The use of hormonal contraception in women with headaches, especially migraine headaches, is an important topic. Approximately 43% of women in the United States report migraines.¹ Roughly the same percentage of reproductive-aged women use hormonal contraception.² Data suggest that all migraineurs have some increased risk of stroke. Therefore, can women with migraine headaches use combination hormonal contraception? And can women with severe headaches that are nonmigrainous use combination hormonal contraception? Let’s examine available data to help us answer these questions.

Risk factors for stroke

Migraine without aura is the most common subset, but migraine with aura is more problematic relative to the increased incidence of stroke.¹

A migraine aura is visual 90% of the time.¹ Symptoms can include flickering lights, spots, zigzag lines, a sense of pins and needles, or dysphasic speech. Aura precedes the headache and usually resolves within 1 hour after the aura begins.

In addition to migraine headaches, risk factors for stroke include increasing age, hypertension, the use of combination oral contraceptives (COCs), the contraceptive patch and ring, and smoking.¹

Data indicate that the risk for ischemic stroke is increased in women with migraines even without the presence of other risk factors. In a meta-analysis of 14 observational studies, the risk of ischemic stroke among all migraineurs was about 2-fold (relative risk [RR], 2.2; 95% confidence interval [CI], 1.9–2.5) compared with the risk of ischemic stroke in women of the same age group who did not have migraine headaches. When there is migraine without aura, it was slightly less than 2-fold (RR, 1.8; 95% CI, 1.1–3.2). The risk of ischemic stroke among migraineurs with aura is increased more than 2 times compared with women without migraine (RR, 2.27; 95% CI, 1.61–3.19).³ However, the absolute risk of ischemic stroke among reproductive-aged women is 11 per 100,000 women years.⁴

Two observational studies show how additional risk factors increase that risk (TABLE).^5,6 There are similar trends in terms of overall risk of stroke among women with all types of migraine. However, when you add smoking as an additional risk factor for women with migraine headaches, there is a substantial increase in the risk of stroke. When a woman who has migraines uses COCs, there is increased risk varying from 2-fold to almost 4-fold. When you combine migraine, smoking, and COCs, a very, very large risk factor (odds ratio [OR], 34.4; 95% CI, 3.27–3.61) was reported by Chang and colleagues.⁶

Although these risks are impressive, it is important to keep in mind that even with a 10-fold increase, we are only talking about 1 case per 1,000 migraineurs.⁴ Unfortunately, stroke often leads to major disability and even death, such that any reduction in risk is still important.

Preventing estrogen withdrawal or menstrual migraines

How should we treat a woman who uses hormonal contraception and reports estrogen withdrawal or menstrual migraines? Based on clinical evidence, there are 2 ways to reduce her symptoms:

• COCs. Reduce the hormone-free interval by having her take COCs for 3 to 4 days instead of 7 days, or eliminate the hormone-free interval altogether by continuous use of COCs, usually 3 months at a time.⁷
• NSAIDs. For those who do not want to alter how they take their hormonal product, use nonsteroidal anti-inflammatory drugs (NSAIDs) starting 7 days before the onset of menses and continuing for 13 days. In a clinical trial by Sances and colleagues, this plan reduced the frequency, duration, and severity of menstrual migraines.⁸

Probably altering how she takes the COC would make the most sense for most individuals instead of taking NSAIDs for 75% of each month.

Recommendations from the US MEC

The US Medical Eligibility Criteria (US MEC) from the Centers for Disease Control and Prevention (CDC) offers recommendations for contraceptive use⁹:

• For nonmigrainous headache, the CDC suggests that the benefits of using COCs outweigh the risks unless the headaches persist after 3 months of COC use.

• For migraine without aura, the benefits outweigh the risks in starting women who are younger than age 35 years on oral contraceptives. However, the risks of COCs outweigh the benefits in women who are age 35 years and older who develop migraine headache while on COCs, or who have risk factors for stroke.

• For migraine with aura, COCs are contraindicated.
• Progestin-only contraceptives. The CDC considers that the benefits of COC use outweigh any theoretical risk of stroke, even in women with risk factors or in women who have migraine with aura. Progestin-only contraceptives do not alter one’s risk of stroke, unlike contraceptives that contain estrogen.

My bottom line

Can women with migraine headaches begin the use of combination hormonal methods? Yes, if there is no aura in their migraines and they are not older than age 35.

Can women with severe headaches that are nonmigrainous use combination hormonal methods? Possibly, but you should discontinue COCs if headache severity persists or worsens, using a 3-month time period for evaluation.

How do you manage women with migraines during the hormone-free interval? Consider the continuous method or shorten the hormone-free interval.

Recommendations for complicated patients. Consulting the CDC’s US MEC database⁷ can provide assistance in your care of more complicated patients requesting contraception. I also recommend the book, “Contraception for the Medically Challenging Patient,” edited by Rebecca Allen and Carrie Cwiak.¹⁰ It links nicely with the CDC guidelines and presents more detail on each subject.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

The use of hormonal contraception in women with headaches, especially migraine headaches, is an important topic. Approximately 43% of women in the United States report migraines.¹ Roughly the same percentage of reproductive-aged women use hormonal contraception.² Data suggest that all migraineurs have some increased risk of stroke. Therefore, can women with migraine headaches use combination hormonal contraception? And can women with severe headaches that are nonmigrainous use combination hormonal contraception? Let’s examine available data to help us answer these questions.

Risk factors for stroke

Migraine without aura is the most common subset, but migraine with aura is more problematic relative to the increased incidence of stroke.¹

A migraine aura is visual 90% of the time.¹ Symptoms can include flickering lights, spots, zigzag lines, a sense of pins and needles, or dysphasic speech. Aura precedes the headache and usually resolves within 1 hour after the aura begins.

In addition to migraine headaches, risk factors for stroke include increasing age, hypertension, the use of combination oral contraceptives (COCs), the contraceptive patch and ring, and smoking.¹

Data indicate that the risk for ischemic stroke is increased in women with migraines even without the presence of other risk factors. In a meta-analysis of 14 observational studies, the risk of ischemic stroke among all migraineurs was about 2-fold (relative risk [RR], 2.2; 95% confidence interval [CI], 1.9–2.5) compared with the risk of ischemic stroke in women of the same age group who did not have migraine headaches. When there is migraine without aura, it was slightly less than 2-fold (RR, 1.8; 95% CI, 1.1–3.2). The risk of ischemic stroke among migraineurs with aura is increased more than 2 times compared with women without migraine (RR, 2.27; 95% CI, 1.61–3.19).³ However, the absolute risk of ischemic stroke among reproductive-aged women is 11 per 100,000 women years.⁴

Two observational studies show how additional risk factors increase that risk (TABLE).^5,6 There are similar trends in terms of overall risk of stroke among women with all types of migraine. However, when you add smoking as an additional risk factor for women with migraine headaches, there is a substantial increase in the risk of stroke. When a woman who has migraines uses COCs, there is increased risk varying from 2-fold to almost 4-fold. When you combine migraine, smoking, and COCs, a very, very large risk factor (odds ratio [OR], 34.4; 95% CI, 3.27–3.61) was reported by Chang and colleagues.⁶

Although these risks are impressive, it is important to keep in mind that even with a 10-fold increase, we are only talking about 1 case per 1,000 migraineurs.⁴ Unfortunately, stroke often leads to major disability and even death, such that any reduction in risk is still important.

Preventing estrogen withdrawal or menstrual migraines

How should we treat a woman who uses hormonal contraception and reports estrogen withdrawal or menstrual migraines? Based on clinical evidence, there are 2 ways to reduce her symptoms:

• COCs. Reduce the hormone-free interval by having her take COCs for 3 to 4 days instead of 7 days, or eliminate the hormone-free interval altogether by continuous use of COCs, usually 3 months at a time.⁷
• NSAIDs. For those who do not want to alter how they take their hormonal product, use nonsteroidal anti-inflammatory drugs (NSAIDs) starting 7 days before the onset of menses and continuing for 13 days. In a clinical trial by Sances and colleagues, this plan reduced the frequency, duration, and severity of menstrual migraines.⁸

Probably altering how she takes the COC would make the most sense for most individuals instead of taking NSAIDs for 75% of each month.

Recommendations from the US MEC

The US Medical Eligibility Criteria (US MEC) from the Centers for Disease Control and Prevention (CDC) offers recommendations for contraceptive use⁹:

• For nonmigrainous headache, the CDC suggests that the benefits of using COCs outweigh the risks unless the headaches persist after 3 months of COC use.

• For migraine without aura, the benefits outweigh the risks in starting women who are younger than age 35 years on oral contraceptives. However, the risks of COCs outweigh the benefits in women who are age 35 years and older who develop migraine headache while on COCs, or who have risk factors for stroke.

• For migraine with aura, COCs are contraindicated.
• Progestin-only contraceptives. The CDC considers that the benefits of COC use outweigh any theoretical risk of stroke, even in women with risk factors or in women who have migraine with aura. Progestin-only contraceptives do not alter one’s risk of stroke, unlike contraceptives that contain estrogen.

My bottom line

Can women with migraine headaches begin the use of combination hormonal methods? Yes, if there is no aura in their migraines and they are not older than age 35.

Can women with severe headaches that are nonmigrainous use combination hormonal methods? Possibly, but you should discontinue COCs if headache severity persists or worsens, using a 3-month time period for evaluation.

How do you manage women with migraines during the hormone-free interval? Consider the continuous method or shorten the hormone-free interval.

Recommendations for complicated patients. Consulting the CDC’s US MEC database⁷ can provide assistance in your care of more complicated patients requesting contraception. I also recommend the book, “Contraception for the Medically Challenging Patient,” edited by Rebecca Allen and Carrie Cwiak.¹⁰ It links nicely with the CDC guidelines and presents more detail on each subject.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

The use of hormonal contraception in women with headaches, especially migraine headaches, is an important topic. Approximately 43% of women in the United States report migraines.¹ Roughly the same percentage of reproductive-aged women use hormonal contraception.² Data suggest that all migraineurs have some increased risk of stroke. Therefore, can women with migraine headaches use combination hormonal contraception? And can women with severe headaches that are nonmigrainous use combination hormonal contraception? Let’s examine available data to help us answer these questions.

Risk factors for stroke

Migraine without aura is the most common subset, but migraine with aura is more problematic relative to the increased incidence of stroke.¹

A migraine aura is visual 90% of the time.¹ Symptoms can include flickering lights, spots, zigzag lines, a sense of pins and needles, or dysphasic speech. Aura precedes the headache and usually resolves within 1 hour after the aura begins.

In addition to migraine headaches, risk factors for stroke include increasing age, hypertension, the use of combination oral contraceptives (COCs), the contraceptive patch and ring, and smoking.¹

Data indicate that the risk for ischemic stroke is increased in women with migraines even without the presence of other risk factors. In a meta-analysis of 14 observational studies, the risk of ischemic stroke among all migraineurs was about 2-fold (relative risk [RR], 2.2; 95% confidence interval [CI], 1.9–2.5) compared with the risk of ischemic stroke in women of the same age group who did not have migraine headaches. When there is migraine without aura, it was slightly less than 2-fold (RR, 1.8; 95% CI, 1.1–3.2). The risk of ischemic stroke among migraineurs with aura is increased more than 2 times compared with women without migraine (RR, 2.27; 95% CI, 1.61–3.19).³ However, the absolute risk of ischemic stroke among reproductive-aged women is 11 per 100,000 women years.⁴

Two observational studies show how additional risk factors increase that risk (TABLE).^5,6 There are similar trends in terms of overall risk of stroke among women with all types of migraine. However, when you add smoking as an additional risk factor for women with migraine headaches, there is a substantial increase in the risk of stroke. When a woman who has migraines uses COCs, there is increased risk varying from 2-fold to almost 4-fold. When you combine migraine, smoking, and COCs, a very, very large risk factor (odds ratio [OR], 34.4; 95% CI, 3.27–3.61) was reported by Chang and colleagues.⁶

Although these risks are impressive, it is important to keep in mind that even with a 10-fold increase, we are only talking about 1 case per 1,000 migraineurs.⁴ Unfortunately, stroke often leads to major disability and even death, such that any reduction in risk is still important.

Preventing estrogen withdrawal or menstrual migraines

How should we treat a woman who uses hormonal contraception and reports estrogen withdrawal or menstrual migraines? Based on clinical evidence, there are 2 ways to reduce her symptoms:

• COCs. Reduce the hormone-free interval by having her take COCs for 3 to 4 days instead of 7 days, or eliminate the hormone-free interval altogether by continuous use of COCs, usually 3 months at a time.⁷
• NSAIDs. For those who do not want to alter how they take their hormonal product, use nonsteroidal anti-inflammatory drugs (NSAIDs) starting 7 days before the onset of menses and continuing for 13 days. In a clinical trial by Sances and colleagues, this plan reduced the frequency, duration, and severity of menstrual migraines.⁸

Probably altering how she takes the COC would make the most sense for most individuals instead of taking NSAIDs for 75% of each month.

Recommendations from the US MEC

The US Medical Eligibility Criteria (US MEC) from the Centers for Disease Control and Prevention (CDC) offers recommendations for contraceptive use⁹:

• For nonmigrainous headache, the CDC suggests that the benefits of using COCs outweigh the risks unless the headaches persist after 3 months of COC use.

• For migraine without aura, the benefits outweigh the risks in starting women who are younger than age 35 years on oral contraceptives. However, the risks of COCs outweigh the benefits in women who are age 35 years and older who develop migraine headache while on COCs, or who have risk factors for stroke.

• For migraine with aura, COCs are contraindicated.
• Progestin-only contraceptives. The CDC considers that the benefits of COC use outweigh any theoretical risk of stroke, even in women with risk factors or in women who have migraine with aura. Progestin-only contraceptives do not alter one’s risk of stroke, unlike contraceptives that contain estrogen.

My bottom line

Can women with migraine headaches begin the use of combination hormonal methods? Yes, if there is no aura in their migraines and they are not older than age 35.

Can women with severe headaches that are nonmigrainous use combination hormonal methods? Possibly, but you should discontinue COCs if headache severity persists or worsens, using a 3-month time period for evaluation.

How do you manage women with migraines during the hormone-free interval? Consider the continuous method or shorten the hormone-free interval.

Recommendations for complicated patients. Consulting the CDC’s US MEC database⁷ can provide assistance in your care of more complicated patients requesting contraception. I also recommend the book, “Contraception for the Medically Challenging Patient,” edited by Rebecca Allen and Carrie Cwiak.¹⁰ It links nicely with the CDC guidelines and presents more detail on each subject.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

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.

A new study, the first of its kind, provided support for guidelines suggesting that the capsular meningococcal B vaccine be given to children with three rare conditions that boost infection risk.

©Micah Young/istockphoto.com

SOURCE: Martinón-Torres F et al. Pediatrics. 2018 Aug 1. doi: 10.1542/peds.2017-4250.

A new study, the first of its kind, provided support for guidelines suggesting that the capsular meningococcal B vaccine be given to children with three rare conditions that boost infection risk.

©Micah Young/istockphoto.com

SOURCE: Martinón-Torres F et al. Pediatrics. 2018 Aug 1. doi: 10.1542/peds.2017-4250.

A new study, the first of its kind, provided support for guidelines suggesting that the capsular meningococcal B vaccine be given to children with three rare conditions that boost infection risk.

©Micah Young/istockphoto.com

SOURCE: Martinón-Torres F et al. Pediatrics. 2018 Aug 1. doi: 10.1542/peds.2017-4250.

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).

MIAMI—Droxidopa is associated with reductions in fall risk and dizziness or lightheadedness among users and nonusers of dopamine decarboxylase inhibitors (DDCIs), according to research described at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. These findings from an open-label, observational study “support previous data showing the efficacy of droxidopa for neurogenic orthostatic hypotension symptom reduction, even with concomitant DDCI use,” said the researchers.

Neurogenic orthostatic hypotension—a sustained blood pressure drop upon standing due to deficient norepinephrine release—is common among patients with disorders associated with autonomic nervous system dysfunction (eg, Parkinson’s disease, multiple system atrophy, and pure autonomic failure). Symptoms include lightheadedness or dizziness, presyncope, syncope, and falls.

A Post Hoc Analysis

To assess the long-term efficacy of droxidopa for the treatment of neurogenic orthostatic hypotension in patients concomitantly receiving DDCIs, Dr. Kymes and colleagues conducted a post hoc analysis of outcomes related to falls and neurogenic orthostatic hypotension symptoms in patients using DDCIs versus patients not using them. The researchers used data from a six-month open-label, prospective, observational study of patients newly initiating droxidopa.

Eligible participants were 18 and older; had underlying Parkinson’s disease, multiple system atrophy, pure autonomic failure, dopamine beta-hydroxylase deficiency, or nondiabetic autonomic neuropathy; were newly initiating droxidopa; and were able to speak and understand English. The researchers excluded patients with a self-reported diagnosis of dementia, Alzheimer disease, schizophrenia, or other psychiatric disorder, as well as those who were nonambulatory or confined to a wheelchair.

Researchers used a patient falls questionnaire to record the number of falls in the past month at baseline and at one, three, and six months. They also used the Orthostatic Hypotension Symptom Assessment (OHSA) Item I test to assess dizziness or lightheadedness. All outcomes were self-reported.

Investigators then compared baseline differences using chi-square tests for categorical variables and t-tests for continuous variables. “The influence of DDCIs on risk of falling and OHSA Item I scores was compared across time points using generalized linear mixed models (logistic for risk of falling) adjusting for repeated measures within individuals,” said the researchers.

Droxidopa Treatment Was Associated With Reduced Falls

A total of 168 patients were included in this study; 55 were DDCI users, and 113 were non-DDCI users. The mean age in the DDCI group was 75, and the mean age in the non-DDCI group was 57. There were 19 women (34.5%) in the DDCI user group and 68 (60.2%) in non-DDCI user group. Most participants were white in both groups (92.7% in the DDCI group and 81.4% in the non-DDCI group).

“There were significant differences in the primary diagnoses between the groups. Parkinson’s disease was the most frequent diagnosis in the DDCI group (89.1%), and autonomic failure with no cause identified was the most frequent diagnosis in the non-DDCI group (92.9%),” Dr. Kymes and colleagues said. “At baseline, 61.8% of patients receiving DDCIs and 46.9 % of patients not receiving DDCI reported at least one fall in the last month.” The mean OHSA Item I scores at baseline were 5 in the DDCI group and 6 in the non-DDCI group.

The proportion of patients receiving DDCIs who experienced one or more falls in the past month after six months of droxidopa treatment significantly decreased from baseline, with a 36.5% reduction over the course of the study.

Among patients not receiving a DDCI, there was a 6.2% reduction in falls over the course of the study, but the reduction was not significant. Changes in the proportion of patients reporting one or more falls in the past month from baseline to six months did not differ significantly between the groups.

In addition, patients receiving DDCIs and nonusers showed significant improvement in OHSA Item I scores from baseline after six months of droxidopa treatment (change of 1.5 and 1.9 units, respectively). The difference between groups was not statistically significant.

“Specifically designed studies are needed to further examine the impact of DDCIs on droxidopa because the current study sample was not powered for subgroup analyses and all data were self-reported by patients,” the researchers concluded.

—Erica Tricarico

MIAMI—Droxidopa is associated with reductions in fall risk and dizziness or lightheadedness among users and nonusers of dopamine decarboxylase inhibitors (DDCIs), according to research described at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. These findings from an open-label, observational study “support previous data showing the efficacy of droxidopa for neurogenic orthostatic hypotension symptom reduction, even with concomitant DDCI use,” said the researchers.

Neurogenic orthostatic hypotension—a sustained blood pressure drop upon standing due to deficient norepinephrine release—is common among patients with disorders associated with autonomic nervous system dysfunction (eg, Parkinson’s disease, multiple system atrophy, and pure autonomic failure). Symptoms include lightheadedness or dizziness, presyncope, syncope, and falls.

A Post Hoc Analysis

To assess the long-term efficacy of droxidopa for the treatment of neurogenic orthostatic hypotension in patients concomitantly receiving DDCIs, Dr. Kymes and colleagues conducted a post hoc analysis of outcomes related to falls and neurogenic orthostatic hypotension symptoms in patients using DDCIs versus patients not using them. The researchers used data from a six-month open-label, prospective, observational study of patients newly initiating droxidopa.

Eligible participants were 18 and older; had underlying Parkinson’s disease, multiple system atrophy, pure autonomic failure, dopamine beta-hydroxylase deficiency, or nondiabetic autonomic neuropathy; were newly initiating droxidopa; and were able to speak and understand English. The researchers excluded patients with a self-reported diagnosis of dementia, Alzheimer disease, schizophrenia, or other psychiatric disorder, as well as those who were nonambulatory or confined to a wheelchair.

Researchers used a patient falls questionnaire to record the number of falls in the past month at baseline and at one, three, and six months. They also used the Orthostatic Hypotension Symptom Assessment (OHSA) Item I test to assess dizziness or lightheadedness. All outcomes were self-reported.

Investigators then compared baseline differences using chi-square tests for categorical variables and t-tests for continuous variables. “The influence of DDCIs on risk of falling and OHSA Item I scores was compared across time points using generalized linear mixed models (logistic for risk of falling) adjusting for repeated measures within individuals,” said the researchers.

Droxidopa Treatment Was Associated With Reduced Falls

A total of 168 patients were included in this study; 55 were DDCI users, and 113 were non-DDCI users. The mean age in the DDCI group was 75, and the mean age in the non-DDCI group was 57. There were 19 women (34.5%) in the DDCI user group and 68 (60.2%) in non-DDCI user group. Most participants were white in both groups (92.7% in the DDCI group and 81.4% in the non-DDCI group).

“There were significant differences in the primary diagnoses between the groups. Parkinson’s disease was the most frequent diagnosis in the DDCI group (89.1%), and autonomic failure with no cause identified was the most frequent diagnosis in the non-DDCI group (92.9%),” Dr. Kymes and colleagues said. “At baseline, 61.8% of patients receiving DDCIs and 46.9 % of patients not receiving DDCI reported at least one fall in the last month.” The mean OHSA Item I scores at baseline were 5 in the DDCI group and 6 in the non-DDCI group.

The proportion of patients receiving DDCIs who experienced one or more falls in the past month after six months of droxidopa treatment significantly decreased from baseline, with a 36.5% reduction over the course of the study.

Among patients not receiving a DDCI, there was a 6.2% reduction in falls over the course of the study, but the reduction was not significant. Changes in the proportion of patients reporting one or more falls in the past month from baseline to six months did not differ significantly between the groups.

In addition, patients receiving DDCIs and nonusers showed significant improvement in OHSA Item I scores from baseline after six months of droxidopa treatment (change of 1.5 and 1.9 units, respectively). The difference between groups was not statistically significant.

“Specifically designed studies are needed to further examine the impact of DDCIs on droxidopa because the current study sample was not powered for subgroup analyses and all data were self-reported by patients,” the researchers concluded.

—Erica Tricarico

MIAMI—Droxidopa is associated with reductions in fall risk and dizziness or lightheadedness among users and nonusers of dopamine decarboxylase inhibitors (DDCIs), according to research described at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. These findings from an open-label, observational study “support previous data showing the efficacy of droxidopa for neurogenic orthostatic hypotension symptom reduction, even with concomitant DDCI use,” said the researchers.

Neurogenic orthostatic hypotension—a sustained blood pressure drop upon standing due to deficient norepinephrine release—is common among patients with disorders associated with autonomic nervous system dysfunction (eg, Parkinson’s disease, multiple system atrophy, and pure autonomic failure). Symptoms include lightheadedness or dizziness, presyncope, syncope, and falls.

A Post Hoc Analysis

To assess the long-term efficacy of droxidopa for the treatment of neurogenic orthostatic hypotension in patients concomitantly receiving DDCIs, Dr. Kymes and colleagues conducted a post hoc analysis of outcomes related to falls and neurogenic orthostatic hypotension symptoms in patients using DDCIs versus patients not using them. The researchers used data from a six-month open-label, prospective, observational study of patients newly initiating droxidopa.

Eligible participants were 18 and older; had underlying Parkinson’s disease, multiple system atrophy, pure autonomic failure, dopamine beta-hydroxylase deficiency, or nondiabetic autonomic neuropathy; were newly initiating droxidopa; and were able to speak and understand English. The researchers excluded patients with a self-reported diagnosis of dementia, Alzheimer disease, schizophrenia, or other psychiatric disorder, as well as those who were nonambulatory or confined to a wheelchair.

Researchers used a patient falls questionnaire to record the number of falls in the past month at baseline and at one, three, and six months. They also used the Orthostatic Hypotension Symptom Assessment (OHSA) Item I test to assess dizziness or lightheadedness. All outcomes were self-reported.

Investigators then compared baseline differences using chi-square tests for categorical variables and t-tests for continuous variables. “The influence of DDCIs on risk of falling and OHSA Item I scores was compared across time points using generalized linear mixed models (logistic for risk of falling) adjusting for repeated measures within individuals,” said the researchers.

Droxidopa Treatment Was Associated With Reduced Falls

A total of 168 patients were included in this study; 55 were DDCI users, and 113 were non-DDCI users. The mean age in the DDCI group was 75, and the mean age in the non-DDCI group was 57. There were 19 women (34.5%) in the DDCI user group and 68 (60.2%) in non-DDCI user group. Most participants were white in both groups (92.7% in the DDCI group and 81.4% in the non-DDCI group).

“There were significant differences in the primary diagnoses between the groups. Parkinson’s disease was the most frequent diagnosis in the DDCI group (89.1%), and autonomic failure with no cause identified was the most frequent diagnosis in the non-DDCI group (92.9%),” Dr. Kymes and colleagues said. “At baseline, 61.8% of patients receiving DDCIs and 46.9 % of patients not receiving DDCI reported at least one fall in the last month.” The mean OHSA Item I scores at baseline were 5 in the DDCI group and 6 in the non-DDCI group.

The proportion of patients receiving DDCIs who experienced one or more falls in the past month after six months of droxidopa treatment significantly decreased from baseline, with a 36.5% reduction over the course of the study.

Among patients not receiving a DDCI, there was a 6.2% reduction in falls over the course of the study, but the reduction was not significant. Changes in the proportion of patients reporting one or more falls in the past month from baseline to six months did not differ significantly between the groups.

In addition, patients receiving DDCIs and nonusers showed significant improvement in OHSA Item I scores from baseline after six months of droxidopa treatment (change of 1.5 and 1.9 units, respectively). The difference between groups was not statistically significant.

“Specifically designed studies are needed to further examine the impact of DDCIs on droxidopa because the current study sample was not powered for subgroup analyses and all data were self-reported by patients,” the researchers concluded.

—Erica Tricarico

MIAMI—Reduced cholinergic nucleus 4 (Ch4) density in Parkinson’s disease, as measured with MRI, is associated with deficits in attention, processing speed, and visuospatial function, according to research described at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. Ch4 density may serve as a surrogate imaging biomarker of cognition in early Parkinson’s disease, said the researchers.

Degeneration of the nucleus basalis of Meynert (NBM) contributes to dementia in Parkinson’s disease through a loss of cholinergic innervation to the neocortex. Cholinergic neurons of the NBM are in Ch4, a structure that can be measured with MRI techniques using cytoarchitectonic maps.

Evaluating Ch4 Density and Cognitive Performance

To determine whether Ch4 density, a proxy measure for NBM volume, is associated with cognitive test performance in de novo Parkinson’s disease, Cody S. Freeman, MD, a fellow at the University of Virginia School of Medicine in Charlottesville, and colleagues analyzed baseline brain MRIs and neuropsychologic test scores for 228 patients with Parkinson’s disease and 101 healthy controls from the Parkinson’s Progression Markers Initiative (PPMI). They also analyzed brain MRIs and neuropsychologic test scores at four years for a subset of 92 participants with Parkinson’s disease in the PPMI.

Neuropsychologic testing included the Montreal Cognitive Assessment (MoCA), Hopkins Verbal Learning Test (HVLT), Judgment of Line Orientation (JLO), Letter Number Sequencing (LNS), Symbol Digit Modalities Test (SDMT), and semantic fluency (animals).

The researchers used MP-RAGE T1 sequences and a probabilistic atlas from the reference Montreal Neurological Institute single subject brain to apply voxel-based morphometry methods to determine Ch4 density. In addition, they used correlation coefficients and linear regression models to analyze relationships between Ch4 density and cognitive scores.

Ch4 Density Was Significantly Associated With Higher MoCA Scores

At baseline, 33.7% of healthy controls and 38.2% of patients with Parkinson’s disease were female. The mean age at neurologic testing was 59.5 among healthy controls and 61.0 in the Parkinson’s disease cohort. The median MoCA score was 28 for controls and patients with Parkinson’s disease at baseline. The mean Ch4 density was 87.9 in the control group and 86.4 in the Parkinson’s disease cohort.

At baseline, Ch4 density was significantly correlated with MoCA, JLO, LNS, and SDMT scores. In a linear regression model adjusted for age and sex, Ch4 density was significantly associated with higher MoCA scores in patients with Parkinson’s disease. In linear regression models adjusted for sex, increasing Ch4 density was associated with higher JLO, LNS, and SDMT scores. The researchers observed no associations between Ch4 density and JLO and semantic fluency in linear regression models adjusted for sex.

For the subset of participants with Parkinson’s disease with brain MRI and neuropsychologic testing available at four years, Ch4 density was significantly correlated with MoCA, JLO, LNS, and SDMT. In a linear regression model adjusted for age and sex, increasing Ch4 density was associated with higher MoCA scores in patients with Parkinson’s disease. In linear regression models adjusted for sex, increasing Ch4 density was associated with higher JLO, LNS, and SDMT scores.

MIAMI—Reduced cholinergic nucleus 4 (Ch4) density in Parkinson’s disease, as measured with MRI, is associated with deficits in attention, processing speed, and visuospatial function, according to research described at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. Ch4 density may serve as a surrogate imaging biomarker of cognition in early Parkinson’s disease, said the researchers.

Degeneration of the nucleus basalis of Meynert (NBM) contributes to dementia in Parkinson’s disease through a loss of cholinergic innervation to the neocortex. Cholinergic neurons of the NBM are in Ch4, a structure that can be measured with MRI techniques using cytoarchitectonic maps.

Evaluating Ch4 Density and Cognitive Performance

To determine whether Ch4 density, a proxy measure for NBM volume, is associated with cognitive test performance in de novo Parkinson’s disease, Cody S. Freeman, MD, a fellow at the University of Virginia School of Medicine in Charlottesville, and colleagues analyzed baseline brain MRIs and neuropsychologic test scores for 228 patients with Parkinson’s disease and 101 healthy controls from the Parkinson’s Progression Markers Initiative (PPMI). They also analyzed brain MRIs and neuropsychologic test scores at four years for a subset of 92 participants with Parkinson’s disease in the PPMI.

Neuropsychologic testing included the Montreal Cognitive Assessment (MoCA), Hopkins Verbal Learning Test (HVLT), Judgment of Line Orientation (JLO), Letter Number Sequencing (LNS), Symbol Digit Modalities Test (SDMT), and semantic fluency (animals).

The researchers used MP-RAGE T1 sequences and a probabilistic atlas from the reference Montreal Neurological Institute single subject brain to apply voxel-based morphometry methods to determine Ch4 density. In addition, they used correlation coefficients and linear regression models to analyze relationships between Ch4 density and cognitive scores.

Ch4 Density Was Significantly Associated With Higher MoCA Scores

At baseline, 33.7% of healthy controls and 38.2% of patients with Parkinson’s disease were female. The mean age at neurologic testing was 59.5 among healthy controls and 61.0 in the Parkinson’s disease cohort. The median MoCA score was 28 for controls and patients with Parkinson’s disease at baseline. The mean Ch4 density was 87.9 in the control group and 86.4 in the Parkinson’s disease cohort.

At baseline, Ch4 density was significantly correlated with MoCA, JLO, LNS, and SDMT scores. In a linear regression model adjusted for age and sex, Ch4 density was significantly associated with higher MoCA scores in patients with Parkinson’s disease. In linear regression models adjusted for sex, increasing Ch4 density was associated with higher JLO, LNS, and SDMT scores. The researchers observed no associations between Ch4 density and JLO and semantic fluency in linear regression models adjusted for sex.

For the subset of participants with Parkinson’s disease with brain MRI and neuropsychologic testing available at four years, Ch4 density was significantly correlated with MoCA, JLO, LNS, and SDMT. In a linear regression model adjusted for age and sex, increasing Ch4 density was associated with higher MoCA scores in patients with Parkinson’s disease. In linear regression models adjusted for sex, increasing Ch4 density was associated with higher JLO, LNS, and SDMT scores.

MIAMI—Reduced cholinergic nucleus 4 (Ch4) density in Parkinson’s disease, as measured with MRI, is associated with deficits in attention, processing speed, and visuospatial function, according to research described at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. Ch4 density may serve as a surrogate imaging biomarker of cognition in early Parkinson’s disease, said the researchers.

Degeneration of the nucleus basalis of Meynert (NBM) contributes to dementia in Parkinson’s disease through a loss of cholinergic innervation to the neocortex. Cholinergic neurons of the NBM are in Ch4, a structure that can be measured with MRI techniques using cytoarchitectonic maps.

Evaluating Ch4 Density and Cognitive Performance

To determine whether Ch4 density, a proxy measure for NBM volume, is associated with cognitive test performance in de novo Parkinson’s disease, Cody S. Freeman, MD, a fellow at the University of Virginia School of Medicine in Charlottesville, and colleagues analyzed baseline brain MRIs and neuropsychologic test scores for 228 patients with Parkinson’s disease and 101 healthy controls from the Parkinson’s Progression Markers Initiative (PPMI). They also analyzed brain MRIs and neuropsychologic test scores at four years for a subset of 92 participants with Parkinson’s disease in the PPMI.

Neuropsychologic testing included the Montreal Cognitive Assessment (MoCA), Hopkins Verbal Learning Test (HVLT), Judgment of Line Orientation (JLO), Letter Number Sequencing (LNS), Symbol Digit Modalities Test (SDMT), and semantic fluency (animals).

The researchers used MP-RAGE T1 sequences and a probabilistic atlas from the reference Montreal Neurological Institute single subject brain to apply voxel-based morphometry methods to determine Ch4 density. In addition, they used correlation coefficients and linear regression models to analyze relationships between Ch4 density and cognitive scores.

Ch4 Density Was Significantly Associated With Higher MoCA Scores

At baseline, 33.7% of healthy controls and 38.2% of patients with Parkinson’s disease were female. The mean age at neurologic testing was 59.5 among healthy controls and 61.0 in the Parkinson’s disease cohort. The median MoCA score was 28 for controls and patients with Parkinson’s disease at baseline. The mean Ch4 density was 87.9 in the control group and 86.4 in the Parkinson’s disease cohort.

At baseline, Ch4 density was significantly correlated with MoCA, JLO, LNS, and SDMT scores. In a linear regression model adjusted for age and sex, Ch4 density was significantly associated with higher MoCA scores in patients with Parkinson’s disease. In linear regression models adjusted for sex, increasing Ch4 density was associated with higher JLO, LNS, and SDMT scores. The researchers observed no associations between Ch4 density and JLO and semantic fluency in linear regression models adjusted for sex.

For the subset of participants with Parkinson’s disease with brain MRI and neuropsychologic testing available at four years, Ch4 density was significantly correlated with MoCA, JLO, LNS, and SDMT. In a linear regression model adjusted for age and sex, increasing Ch4 density was associated with higher MoCA scores in patients with Parkinson’s disease. In linear regression models adjusted for sex, increasing Ch4 density was associated with higher JLO, LNS, and SDMT scores.

MIAMI—Motor fluctuations in Parkinson’s disease can arise from more than one cause, and a clinician needs to consider a range of possibilities. Most commonly, motor fluctuations arise as a consequence of chronic levodopa therapy, though the progression of parkinsonism is a contributing factor, according to an overview presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. The pharmacokinetics of levodopa provide the basis for studying most clinical patterns of motor fluctuations, and new pharmacologic strategies are under development to improve upon existing treatment options.

“In recent years, there have been some exciting and novel directions of Parkinson’s disease therapeutics for motor fluctuations,” said Peter A. LeWitt, MD, Director of the Parkinson’s Disease and Movement Disorder Program at Henry Ford Hospital in West Bloomfield, Michigan.

A Need to Improve Levodopa Delivery

Beyond irregular effects of levodopa, motor fluctuations may be intrinsic to Parkinson’s disease, said Dr. LeWitt. One problem experienced by some patients is freezing of gait, immobility that is often situation-specific irrespective of medication dosing, he added. The sleep-benefit phenomenon, stress-exacerbated tremors and dyskinesias, and end-of-day medication unresponsiveness are further examples. “But for the most part, most motor fluctuations tend to be closely linked to the variable delivery of levodopa to the brain, where, after a short delay, it undergoes conversion to dopamine. This neurotransmitter does not have long to carry out its intended signaling because enzymes and re-uptake mechanisms quickly dispose of it. So, consistent delivery is the key for averting dose-by-dose motor fluctuations.”

During its 50 years of service to the Parkinson’s disease patient, levodopa has revolutionized the identity of this disorder. It has improved longevity, disability, and overall quality of life, and it inspired neurotherapeutic approaches for treating many other disorders. Levodopa use is so pervasive that today it is difficult to follow the untreated natural history of Parkinson’s disease. While levodopa is well known for the range of benefits it offers, less understood is why most patients gradually transition from a long-duration response to relatively brief dose-by-dose effects (on a time-scale roughly mirroring the clearance half-life of levodopa). Levodopa combined with a decarboxylase inhibitor is routinely administered in pill form, but, as Dr. LeWitt noted, “the human gastrointestinal tract is not well suited for optimal uptake of either drug.”

Because the short-duration response pattern is associated with benefits as brief as two to three hours per oral immediate-release dose, the focus for improving levodopa has been the use of extension therapies. Blocking the breakdown of peripheral levodopa metabolism (the mechanism for catechol-O-methyltransferase inhibition) or slowing the central metabolism of dopamine (by inhibiting monoamine oxidase-type B) join extended-release carbidopa-levodopa preparations as ways to improve upon the immediate-release product. “While these strategies do provide some level of effectiveness, the problems of irregular responsiveness and up to several hours of daily ‘off’ time haven’t been solved. ‘Off’ time still imposes a major burden on many patients living with Parkinson’s disease,” said Dr. LeWitt. Like delayed onset of effect and rapid wearing-off, levodopa-induced dyskinesias present another challenge for understanding their origin and optimal control. While new mechanisms of blocking dyskinesia are being sought, a simpler solution can be more continuous levodopa delivery so that drug concentration peaks causing involuntary movements are averted.

Future Therapies Undergoing Trials Today

Several new therapeutic approaches have been developed for dealing with the shortcomings of current therapies, especially levodopa. “The first of these options was a tube inserted through the stomach into the upper small intestine for continuous pumping of a carbidopa-levodopa microsuspension gel –quite effective but not an easy choice for most patients,” said Dr. LeWitt. Less cumbersome ways to extend levodopa effects have been the several sustained-release formulations now under development. One is a gastric-retention product, termed the “Accordion Pill,” which slowly leaches carbidopa and levodopa to enhance their pharmacokinetic absorption profile. Another treatment strategy for motor fluctuations that, like the Accordion Pill, is also in worldwide clinical trials, involves continuous subcutaneous infusion of solubilized levodopa and carbidopa. With the latter approach, the drug is administered by a small pump adjusted to optimized rate of delivery. Dr. LeWitt also described another novel way for administering levodopa for rapid entry into the bloodstream for treating “off” states. This involves an inhalation device for pulmonary uptake of a micro-particulate levodopa formulation. In a recently completed study, “off” states were reversed rapidly with this approach.

Subcutaneous apomorphine infusion has already been used for more than 30 years in treating motor fluctuations. However, just recently, a more complete story of what this adjunctive therapy offers was reported from a large-scale randomized clinical trial in Europe. A similar study is underway in the United States and might lead to availability of apomorphine infusion in the near future, said Dr. LeWitt. Another approach to motor fluctuations can be found in a drug for motor fluctuations that does not act on dopaminergic pathways. This medication is istradefylline, a selective inhibitor of adenosine A2a receptors (which are located in the same pathway targeted by deep brain stimulation). In Japan, istradefylline is marketed for reducing “off” time, and studies with this drug are planned for review in the US, said Dr. LeWitt.

For a nonpharmacologic approach to managing motor fluctuations, neurosurgical targeting of brain circuitry with deep brain electrical stimulation has had several decades of experience. Another direction of neurosurgical intervention is under investigation; this involves gene therapy to improve the efficacy of oral levodopa therapy. “Inserting into the putamen a gene for producing an increase of L-aromatic amino acid decarboxylase appears to offer a way for enhancing dopamine formation. The clinical investigation currently underway is testing whether producing this localized alteration of brain neurochemistry might succeed at attenuating motor fluctuations,” said Dr. LeWitt

“In talking to patients about their experiences with motor fluctuations, my advice is to think both about levodopa pharmacokinetics and how the patient uses levodopa (since schedule compliance, the interaction of meals, and drinking sufficient water with medications commonly contribute to these problems). Fortunately, new treatment options are on their way to help in fighting back against the limitations of levodopa therapy,” Dr. LeWitt concluded.

—Erica Tricarico

Suggested Reading

Anderson E, Nutt J. The long-duration response to levodopa: phenomenology, potential mechanisms and clinical implications. Parkinsonism Relat Disord. 2011;17:587-592.

Cilia R, Akpalu A, Sarfo FS, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain. 2014;137(10);2731-2742.

LeWitt PA. Levodopa therapy for Parkinson’s disease: Pharmacokinetics and pharmacodynamics. Mov Disord. 2015;30(1):64-72.

MIAMI—Motor fluctuations in Parkinson’s disease can arise from more than one cause, and a clinician needs to consider a range of possibilities. Most commonly, motor fluctuations arise as a consequence of chronic levodopa therapy, though the progression of parkinsonism is a contributing factor, according to an overview presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. The pharmacokinetics of levodopa provide the basis for studying most clinical patterns of motor fluctuations, and new pharmacologic strategies are under development to improve upon existing treatment options.

“In recent years, there have been some exciting and novel directions of Parkinson’s disease therapeutics for motor fluctuations,” said Peter A. LeWitt, MD, Director of the Parkinson’s Disease and Movement Disorder Program at Henry Ford Hospital in West Bloomfield, Michigan.

A Need to Improve Levodopa Delivery

Beyond irregular effects of levodopa, motor fluctuations may be intrinsic to Parkinson’s disease, said Dr. LeWitt. One problem experienced by some patients is freezing of gait, immobility that is often situation-specific irrespective of medication dosing, he added. The sleep-benefit phenomenon, stress-exacerbated tremors and dyskinesias, and end-of-day medication unresponsiveness are further examples. “But for the most part, most motor fluctuations tend to be closely linked to the variable delivery of levodopa to the brain, where, after a short delay, it undergoes conversion to dopamine. This neurotransmitter does not have long to carry out its intended signaling because enzymes and re-uptake mechanisms quickly dispose of it. So, consistent delivery is the key for averting dose-by-dose motor fluctuations.”

During its 50 years of service to the Parkinson’s disease patient, levodopa has revolutionized the identity of this disorder. It has improved longevity, disability, and overall quality of life, and it inspired neurotherapeutic approaches for treating many other disorders. Levodopa use is so pervasive that today it is difficult to follow the untreated natural history of Parkinson’s disease. While levodopa is well known for the range of benefits it offers, less understood is why most patients gradually transition from a long-duration response to relatively brief dose-by-dose effects (on a time-scale roughly mirroring the clearance half-life of levodopa). Levodopa combined with a decarboxylase inhibitor is routinely administered in pill form, but, as Dr. LeWitt noted, “the human gastrointestinal tract is not well suited for optimal uptake of either drug.”

Because the short-duration response pattern is associated with benefits as brief as two to three hours per oral immediate-release dose, the focus for improving levodopa has been the use of extension therapies. Blocking the breakdown of peripheral levodopa metabolism (the mechanism for catechol-O-methyltransferase inhibition) or slowing the central metabolism of dopamine (by inhibiting monoamine oxidase-type B) join extended-release carbidopa-levodopa preparations as ways to improve upon the immediate-release product. “While these strategies do provide some level of effectiveness, the problems of irregular responsiveness and up to several hours of daily ‘off’ time haven’t been solved. ‘Off’ time still imposes a major burden on many patients living with Parkinson’s disease,” said Dr. LeWitt. Like delayed onset of effect and rapid wearing-off, levodopa-induced dyskinesias present another challenge for understanding their origin and optimal control. While new mechanisms of blocking dyskinesia are being sought, a simpler solution can be more continuous levodopa delivery so that drug concentration peaks causing involuntary movements are averted.

Future Therapies Undergoing Trials Today

Several new therapeutic approaches have been developed for dealing with the shortcomings of current therapies, especially levodopa. “The first of these options was a tube inserted through the stomach into the upper small intestine for continuous pumping of a carbidopa-levodopa microsuspension gel –quite effective but not an easy choice for most patients,” said Dr. LeWitt. Less cumbersome ways to extend levodopa effects have been the several sustained-release formulations now under development. One is a gastric-retention product, termed the “Accordion Pill,” which slowly leaches carbidopa and levodopa to enhance their pharmacokinetic absorption profile. Another treatment strategy for motor fluctuations that, like the Accordion Pill, is also in worldwide clinical trials, involves continuous subcutaneous infusion of solubilized levodopa and carbidopa. With the latter approach, the drug is administered by a small pump adjusted to optimized rate of delivery. Dr. LeWitt also described another novel way for administering levodopa for rapid entry into the bloodstream for treating “off” states. This involves an inhalation device for pulmonary uptake of a micro-particulate levodopa formulation. In a recently completed study, “off” states were reversed rapidly with this approach.

Subcutaneous apomorphine infusion has already been used for more than 30 years in treating motor fluctuations. However, just recently, a more complete story of what this adjunctive therapy offers was reported from a large-scale randomized clinical trial in Europe. A similar study is underway in the United States and might lead to availability of apomorphine infusion in the near future, said Dr. LeWitt. Another approach to motor fluctuations can be found in a drug for motor fluctuations that does not act on dopaminergic pathways. This medication is istradefylline, a selective inhibitor of adenosine A2a receptors (which are located in the same pathway targeted by deep brain stimulation). In Japan, istradefylline is marketed for reducing “off” time, and studies with this drug are planned for review in the US, said Dr. LeWitt.

For a nonpharmacologic approach to managing motor fluctuations, neurosurgical targeting of brain circuitry with deep brain electrical stimulation has had several decades of experience. Another direction of neurosurgical intervention is under investigation; this involves gene therapy to improve the efficacy of oral levodopa therapy. “Inserting into the putamen a gene for producing an increase of L-aromatic amino acid decarboxylase appears to offer a way for enhancing dopamine formation. The clinical investigation currently underway is testing whether producing this localized alteration of brain neurochemistry might succeed at attenuating motor fluctuations,” said Dr. LeWitt

“In talking to patients about their experiences with motor fluctuations, my advice is to think both about levodopa pharmacokinetics and how the patient uses levodopa (since schedule compliance, the interaction of meals, and drinking sufficient water with medications commonly contribute to these problems). Fortunately, new treatment options are on their way to help in fighting back against the limitations of levodopa therapy,” Dr. LeWitt concluded.

—Erica Tricarico

Suggested Reading

Anderson E, Nutt J. The long-duration response to levodopa: phenomenology, potential mechanisms and clinical implications. Parkinsonism Relat Disord. 2011;17:587-592.

Cilia R, Akpalu A, Sarfo FS, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain. 2014;137(10);2731-2742.

LeWitt PA. Levodopa therapy for Parkinson’s disease: Pharmacokinetics and pharmacodynamics. Mov Disord. 2015;30(1):64-72.

MIAMI—Motor fluctuations in Parkinson’s disease can arise from more than one cause, and a clinician needs to consider a range of possibilities. Most commonly, motor fluctuations arise as a consequence of chronic levodopa therapy, though the progression of parkinsonism is a contributing factor, according to an overview presented at the Second Pan American Parkinson’s Disease and Movement Disorders Congress. The pharmacokinetics of levodopa provide the basis for studying most clinical patterns of motor fluctuations, and new pharmacologic strategies are under development to improve upon existing treatment options.

“In recent years, there have been some exciting and novel directions of Parkinson’s disease therapeutics for motor fluctuations,” said Peter A. LeWitt, MD, Director of the Parkinson’s Disease and Movement Disorder Program at Henry Ford Hospital in West Bloomfield, Michigan.

A Need to Improve Levodopa Delivery

Beyond irregular effects of levodopa, motor fluctuations may be intrinsic to Parkinson’s disease, said Dr. LeWitt. One problem experienced by some patients is freezing of gait, immobility that is often situation-specific irrespective of medication dosing, he added. The sleep-benefit phenomenon, stress-exacerbated tremors and dyskinesias, and end-of-day medication unresponsiveness are further examples. “But for the most part, most motor fluctuations tend to be closely linked to the variable delivery of levodopa to the brain, where, after a short delay, it undergoes conversion to dopamine. This neurotransmitter does not have long to carry out its intended signaling because enzymes and re-uptake mechanisms quickly dispose of it. So, consistent delivery is the key for averting dose-by-dose motor fluctuations.”

During its 50 years of service to the Parkinson’s disease patient, levodopa has revolutionized the identity of this disorder. It has improved longevity, disability, and overall quality of life, and it inspired neurotherapeutic approaches for treating many other disorders. Levodopa use is so pervasive that today it is difficult to follow the untreated natural history of Parkinson’s disease. While levodopa is well known for the range of benefits it offers, less understood is why most patients gradually transition from a long-duration response to relatively brief dose-by-dose effects (on a time-scale roughly mirroring the clearance half-life of levodopa). Levodopa combined with a decarboxylase inhibitor is routinely administered in pill form, but, as Dr. LeWitt noted, “the human gastrointestinal tract is not well suited for optimal uptake of either drug.”

Because the short-duration response pattern is associated with benefits as brief as two to three hours per oral immediate-release dose, the focus for improving levodopa has been the use of extension therapies. Blocking the breakdown of peripheral levodopa metabolism (the mechanism for catechol-O-methyltransferase inhibition) or slowing the central metabolism of dopamine (by inhibiting monoamine oxidase-type B) join extended-release carbidopa-levodopa preparations as ways to improve upon the immediate-release product. “While these strategies do provide some level of effectiveness, the problems of irregular responsiveness and up to several hours of daily ‘off’ time haven’t been solved. ‘Off’ time still imposes a major burden on many patients living with Parkinson’s disease,” said Dr. LeWitt. Like delayed onset of effect and rapid wearing-off, levodopa-induced dyskinesias present another challenge for understanding their origin and optimal control. While new mechanisms of blocking dyskinesia are being sought, a simpler solution can be more continuous levodopa delivery so that drug concentration peaks causing involuntary movements are averted.

Future Therapies Undergoing Trials Today

Several new therapeutic approaches have been developed for dealing with the shortcomings of current therapies, especially levodopa. “The first of these options was a tube inserted through the stomach into the upper small intestine for continuous pumping of a carbidopa-levodopa microsuspension gel –quite effective but not an easy choice for most patients,” said Dr. LeWitt. Less cumbersome ways to extend levodopa effects have been the several sustained-release formulations now under development. One is a gastric-retention product, termed the “Accordion Pill,” which slowly leaches carbidopa and levodopa to enhance their pharmacokinetic absorption profile. Another treatment strategy for motor fluctuations that, like the Accordion Pill, is also in worldwide clinical trials, involves continuous subcutaneous infusion of solubilized levodopa and carbidopa. With the latter approach, the drug is administered by a small pump adjusted to optimized rate of delivery. Dr. LeWitt also described another novel way for administering levodopa for rapid entry into the bloodstream for treating “off” states. This involves an inhalation device for pulmonary uptake of a micro-particulate levodopa formulation. In a recently completed study, “off” states were reversed rapidly with this approach.

Subcutaneous apomorphine infusion has already been used for more than 30 years in treating motor fluctuations. However, just recently, a more complete story of what this adjunctive therapy offers was reported from a large-scale randomized clinical trial in Europe. A similar study is underway in the United States and might lead to availability of apomorphine infusion in the near future, said Dr. LeWitt. Another approach to motor fluctuations can be found in a drug for motor fluctuations that does not act on dopaminergic pathways. This medication is istradefylline, a selective inhibitor of adenosine A2a receptors (which are located in the same pathway targeted by deep brain stimulation). In Japan, istradefylline is marketed for reducing “off” time, and studies with this drug are planned for review in the US, said Dr. LeWitt.

For a nonpharmacologic approach to managing motor fluctuations, neurosurgical targeting of brain circuitry with deep brain electrical stimulation has had several decades of experience. Another direction of neurosurgical intervention is under investigation; this involves gene therapy to improve the efficacy of oral levodopa therapy. “Inserting into the putamen a gene for producing an increase of L-aromatic amino acid decarboxylase appears to offer a way for enhancing dopamine formation. The clinical investigation currently underway is testing whether producing this localized alteration of brain neurochemistry might succeed at attenuating motor fluctuations,” said Dr. LeWitt

“In talking to patients about their experiences with motor fluctuations, my advice is to think both about levodopa pharmacokinetics and how the patient uses levodopa (since schedule compliance, the interaction of meals, and drinking sufficient water with medications commonly contribute to these problems). Fortunately, new treatment options are on their way to help in fighting back against the limitations of levodopa therapy,” Dr. LeWitt concluded.

—Erica Tricarico

Suggested Reading

Anderson E, Nutt J. The long-duration response to levodopa: phenomenology, potential mechanisms and clinical implications. Parkinsonism Relat Disord. 2011;17:587-592.

Cilia R, Akpalu A, Sarfo FS, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain. 2014;137(10);2731-2742.

LeWitt PA. Levodopa therapy for Parkinson’s disease: Pharmacokinetics and pharmacodynamics. Mov Disord. 2015;30(1):64-72.

CASE Endometriosis pain increases despite hormonal treatment

A 25-year-old woman (G0) with severe dysmenorrhea had a laparoscopy showing endometriosis in the cul-de-sac and a peritoneal window near the left uterosacral ligament. Biopsy of a cul-de-sac lesion showed endometriosis on histopathology. The patient was treated with a continuous low-dose estrogen-progestin contraceptive. Initially, the treatment helped relieve her pain symptoms. Over the next year, while on that treatment, her pain gradually increased in severity until it was disabling. At an office visit, the primary clinician renewed the estrogen-progestin contraceptive for another year, even though it was not relieving the patient’s pain. The patient sought a second opinion.

We are the experts in the management of pelvic pain caused by endometriosis

Women’s health clinicians are the specialists best trained to care for patients with severe pain caused by endometriosis. Low-dose continuous estrogen-progestin contraceptives are commonly prescribed as a first-line hormonal treatment for pain caused by endometriosis. My observation is that estrogen-progestincontraceptives are often effective when initially prescribed, but with continued use over years, pain often recurs. Estrogen is known to stimulate endometriosis disease activity. Progestins at high doses suppress endometriosis disease activity. However, endometriosis implants often manifest decreased responsiveness to progestins, permitting the estrogen in the combination contraceptive to exert its disease-stimulating effect.^1,2 I frequently see women with pelvic pain caused by endometriosis, who initially had a significant decrease in pain with continuous estrogen-progestin contraceptive treatment but who develop increasing pain with continued use of the medication. In this clinical situation, it is useful to consider stopping the estrogen-progestin therapy and to prescribe a hormone with a different mechanism of action (TABLE).

Progestin-only medications

Progestin-only medications are often effective in the treatment of pain caused by endometriosis. High-dose progestin-only medications suppress pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thereby suppressing ovarian synthesis of estrogen, resulting in low circulating levels of estrogen. This removes the estrogen stimulus that exacerbates endometriosis disease activity. High-dose progestins also directly suppress cellular activity in endometriosis implants. High-dose progestins often overcome the relative resistance of endometriosis lesions to progestin suppression of disease activity. Hence, high-dose progestin-only medications have two mechanisms of action: suppression of estrogen synthesis through pituitary suppression of LH and FSH, and direct inhibition of cellular activity in the endometriosis lesions. High-dose progestin-only treatments include:

• oral norethindrone acetate 5 mg daily
• oral medroxyprogesterone acetate (MPA) 20 to 40 mg daily
• subcutaneous, or depot MPA
• levonorgestrel-releasing intrauterine device (LNG-IUD).

In my practice, I frequently use oral norethindrone acetate 5 mg daily to treat pelvic pain caused by endometriosis. In one randomized trial, 90 women with pelvic pain and rectovaginal endometriosis were randomly assigned to treatment with norethindrone acetate 2.5 mg daily or an estrogen-progestin contraceptive. After 12 months of treatment, satisfaction with treatment was reported by 73% and 62% of the women in the norethindrone acetate and estrogen-progestin groups, respectively.³ The most common adverse effects reported by women taking norethindrone acetate were weight gain (27%) and decreased libido (9%).

Oral MPA at doses of 30 mg to 100 mg daily has been reported to be effective for the treatment of pelvic pain caused by endometriosis. MPA treatment can induce atrophy and pseudodecidualization in endometrium and endometriosis implants. In my practice I typically prescribe doses in the range of 20 mg to 40 mg daily. With oral MPA treatment, continued uterine bleeding may occur in up to 30% of women, somewhat limiting its efficacy.^4–7

Subcutaneous and depot MPA have been reported to be effective in the treatment of pelvic pain caused by endometriosis.^4,8 In some resource-limited countries, depot MPA may be the most available progestin for the treatment of pelvic pain caused by endometriosis.

The LNG-IUD, inserted after surgery for endometriosis, has been reported to result in decreased pelvic pain in studies with a modest number of participants.^9–11

GnRH analogue medications

Gonadotropin-releasing hormone (GnRH) analogues, including both GnRH agonists (nafarelin, leuprolide, and goserelin) and GnRH antagonists (elagolix) reduce pelvic pain caused by endometriosis by suppressing pituitary secretion of LH and FSH, thereby reducing ovarian synthesis of estradiol. In the absence of estradiol stimulation, cellular activity in endometriosis lesions decreases and pain symptoms improve. In my practice, I frequently use either nafarelin¹² or leuprolide acetate depot plus norethindrone add-back.¹³ I generally avoid the use of leuprolide depot monotherapy because in many women it causes severe vasomotor symptoms.

At standard doses, nafarelin therapy generally results in serum estradiol levels in the range of 20 to 30 pg/mL, a “sweet spot” associated with modest vasomotor symptoms and reduced cellular activity in endometriosis implants.^12,14 In many women who become amenorrheic on nafarelin two sprays daily, the dose can be reduced with maintenance of pain control and ovarian suppression.¹⁵ Leuprolide acetate depot monotherapy results in serum estradiol levels in the range of 5 to 10 pg/mL, causing severe vasomotor symptoms and reduction in cellular activity in endometriosis lesions. To reduce the adverse effects of leuprolide acetate depot monotherapy, I generally initiate concomitant add-back therapy with norethindrone acetate.¹³ A little recognized pharmacokinetic observation is that a very small amount of norethindrone acetate, generally less than 1%, is metabolized to ethinyl estradiol.¹⁶

The oral GnRH antagonist, elagolix, 150 mg daily for up to 24 months or 200 mg twice daily for 6 months, was approved by the US Food and Drug Administration (FDA) in July 2018. It is now available in pharmacies. Elagolix treatment results in significant reduction in pain caused by endometriosis, but only moderately bothersome vasomotor symptoms.^17,18 Elagolix likely will become a widely used medication because of the simplicity of oral administration, efficacy against endometriosis, and acceptable adverse-effect profile. A major disadvantage of the GnRH analogue-class of medications is that they are more expensive than the progestin medications mentioned above. Among the GnRH analogue class of medications, elagolix and goserelin are the least expensive.

Androgens

Estrogen stimulates cellular activity in endometriosis lesions. Androgen and high-dose progestins inhibit cellular activity in endometriosis lesions. Danazol, an attenuated androgen and a progestin is effectivein treating pelvic pain caused by endometriosis.^19,20 However, many women decline to use danazol because it is often associated with weight gain. As an androgen, danazol can permanently change a woman’s voice pitch and should not be used by professional singers or speech therapists.

Aromatase Inhibitors

Estrogen is a critically important stimulus of cell activity in endometriosis lesions. Aromatase inhibitors, which block the synthesis of estrogen, have been explored in the treatment of endometriosis that has proven to be resistant to other therapies. Although the combination of an aromatase inhibitor plus a high-dose progestin or GnRH analogue may be effective, more data are needed before widely using the aromatase inhibitors in clinical practice.²¹

Don’t get stuck in a rut

When treating pelvic pain caused by endometriosis, if the patient’s hormone regimen is not working, prescribe a medication from another class of hormones. In the case presented above, a woman with pelvic pain and surgically proven endometriosis reported inadequate control of her pain symptoms with a continuous estrogen-progestin medication. Her physician prescribed another year of the same estrogen-progestin medication. Instead of renewing the medication, the physician could have offered the patient a hormone medication from another drug class: 1) progestin only, 2) GnRH analogue, or 3) danazol. By using every available hormonal agent, physicians will improve the treatment of pelvic pain caused by endometriosis. Millions of women in our country have pelvic pain caused by endometriosis. They are counting on us, women’s health specialists, to effectively treat their disease.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

CASE Endometriosis pain increases despite hormonal treatment

A 25-year-old woman (G0) with severe dysmenorrhea had a laparoscopy showing endometriosis in the cul-de-sac and a peritoneal window near the left uterosacral ligament. Biopsy of a cul-de-sac lesion showed endometriosis on histopathology. The patient was treated with a continuous low-dose estrogen-progestin contraceptive. Initially, the treatment helped relieve her pain symptoms. Over the next year, while on that treatment, her pain gradually increased in severity until it was disabling. At an office visit, the primary clinician renewed the estrogen-progestin contraceptive for another year, even though it was not relieving the patient’s pain. The patient sought a second opinion.

We are the experts in the management of pelvic pain caused by endometriosis

Women’s health clinicians are the specialists best trained to care for patients with severe pain caused by endometriosis. Low-dose continuous estrogen-progestin contraceptives are commonly prescribed as a first-line hormonal treatment for pain caused by endometriosis. My observation is that estrogen-progestincontraceptives are often effective when initially prescribed, but with continued use over years, pain often recurs. Estrogen is known to stimulate endometriosis disease activity. Progestins at high doses suppress endometriosis disease activity. However, endometriosis implants often manifest decreased responsiveness to progestins, permitting the estrogen in the combination contraceptive to exert its disease-stimulating effect.^1,2 I frequently see women with pelvic pain caused by endometriosis, who initially had a significant decrease in pain with continuous estrogen-progestin contraceptive treatment but who develop increasing pain with continued use of the medication. In this clinical situation, it is useful to consider stopping the estrogen-progestin therapy and to prescribe a hormone with a different mechanism of action (TABLE).

Progestin-only medications

Progestin-only medications are often effective in the treatment of pain caused by endometriosis. High-dose progestin-only medications suppress pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thereby suppressing ovarian synthesis of estrogen, resulting in low circulating levels of estrogen. This removes the estrogen stimulus that exacerbates endometriosis disease activity. High-dose progestins also directly suppress cellular activity in endometriosis implants. High-dose progestins often overcome the relative resistance of endometriosis lesions to progestin suppression of disease activity. Hence, high-dose progestin-only medications have two mechanisms of action: suppression of estrogen synthesis through pituitary suppression of LH and FSH, and direct inhibition of cellular activity in the endometriosis lesions. High-dose progestin-only treatments include:

• oral norethindrone acetate 5 mg daily
• oral medroxyprogesterone acetate (MPA) 20 to 40 mg daily
• subcutaneous, or depot MPA
• levonorgestrel-releasing intrauterine device (LNG-IUD).

In my practice, I frequently use oral norethindrone acetate 5 mg daily to treat pelvic pain caused by endometriosis. In one randomized trial, 90 women with pelvic pain and rectovaginal endometriosis were randomly assigned to treatment with norethindrone acetate 2.5 mg daily or an estrogen-progestin contraceptive. After 12 months of treatment, satisfaction with treatment was reported by 73% and 62% of the women in the norethindrone acetate and estrogen-progestin groups, respectively.³ The most common adverse effects reported by women taking norethindrone acetate were weight gain (27%) and decreased libido (9%).

Oral MPA at doses of 30 mg to 100 mg daily has been reported to be effective for the treatment of pelvic pain caused by endometriosis. MPA treatment can induce atrophy and pseudodecidualization in endometrium and endometriosis implants. In my practice I typically prescribe doses in the range of 20 mg to 40 mg daily. With oral MPA treatment, continued uterine bleeding may occur in up to 30% of women, somewhat limiting its efficacy.^4–7

Subcutaneous and depot MPA have been reported to be effective in the treatment of pelvic pain caused by endometriosis.^4,8 In some resource-limited countries, depot MPA may be the most available progestin for the treatment of pelvic pain caused by endometriosis.

The LNG-IUD, inserted after surgery for endometriosis, has been reported to result in decreased pelvic pain in studies with a modest number of participants.^9–11

GnRH analogue medications

Gonadotropin-releasing hormone (GnRH) analogues, including both GnRH agonists (nafarelin, leuprolide, and goserelin) and GnRH antagonists (elagolix) reduce pelvic pain caused by endometriosis by suppressing pituitary secretion of LH and FSH, thereby reducing ovarian synthesis of estradiol. In the absence of estradiol stimulation, cellular activity in endometriosis lesions decreases and pain symptoms improve. In my practice, I frequently use either nafarelin¹² or leuprolide acetate depot plus norethindrone add-back.¹³ I generally avoid the use of leuprolide depot monotherapy because in many women it causes severe vasomotor symptoms.

At standard doses, nafarelin therapy generally results in serum estradiol levels in the range of 20 to 30 pg/mL, a “sweet spot” associated with modest vasomotor symptoms and reduced cellular activity in endometriosis implants.^12,14 In many women who become amenorrheic on nafarelin two sprays daily, the dose can be reduced with maintenance of pain control and ovarian suppression.¹⁵ Leuprolide acetate depot monotherapy results in serum estradiol levels in the range of 5 to 10 pg/mL, causing severe vasomotor symptoms and reduction in cellular activity in endometriosis lesions. To reduce the adverse effects of leuprolide acetate depot monotherapy, I generally initiate concomitant add-back therapy with norethindrone acetate.¹³ A little recognized pharmacokinetic observation is that a very small amount of norethindrone acetate, generally less than 1%, is metabolized to ethinyl estradiol.¹⁶

The oral GnRH antagonist, elagolix, 150 mg daily for up to 24 months or 200 mg twice daily for 6 months, was approved by the US Food and Drug Administration (FDA) in July 2018. It is now available in pharmacies. Elagolix treatment results in significant reduction in pain caused by endometriosis, but only moderately bothersome vasomotor symptoms.^17,18 Elagolix likely will become a widely used medication because of the simplicity of oral administration, efficacy against endometriosis, and acceptable adverse-effect profile. A major disadvantage of the GnRH analogue-class of medications is that they are more expensive than the progestin medications mentioned above. Among the GnRH analogue class of medications, elagolix and goserelin are the least expensive.

Androgens

Estrogen stimulates cellular activity in endometriosis lesions. Androgen and high-dose progestins inhibit cellular activity in endometriosis lesions. Danazol, an attenuated androgen and a progestin is effectivein treating pelvic pain caused by endometriosis.^19,20 However, many women decline to use danazol because it is often associated with weight gain. As an androgen, danazol can permanently change a woman’s voice pitch and should not be used by professional singers or speech therapists.

Aromatase Inhibitors

Estrogen is a critically important stimulus of cell activity in endometriosis lesions. Aromatase inhibitors, which block the synthesis of estrogen, have been explored in the treatment of endometriosis that has proven to be resistant to other therapies. Although the combination of an aromatase inhibitor plus a high-dose progestin or GnRH analogue may be effective, more data are needed before widely using the aromatase inhibitors in clinical practice.²¹

Don’t get stuck in a rut

When treating pelvic pain caused by endometriosis, if the patient’s hormone regimen is not working, prescribe a medication from another class of hormones. In the case presented above, a woman with pelvic pain and surgically proven endometriosis reported inadequate control of her pain symptoms with a continuous estrogen-progestin medication. Her physician prescribed another year of the same estrogen-progestin medication. Instead of renewing the medication, the physician could have offered the patient a hormone medication from another drug class: 1) progestin only, 2) GnRH analogue, or 3) danazol. By using every available hormonal agent, physicians will improve the treatment of pelvic pain caused by endometriosis. Millions of women in our country have pelvic pain caused by endometriosis. They are counting on us, women’s health specialists, to effectively treat their disease.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

CASE Endometriosis pain increases despite hormonal treatment

A 25-year-old woman (G0) with severe dysmenorrhea had a laparoscopy showing endometriosis in the cul-de-sac and a peritoneal window near the left uterosacral ligament. Biopsy of a cul-de-sac lesion showed endometriosis on histopathology. The patient was treated with a continuous low-dose estrogen-progestin contraceptive. Initially, the treatment helped relieve her pain symptoms. Over the next year, while on that treatment, her pain gradually increased in severity until it was disabling. At an office visit, the primary clinician renewed the estrogen-progestin contraceptive for another year, even though it was not relieving the patient’s pain. The patient sought a second opinion.

We are the experts in the management of pelvic pain caused by endometriosis

Women’s health clinicians are the specialists best trained to care for patients with severe pain caused by endometriosis. Low-dose continuous estrogen-progestin contraceptives are commonly prescribed as a first-line hormonal treatment for pain caused by endometriosis. My observation is that estrogen-progestincontraceptives are often effective when initially prescribed, but with continued use over years, pain often recurs. Estrogen is known to stimulate endometriosis disease activity. Progestins at high doses suppress endometriosis disease activity. However, endometriosis implants often manifest decreased responsiveness to progestins, permitting the estrogen in the combination contraceptive to exert its disease-stimulating effect.^1,2 I frequently see women with pelvic pain caused by endometriosis, who initially had a significant decrease in pain with continuous estrogen-progestin contraceptive treatment but who develop increasing pain with continued use of the medication. In this clinical situation, it is useful to consider stopping the estrogen-progestin therapy and to prescribe a hormone with a different mechanism of action (TABLE).

Progestin-only medications

Progestin-only medications are often effective in the treatment of pain caused by endometriosis. High-dose progestin-only medications suppress pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thereby suppressing ovarian synthesis of estrogen, resulting in low circulating levels of estrogen. This removes the estrogen stimulus that exacerbates endometriosis disease activity. High-dose progestins also directly suppress cellular activity in endometriosis implants. High-dose progestins often overcome the relative resistance of endometriosis lesions to progestin suppression of disease activity. Hence, high-dose progestin-only medications have two mechanisms of action: suppression of estrogen synthesis through pituitary suppression of LH and FSH, and direct inhibition of cellular activity in the endometriosis lesions. High-dose progestin-only treatments include:

• oral norethindrone acetate 5 mg daily
• oral medroxyprogesterone acetate (MPA) 20 to 40 mg daily
• subcutaneous, or depot MPA
• levonorgestrel-releasing intrauterine device (LNG-IUD).

In my practice, I frequently use oral norethindrone acetate 5 mg daily to treat pelvic pain caused by endometriosis. In one randomized trial, 90 women with pelvic pain and rectovaginal endometriosis were randomly assigned to treatment with norethindrone acetate 2.5 mg daily or an estrogen-progestin contraceptive. After 12 months of treatment, satisfaction with treatment was reported by 73% and 62% of the women in the norethindrone acetate and estrogen-progestin groups, respectively.³ The most common adverse effects reported by women taking norethindrone acetate were weight gain (27%) and decreased libido (9%).

Oral MPA at doses of 30 mg to 100 mg daily has been reported to be effective for the treatment of pelvic pain caused by endometriosis. MPA treatment can induce atrophy and pseudodecidualization in endometrium and endometriosis implants. In my practice I typically prescribe doses in the range of 20 mg to 40 mg daily. With oral MPA treatment, continued uterine bleeding may occur in up to 30% of women, somewhat limiting its efficacy.^4–7

Subcutaneous and depot MPA have been reported to be effective in the treatment of pelvic pain caused by endometriosis.^4,8 In some resource-limited countries, depot MPA may be the most available progestin for the treatment of pelvic pain caused by endometriosis.

The LNG-IUD, inserted after surgery for endometriosis, has been reported to result in decreased pelvic pain in studies with a modest number of participants.^9–11

GnRH analogue medications

Gonadotropin-releasing hormone (GnRH) analogues, including both GnRH agonists (nafarelin, leuprolide, and goserelin) and GnRH antagonists (elagolix) reduce pelvic pain caused by endometriosis by suppressing pituitary secretion of LH and FSH, thereby reducing ovarian synthesis of estradiol. In the absence of estradiol stimulation, cellular activity in endometriosis lesions decreases and pain symptoms improve. In my practice, I frequently use either nafarelin¹² or leuprolide acetate depot plus norethindrone add-back.¹³ I generally avoid the use of leuprolide depot monotherapy because in many women it causes severe vasomotor symptoms.

At standard doses, nafarelin therapy generally results in serum estradiol levels in the range of 20 to 30 pg/mL, a “sweet spot” associated with modest vasomotor symptoms and reduced cellular activity in endometriosis implants.^12,14 In many women who become amenorrheic on nafarelin two sprays daily, the dose can be reduced with maintenance of pain control and ovarian suppression.¹⁵ Leuprolide acetate depot monotherapy results in serum estradiol levels in the range of 5 to 10 pg/mL, causing severe vasomotor symptoms and reduction in cellular activity in endometriosis lesions. To reduce the adverse effects of leuprolide acetate depot monotherapy, I generally initiate concomitant add-back therapy with norethindrone acetate.¹³ A little recognized pharmacokinetic observation is that a very small amount of norethindrone acetate, generally less than 1%, is metabolized to ethinyl estradiol.¹⁶

The oral GnRH antagonist, elagolix, 150 mg daily for up to 24 months or 200 mg twice daily for 6 months, was approved by the US Food and Drug Administration (FDA) in July 2018. It is now available in pharmacies. Elagolix treatment results in significant reduction in pain caused by endometriosis, but only moderately bothersome vasomotor symptoms.^17,18 Elagolix likely will become a widely used medication because of the simplicity of oral administration, efficacy against endometriosis, and acceptable adverse-effect profile. A major disadvantage of the GnRH analogue-class of medications is that they are more expensive than the progestin medications mentioned above. Among the GnRH analogue class of medications, elagolix and goserelin are the least expensive.

Androgens

Estrogen stimulates cellular activity in endometriosis lesions. Androgen and high-dose progestins inhibit cellular activity in endometriosis lesions. Danazol, an attenuated androgen and a progestin is effectivein treating pelvic pain caused by endometriosis.^19,20 However, many women decline to use danazol because it is often associated with weight gain. As an androgen, danazol can permanently change a woman’s voice pitch and should not be used by professional singers or speech therapists.

Aromatase Inhibitors

Estrogen is a critically important stimulus of cell activity in endometriosis lesions. Aromatase inhibitors, which block the synthesis of estrogen, have been explored in the treatment of endometriosis that has proven to be resistant to other therapies. Although the combination of an aromatase inhibitor plus a high-dose progestin or GnRH analogue may be effective, more data are needed before widely using the aromatase inhibitors in clinical practice.²¹

Don’t get stuck in a rut

When treating pelvic pain caused by endometriosis, if the patient’s hormone regimen is not working, prescribe a medication from another class of hormones. In the case presented above, a woman with pelvic pain and surgically proven endometriosis reported inadequate control of her pain symptoms with a continuous estrogen-progestin medication. Her physician prescribed another year of the same estrogen-progestin medication. Instead of renewing the medication, the physician could have offered the patient a hormone medication from another drug class: 1) progestin only, 2) GnRH analogue, or 3) danazol. By using every available hormonal agent, physicians will improve the treatment of pelvic pain caused by endometriosis. Millions of women in our country have pelvic pain caused by endometriosis. They are counting on us, women’s health specialists, to effectively treat their disease.

Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.

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.