Migraine ICYMI

SAN FRANCISCO—Although triptans are considered the gold standard for acute migraine therapy, only 37% of migraineurs had ever used a triptan and just 15.9% were current triptan users, according to the results of a study presented at the 60th Annual Scientific Meeting of the American Headache Society. Aftab Alam, MBBS, MBA, from Medical Affairs at Dr. Reddy’s Laboratories in Princeton, New Jersey, and colleagues from the Migraine in America Symptoms and Treatment (MAST) study determined that while oral treatment was the most common route of administration, only 11.5% of their total sample (31.1% of ever triptan users and 40.4% of current triptan users) had ever used a non-oral formulation.

The MAST Study collected detailed information regarding patterns of medication use in a sample of patients with migraine. The objectives of the analysis were to understand past and current usage patterns for triptans by route of administration and the rates and reasons for discontinuation.

Study respondents were recruited from a nationwide online research panel. Stratified random sampling identified a representative cohort of individuals 18 and older. A validated migraine symptom screen based on modified ICHD-3 beta criteria identified those with migraine. Study inclusion required an average of at least one headache day per month over the previous three months. Qualified respondents provided sociodemographic data (age, gender, and race) as well as patterns of past and current medication use. For past triptan users, Dr. Alam and his MAST study collaborators assessed reasons for discontinuation from a pre-coded list of side effects and triptan sensation symptoms. Other responses were allowed and coded. The researchers examined descriptive results for each route of administration, but “the groups are not mutually exclusive,” Dr. Alam noted.

Triptan Usage Results

Among 15,133 respondents with migraine, the mean age was 43.1; 73% were women, and 81% were Caucasian. Median monthly headache frequency was 3.3 days per month. A total of 5,596 (37%) had ever used a triptan. Among this subgroup, 81.8% had used oral, 21.3% had used a nasal spray, and 19.0% had used injectable forms; 22.2% had used more than one route of administration. Among current triptan users (2,421, 15.9%), 84.7% use oral, 16.5% use nasal spray, and 8.1% use injectable; 9.3% currently use more than one route of administration. Discontinuation rates were highest for injectable triptans (81.5%), followed by nasal sprays (66.5%) and oral medications (55.2%).

Reasons for Discontinuation

The most common reason for discontinuation was perceived lack of efficacy (38.4% oral, 39.8% nasal spray, 25.7% injectable), followed by side effects (22.8% oral, 17% nasal spray, 20.6% injectable). The most commonly reported side effects were dizziness (37.4% oral, 29.4% nasal spray, 33.5% injectable) followed by nausea (30.7% oral, 32.4% nasal spray, 24.6% injectable) and fatigue (26.2% oral, 24.3% nasal spray, 21.2% injectable). One or more triptan sensation symptom was reported among 60.3% of injection users, 46.5% of oral users, and 39.7% of nasal spray users.

—Glenn S. Williams

Suggested Reading

Wells RE, Markowitz SY, Baron EP, et al. Identifying factors underlying discontinuation of triptans. Headache. 2014;54(2):278-289.

SAN FRANCISCO—Although triptans are considered the gold standard for acute migraine therapy, only 37% of migraineurs had ever used a triptan and just 15.9% were current triptan users, according to the results of a study presented at the 60th Annual Scientific Meeting of the American Headache Society. Aftab Alam, MBBS, MBA, from Medical Affairs at Dr. Reddy’s Laboratories in Princeton, New Jersey, and colleagues from the Migraine in America Symptoms and Treatment (MAST) study determined that while oral treatment was the most common route of administration, only 11.5% of their total sample (31.1% of ever triptan users and 40.4% of current triptan users) had ever used a non-oral formulation.

The MAST Study collected detailed information regarding patterns of medication use in a sample of patients with migraine. The objectives of the analysis were to understand past and current usage patterns for triptans by route of administration and the rates and reasons for discontinuation.

Study respondents were recruited from a nationwide online research panel. Stratified random sampling identified a representative cohort of individuals 18 and older. A validated migraine symptom screen based on modified ICHD-3 beta criteria identified those with migraine. Study inclusion required an average of at least one headache day per month over the previous three months. Qualified respondents provided sociodemographic data (age, gender, and race) as well as patterns of past and current medication use. For past triptan users, Dr. Alam and his MAST study collaborators assessed reasons for discontinuation from a pre-coded list of side effects and triptan sensation symptoms. Other responses were allowed and coded. The researchers examined descriptive results for each route of administration, but “the groups are not mutually exclusive,” Dr. Alam noted.

Triptan Usage Results

Among 15,133 respondents with migraine, the mean age was 43.1; 73% were women, and 81% were Caucasian. Median monthly headache frequency was 3.3 days per month. A total of 5,596 (37%) had ever used a triptan. Among this subgroup, 81.8% had used oral, 21.3% had used a nasal spray, and 19.0% had used injectable forms; 22.2% had used more than one route of administration. Among current triptan users (2,421, 15.9%), 84.7% use oral, 16.5% use nasal spray, and 8.1% use injectable; 9.3% currently use more than one route of administration. Discontinuation rates were highest for injectable triptans (81.5%), followed by nasal sprays (66.5%) and oral medications (55.2%).

Reasons for Discontinuation

The most common reason for discontinuation was perceived lack of efficacy (38.4% oral, 39.8% nasal spray, 25.7% injectable), followed by side effects (22.8% oral, 17% nasal spray, 20.6% injectable). The most commonly reported side effects were dizziness (37.4% oral, 29.4% nasal spray, 33.5% injectable) followed by nausea (30.7% oral, 32.4% nasal spray, 24.6% injectable) and fatigue (26.2% oral, 24.3% nasal spray, 21.2% injectable). One or more triptan sensation symptom was reported among 60.3% of injection users, 46.5% of oral users, and 39.7% of nasal spray users.

—Glenn S. Williams

Suggested Reading

Wells RE, Markowitz SY, Baron EP, et al. Identifying factors underlying discontinuation of triptans. Headache. 2014;54(2):278-289.

SAN FRANCISCO—Although triptans are considered the gold standard for acute migraine therapy, only 37% of migraineurs had ever used a triptan and just 15.9% were current triptan users, according to the results of a study presented at the 60th Annual Scientific Meeting of the American Headache Society. Aftab Alam, MBBS, MBA, from Medical Affairs at Dr. Reddy’s Laboratories in Princeton, New Jersey, and colleagues from the Migraine in America Symptoms and Treatment (MAST) study determined that while oral treatment was the most common route of administration, only 11.5% of their total sample (31.1% of ever triptan users and 40.4% of current triptan users) had ever used a non-oral formulation.

The MAST Study collected detailed information regarding patterns of medication use in a sample of patients with migraine. The objectives of the analysis were to understand past and current usage patterns for triptans by route of administration and the rates and reasons for discontinuation.

Study respondents were recruited from a nationwide online research panel. Stratified random sampling identified a representative cohort of individuals 18 and older. A validated migraine symptom screen based on modified ICHD-3 beta criteria identified those with migraine. Study inclusion required an average of at least one headache day per month over the previous three months. Qualified respondents provided sociodemographic data (age, gender, and race) as well as patterns of past and current medication use. For past triptan users, Dr. Alam and his MAST study collaborators assessed reasons for discontinuation from a pre-coded list of side effects and triptan sensation symptoms. Other responses were allowed and coded. The researchers examined descriptive results for each route of administration, but “the groups are not mutually exclusive,” Dr. Alam noted.

Triptan Usage Results

Among 15,133 respondents with migraine, the mean age was 43.1; 73% were women, and 81% were Caucasian. Median monthly headache frequency was 3.3 days per month. A total of 5,596 (37%) had ever used a triptan. Among this subgroup, 81.8% had used oral, 21.3% had used a nasal spray, and 19.0% had used injectable forms; 22.2% had used more than one route of administration. Among current triptan users (2,421, 15.9%), 84.7% use oral, 16.5% use nasal spray, and 8.1% use injectable; 9.3% currently use more than one route of administration. Discontinuation rates were highest for injectable triptans (81.5%), followed by nasal sprays (66.5%) and oral medications (55.2%).

Reasons for Discontinuation

The most common reason for discontinuation was perceived lack of efficacy (38.4% oral, 39.8% nasal spray, 25.7% injectable), followed by side effects (22.8% oral, 17% nasal spray, 20.6% injectable). The most commonly reported side effects were dizziness (37.4% oral, 29.4% nasal spray, 33.5% injectable) followed by nausea (30.7% oral, 32.4% nasal spray, 24.6% injectable) and fatigue (26.2% oral, 24.3% nasal spray, 21.2% injectable). One or more triptan sensation symptom was reported among 60.3% of injection users, 46.5% of oral users, and 39.7% of nasal spray users.

—Glenn S. Williams

Suggested Reading

Wells RE, Markowitz SY, Baron EP, et al. Identifying factors underlying discontinuation of triptans. Headache. 2014;54(2):278-289.

SAN FRANCISCO—Most women with migraine develop migraine pattern change, worsening migraine, or new-onset migraine at the age of menopause, according to a study presented at the 60th Annual Scientific Meeting of the American Headache Society. These changes most often occur during the perimenopausal or postmenopausal stages.

Previous research indicates that the prevalence and frequency of migraine are higher in perimenopausal women than in other women. Yu-Chen Cheng, MD, MPH, a postdoctoral fellow at Massachusetts General Hospital in Boston, and colleagues investigated patterns of migraine in women at menopausal age (ie, age 40–60) with migraine who presented to the Partners Healthcare Hospitals. The investigators reviewed participants’ medical records, brain image reports, and laboratory data, including levels of estradiol and follicle-stimulating hormone (FSH).

In their retrospective study, Dr. Cheng and colleagues identified 81 patients with concurrent diagnoses of migraine and menopause who had clinical data available. They excluded patients with missing or inaccessible data, as well as patients with organic brain lesions such as those associated with multiple sclerosis or brain tumor. The researchers included 69 patients in the study.

Sixty patients (86.96%) had a history of migraine, and the other nine patients (13.04%) had new-onset migraine. Among participants with a history of migraine, 35 (58.33%) had a change in migraine pattern or worsening of their migraine headaches. The investigators categorized patients in this group as having migraine worsening (60.00%), migraine pattern change (28.57%), worsening related to other cause (8.57%), and not sure (2.86%). Twenty-five patients with migraine history were stable and had no change in the pattern of their headaches.

Dr. Cheng and colleagues also examined the population’s menopausal status when they had migraine change or worsening or new migraine. Among patients with migraine history, nine of 35 (25.71%) were at the perimenopausal stage, 12 (34.29%) were postmenopausal, five (14.29%) were premenopausal, three (8.57%) had worsening because of other causes, and three (8.57%) did not have records on their menopausal status. For patients with new-onset migraine, three of nine (33%) were perimenopausal, three (33%) were postmenopausal, and one (11.11%) was premenopausal.

Among patients with new-onset migraine, brain MRI was normal in 44.44%, showed pituitary abnormality in 22.22%, and showed other brain lesion in 33.33%. In patients with migraine history, brain MRI was normal in 45%, showed pituitary abnormality in 8.3%, showed nonspecific T2 high white matter lesion in 16.67%, and showed other brain lesion in 11.67%.

“Identifying migraine worsening or new-onset migraine during the menopausal transition age may help the diagnosis and treatment optimization of migraine for women during the menopausal age,” said Dr. Cheng.

SAN FRANCISCO—Most women with migraine develop migraine pattern change, worsening migraine, or new-onset migraine at the age of menopause, according to a study presented at the 60th Annual Scientific Meeting of the American Headache Society. These changes most often occur during the perimenopausal or postmenopausal stages.

Previous research indicates that the prevalence and frequency of migraine are higher in perimenopausal women than in other women. Yu-Chen Cheng, MD, MPH, a postdoctoral fellow at Massachusetts General Hospital in Boston, and colleagues investigated patterns of migraine in women at menopausal age (ie, age 40–60) with migraine who presented to the Partners Healthcare Hospitals. The investigators reviewed participants’ medical records, brain image reports, and laboratory data, including levels of estradiol and follicle-stimulating hormone (FSH).

In their retrospective study, Dr. Cheng and colleagues identified 81 patients with concurrent diagnoses of migraine and menopause who had clinical data available. They excluded patients with missing or inaccessible data, as well as patients with organic brain lesions such as those associated with multiple sclerosis or brain tumor. The researchers included 69 patients in the study.

Sixty patients (86.96%) had a history of migraine, and the other nine patients (13.04%) had new-onset migraine. Among participants with a history of migraine, 35 (58.33%) had a change in migraine pattern or worsening of their migraine headaches. The investigators categorized patients in this group as having migraine worsening (60.00%), migraine pattern change (28.57%), worsening related to other cause (8.57%), and not sure (2.86%). Twenty-five patients with migraine history were stable and had no change in the pattern of their headaches.

Dr. Cheng and colleagues also examined the population’s menopausal status when they had migraine change or worsening or new migraine. Among patients with migraine history, nine of 35 (25.71%) were at the perimenopausal stage, 12 (34.29%) were postmenopausal, five (14.29%) were premenopausal, three (8.57%) had worsening because of other causes, and three (8.57%) did not have records on their menopausal status. For patients with new-onset migraine, three of nine (33%) were perimenopausal, three (33%) were postmenopausal, and one (11.11%) was premenopausal.

Among patients with new-onset migraine, brain MRI was normal in 44.44%, showed pituitary abnormality in 22.22%, and showed other brain lesion in 33.33%. In patients with migraine history, brain MRI was normal in 45%, showed pituitary abnormality in 8.3%, showed nonspecific T2 high white matter lesion in 16.67%, and showed other brain lesion in 11.67%.

“Identifying migraine worsening or new-onset migraine during the menopausal transition age may help the diagnosis and treatment optimization of migraine for women during the menopausal age,” said Dr. Cheng.

SAN FRANCISCO—Most women with migraine develop migraine pattern change, worsening migraine, or new-onset migraine at the age of menopause, according to a study presented at the 60th Annual Scientific Meeting of the American Headache Society. These changes most often occur during the perimenopausal or postmenopausal stages.

Previous research indicates that the prevalence and frequency of migraine are higher in perimenopausal women than in other women. Yu-Chen Cheng, MD, MPH, a postdoctoral fellow at Massachusetts General Hospital in Boston, and colleagues investigated patterns of migraine in women at menopausal age (ie, age 40–60) with migraine who presented to the Partners Healthcare Hospitals. The investigators reviewed participants’ medical records, brain image reports, and laboratory data, including levels of estradiol and follicle-stimulating hormone (FSH).

In their retrospective study, Dr. Cheng and colleagues identified 81 patients with concurrent diagnoses of migraine and menopause who had clinical data available. They excluded patients with missing or inaccessible data, as well as patients with organic brain lesions such as those associated with multiple sclerosis or brain tumor. The researchers included 69 patients in the study.

Sixty patients (86.96%) had a history of migraine, and the other nine patients (13.04%) had new-onset migraine. Among participants with a history of migraine, 35 (58.33%) had a change in migraine pattern or worsening of their migraine headaches. The investigators categorized patients in this group as having migraine worsening (60.00%), migraine pattern change (28.57%), worsening related to other cause (8.57%), and not sure (2.86%). Twenty-five patients with migraine history were stable and had no change in the pattern of their headaches.

Dr. Cheng and colleagues also examined the population’s menopausal status when they had migraine change or worsening or new migraine. Among patients with migraine history, nine of 35 (25.71%) were at the perimenopausal stage, 12 (34.29%) were postmenopausal, five (14.29%) were premenopausal, three (8.57%) had worsening because of other causes, and three (8.57%) did not have records on their menopausal status. For patients with new-onset migraine, three of nine (33%) were perimenopausal, three (33%) were postmenopausal, and one (11.11%) was premenopausal.

Among patients with new-onset migraine, brain MRI was normal in 44.44%, showed pituitary abnormality in 22.22%, and showed other brain lesion in 33.33%. In patients with migraine history, brain MRI was normal in 45%, showed pituitary abnormality in 8.3%, showed nonspecific T2 high white matter lesion in 16.67%, and showed other brain lesion in 11.67%.

“Identifying migraine worsening or new-onset migraine during the menopausal transition age may help the diagnosis and treatment optimization of migraine for women during the menopausal age,” said Dr. Cheng.

SAN FRANCISCO—For the prevention of chronic migraine, onabotulinumtoxinA has a superior tolerability profile versus topiramate based on treatment-related adverse events and overall discontinuations, according to data presented at the 60th Annual Scientific Meeting of the American Headache Society. In addition, “patient-reported outcomes data suggest that changes in cognition, an important adverse event leading to treatment discontinuation with topiramate, may be seen as early as week 12,” said Andrew M. Blumenfeld, MD, Director of the Headache Center of Southern California in Oceanside, and colleagues. Dr. Blumenfeld also reported that onabotulinumtoxinA has a more favorable effect on depressive symptoms than does topiramate.

According to Dr. Blumenfeld and colleagues, many adults with chronic migraine are not receiving appropriate preventive treatment and when prescribed, adherence to treatment is relatively low. To address this problem, he and his colleagues conducted a multicenter, prospective, randomized, parallel-group, open-label study to compare onabotulinumtoxinA and topiramate for headache prevention in adults with chronic migraine (the FORWARD study).

The study assessed the effectiveness of onabotulinumtoxinA 155 U administered to 31 sites across seven head and neck muscles, fixed-site, fixed-dose, every 12 weeks for three cycles versus topiramate 50 to 100 mg/day up to week 36. The primary efficacy measure was the proportion of patients with a 50% or greater reduction in headache days versus baseline in the 28 days before week 32. Safety and tolerability were assessed; adverse events were monitored. Patient-reported outcomes collected from questionnaires at day 1 and weeks 12, 24, and 36 included the Controlled Oral Word Association Test (COWAT) and the nine-item Patient Health Questionnaire (PHQ-9). Baseline observation carried forward (BLOCF) was used to impute missing values at primary time points, followed by questionnaire guidelines for missing questionnaire data.

A total of 282 patients were enrolled—140 in the onabotulinumtoxinA arm and 142 in the topiramate arm. Mean baseline headache days (onabotulinumtoxinA, 22.1; topiramate, 21.8) were similar. Of the patients enrolled, 148 completed randomized treatment (onabotulinumtoxinA, 85.7%; topiramate, 19.7%). Primary reasons for withdrawal were ineffective treatment (onabotulinumtoxinA, 5.0%; topiramate, 19.0%) and adverse events (onabotulinumtoxinA, 3.6%; topiramate, 50.7%). Based on BLOCF, more patients on onabotulinumtoxinA had a 50% or greater reduction in headache frequency compared with baseline versus topiramate (40.0% vs 12.0%). Adverse events were reported by 45.5% of patients who received onabotulinumtoxinA and 76.8% of patients who received topiramate; treatment-related adverse events were reported by 17.3% and 69.0%, respectively. No new safety signals were identified for onabotulinumtoxinA. Adverse events relating to nervous system disorders most commonly led to treatment discontinuation for topiramate. Topiramate reduced mean COWAT scores from as early as week 12, suggesting cognitive changes occurred early in treatment with topiramate. As the study progressed, topiramate’s effect may have been obscured by the BLOCF imputation methodology due to the large proportion of patients withdrawing from topiramate, the investigators said. In contrast, onabotulinumtoxinA resulted in a small increase in COWAT scores from week 12 to week 36. OnabotulinumtoxinA had a significantly greater effect on mean PHQ-9 scores at week 36 (4.4), compared with topiramate (7.1; estimated mean difference, –1.86).

SAN FRANCISCO—For the prevention of chronic migraine, onabotulinumtoxinA has a superior tolerability profile versus topiramate based on treatment-related adverse events and overall discontinuations, according to data presented at the 60th Annual Scientific Meeting of the American Headache Society. In addition, “patient-reported outcomes data suggest that changes in cognition, an important adverse event leading to treatment discontinuation with topiramate, may be seen as early as week 12,” said Andrew M. Blumenfeld, MD, Director of the Headache Center of Southern California in Oceanside, and colleagues. Dr. Blumenfeld also reported that onabotulinumtoxinA has a more favorable effect on depressive symptoms than does topiramate.

According to Dr. Blumenfeld and colleagues, many adults with chronic migraine are not receiving appropriate preventive treatment and when prescribed, adherence to treatment is relatively low. To address this problem, he and his colleagues conducted a multicenter, prospective, randomized, parallel-group, open-label study to compare onabotulinumtoxinA and topiramate for headache prevention in adults with chronic migraine (the FORWARD study).

The study assessed the effectiveness of onabotulinumtoxinA 155 U administered to 31 sites across seven head and neck muscles, fixed-site, fixed-dose, every 12 weeks for three cycles versus topiramate 50 to 100 mg/day up to week 36. The primary efficacy measure was the proportion of patients with a 50% or greater reduction in headache days versus baseline in the 28 days before week 32. Safety and tolerability were assessed; adverse events were monitored. Patient-reported outcomes collected from questionnaires at day 1 and weeks 12, 24, and 36 included the Controlled Oral Word Association Test (COWAT) and the nine-item Patient Health Questionnaire (PHQ-9). Baseline observation carried forward (BLOCF) was used to impute missing values at primary time points, followed by questionnaire guidelines for missing questionnaire data.

A total of 282 patients were enrolled—140 in the onabotulinumtoxinA arm and 142 in the topiramate arm. Mean baseline headache days (onabotulinumtoxinA, 22.1; topiramate, 21.8) were similar. Of the patients enrolled, 148 completed randomized treatment (onabotulinumtoxinA, 85.7%; topiramate, 19.7%). Primary reasons for withdrawal were ineffective treatment (onabotulinumtoxinA, 5.0%; topiramate, 19.0%) and adverse events (onabotulinumtoxinA, 3.6%; topiramate, 50.7%). Based on BLOCF, more patients on onabotulinumtoxinA had a 50% or greater reduction in headache frequency compared with baseline versus topiramate (40.0% vs 12.0%). Adverse events were reported by 45.5% of patients who received onabotulinumtoxinA and 76.8% of patients who received topiramate; treatment-related adverse events were reported by 17.3% and 69.0%, respectively. No new safety signals were identified for onabotulinumtoxinA. Adverse events relating to nervous system disorders most commonly led to treatment discontinuation for topiramate. Topiramate reduced mean COWAT scores from as early as week 12, suggesting cognitive changes occurred early in treatment with topiramate. As the study progressed, topiramate’s effect may have been obscured by the BLOCF imputation methodology due to the large proportion of patients withdrawing from topiramate, the investigators said. In contrast, onabotulinumtoxinA resulted in a small increase in COWAT scores from week 12 to week 36. OnabotulinumtoxinA had a significantly greater effect on mean PHQ-9 scores at week 36 (4.4), compared with topiramate (7.1; estimated mean difference, –1.86).

SAN FRANCISCO—For the prevention of chronic migraine, onabotulinumtoxinA has a superior tolerability profile versus topiramate based on treatment-related adverse events and overall discontinuations, according to data presented at the 60th Annual Scientific Meeting of the American Headache Society. In addition, “patient-reported outcomes data suggest that changes in cognition, an important adverse event leading to treatment discontinuation with topiramate, may be seen as early as week 12,” said Andrew M. Blumenfeld, MD, Director of the Headache Center of Southern California in Oceanside, and colleagues. Dr. Blumenfeld also reported that onabotulinumtoxinA has a more favorable effect on depressive symptoms than does topiramate.

According to Dr. Blumenfeld and colleagues, many adults with chronic migraine are not receiving appropriate preventive treatment and when prescribed, adherence to treatment is relatively low. To address this problem, he and his colleagues conducted a multicenter, prospective, randomized, parallel-group, open-label study to compare onabotulinumtoxinA and topiramate for headache prevention in adults with chronic migraine (the FORWARD study).

The study assessed the effectiveness of onabotulinumtoxinA 155 U administered to 31 sites across seven head and neck muscles, fixed-site, fixed-dose, every 12 weeks for three cycles versus topiramate 50 to 100 mg/day up to week 36. The primary efficacy measure was the proportion of patients with a 50% or greater reduction in headache days versus baseline in the 28 days before week 32. Safety and tolerability were assessed; adverse events were monitored. Patient-reported outcomes collected from questionnaires at day 1 and weeks 12, 24, and 36 included the Controlled Oral Word Association Test (COWAT) and the nine-item Patient Health Questionnaire (PHQ-9). Baseline observation carried forward (BLOCF) was used to impute missing values at primary time points, followed by questionnaire guidelines for missing questionnaire data.

A total of 282 patients were enrolled—140 in the onabotulinumtoxinA arm and 142 in the topiramate arm. Mean baseline headache days (onabotulinumtoxinA, 22.1; topiramate, 21.8) were similar. Of the patients enrolled, 148 completed randomized treatment (onabotulinumtoxinA, 85.7%; topiramate, 19.7%). Primary reasons for withdrawal were ineffective treatment (onabotulinumtoxinA, 5.0%; topiramate, 19.0%) and adverse events (onabotulinumtoxinA, 3.6%; topiramate, 50.7%). Based on BLOCF, more patients on onabotulinumtoxinA had a 50% or greater reduction in headache frequency compared with baseline versus topiramate (40.0% vs 12.0%). Adverse events were reported by 45.5% of patients who received onabotulinumtoxinA and 76.8% of patients who received topiramate; treatment-related adverse events were reported by 17.3% and 69.0%, respectively. No new safety signals were identified for onabotulinumtoxinA. Adverse events relating to nervous system disorders most commonly led to treatment discontinuation for topiramate. Topiramate reduced mean COWAT scores from as early as week 12, suggesting cognitive changes occurred early in treatment with topiramate. As the study progressed, topiramate’s effect may have been obscured by the BLOCF imputation methodology due to the large proportion of patients withdrawing from topiramate, the investigators said. In contrast, onabotulinumtoxinA resulted in a small increase in COWAT scores from week 12 to week 36. OnabotulinumtoxinA had a significantly greater effect on mean PHQ-9 scores at week 36 (4.4), compared with topiramate (7.1; estimated mean difference, –1.86).

SAN FRANCISCO—Greater occipital nerve blocks with bupivacaine may be an effective treatment for patients with acute migraine in the emergency department who continue to experience moderate or severe headache after administration of intravenous metoclopramide, according to a presentation at the 60th Annual Scientific Meeting of the American Headache Society.

Greater occipital nerve block is thought to be an effective treatment for acute migraine, although no randomized efficacy data have been published for this indication. Benjamin W. Friedman, MD, Professor of Emergency Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, and colleagues hypothesized that bilateral greater occipital nerve block with bupivacaine would provide greater rates of headache freedom than a sham injection among a population of emergency department patients who reported persistence of moderate or severe headache despite standard treatment with intravenous metoclopramide.

Dr. Friedman and colleagues conducted a randomized, sham-controlled trial of bilateral greater occipital nerve blocks with bupivacaine in two urban emergency departments. Patients with acute migraine who reported persistence of a moderate or severe headache for at least one hour or longer after treatment with 10 mg of intravenous metoclopramide were randomized to bilateral greater occipital nerve block with a total of 6 cc of 0.5% bupivacaine or bilateral intradermal scalp injection with a total of 1 cc of 0.5% bupivacaine. The primary outcome was complete headache freedom 30 minutes after the injection. An important secondary outcome was sustained headache relief, defined as achieving a headache level of mild or none in the emergency department and maintaining a level of mild or no headache without the use of any additional medication for 48 hours.

Over a 32-month period, 76 patients were screened for participation and 28 were enrolled, of whom 15 received sham injection and 13 received greater occipital nerve block. The primary outcome, headache freedom at 30 minutes, was achieved by none of the patients in the sham arm and by four patients (31%) in the nerve block arm. The secondary outcome, sustained headache relief for 48 hours, was reported by none of the patients who received sham and by three of the patients (23%) who received greater occipital nerve blocks. Reported side effects did not differ substantially between the two groups.

SAN FRANCISCO—Greater occipital nerve blocks with bupivacaine may be an effective treatment for patients with acute migraine in the emergency department who continue to experience moderate or severe headache after administration of intravenous metoclopramide, according to a presentation at the 60th Annual Scientific Meeting of the American Headache Society.

Greater occipital nerve block is thought to be an effective treatment for acute migraine, although no randomized efficacy data have been published for this indication. Benjamin W. Friedman, MD, Professor of Emergency Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, and colleagues hypothesized that bilateral greater occipital nerve block with bupivacaine would provide greater rates of headache freedom than a sham injection among a population of emergency department patients who reported persistence of moderate or severe headache despite standard treatment with intravenous metoclopramide.

Dr. Friedman and colleagues conducted a randomized, sham-controlled trial of bilateral greater occipital nerve blocks with bupivacaine in two urban emergency departments. Patients with acute migraine who reported persistence of a moderate or severe headache for at least one hour or longer after treatment with 10 mg of intravenous metoclopramide were randomized to bilateral greater occipital nerve block with a total of 6 cc of 0.5% bupivacaine or bilateral intradermal scalp injection with a total of 1 cc of 0.5% bupivacaine. The primary outcome was complete headache freedom 30 minutes after the injection. An important secondary outcome was sustained headache relief, defined as achieving a headache level of mild or none in the emergency department and maintaining a level of mild or no headache without the use of any additional medication for 48 hours.

Over a 32-month period, 76 patients were screened for participation and 28 were enrolled, of whom 15 received sham injection and 13 received greater occipital nerve block. The primary outcome, headache freedom at 30 minutes, was achieved by none of the patients in the sham arm and by four patients (31%) in the nerve block arm. The secondary outcome, sustained headache relief for 48 hours, was reported by none of the patients who received sham and by three of the patients (23%) who received greater occipital nerve blocks. Reported side effects did not differ substantially between the two groups.

SAN FRANCISCO—Greater occipital nerve blocks with bupivacaine may be an effective treatment for patients with acute migraine in the emergency department who continue to experience moderate or severe headache after administration of intravenous metoclopramide, according to a presentation at the 60th Annual Scientific Meeting of the American Headache Society.

Greater occipital nerve block is thought to be an effective treatment for acute migraine, although no randomized efficacy data have been published for this indication. Benjamin W. Friedman, MD, Professor of Emergency Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, and colleagues hypothesized that bilateral greater occipital nerve block with bupivacaine would provide greater rates of headache freedom than a sham injection among a population of emergency department patients who reported persistence of moderate or severe headache despite standard treatment with intravenous metoclopramide.

Dr. Friedman and colleagues conducted a randomized, sham-controlled trial of bilateral greater occipital nerve blocks with bupivacaine in two urban emergency departments. Patients with acute migraine who reported persistence of a moderate or severe headache for at least one hour or longer after treatment with 10 mg of intravenous metoclopramide were randomized to bilateral greater occipital nerve block with a total of 6 cc of 0.5% bupivacaine or bilateral intradermal scalp injection with a total of 1 cc of 0.5% bupivacaine. The primary outcome was complete headache freedom 30 minutes after the injection. An important secondary outcome was sustained headache relief, defined as achieving a headache level of mild or none in the emergency department and maintaining a level of mild or no headache without the use of any additional medication for 48 hours.

Over a 32-month period, 76 patients were screened for participation and 28 were enrolled, of whom 15 received sham injection and 13 received greater occipital nerve block. The primary outcome, headache freedom at 30 minutes, was achieved by none of the patients in the sham arm and by four patients (31%) in the nerve block arm. The secondary outcome, sustained headache relief for 48 hours, was reported by none of the patients who received sham and by three of the patients (23%) who received greater occipital nerve blocks. Reported side effects did not differ substantially between the two groups.

SAN FRANCISCO—Treatment with fremanezumab is associated with reduced overuse of acute medications and a corresponding decrease in days on which a patient uses acute medications, according to a phase III study described at the 60th Annual Scientific Meeting of the American Headache Society.

The overuse of acute or symptomatic headache medications (eg, triptans, ergot derivatives, opioids, and combination analgesics) can cause medication overuse headache (MOH). Chronic migraine is often accompanied by MOH, and the prevention of MOH is one of the main goals in the preventive treatment of migraine.

Comparing Two Fremanezumab Doses With Placebo

The investigators conducted a multicenter, randomized, double-blind, placebo-controlled, phase III study, during which they randomized eligible patients with chronic migraine in equal groups to receive subcutaneous injections of fremanezumab quarterly dosing (ie, 675 mg at baseline and placebo at Weeks 4 and 8), fremanezumab monthly dosing (ie, 675 mg at baseline and 225 mg at Weeks 4 and 8), or placebo at each time point over a 12-week treatment period. Dr. Silberstein’s group defined medication overuse as the use of acute headache medication on 15 or more days, the use of migraine-specific acute medication on 10 or more days, or the use of combination medications for headache on 10 or more days during the 28-day baseline period.

In a post hoc analysis, the researchers assessed the proportion of patients who reverted from overusing medications at baseline to not overusing medications at Week 12, as well as the change from baseline in the number of days of acute headache medication use among these patients. Analyses were performed using data for all randomized patients who received at least one dose of study drug and had at least 10 days of postbaseline efficacy assessments on the primary end point.

Fremanezumab Was More Likely to Reduce Overuse

At baseline, the number of patients with medication overuse was 201 in the quarterly arm, 198 in the monthly arm, and 188 in the placebo arm. Among these participants, significantly more fremanezumab-treated patients reported no medication overuse during the 12-week treatment period. The number of patients reporting no medication overuse was 111 (55%) in the quarterly arm, 120 (61%) in the monthly arm, and 87 (46%) in the placebo arm. The investigators observed a response to treatment as early as Week 4 (102 [51%] quarterly patients, 107 [54%] monthly patients, and 73 [39%] controls).

Among the patients who responded to treatment over the 12-week treatment period, the baseline number of days with medication overuse was similar across treatment groups (approximately 16.6). Within this population, fremanezumab treatment significantly reduced the number of days of acute headache medication use over the 12-week treatment period by nine in the quarterly arm and 8.9 in the monthly arm, compared with 7.1 among controls.

SAN FRANCISCO—Treatment with fremanezumab is associated with reduced overuse of acute medications and a corresponding decrease in days on which a patient uses acute medications, according to a phase III study described at the 60th Annual Scientific Meeting of the American Headache Society.

The overuse of acute or symptomatic headache medications (eg, triptans, ergot derivatives, opioids, and combination analgesics) can cause medication overuse headache (MOH). Chronic migraine is often accompanied by MOH, and the prevention of MOH is one of the main goals in the preventive treatment of migraine.

Comparing Two Fremanezumab Doses With Placebo

The investigators conducted a multicenter, randomized, double-blind, placebo-controlled, phase III study, during which they randomized eligible patients with chronic migraine in equal groups to receive subcutaneous injections of fremanezumab quarterly dosing (ie, 675 mg at baseline and placebo at Weeks 4 and 8), fremanezumab monthly dosing (ie, 675 mg at baseline and 225 mg at Weeks 4 and 8), or placebo at each time point over a 12-week treatment period. Dr. Silberstein’s group defined medication overuse as the use of acute headache medication on 15 or more days, the use of migraine-specific acute medication on 10 or more days, or the use of combination medications for headache on 10 or more days during the 28-day baseline period.

In a post hoc analysis, the researchers assessed the proportion of patients who reverted from overusing medications at baseline to not overusing medications at Week 12, as well as the change from baseline in the number of days of acute headache medication use among these patients. Analyses were performed using data for all randomized patients who received at least one dose of study drug and had at least 10 days of postbaseline efficacy assessments on the primary end point.

Fremanezumab Was More Likely to Reduce Overuse

At baseline, the number of patients with medication overuse was 201 in the quarterly arm, 198 in the monthly arm, and 188 in the placebo arm. Among these participants, significantly more fremanezumab-treated patients reported no medication overuse during the 12-week treatment period. The number of patients reporting no medication overuse was 111 (55%) in the quarterly arm, 120 (61%) in the monthly arm, and 87 (46%) in the placebo arm. The investigators observed a response to treatment as early as Week 4 (102 [51%] quarterly patients, 107 [54%] monthly patients, and 73 [39%] controls).

Among the patients who responded to treatment over the 12-week treatment period, the baseline number of days with medication overuse was similar across treatment groups (approximately 16.6). Within this population, fremanezumab treatment significantly reduced the number of days of acute headache medication use over the 12-week treatment period by nine in the quarterly arm and 8.9 in the monthly arm, compared with 7.1 among controls.

SAN FRANCISCO—Treatment with fremanezumab is associated with reduced overuse of acute medications and a corresponding decrease in days on which a patient uses acute medications, according to a phase III study described at the 60th Annual Scientific Meeting of the American Headache Society.

The overuse of acute or symptomatic headache medications (eg, triptans, ergot derivatives, opioids, and combination analgesics) can cause medication overuse headache (MOH). Chronic migraine is often accompanied by MOH, and the prevention of MOH is one of the main goals in the preventive treatment of migraine.

Comparing Two Fremanezumab Doses With Placebo

The investigators conducted a multicenter, randomized, double-blind, placebo-controlled, phase III study, during which they randomized eligible patients with chronic migraine in equal groups to receive subcutaneous injections of fremanezumab quarterly dosing (ie, 675 mg at baseline and placebo at Weeks 4 and 8), fremanezumab monthly dosing (ie, 675 mg at baseline and 225 mg at Weeks 4 and 8), or placebo at each time point over a 12-week treatment period. Dr. Silberstein’s group defined medication overuse as the use of acute headache medication on 15 or more days, the use of migraine-specific acute medication on 10 or more days, or the use of combination medications for headache on 10 or more days during the 28-day baseline period.

In a post hoc analysis, the researchers assessed the proportion of patients who reverted from overusing medications at baseline to not overusing medications at Week 12, as well as the change from baseline in the number of days of acute headache medication use among these patients. Analyses were performed using data for all randomized patients who received at least one dose of study drug and had at least 10 days of postbaseline efficacy assessments on the primary end point.

Fremanezumab Was More Likely to Reduce Overuse

At baseline, the number of patients with medication overuse was 201 in the quarterly arm, 198 in the monthly arm, and 188 in the placebo arm. Among these participants, significantly more fremanezumab-treated patients reported no medication overuse during the 12-week treatment period. The number of patients reporting no medication overuse was 111 (55%) in the quarterly arm, 120 (61%) in the monthly arm, and 87 (46%) in the placebo arm. The investigators observed a response to treatment as early as Week 4 (102 [51%] quarterly patients, 107 [54%] monthly patients, and 73 [39%] controls).

Among the patients who responded to treatment over the 12-week treatment period, the baseline number of days with medication overuse was similar across treatment groups (approximately 16.6). Within this population, fremanezumab treatment significantly reduced the number of days of acute headache medication use over the 12-week treatment period by nine in the quarterly arm and 8.9 in the monthly arm, compared with 7.1 among controls.

Dr. Charles is Clinical Associate Professor Neurology, Rutgers–New Jersey Medical School, Newark, NJ; Neurology Attending, Holy Name Medical Center, Teaneck, NJ ([email protected]).

Dr. Gallo is Interventional Radiology Attending, Holy Name Medical Center, Teaneck, NJ ([email protected]).

DISCLOSURES

The authors have no financial relationships to disclose relevant to the manuscript. There was no sponsorship of, or funding for, the study.

Dr. Charles designed and conceptualized the study; analyzed study data and performed the statistical analysis; and drafted the manuscript for intellectual content. Dr. Gallo had a major role in the acquisition of interventional sphenopalatine ganglion data.

ABSTRACT

Objective

Chronic refractory migraine patients who failed repetitive dihydroergotamine/dopamine infusion protocols and conventional preventives were treated with repeated low-dose ketamine-based parenteral protocols, followed by memantine-based preventive therapy, and observed for immediate reduction in pain intensity and headache frequency.

Methods

Ten patients were treated at an outpatient infusion center for 2 to 5 sequential days with AM and PM courses of intravenous diphenhydramine, prochlorperazine, and dihydroergotamine. A daily sphenopalatine ganglion block and low-dose intramuscular ketamine were given midday between treatments, with dexamethasone given on the last infusion day. The Numeric Pain Rating Scale was measured after infusion. Carryover effect was assessed 1 month and 2 months after infusion by headache frequency while being treated with memantine and various other preventive and abortive therapies.

Results

Reduction in headache pain of 71% was achieved at the end of the infusion period. Sedation was the only adverse effect. Decreased headache frequency persisted beyond the infusion period, with an 88.6% reduction in headache days per month at 1 month and a 79.4% reduction in headache days per month at 2 months, without adverse effects.

Conclusions

Data indicate that 1) repetitive low-dose, ketamine-based parenteral therapy, followed by memantine-based preventive therapy, reduced refractory headache pain and 2) the decremental effect on headache frequency persisted beyond the infusion period. Our results support the hypothesis that multimechanistic therapies might be better than single-modality treatment. More studies, with a larger patient population, are needed to confirm whether these multimodality ketamine/memantine therapies should become the preferred approach for these extremely disabled patients.

Chronic refractory migraine (CRM) degrades function and quality of life despite elimination of triggers and adequate trials of acute and preventive medicines that have established efficacy. This definition requires that patients with chronic migraine fail adequate trials of preventive drugs, alone or in combination, in at least 2 of 4 drug classes, including beta blockers, anticonvulsants, tricyclic antidepressants, onabotulinumtoxin A, and calcium-channel blockers. Patients must also fail adequate trials of abortive medicines, including both a triptan and dihydroergotamine (DHE), intranasal or injectable formulation, and either a nonsteroidal anti-inflammatory drug or a combination analgesic, unless contraindicated.^1-4

In 1986, Raskin published a nonrandomized, nonblinded study of 2 treatments for intractable migraine in which repetitive inpatient intravenous (IV) DHE, administered in the hospital, was statistically more effective than IV diazepam in terminating cycles of intractable migraine.⁵ Most headache specialists have adopted the so-called Raskin protocol, as originally described or in any of several variations, as cornerstone therapy for CRM, chronic migraine, and prolonged status migrainosus.⁶ However, DHE-based infusion protocols do not always effectively reset the brain’s pain modulatory pathways in chronic migraine immediately posttreatment and might not induce a meaningful carryover effect.

We present 10 patients with CRM who met criteria for refractory migraine, including failure to terminate their headache with repetitive DHE/prochlorperazine/diphenhydramine/ketorolac/dexamethasone IV protocols, with or without sporadic administration of a sphenopalatine ganglion block. We treated these patients multimechanistically with repetitive IV DHE, a dopamine antagonist, an antihistamine, sphenopalatine ganglion (SPG) block, and low-dose ketamine, plus last-infusion-day dexamethasone, followed by outpatient oral memantine. Subsequently, we observed them for 2 months.

Ketamine is a phencyclidine derivative introduced the early 1960s as an IV anesthetic. Low-dose ketamine has been used successfully in the treatment of chronic pain. Today, increased interest in the application of low-dose ketamine includes cancer pain; treatment and prevention of acute and chronic pain, with and without neuropathic analgesia; fibromyalgia; complex regional pain; and migraine.^7,8 The effectiveness of ketamine in different pain disorders may arise through different pathways and/or by way of activity at various receptor systems. Effects arise predominantly by noncompetitive antagonism of the glutamate N-methyl-D-aspartate (NMDA ) receptor.^7,8

Memantine also is an NMDA receptor antagonist that is used effectively as an oral agent in CRM.⁹

METHODS

Patients enrolled in this prospective study had CRM for periods ranging from 1 to 2 years. All had daily headache that could not be terminated with repetitive DHE/prochlorperazine/diphenhydramine/ketorolac/dexamethasone IV protocols with or without sporadic administration of an SPG block. Age ranged from 18 and 68 years; all patients were female. Patients were excluded if they had known coronary artery disease, uncontrolled hypertension, or peripheral arterial disease; a history of stroke, transient ischemic attack, or pregnancy; impaired liver or renal function; smoked a tobacco product; or were taking a protease inhibitor or macrolide antibiotic.

 Approval by the institutional review board was unnecessary because all drugs and procedures are FDA-approved and have published evidence-based efficacy for migraine and other diseases.

 The Numeric Pain Rating Scale (NPRS; a scale of 0 to 10) was utilized to rate the intensity of pain from the beginning of the infusion to the end of the multiday infusion protocol, when the catheter was removed. All patients but 1 were treated for 5 days; for the 1 exception, treatment was terminated after 48 hours because of a scheduling conflict. The observational follow‐up periods for assessment of outcomes were 1 month and 2 months post-infusion.

Patients started the study with a baseline NPRS of 9 or 10. They were treated at the institution’s headache outpatient infusion center. In the morning, patients received, by sequential IV infusion, diphenhydramine, 50 mg; prochlorperazine, 10 mg; and DHE, 1 mg. They then received a midday SPG block under fluoroscopic guidance and ketamine, 0.45 mg/kg intramuscularly (IM), given in the post-anesthesia care unit. In the late afternoon, the patients received diphenhydramine, 50 mg; prochlorperazine, 10 mg; and DHE, 0.5 mg, in the Headache Outpatient Infusion Center. Patients were discharged to home by 6 PM. They received IV dexamethasone, 20 mg, on the last day of therapy.

Oral preventive agents were continued and abortives were temporarily discontinued during infusion therapy. Oral memantine was used immediately before, during, and, in all cases, after infusion, at a daily dosage that ranged from 10 mg BID to 28 mg, once-daily extended release.

RESULTS

Therapies were well-tolerated by all patients. On the last day of treatment, the entire cohort (N = 10) demonstrated an average of 71% (mean standard deviation [SD], 10.1%) reduction in pain intensity. The average reduction in headache days per month at 1 month was 88.6% (mean SD, 6.24%) and at 2 months was 79.4% (mean SD, 17.13%) (Table). Adverse effects were mild temporary sedation from ketamine. Pulse oximetry revealed no abnormal decrease in O₂ saturation. All patients reported marked overall reduction in headache disability at the end of the infusion protocol. Self-administered abortive therapies posttreatment were more efficacious than they were pretreatment. All patients indicated less headache disability overall by the end of the 2-month observation period.
 

Table. Chronic Refractory Migraine Baseline Data and Treatment Results^a

^aAll patients had daily headache at initiation of treatment.

^bHeadache days/month.

NPRS, Numeric Pain Rating Scale.

DISCUSSION

In our study of 10 patients with CRM who had daily headache treated repetitively in an outpatient infusion center with multimodality therapies, including sub-anesthetic doses of ketamine, all patients experienced marked reduction in headache pain intensity, with a whole-group average reduction of 71% by the end of infusion treatment. During post-infusion observation, all patients continued various preventive therapies, including memantine. At 1 month, the average reduction in headache frequency was 88.6%. Two months post-infusion, the average reduction in headache frequency was 79.4%. Adverse effects were minimal. Overall, the treatment was found to be safe and efficacious. All patients felt less headache disability after 2 months.

Because the protocol was administered comfortably in the Headache Outpatient Infusion Center, the inconvenience and higher cost of inpatient parenteral treatment were avoided. Ketamine, 0.45 mg/kg IM is a sub-anesthetic dose with proven efficacy in treating migraine without adverse effects in an outpatient setting.⁸ Low-dose ketamine obviated the need for anesthesia personnel and precautions. Temporary sedation was the only adverse effect. Ketamine was administered by a nurse in the post-anesthesia care unit while patients were under observation with conventional measurement of vital signs and pulse oximetry. Memantine, also an NMDA receptor antagonist, is postulated to prolong the NMDA antagonism of ketamine.

Inpatient and outpatient continuous IV DHE and repetitive IV DHE, often combined with dopamine antagonists in controlled and comparator studies, have demonstrated equal effectiveness for the treatment of chronic migraine.^5,10,11 Our patients failed these therapies. This raises the question: Should our combined multimodality, ketamine-based approach be standard parenteral therapy for CRM?

In a recent study of continuous inpatient single-modality IV ketamine, a less-impressive carryover effect was obtained, with 23% to 50% 1-month sustained responders.¹² Multimechanistic treatment superiority over monotherapy is legendary in the treatment of cancer and human immunodeficiency infection. Sumatriptan plus naproxen sodium as a single tablet for acute treatment of migraine resulted in more favorable clinical benefit compared with either monotherapy, with an acceptable, well-tolerated adverse effect profile. Because multiple pathogenic mechanisms putatively are involved in generation of the migraine symptom complex, multimechanism-targeted therapy may confer advantages over individual monotherapy. Drugs in 2 classes of migraine pharmacotherapy—triptans and nonsteroidal anti-inflammatory drugs —target distinct aspects of the vascular and inflammatory processes hypothesized to underlie migraine.¹³

Although combination therapy for CRM has not been systematically studied in randomized trials, clinical experience suggests that a rational approach to CRM treatment, utilizing a combination of treatments, may be effective when monotherapy has failed.¹⁴ During the infusion protocol, we re-set the trigeminovascular pain pathways 1) by repetitively blocking NMDA receptors (with ketamine), dopamine receptors (with prochlorperazine), and histamine receptors (with diphenhydramine); 2) by lidocaine anesthetic block of the sphenopalatine ganglia; and, on the last day of the protocol, 3) administering 1 large dose of IV dexamethasone to help prevent recurrence.¹⁵ NMDA blockade continued with oral outpatient memantine.

Virtually all patients were taking other preventives during the pretreatment period and 2-month observation period, including topiramate, venlafaxine, beta blockers, candesartan, zonisamide, onabotulinumtoxin A, neuromodulation (Cefaly Technology), and transcranial magnetic stimulation (springTMS®). Self-administered abortives were more effective in the 2-month observational period; these included IM/IV DHE; oral, spray, and subcutaneous triptans; IM ketorolac; diclofenac buffered solution; and transcranial magnetic stimulation (springTMS®). The cornerstone strategy of our treatment group that was a constant was the use of low-dose IM sub-anesthetic ketamine at a dosage of 0.45 mg/kg/d and the use of oral memantine during the follow-up observation period, at dosages ranging from 10 mg BID to 28 mg, once-daily extended release.

Limitations of this study design are:

• lack of a control group
• lack of subject randomization for comparative outcomes
• patients remaining on a variety of prophylactic regimens
• patients permitted to take any rescue therapy.

 The effect of repetitive SPG block cannot be teased out of the efficacy data, but many of our patients had a poor or temporary response to infrequent sporadic SPG blocks prior to participating in our protocol.

Many migraineurs who seek care in a headache clinic are refractory to treatment, despite advances in headache therapy; refractory migraine was found in 5.1% of these patients.¹⁶ In this small series of patients, we demonstrated immediate relief and a significant 2-month carryover effect with our multimodality parenteral protocol. Larger, controlled studies are needed to further explore this protocol with repetitive DHE, diphenhydramine, prochlorperazine, SPG block, and low-dose IM ketamine, followed by outpatient memantine. Such studies would determine whether our protocol should be utilized as a primary treatment, instead of the conventional DHE-based Raskin and modified Raskin protocols.

Although this is a small series of patients, lack of adverse effects and impressive results should give credence to utilizing our protocol as treatment for this extremely debilitated, often desperate subset of headache patients. Data indicate that, whereas ketamine combined with other therapies immediately reduced refractory headache pain, the ameliorating effect of ketamine on CRM headache frequency and pain in our protocol persisted beyond the infusion period. This phenomenon indicates a disease-modulating role for ketamine in refractory migraine pain, possibly by means of desensitization of NMDA receptors in the trigeminal nucleus caudalis—desensitization that continued with the NMDA receptor antagonist memantine and/or restoration of inhibitory sensory control in the brain.

CONCLUSION

Our results support the hypothesis that multimechanistic therapies, including low-dose IM ketamine and memantine, might be better than single-modality treatment in this debilitated, refractory population. Future studies, with larger patient populations, are needed to confirm whether these multimodality ketamine/memantine-inclusive therapies should become the preferred approach for these extremely disabled patients.

REFERENCES

1. Goadsby PJ, Schoenen J, Ferrari MD, Silberstein SD, Dodick DW. Towards a definition of intractable headache for use in clinical practice and trials. Cephalalgia. 2006;26(9):1168-1170.
2. Schulman EA, Lipton R, Peterlin BL, Levin M, Grosberg BM. Commentary from the Refractory Headache Special Interest Section on defining the pharmacologically intractable headache for clinical trials and clinical practice. Headache. 2010;50(10):1637-1639.
3. Martelletti P, Jensen RH, Antal A, et al. Neuromodulation of chronic headaches: position statement from the European Headache Federation. J Headache Pain. 2013;14:86.
4. Dodick DW, Turkel CC, DeGryse RE, et al; PREEMPT Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. 2010;50(6):921-936.
5. Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology. 1986;36(7):995‐997.
6. Charles JA, von Dohln P. Outpatient home-based continuous intravenous dihydroergotamine therapy for intractable migraine. Headache. 2010;50(5):852-860.
7. Sigtermans M, Noppers I, Sarton E, et al. An observational study on the effect of S+-ketamine on chronic pain versus experimental acute pain in complex regional pain syndrome type 1 patients. Eur J Pain. 2010;14(3):302-307.
8. Krusz J, Cagle J, Hall S. Intramuscular (IM) ketamine for treating headache and pain flare-ups in the clinic. J Pain. 2008;9(4):30.
9. Bigal M Rapoport A, Sheftell F, Tepper D, Tepper S. Memantine in the preventive treatment of refractory migraine. Headache. 2008;48(9):1337-1342.
10. Ford RG, Ford KT. Continuous intravenous dihydroergotamine for treatment of intractable headache. Headache. 1997;37(3):129‐136.
11. Boudreau G, Aghai E, Marchand L, Langlois M. Outpatient intravenous dihydroergotamine for probable medication overuse headache. Headache Care. 2006;3(1):45‐49.
12. Pomeroy JL, Marmura MJ, Nahas SJ, Viscusi ER. Ketamine infusions for treatment refractory headache. Headache. 2017;57(2):276-282.
13. Brandes JL, Kudrow D, Stark SR, et al. Sumatriptan-naproxen for acute treatment of migraine: a randomized trial. JAMA. 2007;297(13):1443-1454.
14. Peterlin BL, Calhoun AH, Siegel S, Mathew NT. Rational combination therapy in refractory migraine. Headache. 2008;48(6):805-819.
15. Innes G, Macphail I, Dillon EC, Metcalfe C, Gao M. Dexamethasone prevents relapse after emergency department treatment of acute migraine: a randomized clinical trial. CJEM. 2015;1(1):26-33.
16. Irimia P, Palma JA, Fernandez-Torron R, Martinez-Vila E. Refractory migraine in a headache clinic population. BMC Neurol. 2011;11:94.

Dr. Charles is Clinical Associate Professor Neurology, Rutgers–New Jersey Medical School, Newark, NJ; Neurology Attending, Holy Name Medical Center, Teaneck, NJ ([email protected]).

Dr. Gallo is Interventional Radiology Attending, Holy Name Medical Center, Teaneck, NJ ([email protected]).

DISCLOSURES

The authors have no financial relationships to disclose relevant to the manuscript. There was no sponsorship of, or funding for, the study.

Dr. Charles designed and conceptualized the study; analyzed study data and performed the statistical analysis; and drafted the manuscript for intellectual content. Dr. Gallo had a major role in the acquisition of interventional sphenopalatine ganglion data.

ABSTRACT

Objective

Chronic refractory migraine patients who failed repetitive dihydroergotamine/dopamine infusion protocols and conventional preventives were treated with repeated low-dose ketamine-based parenteral protocols, followed by memantine-based preventive therapy, and observed for immediate reduction in pain intensity and headache frequency.

Methods

Ten patients were treated at an outpatient infusion center for 2 to 5 sequential days with AM and PM courses of intravenous diphenhydramine, prochlorperazine, and dihydroergotamine. A daily sphenopalatine ganglion block and low-dose intramuscular ketamine were given midday between treatments, with dexamethasone given on the last infusion day. The Numeric Pain Rating Scale was measured after infusion. Carryover effect was assessed 1 month and 2 months after infusion by headache frequency while being treated with memantine and various other preventive and abortive therapies.

Results

Reduction in headache pain of 71% was achieved at the end of the infusion period. Sedation was the only adverse effect. Decreased headache frequency persisted beyond the infusion period, with an 88.6% reduction in headache days per month at 1 month and a 79.4% reduction in headache days per month at 2 months, without adverse effects.

Conclusions

Data indicate that 1) repetitive low-dose, ketamine-based parenteral therapy, followed by memantine-based preventive therapy, reduced refractory headache pain and 2) the decremental effect on headache frequency persisted beyond the infusion period. Our results support the hypothesis that multimechanistic therapies might be better than single-modality treatment. More studies, with a larger patient population, are needed to confirm whether these multimodality ketamine/memantine therapies should become the preferred approach for these extremely disabled patients.

Chronic refractory migraine (CRM) degrades function and quality of life despite elimination of triggers and adequate trials of acute and preventive medicines that have established efficacy. This definition requires that patients with chronic migraine fail adequate trials of preventive drugs, alone or in combination, in at least 2 of 4 drug classes, including beta blockers, anticonvulsants, tricyclic antidepressants, onabotulinumtoxin A, and calcium-channel blockers. Patients must also fail adequate trials of abortive medicines, including both a triptan and dihydroergotamine (DHE), intranasal or injectable formulation, and either a nonsteroidal anti-inflammatory drug or a combination analgesic, unless contraindicated.^1-4

In 1986, Raskin published a nonrandomized, nonblinded study of 2 treatments for intractable migraine in which repetitive inpatient intravenous (IV) DHE, administered in the hospital, was statistically more effective than IV diazepam in terminating cycles of intractable migraine.⁵ Most headache specialists have adopted the so-called Raskin protocol, as originally described or in any of several variations, as cornerstone therapy for CRM, chronic migraine, and prolonged status migrainosus.⁶ However, DHE-based infusion protocols do not always effectively reset the brain’s pain modulatory pathways in chronic migraine immediately posttreatment and might not induce a meaningful carryover effect.

We present 10 patients with CRM who met criteria for refractory migraine, including failure to terminate their headache with repetitive DHE/prochlorperazine/diphenhydramine/ketorolac/dexamethasone IV protocols, with or without sporadic administration of a sphenopalatine ganglion block. We treated these patients multimechanistically with repetitive IV DHE, a dopamine antagonist, an antihistamine, sphenopalatine ganglion (SPG) block, and low-dose ketamine, plus last-infusion-day dexamethasone, followed by outpatient oral memantine. Subsequently, we observed them for 2 months.

Ketamine is a phencyclidine derivative introduced the early 1960s as an IV anesthetic. Low-dose ketamine has been used successfully in the treatment of chronic pain. Today, increased interest in the application of low-dose ketamine includes cancer pain; treatment and prevention of acute and chronic pain, with and without neuropathic analgesia; fibromyalgia; complex regional pain; and migraine.^7,8 The effectiveness of ketamine in different pain disorders may arise through different pathways and/or by way of activity at various receptor systems. Effects arise predominantly by noncompetitive antagonism of the glutamate N-methyl-D-aspartate (NMDA ) receptor.^7,8

Memantine also is an NMDA receptor antagonist that is used effectively as an oral agent in CRM.⁹

METHODS

Patients enrolled in this prospective study had CRM for periods ranging from 1 to 2 years. All had daily headache that could not be terminated with repetitive DHE/prochlorperazine/diphenhydramine/ketorolac/dexamethasone IV protocols with or without sporadic administration of an SPG block. Age ranged from 18 and 68 years; all patients were female. Patients were excluded if they had known coronary artery disease, uncontrolled hypertension, or peripheral arterial disease; a history of stroke, transient ischemic attack, or pregnancy; impaired liver or renal function; smoked a tobacco product; or were taking a protease inhibitor or macrolide antibiotic.

 Approval by the institutional review board was unnecessary because all drugs and procedures are FDA-approved and have published evidence-based efficacy for migraine and other diseases.

 The Numeric Pain Rating Scale (NPRS; a scale of 0 to 10) was utilized to rate the intensity of pain from the beginning of the infusion to the end of the multiday infusion protocol, when the catheter was removed. All patients but 1 were treated for 5 days; for the 1 exception, treatment was terminated after 48 hours because of a scheduling conflict. The observational follow‐up periods for assessment of outcomes were 1 month and 2 months post-infusion.

Patients started the study with a baseline NPRS of 9 or 10. They were treated at the institution’s headache outpatient infusion center. In the morning, patients received, by sequential IV infusion, diphenhydramine, 50 mg; prochlorperazine, 10 mg; and DHE, 1 mg. They then received a midday SPG block under fluoroscopic guidance and ketamine, 0.45 mg/kg intramuscularly (IM), given in the post-anesthesia care unit. In the late afternoon, the patients received diphenhydramine, 50 mg; prochlorperazine, 10 mg; and DHE, 0.5 mg, in the Headache Outpatient Infusion Center. Patients were discharged to home by 6 PM. They received IV dexamethasone, 20 mg, on the last day of therapy.

Oral preventive agents were continued and abortives were temporarily discontinued during infusion therapy. Oral memantine was used immediately before, during, and, in all cases, after infusion, at a daily dosage that ranged from 10 mg BID to 28 mg, once-daily extended release.

RESULTS

Therapies were well-tolerated by all patients. On the last day of treatment, the entire cohort (N = 10) demonstrated an average of 71% (mean standard deviation [SD], 10.1%) reduction in pain intensity. The average reduction in headache days per month at 1 month was 88.6% (mean SD, 6.24%) and at 2 months was 79.4% (mean SD, 17.13%) (Table). Adverse effects were mild temporary sedation from ketamine. Pulse oximetry revealed no abnormal decrease in O₂ saturation. All patients reported marked overall reduction in headache disability at the end of the infusion protocol. Self-administered abortive therapies posttreatment were more efficacious than they were pretreatment. All patients indicated less headache disability overall by the end of the 2-month observation period.
 

Table. Chronic Refractory Migraine Baseline Data and Treatment Results^a

^aAll patients had daily headache at initiation of treatment.

^bHeadache days/month.

NPRS, Numeric Pain Rating Scale.

DISCUSSION

In our study of 10 patients with CRM who had daily headache treated repetitively in an outpatient infusion center with multimodality therapies, including sub-anesthetic doses of ketamine, all patients experienced marked reduction in headache pain intensity, with a whole-group average reduction of 71% by the end of infusion treatment. During post-infusion observation, all patients continued various preventive therapies, including memantine. At 1 month, the average reduction in headache frequency was 88.6%. Two months post-infusion, the average reduction in headache frequency was 79.4%. Adverse effects were minimal. Overall, the treatment was found to be safe and efficacious. All patients felt less headache disability after 2 months.

Because the protocol was administered comfortably in the Headache Outpatient Infusion Center, the inconvenience and higher cost of inpatient parenteral treatment were avoided. Ketamine, 0.45 mg/kg IM is a sub-anesthetic dose with proven efficacy in treating migraine without adverse effects in an outpatient setting.⁸ Low-dose ketamine obviated the need for anesthesia personnel and precautions. Temporary sedation was the only adverse effect. Ketamine was administered by a nurse in the post-anesthesia care unit while patients were under observation with conventional measurement of vital signs and pulse oximetry. Memantine, also an NMDA receptor antagonist, is postulated to prolong the NMDA antagonism of ketamine.

Inpatient and outpatient continuous IV DHE and repetitive IV DHE, often combined with dopamine antagonists in controlled and comparator studies, have demonstrated equal effectiveness for the treatment of chronic migraine.^5,10,11 Our patients failed these therapies. This raises the question: Should our combined multimodality, ketamine-based approach be standard parenteral therapy for CRM?

In a recent study of continuous inpatient single-modality IV ketamine, a less-impressive carryover effect was obtained, with 23% to 50% 1-month sustained responders.¹² Multimechanistic treatment superiority over monotherapy is legendary in the treatment of cancer and human immunodeficiency infection. Sumatriptan plus naproxen sodium as a single tablet for acute treatment of migraine resulted in more favorable clinical benefit compared with either monotherapy, with an acceptable, well-tolerated adverse effect profile. Because multiple pathogenic mechanisms putatively are involved in generation of the migraine symptom complex, multimechanism-targeted therapy may confer advantages over individual monotherapy. Drugs in 2 classes of migraine pharmacotherapy—triptans and nonsteroidal anti-inflammatory drugs —target distinct aspects of the vascular and inflammatory processes hypothesized to underlie migraine.¹³

Although combination therapy for CRM has not been systematically studied in randomized trials, clinical experience suggests that a rational approach to CRM treatment, utilizing a combination of treatments, may be effective when monotherapy has failed.¹⁴ During the infusion protocol, we re-set the trigeminovascular pain pathways 1) by repetitively blocking NMDA receptors (with ketamine), dopamine receptors (with prochlorperazine), and histamine receptors (with diphenhydramine); 2) by lidocaine anesthetic block of the sphenopalatine ganglia; and, on the last day of the protocol, 3) administering 1 large dose of IV dexamethasone to help prevent recurrence.¹⁵ NMDA blockade continued with oral outpatient memantine.

Virtually all patients were taking other preventives during the pretreatment period and 2-month observation period, including topiramate, venlafaxine, beta blockers, candesartan, zonisamide, onabotulinumtoxin A, neuromodulation (Cefaly Technology), and transcranial magnetic stimulation (springTMS®). Self-administered abortives were more effective in the 2-month observational period; these included IM/IV DHE; oral, spray, and subcutaneous triptans; IM ketorolac; diclofenac buffered solution; and transcranial magnetic stimulation (springTMS®). The cornerstone strategy of our treatment group that was a constant was the use of low-dose IM sub-anesthetic ketamine at a dosage of 0.45 mg/kg/d and the use of oral memantine during the follow-up observation period, at dosages ranging from 10 mg BID to 28 mg, once-daily extended release.

Limitations of this study design are:

• lack of a control group
• lack of subject randomization for comparative outcomes
• patients remaining on a variety of prophylactic regimens
• patients permitted to take any rescue therapy.

 The effect of repetitive SPG block cannot be teased out of the efficacy data, but many of our patients had a poor or temporary response to infrequent sporadic SPG blocks prior to participating in our protocol.

Many migraineurs who seek care in a headache clinic are refractory to treatment, despite advances in headache therapy; refractory migraine was found in 5.1% of these patients.¹⁶ In this small series of patients, we demonstrated immediate relief and a significant 2-month carryover effect with our multimodality parenteral protocol. Larger, controlled studies are needed to further explore this protocol with repetitive DHE, diphenhydramine, prochlorperazine, SPG block, and low-dose IM ketamine, followed by outpatient memantine. Such studies would determine whether our protocol should be utilized as a primary treatment, instead of the conventional DHE-based Raskin and modified Raskin protocols.

Although this is a small series of patients, lack of adverse effects and impressive results should give credence to utilizing our protocol as treatment for this extremely debilitated, often desperate subset of headache patients. Data indicate that, whereas ketamine combined with other therapies immediately reduced refractory headache pain, the ameliorating effect of ketamine on CRM headache frequency and pain in our protocol persisted beyond the infusion period. This phenomenon indicates a disease-modulating role for ketamine in refractory migraine pain, possibly by means of desensitization of NMDA receptors in the trigeminal nucleus caudalis—desensitization that continued with the NMDA receptor antagonist memantine and/or restoration of inhibitory sensory control in the brain.

CONCLUSION

Our results support the hypothesis that multimechanistic therapies, including low-dose IM ketamine and memantine, might be better than single-modality treatment in this debilitated, refractory population. Future studies, with larger patient populations, are needed to confirm whether these multimodality ketamine/memantine-inclusive therapies should become the preferred approach for these extremely disabled patients.

REFERENCES

1. Goadsby PJ, Schoenen J, Ferrari MD, Silberstein SD, Dodick DW. Towards a definition of intractable headache for use in clinical practice and trials. Cephalalgia. 2006;26(9):1168-1170.
2. Schulman EA, Lipton R, Peterlin BL, Levin M, Grosberg BM. Commentary from the Refractory Headache Special Interest Section on defining the pharmacologically intractable headache for clinical trials and clinical practice. Headache. 2010;50(10):1637-1639.
3. Martelletti P, Jensen RH, Antal A, et al. Neuromodulation of chronic headaches: position statement from the European Headache Federation. J Headache Pain. 2013;14:86.
4. Dodick DW, Turkel CC, DeGryse RE, et al; PREEMPT Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. 2010;50(6):921-936.
5. Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology. 1986;36(7):995‐997.
6. Charles JA, von Dohln P. Outpatient home-based continuous intravenous dihydroergotamine therapy for intractable migraine. Headache. 2010;50(5):852-860.
7. Sigtermans M, Noppers I, Sarton E, et al. An observational study on the effect of S+-ketamine on chronic pain versus experimental acute pain in complex regional pain syndrome type 1 patients. Eur J Pain. 2010;14(3):302-307.
8. Krusz J, Cagle J, Hall S. Intramuscular (IM) ketamine for treating headache and pain flare-ups in the clinic. J Pain. 2008;9(4):30.
9. Bigal M Rapoport A, Sheftell F, Tepper D, Tepper S. Memantine in the preventive treatment of refractory migraine. Headache. 2008;48(9):1337-1342.
10. Ford RG, Ford KT. Continuous intravenous dihydroergotamine for treatment of intractable headache. Headache. 1997;37(3):129‐136.
11. Boudreau G, Aghai E, Marchand L, Langlois M. Outpatient intravenous dihydroergotamine for probable medication overuse headache. Headache Care. 2006;3(1):45‐49.
12. Pomeroy JL, Marmura MJ, Nahas SJ, Viscusi ER. Ketamine infusions for treatment refractory headache. Headache. 2017;57(2):276-282.
13. Brandes JL, Kudrow D, Stark SR, et al. Sumatriptan-naproxen for acute treatment of migraine: a randomized trial. JAMA. 2007;297(13):1443-1454.
14. Peterlin BL, Calhoun AH, Siegel S, Mathew NT. Rational combination therapy in refractory migraine. Headache. 2008;48(6):805-819.
15. Innes G, Macphail I, Dillon EC, Metcalfe C, Gao M. Dexamethasone prevents relapse after emergency department treatment of acute migraine: a randomized clinical trial. CJEM. 2015;1(1):26-33.
16. Irimia P, Palma JA, Fernandez-Torron R, Martinez-Vila E. Refractory migraine in a headache clinic population. BMC Neurol. 2011;11:94.

Dr. Charles is Clinical Associate Professor Neurology, Rutgers–New Jersey Medical School, Newark, NJ; Neurology Attending, Holy Name Medical Center, Teaneck, NJ ([email protected]).

Dr. Gallo is Interventional Radiology Attending, Holy Name Medical Center, Teaneck, NJ ([email protected]).

DISCLOSURES

The authors have no financial relationships to disclose relevant to the manuscript. There was no sponsorship of, or funding for, the study.

Dr. Charles designed and conceptualized the study; analyzed study data and performed the statistical analysis; and drafted the manuscript for intellectual content. Dr. Gallo had a major role in the acquisition of interventional sphenopalatine ganglion data.

ABSTRACT

Objective

Chronic refractory migraine patients who failed repetitive dihydroergotamine/dopamine infusion protocols and conventional preventives were treated with repeated low-dose ketamine-based parenteral protocols, followed by memantine-based preventive therapy, and observed for immediate reduction in pain intensity and headache frequency.

Methods

Ten patients were treated at an outpatient infusion center for 2 to 5 sequential days with AM and PM courses of intravenous diphenhydramine, prochlorperazine, and dihydroergotamine. A daily sphenopalatine ganglion block and low-dose intramuscular ketamine were given midday between treatments, with dexamethasone given on the last infusion day. The Numeric Pain Rating Scale was measured after infusion. Carryover effect was assessed 1 month and 2 months after infusion by headache frequency while being treated with memantine and various other preventive and abortive therapies.

Results

Reduction in headache pain of 71% was achieved at the end of the infusion period. Sedation was the only adverse effect. Decreased headache frequency persisted beyond the infusion period, with an 88.6% reduction in headache days per month at 1 month and a 79.4% reduction in headache days per month at 2 months, without adverse effects.

Conclusions

Data indicate that 1) repetitive low-dose, ketamine-based parenteral therapy, followed by memantine-based preventive therapy, reduced refractory headache pain and 2) the decremental effect on headache frequency persisted beyond the infusion period. Our results support the hypothesis that multimechanistic therapies might be better than single-modality treatment. More studies, with a larger patient population, are needed to confirm whether these multimodality ketamine/memantine therapies should become the preferred approach for these extremely disabled patients.

Chronic refractory migraine (CRM) degrades function and quality of life despite elimination of triggers and adequate trials of acute and preventive medicines that have established efficacy. This definition requires that patients with chronic migraine fail adequate trials of preventive drugs, alone or in combination, in at least 2 of 4 drug classes, including beta blockers, anticonvulsants, tricyclic antidepressants, onabotulinumtoxin A, and calcium-channel blockers. Patients must also fail adequate trials of abortive medicines, including both a triptan and dihydroergotamine (DHE), intranasal or injectable formulation, and either a nonsteroidal anti-inflammatory drug or a combination analgesic, unless contraindicated.^1-4

In 1986, Raskin published a nonrandomized, nonblinded study of 2 treatments for intractable migraine in which repetitive inpatient intravenous (IV) DHE, administered in the hospital, was statistically more effective than IV diazepam in terminating cycles of intractable migraine.⁵ Most headache specialists have adopted the so-called Raskin protocol, as originally described or in any of several variations, as cornerstone therapy for CRM, chronic migraine, and prolonged status migrainosus.⁶ However, DHE-based infusion protocols do not always effectively reset the brain’s pain modulatory pathways in chronic migraine immediately posttreatment and might not induce a meaningful carryover effect.

We present 10 patients with CRM who met criteria for refractory migraine, including failure to terminate their headache with repetitive DHE/prochlorperazine/diphenhydramine/ketorolac/dexamethasone IV protocols, with or without sporadic administration of a sphenopalatine ganglion block. We treated these patients multimechanistically with repetitive IV DHE, a dopamine antagonist, an antihistamine, sphenopalatine ganglion (SPG) block, and low-dose ketamine, plus last-infusion-day dexamethasone, followed by outpatient oral memantine. Subsequently, we observed them for 2 months.

Ketamine is a phencyclidine derivative introduced the early 1960s as an IV anesthetic. Low-dose ketamine has been used successfully in the treatment of chronic pain. Today, increased interest in the application of low-dose ketamine includes cancer pain; treatment and prevention of acute and chronic pain, with and without neuropathic analgesia; fibromyalgia; complex regional pain; and migraine.^7,8 The effectiveness of ketamine in different pain disorders may arise through different pathways and/or by way of activity at various receptor systems. Effects arise predominantly by noncompetitive antagonism of the glutamate N-methyl-D-aspartate (NMDA ) receptor.^7,8

Memantine also is an NMDA receptor antagonist that is used effectively as an oral agent in CRM.⁹

METHODS

Patients enrolled in this prospective study had CRM for periods ranging from 1 to 2 years. All had daily headache that could not be terminated with repetitive DHE/prochlorperazine/diphenhydramine/ketorolac/dexamethasone IV protocols with or without sporadic administration of an SPG block. Age ranged from 18 and 68 years; all patients were female. Patients were excluded if they had known coronary artery disease, uncontrolled hypertension, or peripheral arterial disease; a history of stroke, transient ischemic attack, or pregnancy; impaired liver or renal function; smoked a tobacco product; or were taking a protease inhibitor or macrolide antibiotic.

 Approval by the institutional review board was unnecessary because all drugs and procedures are FDA-approved and have published evidence-based efficacy for migraine and other diseases.

 The Numeric Pain Rating Scale (NPRS; a scale of 0 to 10) was utilized to rate the intensity of pain from the beginning of the infusion to the end of the multiday infusion protocol, when the catheter was removed. All patients but 1 were treated for 5 days; for the 1 exception, treatment was terminated after 48 hours because of a scheduling conflict. The observational follow‐up periods for assessment of outcomes were 1 month and 2 months post-infusion.

Patients started the study with a baseline NPRS of 9 or 10. They were treated at the institution’s headache outpatient infusion center. In the morning, patients received, by sequential IV infusion, diphenhydramine, 50 mg; prochlorperazine, 10 mg; and DHE, 1 mg. They then received a midday SPG block under fluoroscopic guidance and ketamine, 0.45 mg/kg intramuscularly (IM), given in the post-anesthesia care unit. In the late afternoon, the patients received diphenhydramine, 50 mg; prochlorperazine, 10 mg; and DHE, 0.5 mg, in the Headache Outpatient Infusion Center. Patients were discharged to home by 6 PM. They received IV dexamethasone, 20 mg, on the last day of therapy.

Oral preventive agents were continued and abortives were temporarily discontinued during infusion therapy. Oral memantine was used immediately before, during, and, in all cases, after infusion, at a daily dosage that ranged from 10 mg BID to 28 mg, once-daily extended release.

RESULTS

Therapies were well-tolerated by all patients. On the last day of treatment, the entire cohort (N = 10) demonstrated an average of 71% (mean standard deviation [SD], 10.1%) reduction in pain intensity. The average reduction in headache days per month at 1 month was 88.6% (mean SD, 6.24%) and at 2 months was 79.4% (mean SD, 17.13%) (Table). Adverse effects were mild temporary sedation from ketamine. Pulse oximetry revealed no abnormal decrease in O₂ saturation. All patients reported marked overall reduction in headache disability at the end of the infusion protocol. Self-administered abortive therapies posttreatment were more efficacious than they were pretreatment. All patients indicated less headache disability overall by the end of the 2-month observation period.
 

Table. Chronic Refractory Migraine Baseline Data and Treatment Results^a

^aAll patients had daily headache at initiation of treatment.

^bHeadache days/month.

NPRS, Numeric Pain Rating Scale.

DISCUSSION

In our study of 10 patients with CRM who had daily headache treated repetitively in an outpatient infusion center with multimodality therapies, including sub-anesthetic doses of ketamine, all patients experienced marked reduction in headache pain intensity, with a whole-group average reduction of 71% by the end of infusion treatment. During post-infusion observation, all patients continued various preventive therapies, including memantine. At 1 month, the average reduction in headache frequency was 88.6%. Two months post-infusion, the average reduction in headache frequency was 79.4%. Adverse effects were minimal. Overall, the treatment was found to be safe and efficacious. All patients felt less headache disability after 2 months.

Because the protocol was administered comfortably in the Headache Outpatient Infusion Center, the inconvenience and higher cost of inpatient parenteral treatment were avoided. Ketamine, 0.45 mg/kg IM is a sub-anesthetic dose with proven efficacy in treating migraine without adverse effects in an outpatient setting.⁸ Low-dose ketamine obviated the need for anesthesia personnel and precautions. Temporary sedation was the only adverse effect. Ketamine was administered by a nurse in the post-anesthesia care unit while patients were under observation with conventional measurement of vital signs and pulse oximetry. Memantine, also an NMDA receptor antagonist, is postulated to prolong the NMDA antagonism of ketamine.

Inpatient and outpatient continuous IV DHE and repetitive IV DHE, often combined with dopamine antagonists in controlled and comparator studies, have demonstrated equal effectiveness for the treatment of chronic migraine.^5,10,11 Our patients failed these therapies. This raises the question: Should our combined multimodality, ketamine-based approach be standard parenteral therapy for CRM?

In a recent study of continuous inpatient single-modality IV ketamine, a less-impressive carryover effect was obtained, with 23% to 50% 1-month sustained responders.¹² Multimechanistic treatment superiority over monotherapy is legendary in the treatment of cancer and human immunodeficiency infection. Sumatriptan plus naproxen sodium as a single tablet for acute treatment of migraine resulted in more favorable clinical benefit compared with either monotherapy, with an acceptable, well-tolerated adverse effect profile. Because multiple pathogenic mechanisms putatively are involved in generation of the migraine symptom complex, multimechanism-targeted therapy may confer advantages over individual monotherapy. Drugs in 2 classes of migraine pharmacotherapy—triptans and nonsteroidal anti-inflammatory drugs —target distinct aspects of the vascular and inflammatory processes hypothesized to underlie migraine.¹³

Although combination therapy for CRM has not been systematically studied in randomized trials, clinical experience suggests that a rational approach to CRM treatment, utilizing a combination of treatments, may be effective when monotherapy has failed.¹⁴ During the infusion protocol, we re-set the trigeminovascular pain pathways 1) by repetitively blocking NMDA receptors (with ketamine), dopamine receptors (with prochlorperazine), and histamine receptors (with diphenhydramine); 2) by lidocaine anesthetic block of the sphenopalatine ganglia; and, on the last day of the protocol, 3) administering 1 large dose of IV dexamethasone to help prevent recurrence.¹⁵ NMDA blockade continued with oral outpatient memantine.

Virtually all patients were taking other preventives during the pretreatment period and 2-month observation period, including topiramate, venlafaxine, beta blockers, candesartan, zonisamide, onabotulinumtoxin A, neuromodulation (Cefaly Technology), and transcranial magnetic stimulation (springTMS®). Self-administered abortives were more effective in the 2-month observational period; these included IM/IV DHE; oral, spray, and subcutaneous triptans; IM ketorolac; diclofenac buffered solution; and transcranial magnetic stimulation (springTMS®). The cornerstone strategy of our treatment group that was a constant was the use of low-dose IM sub-anesthetic ketamine at a dosage of 0.45 mg/kg/d and the use of oral memantine during the follow-up observation period, at dosages ranging from 10 mg BID to 28 mg, once-daily extended release.

Limitations of this study design are:

• lack of a control group
• lack of subject randomization for comparative outcomes
• patients remaining on a variety of prophylactic regimens
• patients permitted to take any rescue therapy.

 The effect of repetitive SPG block cannot be teased out of the efficacy data, but many of our patients had a poor or temporary response to infrequent sporadic SPG blocks prior to participating in our protocol.

Many migraineurs who seek care in a headache clinic are refractory to treatment, despite advances in headache therapy; refractory migraine was found in 5.1% of these patients.¹⁶ In this small series of patients, we demonstrated immediate relief and a significant 2-month carryover effect with our multimodality parenteral protocol. Larger, controlled studies are needed to further explore this protocol with repetitive DHE, diphenhydramine, prochlorperazine, SPG block, and low-dose IM ketamine, followed by outpatient memantine. Such studies would determine whether our protocol should be utilized as a primary treatment, instead of the conventional DHE-based Raskin and modified Raskin protocols.

Although this is a small series of patients, lack of adverse effects and impressive results should give credence to utilizing our protocol as treatment for this extremely debilitated, often desperate subset of headache patients. Data indicate that, whereas ketamine combined with other therapies immediately reduced refractory headache pain, the ameliorating effect of ketamine on CRM headache frequency and pain in our protocol persisted beyond the infusion period. This phenomenon indicates a disease-modulating role for ketamine in refractory migraine pain, possibly by means of desensitization of NMDA receptors in the trigeminal nucleus caudalis—desensitization that continued with the NMDA receptor antagonist memantine and/or restoration of inhibitory sensory control in the brain.

CONCLUSION

Our results support the hypothesis that multimechanistic therapies, including low-dose IM ketamine and memantine, might be better than single-modality treatment in this debilitated, refractory population. Future studies, with larger patient populations, are needed to confirm whether these multimodality ketamine/memantine-inclusive therapies should become the preferred approach for these extremely disabled patients.

REFERENCES

1. Goadsby PJ, Schoenen J, Ferrari MD, Silberstein SD, Dodick DW. Towards a definition of intractable headache for use in clinical practice and trials. Cephalalgia. 2006;26(9):1168-1170.
2. Schulman EA, Lipton R, Peterlin BL, Levin M, Grosberg BM. Commentary from the Refractory Headache Special Interest Section on defining the pharmacologically intractable headache for clinical trials and clinical practice. Headache. 2010;50(10):1637-1639.
3. Martelletti P, Jensen RH, Antal A, et al. Neuromodulation of chronic headaches: position statement from the European Headache Federation. J Headache Pain. 2013;14:86.
4. Dodick DW, Turkel CC, DeGryse RE, et al; PREEMPT Chronic Migraine Study Group. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. 2010;50(6):921-936.
5. Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology. 1986;36(7):995‐997.
6. Charles JA, von Dohln P. Outpatient home-based continuous intravenous dihydroergotamine therapy for intractable migraine. Headache. 2010;50(5):852-860.
7. Sigtermans M, Noppers I, Sarton E, et al. An observational study on the effect of S+-ketamine on chronic pain versus experimental acute pain in complex regional pain syndrome type 1 patients. Eur J Pain. 2010;14(3):302-307.
8. Krusz J, Cagle J, Hall S. Intramuscular (IM) ketamine for treating headache and pain flare-ups in the clinic. J Pain. 2008;9(4):30.
9. Bigal M Rapoport A, Sheftell F, Tepper D, Tepper S. Memantine in the preventive treatment of refractory migraine. Headache. 2008;48(9):1337-1342.
10. Ford RG, Ford KT. Continuous intravenous dihydroergotamine for treatment of intractable headache. Headache. 1997;37(3):129‐136.
11. Boudreau G, Aghai E, Marchand L, Langlois M. Outpatient intravenous dihydroergotamine for probable medication overuse headache. Headache Care. 2006;3(1):45‐49.
12. Pomeroy JL, Marmura MJ, Nahas SJ, Viscusi ER. Ketamine infusions for treatment refractory headache. Headache. 2017;57(2):276-282.
13. Brandes JL, Kudrow D, Stark SR, et al. Sumatriptan-naproxen for acute treatment of migraine: a randomized trial. JAMA. 2007;297(13):1443-1454.
14. Peterlin BL, Calhoun AH, Siegel S, Mathew NT. Rational combination therapy in refractory migraine. Headache. 2008;48(6):805-819.
15. Innes G, Macphail I, Dillon EC, Metcalfe C, Gao M. Dexamethasone prevents relapse after emergency department treatment of acute migraine: a randomized clinical trial. CJEM. 2015;1(1):26-33.
16. Irimia P, Palma JA, Fernandez-Torron R, Martinez-Vila E. Refractory migraine in a headache clinic population. BMC Neurol. 2011;11:94.

Current migraine forecasting models represent an important first step in accurately predicting future headache activity, according to a recent investigation. However, to utilize these models in a preemptive treatment paradigm where the risk of headache is treated prior to the actual experience of pain, these models must achieve greater precision with good calibration and generate predictions that are clinically actionable by individuals in their real-time home environments.

A substantial pool of candidate migraine trigger factors could be considered in the creation of forecasting models. However, since mechanistic information about causal factors that precede a migraine attack is not well understood, and such factors are difficult to measure, empirical models that are based on trigger factors that are merely associated with the onset of headache activity are likely to be the focus of forecasting efforts. Of such factors, stress has considerable empirical support and has been used to successfully forecast future headache attacks within individuals over time. At present, however, existing models possess only modest levels of discrimination and lack strong resolution in generated predictions.

Curr Pain Headache Rep. Forecasting migraine attacks and the utility of identifying triggers. 2018;22:62. doi:10.1007/s11916-018-0715-3.

Current migraine forecasting models represent an important first step in accurately predicting future headache activity, according to a recent investigation. However, to utilize these models in a preemptive treatment paradigm where the risk of headache is treated prior to the actual experience of pain, these models must achieve greater precision with good calibration and generate predictions that are clinically actionable by individuals in their real-time home environments.

A substantial pool of candidate migraine trigger factors could be considered in the creation of forecasting models. However, since mechanistic information about causal factors that precede a migraine attack is not well understood, and such factors are difficult to measure, empirical models that are based on trigger factors that are merely associated with the onset of headache activity are likely to be the focus of forecasting efforts. Of such factors, stress has considerable empirical support and has been used to successfully forecast future headache attacks within individuals over time. At present, however, existing models possess only modest levels of discrimination and lack strong resolution in generated predictions.

Curr Pain Headache Rep. Forecasting migraine attacks and the utility of identifying triggers. 2018;22:62. doi:10.1007/s11916-018-0715-3.

Current migraine forecasting models represent an important first step in accurately predicting future headache activity, according to a recent investigation. However, to utilize these models in a preemptive treatment paradigm where the risk of headache is treated prior to the actual experience of pain, these models must achieve greater precision with good calibration and generate predictions that are clinically actionable by individuals in their real-time home environments.

A substantial pool of candidate migraine trigger factors could be considered in the creation of forecasting models. However, since mechanistic information about causal factors that precede a migraine attack is not well understood, and such factors are difficult to measure, empirical models that are based on trigger factors that are merely associated with the onset of headache activity are likely to be the focus of forecasting efforts. Of such factors, stress has considerable empirical support and has been used to successfully forecast future headache attacks within individuals over time. At present, however, existing models possess only modest levels of discrimination and lack strong resolution in generated predictions.

Curr Pain Headache Rep. Forecasting migraine attacks and the utility of identifying triggers. 2018;22:62. doi:10.1007/s11916-018-0715-3.

Although unilateral pain location can be helpful in making a migraine diagnosis, it does not appear to have additional clinical implications, according to a recent study. Additionally, its absence does not rule out a diagnosis of migraine since more than half of migraineurs have bilateral head pain. Medical record information was extracted for 477 randomly selected patients with migraine seen in 2011 in a tertiary headache clinic. This included demographic data, pain location, handedness, comorbid psychiatric diagnoses, medical and emergency department visits, and use of selected headache medications. Researchers found:

• Of 477 patients, 228 (47.8%) reported lateralized pain, of which 107 (47.9%) patients were right-sided compared with 65 (28.5%) left-sided patients, while 56 (24.5%) reported unilateral pain with no side predominance.
• Contrary to expectations, with the exception of self-reported posttraumatic stress disorder, there were no statistically significant differences between left and right in measures of psychiatric distress, emergency department visits, or healthcare use.

Migraine pain location and measures of healthcare use and distress: An observational study. Pain Res Manag. 2018;6157982. doi:10.1155/2018/6157982.

Although unilateral pain location can be helpful in making a migraine diagnosis, it does not appear to have additional clinical implications, according to a recent study. Additionally, its absence does not rule out a diagnosis of migraine since more than half of migraineurs have bilateral head pain. Medical record information was extracted for 477 randomly selected patients with migraine seen in 2011 in a tertiary headache clinic. This included demographic data, pain location, handedness, comorbid psychiatric diagnoses, medical and emergency department visits, and use of selected headache medications. Researchers found:

• Of 477 patients, 228 (47.8%) reported lateralized pain, of which 107 (47.9%) patients were right-sided compared with 65 (28.5%) left-sided patients, while 56 (24.5%) reported unilateral pain with no side predominance.
• Contrary to expectations, with the exception of self-reported posttraumatic stress disorder, there were no statistically significant differences between left and right in measures of psychiatric distress, emergency department visits, or healthcare use.

Migraine pain location and measures of healthcare use and distress: An observational study. Pain Res Manag. 2018;6157982. doi:10.1155/2018/6157982.

Although unilateral pain location can be helpful in making a migraine diagnosis, it does not appear to have additional clinical implications, according to a recent study. Additionally, its absence does not rule out a diagnosis of migraine since more than half of migraineurs have bilateral head pain. Medical record information was extracted for 477 randomly selected patients with migraine seen in 2011 in a tertiary headache clinic. This included demographic data, pain location, handedness, comorbid psychiatric diagnoses, medical and emergency department visits, and use of selected headache medications. Researchers found:

• Of 477 patients, 228 (47.8%) reported lateralized pain, of which 107 (47.9%) patients were right-sided compared with 65 (28.5%) left-sided patients, while 56 (24.5%) reported unilateral pain with no side predominance.
• Contrary to expectations, with the exception of self-reported posttraumatic stress disorder, there were no statistically significant differences between left and right in measures of psychiatric distress, emergency department visits, or healthcare use.

Migraine pain location and measures of healthcare use and distress: An observational study. Pain Res Manag. 2018;6157982. doi:10.1155/2018/6157982.

A recent study found a much higher prevalence of vestibular migraine (VM) in the United States than previously reported. These results, therefore, indicate a likely under-diagnosis of VM. Researchers evaluated the responses of participants (n=21,781) in the 2008 National Health Interview Survey (NHIS) balance and dizziness supplement, which were analyzed using statistical software. They found:

• The 1-year prevalence of a dizziness or balance problem in the United States was 11.9% (2490 respondents).
• Of respondents with dizziness, 584 (23.4%) met the case definition of VM, which represents a prevalence of VM in 2.7% of adults.
• There was a female preponderance (64.1%) and a slightly younger mean age (40.9 years) for those with VM as compared with all respondents (51.7% females and 46 years, respectively).
• Multivariate analysis showed that age <40, female sex, anxiety, depression, and prior head trauma were all associated with significantly increased odds of experiencing VM.
• Only 10% of subjects meeting criteria for VM were told that migraine was the cause of their dizziness.

The epidemiology of vestibular migraine: A population-based survey study. [Published online ahead of print July 16, 2018]. Otol Neurotol. doi:10.1097/MAO.0000000000001900.

A recent study found a much higher prevalence of vestibular migraine (VM) in the United States than previously reported. These results, therefore, indicate a likely under-diagnosis of VM. Researchers evaluated the responses of participants (n=21,781) in the 2008 National Health Interview Survey (NHIS) balance and dizziness supplement, which were analyzed using statistical software. They found:

• The 1-year prevalence of a dizziness or balance problem in the United States was 11.9% (2490 respondents).
• Of respondents with dizziness, 584 (23.4%) met the case definition of VM, which represents a prevalence of VM in 2.7% of adults.
• There was a female preponderance (64.1%) and a slightly younger mean age (40.9 years) for those with VM as compared with all respondents (51.7% females and 46 years, respectively).
• Multivariate analysis showed that age <40, female sex, anxiety, depression, and prior head trauma were all associated with significantly increased odds of experiencing VM.
• Only 10% of subjects meeting criteria for VM were told that migraine was the cause of their dizziness.

The epidemiology of vestibular migraine: A population-based survey study. [Published online ahead of print July 16, 2018]. Otol Neurotol. doi:10.1097/MAO.0000000000001900.

A recent study found a much higher prevalence of vestibular migraine (VM) in the United States than previously reported. These results, therefore, indicate a likely under-diagnosis of VM. Researchers evaluated the responses of participants (n=21,781) in the 2008 National Health Interview Survey (NHIS) balance and dizziness supplement, which were analyzed using statistical software. They found:

• The 1-year prevalence of a dizziness or balance problem in the United States was 11.9% (2490 respondents).
• Of respondents with dizziness, 584 (23.4%) met the case definition of VM, which represents a prevalence of VM in 2.7% of adults.
• There was a female preponderance (64.1%) and a slightly younger mean age (40.9 years) for those with VM as compared with all respondents (51.7% females and 46 years, respectively).
• Multivariate analysis showed that age <40, female sex, anxiety, depression, and prior head trauma were all associated with significantly increased odds of experiencing VM.
• Only 10% of subjects meeting criteria for VM were told that migraine was the cause of their dizziness.

The epidemiology of vestibular migraine: A population-based survey study. [Published online ahead of print July 16, 2018]. Otol Neurotol. doi:10.1097/MAO.0000000000001900.