRP acute migraine therapies, as well as “ditans” (5HT-1f antagonist) are under regulatory review and may address the needs of these patients. In the context of acute migraine therapy, diclofenac and NSAIDs are typically used instead of triptans, or with triptans when additional efficacy is needed. We certainly find that the use of diclofenac in these situations should be judicious, and reserved to those who clearly need it, have infrequent migraine attacks, and are otherwise healthy.

Diclofenac is also often used in the emergency department in many countries as a rescue therapy. In a series of clinical trials where we tested most commonly used drugs in this setting in Brazil, we found that efficacies were 83.6% for intravenous dipyrone, 66.7% for intramuscular diclofenac and 81.8% for intravenous chlorpromazine. We continue to believe that diclofenac is an important, non-sedative and non-opioid option for the management of headaches in the emergency department, assuming that at discharge, patients would receive proper guidance on the management of migraine without relying on frequent use of NSAIDs.

Jack Schim, MD
Co-Director, The Headache Center of Southern California

This article supports findings of prior epidemiologic studies correlating exposure to NSAIDs with increased cerebrovascular and cardiovascular risk. Prior studies have shown a dose-related response in risk associated with NSAID therapy, supporting a causal association. However, while relative risk is significantly higher in individuals with NSAID exposure, the absolute risk remains very low. The greater risk from NSAIDs continues to be to the kidneys, and to the stomach.  

As with all therapies, we need to weigh the advantages and disadvantages of NSAID therapy with our headache patients. All medications carry their own risks. For acute treatment of migraines, our primary tool, triptans, are contraindicated in a significant subset of individuals, including patients with ischemic coronary artery as well as those with history of stroke or transient ischemic attack (TIA). The alternatives, NSAIDs, dopamine blocking agents, have utility and risks.

Diclofenac powder to be dissolved in water is an effective abortive for migraine for many individuals. In general, our patients have intermittent exposure, preferably not more than 2 days per week. For the appropriate individual, NSAIDS, including diclofenac, remain an important tool in the acute care armamentarium.

Rob Cowan, MD, FAAN, FAHS
Higgins Professor of Neurology and Neurosciences
Chief, Division of Headache Medicine, Dept. of Neurology and Neurosciences
Director, Stanford University School of Medicine

These kinds of large, population-based studies must be interpreted with caution. While they may emulate the protocol of prospective studies, they lack proper inclusion/exclusion criteria, particularly with respect to indication. It may be reasonable to assume that the population of diclofenac users is "sicker" than the general population and the population that is using cheaper, more accessible NSAIDs or paracetamol. Without knowing the access and economic issues in Denmark, it is difficult to weigh these variables in the study. Thus, while it is certainly an important issue to explore (the relative risks and benefits of a given medication within a class), the absence of a well-designed, prospective study precludes any definitive conclusion regarding relative safety and risk profile for Diclofenac.

+++

These are great comments by my colleagues. My impression after seeing the data and reading my colleague’s comments, is that diclofenac may be riskier than other NSAIDs in this study; but when used properly in generally healthy migraineurs, it is probably more effective than dangerous when evaluating the risk/benefit ratio. When diclofenac is used as an oral solution (Cambia), 2 days per week or less, in a patient without serious gastrointestinal, renal, cardiac or hypertensive issues, it appears to pose little risk to the patient. When given to the wrong patient, or when taken too frequently, is could be dangerous. What I really like about this preparation is that it causes fewer adverse events compared to triptans and works very quickly. It can be used when triptans have been used enough that week or if they tend to cause significant adverse events when taken. We can use diclofenac for our headache patients, but we should remain vigilant to give it cautiously and only to patients who have no contraindication to its use.

Please write to us at Neurology Reviews Migraine Resource Center ([email protected]) with your opinions.

Alan M. Rapoport, M.D.
Editor-in-Chief
Migraine Resource Center

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