Literature Review

Race and socioeconomic status can hinder and delay patient access to migraine treatment and result in poorer outcomes, according to a study published in the April issue of Headache. People of African descent and Latinx ethnicity tend to fare worse than other people of color and their White counterparts.

“It should be shocking to neurologists and other clinicians who care for migraine patients how few are able to successfully traverse the barriers to achieve an accurate diagnosis and proper, evidence-based, acute and preventative treatment,” commented Peter McAllister, MD, medical director at the New England Institute for Neurology and Headache and chief medical officer for clinical research at Ki Clinical Research in Stamford, Conn. Dr. McAllister was not involved in this study.
 

Assessing barriers to care

Researchers designed the study with the primary objective of estimating the number of patients with migraines with unmet clinical needs and who were impacted by four preidentified barriers to care. To evaluate their objective, researchers conducted a longitudinal, Internet-based survey known as the Chronic Migraine Epidemiology and Outcomes (CaMEO) study. They collected data over 1 year examining a cohort of patients that mimicked the diverse demographics of the U.S. population. Researchers conducted longitudinal assessments every 3 months for 15 months, incorporating cross-sectional analyses that surveyed health care use, family burden, and comorbidities or endophenotypes.

Eligible enrollees were 18 years of age or older.

Researchers identified four barriers that hindered patient outcomes, and they served as the primary outcomes of the studies. They were:

• Health care provider consultations. Investigators used study participants’ responses to the following question during their interactions with their health care providers to help evaluate the quality of their consultation experience: “What type of doctor is currently managing your headaches?” Researchers included data from patients whose practitioners fit the description of those they deemed best suited to address ongoing headache challenges. These medical professionals included general practitioners, family physicians, internal medicine doctors, nurse practitioners, physician assistants, neurologists, pain specialists, headache specialists, and obstetrician-gynecologists.
• Diagnosis. Carefully evaluating patients’ responses to a series of questions helped researchers gauge the accuracy of diagnosis. Questions included: “Have you ever been diagnosed by a doctor or other health professional with any of the following types of headaches?” Respondents were also given a list of options that provided additional context around their headaches and were encouraged to select all appropriate responses. The list included a fictional response option of “citrene headache” to determine incorrect responses. For this study, researchers deemed it necessary to recognize a chronic migraine diagnosis to ensure that patients received appropriate treatment.
• Minimally appropriate pharmacologic treatment. Researchers used the following question to determine whether patients’ chronic migraine and episodic migraine were being managed with the least amount of pharmacological treatment necessary. “Which of these medications (if any) are you currently using (or typically keep on hand) to treat your headaches when you have them?” Researchers defined “minimally appropriate acute pharmacologic treatment” as the use of any prescription nonsteroidal anti-inflammatory drug (NSAID), triptan, ergotamine derivative, or isometheptene.
• Avoidance of medication overuse. The study authors pointed out the sometimes nebulous process of characterizing the appropriate use of preventative medication in patients with episodic migraines as “not straightforward” for some patients because not all patients require preventive treatment. Study participants were required to report having received any form of preventative therapy, defined as pharmacological therapies approved by guidelines and supported by data. Such therapies included various antiseizure medication, antidepressants (for example, doxepin, venlafaxine, duloxetine, amitriptyline, imipramine, nortriptyline, and desvenlafaxine), antihypertensives, and toxin injections. Treatments such as behavioral and neuromodulatory therapies were excluded from the list.

According to lead author Dawn C. Buse, PhD, of the department of neurology at Albert Einstein College of Medicine, New York, acute medication overuse provides an important modifiable target for intervention and recommends that clinicians use the opportunity to optimize migraine care by reducing the patients’ reliance on acute therapies. Taking such initiatives to decrease medication overuse is especially important in communities of color, who are more likely to overuse medications for migraines.

Patients with higher income levels were more likely to overcome each barrier. People of African, African American, or multiracial descent were more prone to overuse of medications to manage their migraines.

Of the 489,537 respondents invited to participate in the CaMEO study, 16,879 qualified for inclusion. Slightly more than half of the respondents (n = 9,184 [54.7%]) had a migraine-related disability (MIDAS) score of 6 or greater – an indicator of disability that is least mild in nature. Most patients who had episodic migraines or chronic migraines (86.2%) had some form of health insurance coverage (n = 9.184; 84.1%; P = .048). Of those patients who were insured, 7,930 patients experienced episodic migraine (86.3%) and the remainder had chronic migraine (n = 1,254; 13.7%). Higher-income patients were more likely to traverse barriers to care. While patients of African descent had higher consultation rates, they also had higher rates of acute medication overuse.

Patients with chronic migraine were more likely to be older than patients with episodic migraine (41.0 vs. 39.6 years; P = .0001) and female (83.0% vs. 79.0%; P = .001), and White (84.5% vs. 79.1%; P < .001). Similarly, patients with chronic migraine were more likely to have a higher mean body mass index (29.8 kg/m² vs. 28.9 kg/m²; P < .001) and lower rates of full- or part-time employment (56.8% vs. 67.1%; P < .001), and were less likely to have a 4-year degree (64.8 vs. 55.6; P < .001) and annual household incomes below $75,000 (72.6% vs. 64.6%; P < .001). Approximately three-quarters of the patients with episodic migraine (75.7%; 1655/2187) and one-third of patients with chronic migraine (32.8%; 168/512) received accurate diagnoses.

The data uncovered an association with acute medication overuse. Among current consulters who had received an accurate diagnosis and minimally adequate treatment, medication overuse rates were highest among those reporting two or more races (53%) and Blacks and African Americans (45%) and lowest among Whites (33%) and those categorized as “other” race (32%). Ethnic and cultural differences in headache literacy may contribute to differences in medication overuse. 
 

Strategies to improve outcomes

Both Dr. Buse and Dr. McAllister see the value advocacy and education offer in helping to improve outcomes in marginalized communities and other groups negatively impacted by various barriers.

“Patient advocacy and outreach are key here, especially in those traditionally underrepresented in the migraine space, such as men, people of color, blue-collar workers, etc.,” Dr. McAllister noted.

Dr. Buse emphasized the importance of education for patients and health care professionals alike. “A large percentage of people who meet criteria for migraine in the U.S. do not seek care or possibly even know that they have migraines,” Dr. Buse said. “This finding underscores the importance of public health education about migraine as well as well as providing migraine support, education, and resources to health care professionals on the front lines.”

Other strategies recommended by Dr, Buse to ease the impact of barriers include encouraging patient discussion, setting up time for follow-up appointments and education, referring patients for neurological and other specialty consults when warranted, reviewing essential lifestyle habits for migraine management, and creating personalized, mutually agreed-upon treatment plans.

Dr. Buse has received support and honoraria from AbbVie, Amgen, Avanir, Biohaven, Eli Lilly, and Promius.

Race and socioeconomic status can hinder and delay patient access to migraine treatment and result in poorer outcomes, according to a study published in the April issue of Headache. People of African descent and Latinx ethnicity tend to fare worse than other people of color and their White counterparts.

“It should be shocking to neurologists and other clinicians who care for migraine patients how few are able to successfully traverse the barriers to achieve an accurate diagnosis and proper, evidence-based, acute and preventative treatment,” commented Peter McAllister, MD, medical director at the New England Institute for Neurology and Headache and chief medical officer for clinical research at Ki Clinical Research in Stamford, Conn. Dr. McAllister was not involved in this study.
 

Assessing barriers to care

Researchers designed the study with the primary objective of estimating the number of patients with migraines with unmet clinical needs and who were impacted by four preidentified barriers to care. To evaluate their objective, researchers conducted a longitudinal, Internet-based survey known as the Chronic Migraine Epidemiology and Outcomes (CaMEO) study. They collected data over 1 year examining a cohort of patients that mimicked the diverse demographics of the U.S. population. Researchers conducted longitudinal assessments every 3 months for 15 months, incorporating cross-sectional analyses that surveyed health care use, family burden, and comorbidities or endophenotypes.

Eligible enrollees were 18 years of age or older.

Researchers identified four barriers that hindered patient outcomes, and they served as the primary outcomes of the studies. They were:

• Health care provider consultations. Investigators used study participants’ responses to the following question during their interactions with their health care providers to help evaluate the quality of their consultation experience: “What type of doctor is currently managing your headaches?” Researchers included data from patients whose practitioners fit the description of those they deemed best suited to address ongoing headache challenges. These medical professionals included general practitioners, family physicians, internal medicine doctors, nurse practitioners, physician assistants, neurologists, pain specialists, headache specialists, and obstetrician-gynecologists.
• Diagnosis. Carefully evaluating patients’ responses to a series of questions helped researchers gauge the accuracy of diagnosis. Questions included: “Have you ever been diagnosed by a doctor or other health professional with any of the following types of headaches?” Respondents were also given a list of options that provided additional context around their headaches and were encouraged to select all appropriate responses. The list included a fictional response option of “citrene headache” to determine incorrect responses. For this study, researchers deemed it necessary to recognize a chronic migraine diagnosis to ensure that patients received appropriate treatment.
• Minimally appropriate pharmacologic treatment. Researchers used the following question to determine whether patients’ chronic migraine and episodic migraine were being managed with the least amount of pharmacological treatment necessary. “Which of these medications (if any) are you currently using (or typically keep on hand) to treat your headaches when you have them?” Researchers defined “minimally appropriate acute pharmacologic treatment” as the use of any prescription nonsteroidal anti-inflammatory drug (NSAID), triptan, ergotamine derivative, or isometheptene.
• Avoidance of medication overuse. The study authors pointed out the sometimes nebulous process of characterizing the appropriate use of preventative medication in patients with episodic migraines as “not straightforward” for some patients because not all patients require preventive treatment. Study participants were required to report having received any form of preventative therapy, defined as pharmacological therapies approved by guidelines and supported by data. Such therapies included various antiseizure medication, antidepressants (for example, doxepin, venlafaxine, duloxetine, amitriptyline, imipramine, nortriptyline, and desvenlafaxine), antihypertensives, and toxin injections. Treatments such as behavioral and neuromodulatory therapies were excluded from the list.

According to lead author Dawn C. Buse, PhD, of the department of neurology at Albert Einstein College of Medicine, New York, acute medication overuse provides an important modifiable target for intervention and recommends that clinicians use the opportunity to optimize migraine care by reducing the patients’ reliance on acute therapies. Taking such initiatives to decrease medication overuse is especially important in communities of color, who are more likely to overuse medications for migraines.

Patients with higher income levels were more likely to overcome each barrier. People of African, African American, or multiracial descent were more prone to overuse of medications to manage their migraines.

Of the 489,537 respondents invited to participate in the CaMEO study, 16,879 qualified for inclusion. Slightly more than half of the respondents (n = 9,184 [54.7%]) had a migraine-related disability (MIDAS) score of 6 or greater – an indicator of disability that is least mild in nature. Most patients who had episodic migraines or chronic migraines (86.2%) had some form of health insurance coverage (n = 9.184; 84.1%; P = .048). Of those patients who were insured, 7,930 patients experienced episodic migraine (86.3%) and the remainder had chronic migraine (n = 1,254; 13.7%). Higher-income patients were more likely to traverse barriers to care. While patients of African descent had higher consultation rates, they also had higher rates of acute medication overuse.

Patients with chronic migraine were more likely to be older than patients with episodic migraine (41.0 vs. 39.6 years; P = .0001) and female (83.0% vs. 79.0%; P = .001), and White (84.5% vs. 79.1%; P < .001). Similarly, patients with chronic migraine were more likely to have a higher mean body mass index (29.8 kg/m² vs. 28.9 kg/m²; P < .001) and lower rates of full- or part-time employment (56.8% vs. 67.1%; P < .001), and were less likely to have a 4-year degree (64.8 vs. 55.6; P < .001) and annual household incomes below $75,000 (72.6% vs. 64.6%; P < .001). Approximately three-quarters of the patients with episodic migraine (75.7%; 1655/2187) and one-third of patients with chronic migraine (32.8%; 168/512) received accurate diagnoses.

The data uncovered an association with acute medication overuse. Among current consulters who had received an accurate diagnosis and minimally adequate treatment, medication overuse rates were highest among those reporting two or more races (53%) and Blacks and African Americans (45%) and lowest among Whites (33%) and those categorized as “other” race (32%). Ethnic and cultural differences in headache literacy may contribute to differences in medication overuse. 
 

Strategies to improve outcomes

Both Dr. Buse and Dr. McAllister see the value advocacy and education offer in helping to improve outcomes in marginalized communities and other groups negatively impacted by various barriers.

“Patient advocacy and outreach are key here, especially in those traditionally underrepresented in the migraine space, such as men, people of color, blue-collar workers, etc.,” Dr. McAllister noted.

Dr. Buse emphasized the importance of education for patients and health care professionals alike. “A large percentage of people who meet criteria for migraine in the U.S. do not seek care or possibly even know that they have migraines,” Dr. Buse said. “This finding underscores the importance of public health education about migraine as well as well as providing migraine support, education, and resources to health care professionals on the front lines.”

Other strategies recommended by Dr, Buse to ease the impact of barriers include encouraging patient discussion, setting up time for follow-up appointments and education, referring patients for neurological and other specialty consults when warranted, reviewing essential lifestyle habits for migraine management, and creating personalized, mutually agreed-upon treatment plans.

Dr. Buse has received support and honoraria from AbbVie, Amgen, Avanir, Biohaven, Eli Lilly, and Promius.

Race and socioeconomic status can hinder and delay patient access to migraine treatment and result in poorer outcomes, according to a study published in the April issue of Headache. People of African descent and Latinx ethnicity tend to fare worse than other people of color and their White counterparts.

“It should be shocking to neurologists and other clinicians who care for migraine patients how few are able to successfully traverse the barriers to achieve an accurate diagnosis and proper, evidence-based, acute and preventative treatment,” commented Peter McAllister, MD, medical director at the New England Institute for Neurology and Headache and chief medical officer for clinical research at Ki Clinical Research in Stamford, Conn. Dr. McAllister was not involved in this study.
 

Assessing barriers to care

Researchers designed the study with the primary objective of estimating the number of patients with migraines with unmet clinical needs and who were impacted by four preidentified barriers to care. To evaluate their objective, researchers conducted a longitudinal, Internet-based survey known as the Chronic Migraine Epidemiology and Outcomes (CaMEO) study. They collected data over 1 year examining a cohort of patients that mimicked the diverse demographics of the U.S. population. Researchers conducted longitudinal assessments every 3 months for 15 months, incorporating cross-sectional analyses that surveyed health care use, family burden, and comorbidities or endophenotypes.

Eligible enrollees were 18 years of age or older.

Researchers identified four barriers that hindered patient outcomes, and they served as the primary outcomes of the studies. They were:

• Health care provider consultations. Investigators used study participants’ responses to the following question during their interactions with their health care providers to help evaluate the quality of their consultation experience: “What type of doctor is currently managing your headaches?” Researchers included data from patients whose practitioners fit the description of those they deemed best suited to address ongoing headache challenges. These medical professionals included general practitioners, family physicians, internal medicine doctors, nurse practitioners, physician assistants, neurologists, pain specialists, headache specialists, and obstetrician-gynecologists.
• Diagnosis. Carefully evaluating patients’ responses to a series of questions helped researchers gauge the accuracy of diagnosis. Questions included: “Have you ever been diagnosed by a doctor or other health professional with any of the following types of headaches?” Respondents were also given a list of options that provided additional context around their headaches and were encouraged to select all appropriate responses. The list included a fictional response option of “citrene headache” to determine incorrect responses. For this study, researchers deemed it necessary to recognize a chronic migraine diagnosis to ensure that patients received appropriate treatment.
• Minimally appropriate pharmacologic treatment. Researchers used the following question to determine whether patients’ chronic migraine and episodic migraine were being managed with the least amount of pharmacological treatment necessary. “Which of these medications (if any) are you currently using (or typically keep on hand) to treat your headaches when you have them?” Researchers defined “minimally appropriate acute pharmacologic treatment” as the use of any prescription nonsteroidal anti-inflammatory drug (NSAID), triptan, ergotamine derivative, or isometheptene.
• Avoidance of medication overuse. The study authors pointed out the sometimes nebulous process of characterizing the appropriate use of preventative medication in patients with episodic migraines as “not straightforward” for some patients because not all patients require preventive treatment. Study participants were required to report having received any form of preventative therapy, defined as pharmacological therapies approved by guidelines and supported by data. Such therapies included various antiseizure medication, antidepressants (for example, doxepin, venlafaxine, duloxetine, amitriptyline, imipramine, nortriptyline, and desvenlafaxine), antihypertensives, and toxin injections. Treatments such as behavioral and neuromodulatory therapies were excluded from the list.

According to lead author Dawn C. Buse, PhD, of the department of neurology at Albert Einstein College of Medicine, New York, acute medication overuse provides an important modifiable target for intervention and recommends that clinicians use the opportunity to optimize migraine care by reducing the patients’ reliance on acute therapies. Taking such initiatives to decrease medication overuse is especially important in communities of color, who are more likely to overuse medications for migraines.

Patients with higher income levels were more likely to overcome each barrier. People of African, African American, or multiracial descent were more prone to overuse of medications to manage their migraines.

Of the 489,537 respondents invited to participate in the CaMEO study, 16,879 qualified for inclusion. Slightly more than half of the respondents (n = 9,184 [54.7%]) had a migraine-related disability (MIDAS) score of 6 or greater – an indicator of disability that is least mild in nature. Most patients who had episodic migraines or chronic migraines (86.2%) had some form of health insurance coverage (n = 9.184; 84.1%; P = .048). Of those patients who were insured, 7,930 patients experienced episodic migraine (86.3%) and the remainder had chronic migraine (n = 1,254; 13.7%). Higher-income patients were more likely to traverse barriers to care. While patients of African descent had higher consultation rates, they also had higher rates of acute medication overuse.

Patients with chronic migraine were more likely to be older than patients with episodic migraine (41.0 vs. 39.6 years; P = .0001) and female (83.0% vs. 79.0%; P = .001), and White (84.5% vs. 79.1%; P < .001). Similarly, patients with chronic migraine were more likely to have a higher mean body mass index (29.8 kg/m² vs. 28.9 kg/m²; P < .001) and lower rates of full- or part-time employment (56.8% vs. 67.1%; P < .001), and were less likely to have a 4-year degree (64.8 vs. 55.6; P < .001) and annual household incomes below $75,000 (72.6% vs. 64.6%; P < .001). Approximately three-quarters of the patients with episodic migraine (75.7%; 1655/2187) and one-third of patients with chronic migraine (32.8%; 168/512) received accurate diagnoses.

The data uncovered an association with acute medication overuse. Among current consulters who had received an accurate diagnosis and minimally adequate treatment, medication overuse rates were highest among those reporting two or more races (53%) and Blacks and African Americans (45%) and lowest among Whites (33%) and those categorized as “other” race (32%). Ethnic and cultural differences in headache literacy may contribute to differences in medication overuse. 
 

Strategies to improve outcomes

Both Dr. Buse and Dr. McAllister see the value advocacy and education offer in helping to improve outcomes in marginalized communities and other groups negatively impacted by various barriers.

“Patient advocacy and outreach are key here, especially in those traditionally underrepresented in the migraine space, such as men, people of color, blue-collar workers, etc.,” Dr. McAllister noted.

Dr. Buse emphasized the importance of education for patients and health care professionals alike. “A large percentage of people who meet criteria for migraine in the U.S. do not seek care or possibly even know that they have migraines,” Dr. Buse said. “This finding underscores the importance of public health education about migraine as well as well as providing migraine support, education, and resources to health care professionals on the front lines.”

Other strategies recommended by Dr, Buse to ease the impact of barriers include encouraging patient discussion, setting up time for follow-up appointments and education, referring patients for neurological and other specialty consults when warranted, reviewing essential lifestyle habits for migraine management, and creating personalized, mutually agreed-upon treatment plans.

Dr. Buse has received support and honoraria from AbbVie, Amgen, Avanir, Biohaven, Eli Lilly, and Promius.

Noninvasive brain stimulation has the potential to boost a patient’s placebo experience or blunt the nocebo experience, according to results of a new study published in the Proceedings of the National Academy of Sciences (PNAS).

“Placebo and nocebo effects are a critical component of clinical care and efficacy studies,” said senior author Jian Kong, MD, associate professor in the department of psychiatry at Massachusetts General Hospital, Charlestown campus. “Harnessing these effects in clinical practice and research could facilitate the development of new pain management methods,” he said. “Healing may involve multiple components: the self-healing properties of the body; the nonspecific effects of treatment (i.e., placebo effect); and the specific effect of a physical or pharmacologic intervention. Therefore, enhancing the placebo effect may ultimately boost the overall therapeutic effect of existing treatment,” he explained, emphasizing that the results are preliminary and should be interpreted with caution.

The authors noted that reducing nocebo effects could also be a major benefit “since patients discontinue prescribed medications, make unnecessary medical visits, and take additional medications to counteract adverse effects that are actually nocebo effects.”


 

Testing the hypothesis

The randomized, double-blind, sham-controlled study used transcranial direct current stimulation (tDCS), which delivers an electrical current to the brain via scalp electrodes. The aim was to see if stimulating the dorsolateral prefrontal cortex with tDCS could alter the brain’s perception of placebo and nocebo experiences.

The study included 81 participants (37 females, mean age: 27.4 years), who were randomized into one of three tDCS groups (anodal, cathodal, or sham).

All participants were first conditioned to believe that an inert cream was either lidocaine or capsaicin and that this cream could either dull the impact of a painful heat stimulus (placebo analgesia) or exacerbate it (nocebo hyperalgesia). Participants were then placed into a functional MRI scanner where tDCS was initiated. Painful stimuli were then applied to spots on their forearms where they believed they had either lidocaine, capsaicin, or a neutral control cream and they rated the pain using the Gracely Sensory Scale.

Placebo analgesia was defined as the difference between perceived pain intensity where participants believed they had lidocaine cream compared with where they believed they had control cream. Nocebo hyperalgesia was defined as the difference between perceived pain intensity where they believed they had capsaicin cream compared with where they believed they had control cream.

The researchers found that compared with sham tDCS, cathodal tDCS showed significant effects in increasing placebo analgesia and brain responses in the ventromedial prefrontal cortex (vmPFC), while anodal tDCS showed significant effects in inhibiting nocebo hyperalgesia and brain responses in the insula.

“The potential to enhance salubrious placebo effects and/or diminish treatment-interfering nocebo effects may have clinical significance,” the authors noted. “For example, clinical studies have suggested that expectancy is positively associated with chronic pain improvement, and using conditioning-like expectancy manipulation, we have shown that significantly boosting expectancy can improve treatment outcome.”
 

Proof of concept

Asked to comment on the study, Brian E. McGeeney, MD, of the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital in Boston, said “the findings are a proof of concept that it is possible to use noninvasive brain stimulation to modulate placebo and nocebo pain effects.”

Although the findings do not have immediate clinical application, they are “exciting” and “break new ground in expectancy research,” he said.

“It is important to recognize that the researchers are trying to utilize a purported expectancy mechanism rather than attempting to alter placebo/nocebo by verbal and other cues. It remains to be seen whether the manipulation of brief experimental pain like this can translate into altered chronic pain over time, the main clinical goal. Current tDCS therapy for various reasons is necessarily brief and one can ask whether there are meaningful changes from brief stimulation. Such results can foster speculation as to whether direct strategic placement of intracranial stimulation leads could result in more longstanding similar benefits.”

Dr. Kong holds equity in a startup company (MNT) and a pending patent to develop new peripheral neuromodulation tools, but declares no conflict of interest. All other authors declare no conflict of interest.

Noninvasive brain stimulation has the potential to boost a patient’s placebo experience or blunt the nocebo experience, according to results of a new study published in the Proceedings of the National Academy of Sciences (PNAS).

“Placebo and nocebo effects are a critical component of clinical care and efficacy studies,” said senior author Jian Kong, MD, associate professor in the department of psychiatry at Massachusetts General Hospital, Charlestown campus. “Harnessing these effects in clinical practice and research could facilitate the development of new pain management methods,” he said. “Healing may involve multiple components: the self-healing properties of the body; the nonspecific effects of treatment (i.e., placebo effect); and the specific effect of a physical or pharmacologic intervention. Therefore, enhancing the placebo effect may ultimately boost the overall therapeutic effect of existing treatment,” he explained, emphasizing that the results are preliminary and should be interpreted with caution.

The authors noted that reducing nocebo effects could also be a major benefit “since patients discontinue prescribed medications, make unnecessary medical visits, and take additional medications to counteract adverse effects that are actually nocebo effects.”


 

Testing the hypothesis

The randomized, double-blind, sham-controlled study used transcranial direct current stimulation (tDCS), which delivers an electrical current to the brain via scalp electrodes. The aim was to see if stimulating the dorsolateral prefrontal cortex with tDCS could alter the brain’s perception of placebo and nocebo experiences.

The study included 81 participants (37 females, mean age: 27.4 years), who were randomized into one of three tDCS groups (anodal, cathodal, or sham).

All participants were first conditioned to believe that an inert cream was either lidocaine or capsaicin and that this cream could either dull the impact of a painful heat stimulus (placebo analgesia) or exacerbate it (nocebo hyperalgesia). Participants were then placed into a functional MRI scanner where tDCS was initiated. Painful stimuli were then applied to spots on their forearms where they believed they had either lidocaine, capsaicin, or a neutral control cream and they rated the pain using the Gracely Sensory Scale.

Placebo analgesia was defined as the difference between perceived pain intensity where participants believed they had lidocaine cream compared with where they believed they had control cream. Nocebo hyperalgesia was defined as the difference between perceived pain intensity where they believed they had capsaicin cream compared with where they believed they had control cream.

The researchers found that compared with sham tDCS, cathodal tDCS showed significant effects in increasing placebo analgesia and brain responses in the ventromedial prefrontal cortex (vmPFC), while anodal tDCS showed significant effects in inhibiting nocebo hyperalgesia and brain responses in the insula.

“The potential to enhance salubrious placebo effects and/or diminish treatment-interfering nocebo effects may have clinical significance,” the authors noted. “For example, clinical studies have suggested that expectancy is positively associated with chronic pain improvement, and using conditioning-like expectancy manipulation, we have shown that significantly boosting expectancy can improve treatment outcome.”
 

Proof of concept

Asked to comment on the study, Brian E. McGeeney, MD, of the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital in Boston, said “the findings are a proof of concept that it is possible to use noninvasive brain stimulation to modulate placebo and nocebo pain effects.”

Although the findings do not have immediate clinical application, they are “exciting” and “break new ground in expectancy research,” he said.

“It is important to recognize that the researchers are trying to utilize a purported expectancy mechanism rather than attempting to alter placebo/nocebo by verbal and other cues. It remains to be seen whether the manipulation of brief experimental pain like this can translate into altered chronic pain over time, the main clinical goal. Current tDCS therapy for various reasons is necessarily brief and one can ask whether there are meaningful changes from brief stimulation. Such results can foster speculation as to whether direct strategic placement of intracranial stimulation leads could result in more longstanding similar benefits.”

Dr. Kong holds equity in a startup company (MNT) and a pending patent to develop new peripheral neuromodulation tools, but declares no conflict of interest. All other authors declare no conflict of interest.

Noninvasive brain stimulation has the potential to boost a patient’s placebo experience or blunt the nocebo experience, according to results of a new study published in the Proceedings of the National Academy of Sciences (PNAS).

“Placebo and nocebo effects are a critical component of clinical care and efficacy studies,” said senior author Jian Kong, MD, associate professor in the department of psychiatry at Massachusetts General Hospital, Charlestown campus. “Harnessing these effects in clinical practice and research could facilitate the development of new pain management methods,” he said. “Healing may involve multiple components: the self-healing properties of the body; the nonspecific effects of treatment (i.e., placebo effect); and the specific effect of a physical or pharmacologic intervention. Therefore, enhancing the placebo effect may ultimately boost the overall therapeutic effect of existing treatment,” he explained, emphasizing that the results are preliminary and should be interpreted with caution.

The authors noted that reducing nocebo effects could also be a major benefit “since patients discontinue prescribed medications, make unnecessary medical visits, and take additional medications to counteract adverse effects that are actually nocebo effects.”


 

Testing the hypothesis

The randomized, double-blind, sham-controlled study used transcranial direct current stimulation (tDCS), which delivers an electrical current to the brain via scalp electrodes. The aim was to see if stimulating the dorsolateral prefrontal cortex with tDCS could alter the brain’s perception of placebo and nocebo experiences.

The study included 81 participants (37 females, mean age: 27.4 years), who were randomized into one of three tDCS groups (anodal, cathodal, or sham).

All participants were first conditioned to believe that an inert cream was either lidocaine or capsaicin and that this cream could either dull the impact of a painful heat stimulus (placebo analgesia) or exacerbate it (nocebo hyperalgesia). Participants were then placed into a functional MRI scanner where tDCS was initiated. Painful stimuli were then applied to spots on their forearms where they believed they had either lidocaine, capsaicin, or a neutral control cream and they rated the pain using the Gracely Sensory Scale.

Placebo analgesia was defined as the difference between perceived pain intensity where participants believed they had lidocaine cream compared with where they believed they had control cream. Nocebo hyperalgesia was defined as the difference between perceived pain intensity where they believed they had capsaicin cream compared with where they believed they had control cream.

The researchers found that compared with sham tDCS, cathodal tDCS showed significant effects in increasing placebo analgesia and brain responses in the ventromedial prefrontal cortex (vmPFC), while anodal tDCS showed significant effects in inhibiting nocebo hyperalgesia and brain responses in the insula.

“The potential to enhance salubrious placebo effects and/or diminish treatment-interfering nocebo effects may have clinical significance,” the authors noted. “For example, clinical studies have suggested that expectancy is positively associated with chronic pain improvement, and using conditioning-like expectancy manipulation, we have shown that significantly boosting expectancy can improve treatment outcome.”
 

Proof of concept

Asked to comment on the study, Brian E. McGeeney, MD, of the John R. Graham Headache Center at Brigham and Women’s Faulkner Hospital in Boston, said “the findings are a proof of concept that it is possible to use noninvasive brain stimulation to modulate placebo and nocebo pain effects.”

Although the findings do not have immediate clinical application, they are “exciting” and “break new ground in expectancy research,” he said.

“It is important to recognize that the researchers are trying to utilize a purported expectancy mechanism rather than attempting to alter placebo/nocebo by verbal and other cues. It remains to be seen whether the manipulation of brief experimental pain like this can translate into altered chronic pain over time, the main clinical goal. Current tDCS therapy for various reasons is necessarily brief and one can ask whether there are meaningful changes from brief stimulation. Such results can foster speculation as to whether direct strategic placement of intracranial stimulation leads could result in more longstanding similar benefits.”

Dr. Kong holds equity in a startup company (MNT) and a pending patent to develop new peripheral neuromodulation tools, but declares no conflict of interest. All other authors declare no conflict of interest.

Motor and cognitive aspects of Parkinson’s disease are associated with discrete neural microcircuits within the brain’s basal ganglia, according to a new study using a mouse model of disease. 

Parkinson’s disease is characterized by a range of cognitive and motor symptoms, which appear at different disease stages. While recent research has pointed to specific neuronal subpopulations, or microcircuits, operating in the basal ganglia, researchers lacked a clear understanding of how they might correspond with specific symptom domains. 

In a study published online March 15 in Nature Neuroscience, lead author Varoth Lilascharoen, PhD, of the University of California, San Diego, and colleagues reported that two different neuronal subpopulations within the external globus pallidus, an important nucleus within the basal ganglia, are associated, respectively, with movement and with reversal learning (having to adapt to a reward pattern that is the reverse of a previous pattern). This is the first time, the investigators said, that the contributions of specific microcircuits in the basal ganglia have been linked to different behaviors.

Using electrophysiology, viral tracing, and other approaches, Dr. Lilascharoen and colleagues demonstrated that two microcircuits or populations of parvalbumin-expressing neurons could be manipulated to exacerbate or alleviate the motor or cognitive deficits in the dopamine-depleted mice. 

One of these microcircuits, made up of substantia nigra pars reticulata-projecting GPe-PV neurons, could be manipulated in ways that promoted or inhibited the mice’s movement. The other, which comprises parafascicular thalamus-projecting GPe-PV neurons, could be manipulated to affect reversal learning, the researchers found. Activation or inhibition of either circuit was not seen affecting function in the other. 

The results shed light on the functional organization of the different basal ganglia nuclei at the circuit level, and suggest, the authors argued, that differences in how different neuronal subpopulations adapt to dopamine loss could explain some of the patterns of progression seen in Parkinson’s disease.

The findings “establish the differential contributions from two distinct GPe-PV microcircuits in specific Parkinsonian-like behaviors linked to early and late stages of the disease,” Dr. Lilascharoen and colleagues wrote in their analysis. “[F]urther elucidation of the detailed connectivity of GPe subpopulations to their downstream targets … is needed to fully define the function of each microcircuit and design better therapeutic strategies for the various behavioral impairments of Parkinson’s disease.” 

Commenting on the research, Stefan Lang, MD, PhD, of the University of Calgary in Alberta said, “While Parkinson’s disease is often referred to as a movement disorder, it is well known that nonmotor symptoms, including cognitive and behavioral impairment, are common and debilitating. Impairment of basal ganglia function is known to contribute to these different symptom domains, though the specific circuits have never been elucidated. [Dr.] Lilascharoen et al. tease apart specific basal ganglia circuits associated with motor and behavioral symptoms, thereby providing evidence that distinct microcircuits might contribute to unique behaviours. As technological advances in neuromodulatory therapies continue to improve the spatial and temporal resolution of stimulation, future treatments may allow for specific targeting of behavioral impairment symptoms in Parkinson’s disease.”

Dr. Lilascharoen and Dr. Lang did not report outside funding or conflicts of interest.

Motor and cognitive aspects of Parkinson’s disease are associated with discrete neural microcircuits within the brain’s basal ganglia, according to a new study using a mouse model of disease. 

Parkinson’s disease is characterized by a range of cognitive and motor symptoms, which appear at different disease stages. While recent research has pointed to specific neuronal subpopulations, or microcircuits, operating in the basal ganglia, researchers lacked a clear understanding of how they might correspond with specific symptom domains. 

In a study published online March 15 in Nature Neuroscience, lead author Varoth Lilascharoen, PhD, of the University of California, San Diego, and colleagues reported that two different neuronal subpopulations within the external globus pallidus, an important nucleus within the basal ganglia, are associated, respectively, with movement and with reversal learning (having to adapt to a reward pattern that is the reverse of a previous pattern). This is the first time, the investigators said, that the contributions of specific microcircuits in the basal ganglia have been linked to different behaviors.

Using electrophysiology, viral tracing, and other approaches, Dr. Lilascharoen and colleagues demonstrated that two microcircuits or populations of parvalbumin-expressing neurons could be manipulated to exacerbate or alleviate the motor or cognitive deficits in the dopamine-depleted mice. 

One of these microcircuits, made up of substantia nigra pars reticulata-projecting GPe-PV neurons, could be manipulated in ways that promoted or inhibited the mice’s movement. The other, which comprises parafascicular thalamus-projecting GPe-PV neurons, could be manipulated to affect reversal learning, the researchers found. Activation or inhibition of either circuit was not seen affecting function in the other. 

The results shed light on the functional organization of the different basal ganglia nuclei at the circuit level, and suggest, the authors argued, that differences in how different neuronal subpopulations adapt to dopamine loss could explain some of the patterns of progression seen in Parkinson’s disease.

The findings “establish the differential contributions from two distinct GPe-PV microcircuits in specific Parkinsonian-like behaviors linked to early and late stages of the disease,” Dr. Lilascharoen and colleagues wrote in their analysis. “[F]urther elucidation of the detailed connectivity of GPe subpopulations to their downstream targets … is needed to fully define the function of each microcircuit and design better therapeutic strategies for the various behavioral impairments of Parkinson’s disease.” 

Commenting on the research, Stefan Lang, MD, PhD, of the University of Calgary in Alberta said, “While Parkinson’s disease is often referred to as a movement disorder, it is well known that nonmotor symptoms, including cognitive and behavioral impairment, are common and debilitating. Impairment of basal ganglia function is known to contribute to these different symptom domains, though the specific circuits have never been elucidated. [Dr.] Lilascharoen et al. tease apart specific basal ganglia circuits associated with motor and behavioral symptoms, thereby providing evidence that distinct microcircuits might contribute to unique behaviours. As technological advances in neuromodulatory therapies continue to improve the spatial and temporal resolution of stimulation, future treatments may allow for specific targeting of behavioral impairment symptoms in Parkinson’s disease.”

Dr. Lilascharoen and Dr. Lang did not report outside funding or conflicts of interest.

Motor and cognitive aspects of Parkinson’s disease are associated with discrete neural microcircuits within the brain’s basal ganglia, according to a new study using a mouse model of disease. 

Parkinson’s disease is characterized by a range of cognitive and motor symptoms, which appear at different disease stages. While recent research has pointed to specific neuronal subpopulations, or microcircuits, operating in the basal ganglia, researchers lacked a clear understanding of how they might correspond with specific symptom domains. 

In a study published online March 15 in Nature Neuroscience, lead author Varoth Lilascharoen, PhD, of the University of California, San Diego, and colleagues reported that two different neuronal subpopulations within the external globus pallidus, an important nucleus within the basal ganglia, are associated, respectively, with movement and with reversal learning (having to adapt to a reward pattern that is the reverse of a previous pattern). This is the first time, the investigators said, that the contributions of specific microcircuits in the basal ganglia have been linked to different behaviors.

Using electrophysiology, viral tracing, and other approaches, Dr. Lilascharoen and colleagues demonstrated that two microcircuits or populations of parvalbumin-expressing neurons could be manipulated to exacerbate or alleviate the motor or cognitive deficits in the dopamine-depleted mice. 

One of these microcircuits, made up of substantia nigra pars reticulata-projecting GPe-PV neurons, could be manipulated in ways that promoted or inhibited the mice’s movement. The other, which comprises parafascicular thalamus-projecting GPe-PV neurons, could be manipulated to affect reversal learning, the researchers found. Activation or inhibition of either circuit was not seen affecting function in the other. 

The results shed light on the functional organization of the different basal ganglia nuclei at the circuit level, and suggest, the authors argued, that differences in how different neuronal subpopulations adapt to dopamine loss could explain some of the patterns of progression seen in Parkinson’s disease.

The findings “establish the differential contributions from two distinct GPe-PV microcircuits in specific Parkinsonian-like behaviors linked to early and late stages of the disease,” Dr. Lilascharoen and colleagues wrote in their analysis. “[F]urther elucidation of the detailed connectivity of GPe subpopulations to their downstream targets … is needed to fully define the function of each microcircuit and design better therapeutic strategies for the various behavioral impairments of Parkinson’s disease.” 

Commenting on the research, Stefan Lang, MD, PhD, of the University of Calgary in Alberta said, “While Parkinson’s disease is often referred to as a movement disorder, it is well known that nonmotor symptoms, including cognitive and behavioral impairment, are common and debilitating. Impairment of basal ganglia function is known to contribute to these different symptom domains, though the specific circuits have never been elucidated. [Dr.] Lilascharoen et al. tease apart specific basal ganglia circuits associated with motor and behavioral symptoms, thereby providing evidence that distinct microcircuits might contribute to unique behaviours. As technological advances in neuromodulatory therapies continue to improve the spatial and temporal resolution of stimulation, future treatments may allow for specific targeting of behavioral impairment symptoms in Parkinson’s disease.”

Dr. Lilascharoen and Dr. Lang did not report outside funding or conflicts of interest.

Previous and concomitant triptan therapy bears no effect on ubrogepant efficacy and tolerability, according to a study published in Headache.

“The goal is to get migraine attacks under control as quickly as you can with as few adverse events as possible,” said lead author Andrew Blumenfeld, MD, director of the Headache Center of Southern California in Carlsbad, California. “Ubrogepant is very efficacious and well tolerated because it has few adverse events.”

Migraine disorder is the third most prevalent disease, and at least one person living in 25% of all U.S. households has the condition.

Clinicians have a wide range of medications at their disposal to treat migraines. These drug classes include triptans, ditans, NSAIDs, dihydroergotamine, and combination analgesics. Although numerous pharmacologic options are available to manage this patient population, an estimated 95% of patients who take oral medications to alleviate their migraine symptoms still fail to achieve relief with at least one acute episode.

Triptans remain a common option and first-line choice for acute migraine relief, but poor tolerability, among other factors, continue to limit their effectiveness. Moreover, their vasoconstrictive properties preclude their use in specific patient populations, such as those who have hypertension, peripheral vascular disease, and cerebral vascular accident. These circumstances, combined with other unmet clinical needs in migraine, have prompted researchers to explore new options, including a newer class of drugs – CGRP receptor antagonists. An endogenous protein, CGRP, has inflammatory and pronociceptive properties that play an active role in contributing to migraine pathogenesis.
 

Efficacy analyzed by triptan response

To investigate the effects of anti-CGRP treatment in patients with migraine who have a previous history of triptan use, researchers conducted two phase 3, randomized, double-blind, multicenter, single-attack trials, known as ACHIEVE I and ACHIEVE II.

Trial participants ranged in age from 18 to 75 years with a documented history of migraines with or without aura. In ACHIEVE I, investigators randomized 1,327 participants 1:1:1 to receive placebo, ubrogepant 50 mg, or ubrogepant 100 mg and placebo. Randomized patients in ACHIEVE II (n = 1,355) received placebo, ubrogepant 25 mg, or ubrogepant 50 mg to treat a single episode. During the screening process, researchers further placed patients in one of three groups based on their previous triptan use – triptan responder, triptan-insufficient responder, and triptan naive. Patients were further randomized based on their previous experience with triptans and whether they currently used them for migraine prevention. Patients participating in the study had up to 60 days to treat one qualifying migraine of moderate or severe nature at home.

The studies had two primary endpoints. The first was freedom from pain at the 2-hour mark following the initial dose, defined as decreased headache severity from moderate or severe at baseline to no pain. The other primary endpoint was the absence of most bothersome migraine-associated symptom (MBS) – photophobia, phonophobia, or nausea – 2 hours after the initial ubrogepant dose.

The pooled analysis collated data from 1,799 patients in both studies (placebo, n = 912; ubrogepant 50 mg, n = 887). Patients fell into the following categories: 682 triptan responders (placebo, n = 350; ubrogepant, n = 332); 451 triptan-insufficient responders (placebo, n = 223; ubrogepant, n = 228), and 666 triptan naive (placebo, n = 339; ubrogepant, n = 337).

Based on the data, approximately 25% of the patients enrolled in the study fell into the triptan-insufficient category. Of this subpopulation, about 80% of the patients in each treatment group experienced insufficient efficacy when using triptans. In each treatment group of insufficient responders, approximately 17% of patients cited tolerability issues, and 3% had contraindications that precluded them from triptan therapy.

The incidence of treatment-emergent adverse events (TEAEs) and treatment-related TEAEs did not differ appreciably across historical triptan experience subgroups. The highest percentage of participants experiencing a treatment-related TEAE in the pooled ubrogepant 50-mg treatment group was found in the triptan-insufficient responders (10.4%), whereas the highest percentage in the placebo group was found in the triptan-naive subgroup (9.7%). No serious AEs (SAEs) were reported in any subgroup.

The researchers concluded that “ubrogepant efficacy and tolerability did not differ for the acute treatment of migraine in participants classified as triptan responders, triptan-insufficient responders, and triptan naive based on their historical experience with triptans.”
 

Payers limit use

Despite the promising data, payer hurdles limit ubrogepant’s use, said Stewart Tepper, MD, who was asked to comment on the study. Dr. Tepper, a professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H., was not involved in the study. “The study shows that ubrogepant will work as well as those who have not responded well to triptans, which is key,” Dr. Tepper said. “However, payers have set up step edits in which patients aren’t allowed to get ubrogepant unless they fail therapy with at least two triptans.”

Dr. Blumenfeld discounts the rationale behind requiring patients to try a second triptan after failing initial triptan therapy. “There are plenty of studies showing that if you fail one triptan, you’re likely to fail another,” he said. “Why would you put the patient on a different triptan when you could switch them to another drug with a different mechanism of action?”

The results showed that more patients in the ubrogepant 50-mg arm achieved pain freedom than those in the placebo arm within 2 hours after the initial dose in each group.

“Migraine is a very disabling condition, so you want to get the attack under control as quickly as possible while limiting the risk for potential side effects,” said Dr. Blumenfeld. “Ubrogepant is very efficacious and with very few adverse effects, but its use is limited because insurance companies require the failure of several triptans.”

One limitation of the study is that it is a subanalysis.

Dr. Blumenfeld has disclosed advisory board service, consulting, speaking, and authorship for AbbVie, Alder, Amgen, Biohaven, Lilly, Novartis, Teva, Theranica, and Zoscano.

Previous and concomitant triptan therapy bears no effect on ubrogepant efficacy and tolerability, according to a study published in Headache.

“The goal is to get migraine attacks under control as quickly as you can with as few adverse events as possible,” said lead author Andrew Blumenfeld, MD, director of the Headache Center of Southern California in Carlsbad, California. “Ubrogepant is very efficacious and well tolerated because it has few adverse events.”

Migraine disorder is the third most prevalent disease, and at least one person living in 25% of all U.S. households has the condition.

Clinicians have a wide range of medications at their disposal to treat migraines. These drug classes include triptans, ditans, NSAIDs, dihydroergotamine, and combination analgesics. Although numerous pharmacologic options are available to manage this patient population, an estimated 95% of patients who take oral medications to alleviate their migraine symptoms still fail to achieve relief with at least one acute episode.

Triptans remain a common option and first-line choice for acute migraine relief, but poor tolerability, among other factors, continue to limit their effectiveness. Moreover, their vasoconstrictive properties preclude their use in specific patient populations, such as those who have hypertension, peripheral vascular disease, and cerebral vascular accident. These circumstances, combined with other unmet clinical needs in migraine, have prompted researchers to explore new options, including a newer class of drugs – CGRP receptor antagonists. An endogenous protein, CGRP, has inflammatory and pronociceptive properties that play an active role in contributing to migraine pathogenesis.
 

Efficacy analyzed by triptan response

To investigate the effects of anti-CGRP treatment in patients with migraine who have a previous history of triptan use, researchers conducted two phase 3, randomized, double-blind, multicenter, single-attack trials, known as ACHIEVE I and ACHIEVE II.

Trial participants ranged in age from 18 to 75 years with a documented history of migraines with or without aura. In ACHIEVE I, investigators randomized 1,327 participants 1:1:1 to receive placebo, ubrogepant 50 mg, or ubrogepant 100 mg and placebo. Randomized patients in ACHIEVE II (n = 1,355) received placebo, ubrogepant 25 mg, or ubrogepant 50 mg to treat a single episode. During the screening process, researchers further placed patients in one of three groups based on their previous triptan use – triptan responder, triptan-insufficient responder, and triptan naive. Patients were further randomized based on their previous experience with triptans and whether they currently used them for migraine prevention. Patients participating in the study had up to 60 days to treat one qualifying migraine of moderate or severe nature at home.

The studies had two primary endpoints. The first was freedom from pain at the 2-hour mark following the initial dose, defined as decreased headache severity from moderate or severe at baseline to no pain. The other primary endpoint was the absence of most bothersome migraine-associated symptom (MBS) – photophobia, phonophobia, or nausea – 2 hours after the initial ubrogepant dose.

The pooled analysis collated data from 1,799 patients in both studies (placebo, n = 912; ubrogepant 50 mg, n = 887). Patients fell into the following categories: 682 triptan responders (placebo, n = 350; ubrogepant, n = 332); 451 triptan-insufficient responders (placebo, n = 223; ubrogepant, n = 228), and 666 triptan naive (placebo, n = 339; ubrogepant, n = 337).

Based on the data, approximately 25% of the patients enrolled in the study fell into the triptan-insufficient category. Of this subpopulation, about 80% of the patients in each treatment group experienced insufficient efficacy when using triptans. In each treatment group of insufficient responders, approximately 17% of patients cited tolerability issues, and 3% had contraindications that precluded them from triptan therapy.

The incidence of treatment-emergent adverse events (TEAEs) and treatment-related TEAEs did not differ appreciably across historical triptan experience subgroups. The highest percentage of participants experiencing a treatment-related TEAE in the pooled ubrogepant 50-mg treatment group was found in the triptan-insufficient responders (10.4%), whereas the highest percentage in the placebo group was found in the triptan-naive subgroup (9.7%). No serious AEs (SAEs) were reported in any subgroup.

The researchers concluded that “ubrogepant efficacy and tolerability did not differ for the acute treatment of migraine in participants classified as triptan responders, triptan-insufficient responders, and triptan naive based on their historical experience with triptans.”
 

Payers limit use

Despite the promising data, payer hurdles limit ubrogepant’s use, said Stewart Tepper, MD, who was asked to comment on the study. Dr. Tepper, a professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H., was not involved in the study. “The study shows that ubrogepant will work as well as those who have not responded well to triptans, which is key,” Dr. Tepper said. “However, payers have set up step edits in which patients aren’t allowed to get ubrogepant unless they fail therapy with at least two triptans.”

Dr. Blumenfeld discounts the rationale behind requiring patients to try a second triptan after failing initial triptan therapy. “There are plenty of studies showing that if you fail one triptan, you’re likely to fail another,” he said. “Why would you put the patient on a different triptan when you could switch them to another drug with a different mechanism of action?”

The results showed that more patients in the ubrogepant 50-mg arm achieved pain freedom than those in the placebo arm within 2 hours after the initial dose in each group.

“Migraine is a very disabling condition, so you want to get the attack under control as quickly as possible while limiting the risk for potential side effects,” said Dr. Blumenfeld. “Ubrogepant is very efficacious and with very few adverse effects, but its use is limited because insurance companies require the failure of several triptans.”

One limitation of the study is that it is a subanalysis.

Dr. Blumenfeld has disclosed advisory board service, consulting, speaking, and authorship for AbbVie, Alder, Amgen, Biohaven, Lilly, Novartis, Teva, Theranica, and Zoscano.

Previous and concomitant triptan therapy bears no effect on ubrogepant efficacy and tolerability, according to a study published in Headache.

“The goal is to get migraine attacks under control as quickly as you can with as few adverse events as possible,” said lead author Andrew Blumenfeld, MD, director of the Headache Center of Southern California in Carlsbad, California. “Ubrogepant is very efficacious and well tolerated because it has few adverse events.”

Migraine disorder is the third most prevalent disease, and at least one person living in 25% of all U.S. households has the condition.

Clinicians have a wide range of medications at their disposal to treat migraines. These drug classes include triptans, ditans, NSAIDs, dihydroergotamine, and combination analgesics. Although numerous pharmacologic options are available to manage this patient population, an estimated 95% of patients who take oral medications to alleviate their migraine symptoms still fail to achieve relief with at least one acute episode.

Triptans remain a common option and first-line choice for acute migraine relief, but poor tolerability, among other factors, continue to limit their effectiveness. Moreover, their vasoconstrictive properties preclude their use in specific patient populations, such as those who have hypertension, peripheral vascular disease, and cerebral vascular accident. These circumstances, combined with other unmet clinical needs in migraine, have prompted researchers to explore new options, including a newer class of drugs – CGRP receptor antagonists. An endogenous protein, CGRP, has inflammatory and pronociceptive properties that play an active role in contributing to migraine pathogenesis.
 

Efficacy analyzed by triptan response

To investigate the effects of anti-CGRP treatment in patients with migraine who have a previous history of triptan use, researchers conducted two phase 3, randomized, double-blind, multicenter, single-attack trials, known as ACHIEVE I and ACHIEVE II.

Trial participants ranged in age from 18 to 75 years with a documented history of migraines with or without aura. In ACHIEVE I, investigators randomized 1,327 participants 1:1:1 to receive placebo, ubrogepant 50 mg, or ubrogepant 100 mg and placebo. Randomized patients in ACHIEVE II (n = 1,355) received placebo, ubrogepant 25 mg, or ubrogepant 50 mg to treat a single episode. During the screening process, researchers further placed patients in one of three groups based on their previous triptan use – triptan responder, triptan-insufficient responder, and triptan naive. Patients were further randomized based on their previous experience with triptans and whether they currently used them for migraine prevention. Patients participating in the study had up to 60 days to treat one qualifying migraine of moderate or severe nature at home.

The studies had two primary endpoints. The first was freedom from pain at the 2-hour mark following the initial dose, defined as decreased headache severity from moderate or severe at baseline to no pain. The other primary endpoint was the absence of most bothersome migraine-associated symptom (MBS) – photophobia, phonophobia, or nausea – 2 hours after the initial ubrogepant dose.

The pooled analysis collated data from 1,799 patients in both studies (placebo, n = 912; ubrogepant 50 mg, n = 887). Patients fell into the following categories: 682 triptan responders (placebo, n = 350; ubrogepant, n = 332); 451 triptan-insufficient responders (placebo, n = 223; ubrogepant, n = 228), and 666 triptan naive (placebo, n = 339; ubrogepant, n = 337).

Based on the data, approximately 25% of the patients enrolled in the study fell into the triptan-insufficient category. Of this subpopulation, about 80% of the patients in each treatment group experienced insufficient efficacy when using triptans. In each treatment group of insufficient responders, approximately 17% of patients cited tolerability issues, and 3% had contraindications that precluded them from triptan therapy.

The incidence of treatment-emergent adverse events (TEAEs) and treatment-related TEAEs did not differ appreciably across historical triptan experience subgroups. The highest percentage of participants experiencing a treatment-related TEAE in the pooled ubrogepant 50-mg treatment group was found in the triptan-insufficient responders (10.4%), whereas the highest percentage in the placebo group was found in the triptan-naive subgroup (9.7%). No serious AEs (SAEs) were reported in any subgroup.

The researchers concluded that “ubrogepant efficacy and tolerability did not differ for the acute treatment of migraine in participants classified as triptan responders, triptan-insufficient responders, and triptan naive based on their historical experience with triptans.”
 

Payers limit use

Despite the promising data, payer hurdles limit ubrogepant’s use, said Stewart Tepper, MD, who was asked to comment on the study. Dr. Tepper, a professor of neurology at the Geisel School of Medicine at Dartmouth, Hanover, N.H., was not involved in the study. “The study shows that ubrogepant will work as well as those who have not responded well to triptans, which is key,” Dr. Tepper said. “However, payers have set up step edits in which patients aren’t allowed to get ubrogepant unless they fail therapy with at least two triptans.”

Dr. Blumenfeld discounts the rationale behind requiring patients to try a second triptan after failing initial triptan therapy. “There are plenty of studies showing that if you fail one triptan, you’re likely to fail another,” he said. “Why would you put the patient on a different triptan when you could switch them to another drug with a different mechanism of action?”

The results showed that more patients in the ubrogepant 50-mg arm achieved pain freedom than those in the placebo arm within 2 hours after the initial dose in each group.

“Migraine is a very disabling condition, so you want to get the attack under control as quickly as possible while limiting the risk for potential side effects,” said Dr. Blumenfeld. “Ubrogepant is very efficacious and with very few adverse effects, but its use is limited because insurance companies require the failure of several triptans.”

One limitation of the study is that it is a subanalysis.

Dr. Blumenfeld has disclosed advisory board service, consulting, speaking, and authorship for AbbVie, Alder, Amgen, Biohaven, Lilly, Novartis, Teva, Theranica, and Zoscano.

Exercise may help prevent cognitive decline in high-risk patients with early Parkinson’s disease, new research suggests. Investigators found that patients with Parkinson’s disease who were APOE epsilon4 carriers had greater cognitive decline compared with non-APOE epsilon4 carriers, but the findings also revealed higher physical activity appeared to slow cognitive decline in this higher risk group.

“The main finding of the current study is that higher physical activity was related to slower APOE epsilon4-associated cognitive decline in patients with early Parkinson’s disease, which was shown to be robust in sensitivity analyses,” wrote the researchers, led by Ryul Kim, MD, Inha University Hospital, Incheon, Korea.

The study was published online March 31 in Neurology.
 

Unclear mechanism

The APOE epsilon4 allele is known to be a “major risk factor” for Alzheimer’s disease, but “accumulating evidence shows that this allele also has a potential role in cognitive impairment in Parkinson’s disease,” the authors noted.

Previous research shows physical activity has beneficial effects in patients with Parkinson’s disease, but the mechanisms underlying these effects are “not well understood.” Additional data suggest physical activity modifies the APOE epsilon4 effect on the development and progression of Alzheimer’s disease.

“These observations led us to hypothesize that physical activity also plays a role in modulating the association between APOE [epsilon4] and cognition in Parkinson’s disease,” but no studies have yet reported on this interaction in patients with Parkinson’s disease, the authors noted.

To investigate, they drew on data from the Parkinson’s Progression Markers Initiative (PPMI) – a cohort study conducted to identify Parkinson’s disease progression markers.

The current analysis included 173 patients recently diagnosed with Parkinson’s disease but not yet treated for the condition. The cohort’s mean age was 63.3 ± 10.0 years, age of Parkinson’s disease onset was 59.4 ± 10.0 years, and 68% were male. Of these participants, 46 were APOE epsilon4 carriers.

Dopamine transporter (DAT) activity was assessed using imaging at enrollment and again at years 2 and 4. Cognitive function was assessed at years 2, 3, and 4 using the Montreal Cognitive Assessment (MoCA) test.
 

Protective effect

Although APOE epsilon4 carriers tended to be younger than noncarriers, the age of Parkinson’s disease onset did not differ between the 2 groups, and there were also no significant differences between the groups in demographic and clinical variables.

There were larger declines in MoCA scores in the APOE epsilon4 carriers versus the noncarriers (0.21 ± 1.40 and 0.08 ± 1.15 respectively).

The APOE epsilon4 allele was associated with a “steeper” rate of cognitive decline, compared with the non-APOE epsilon4 allele (estimate −1.33 [95% confidence interval, −2.12 to −0.47, P = .002).

There was a significant interaction of physical activity, APOE epsilon4, and time: Higher physical activity was associated with slower APOE epsilon4-related cognitive decline (estimate 0.007 [0.003 to 0.011, P = .001).

However, the researchers found no significant main effects of the APOE epsilon4 allele or physical activity on the change in the MoCA score.

“Considering that dopaminergic treatment may affect cognitive function, particularly in the early stage of Parkinson’s disease, we additionally included the levodopa daily equivalent dose (LEDD) and its interaction with time as covariates in the model,” the investigators noted.

They found that the interactive association between physical activity and the APOE epsilon4 allele on cognitive decline remained significant, even when participants who had normal cognitive performance at year 2 were included in the study population or when LEDD variables were included as covariates in the model.

Both high- and low-intensity exercise were significantly associated with slower APOE epsilon4-related cognitive decline.

There was no significant interaction between physical activity and APOE epsilon4 with changes in striatal DAT activities.

“Increased physical activity attenuated APOE epsilon4-related vulnerability to early cognitive decline in patients with Parkinson’s disease,” the authors noted, adding that the effect “did not appear to be mediated by striatal dopamine activity.”

They hypothesized that physical activity may “offer a greater protective effect” on cerebral amyloid accumulation in APOE epsilon4 carriers. It is also possible that physical activity will counteract the negative impact of the APOE epsilon4 allele through improved brain mechanism and decreased neuroinflammation.
 

‘The next blockbuster drug’

Commenting on the study in an interview, Bastiaan R. Bloem, MD, PhD, director of the center of expertise for Parkinson & movement disorders, Radboud University Medical Center, Nijmegen, Netherlands, said exercise might be seen as “the next blockbuster drug.”

Dr. Bloem, who was not involved in the study, noted there is “quite robust evidence now that exercise acts as symptomatic therapy, like a drug, alleviating sleep [disturbances], depression, constipation, and motor symptoms.”

The study “sheds new light on the idea of exercise as not only alleviating symptoms but actually as a potential disease modifier,” said Dr. Bloem, whose research has focused on the beneficial effects of a rigorous exercise program, combined with tablet-based gamificaton and a reward system in stabilizing motor symptoms in patients with Parkinson’s disease over time.

“The reward system created additional motivation for the patients with Parkinson’s disease who often experience depression and apathy that interfere with motivation,” he said.

The current study has important take-home messages for practicing clinicians. “Physicians should encourage exercise in patients, and patients should also take the lead themselves,” Dr. Bloem said. “It doesn’t matter what type of exercise you do, but it should have an aerobic component, should be safe so the patient doesn’t fall down, should have enough intensity to cause the patient to pant, and should be individualized and enjoyable so the patients stick to it,” he emphasized.

Dr. Bloem noted that yoga and mindfulness are also helpful. “If we’ve learned anything from the COVID-19 crisis, it’s that chronic stress is deleterious to all of us and particularly bad for people with PD, because you need dopamine to be able to handle stress, and the lack of dopamine in people with PD makes them deteriorate faster.”

The study was supported by a research grant of National Research Foundation by the Ministry of Science and ICT (MSIT) in Korea. The authors and Dr. Bloem have disclosed no relevant financial relationships.

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

Exercise may help prevent cognitive decline in high-risk patients with early Parkinson’s disease, new research suggests. Investigators found that patients with Parkinson’s disease who were APOE epsilon4 carriers had greater cognitive decline compared with non-APOE epsilon4 carriers, but the findings also revealed higher physical activity appeared to slow cognitive decline in this higher risk group.

“The main finding of the current study is that higher physical activity was related to slower APOE epsilon4-associated cognitive decline in patients with early Parkinson’s disease, which was shown to be robust in sensitivity analyses,” wrote the researchers, led by Ryul Kim, MD, Inha University Hospital, Incheon, Korea.

The study was published online March 31 in Neurology.
 

Unclear mechanism

The APOE epsilon4 allele is known to be a “major risk factor” for Alzheimer’s disease, but “accumulating evidence shows that this allele also has a potential role in cognitive impairment in Parkinson’s disease,” the authors noted.

Previous research shows physical activity has beneficial effects in patients with Parkinson’s disease, but the mechanisms underlying these effects are “not well understood.” Additional data suggest physical activity modifies the APOE epsilon4 effect on the development and progression of Alzheimer’s disease.

“These observations led us to hypothesize that physical activity also plays a role in modulating the association between APOE [epsilon4] and cognition in Parkinson’s disease,” but no studies have yet reported on this interaction in patients with Parkinson’s disease, the authors noted.

To investigate, they drew on data from the Parkinson’s Progression Markers Initiative (PPMI) – a cohort study conducted to identify Parkinson’s disease progression markers.

The current analysis included 173 patients recently diagnosed with Parkinson’s disease but not yet treated for the condition. The cohort’s mean age was 63.3 ± 10.0 years, age of Parkinson’s disease onset was 59.4 ± 10.0 years, and 68% were male. Of these participants, 46 were APOE epsilon4 carriers.

Dopamine transporter (DAT) activity was assessed using imaging at enrollment and again at years 2 and 4. Cognitive function was assessed at years 2, 3, and 4 using the Montreal Cognitive Assessment (MoCA) test.
 

Protective effect

Although APOE epsilon4 carriers tended to be younger than noncarriers, the age of Parkinson’s disease onset did not differ between the 2 groups, and there were also no significant differences between the groups in demographic and clinical variables.

There were larger declines in MoCA scores in the APOE epsilon4 carriers versus the noncarriers (0.21 ± 1.40 and 0.08 ± 1.15 respectively).

The APOE epsilon4 allele was associated with a “steeper” rate of cognitive decline, compared with the non-APOE epsilon4 allele (estimate −1.33 [95% confidence interval, −2.12 to −0.47, P = .002).

There was a significant interaction of physical activity, APOE epsilon4, and time: Higher physical activity was associated with slower APOE epsilon4-related cognitive decline (estimate 0.007 [0.003 to 0.011, P = .001).

However, the researchers found no significant main effects of the APOE epsilon4 allele or physical activity on the change in the MoCA score.

“Considering that dopaminergic treatment may affect cognitive function, particularly in the early stage of Parkinson’s disease, we additionally included the levodopa daily equivalent dose (LEDD) and its interaction with time as covariates in the model,” the investigators noted.

They found that the interactive association between physical activity and the APOE epsilon4 allele on cognitive decline remained significant, even when participants who had normal cognitive performance at year 2 were included in the study population or when LEDD variables were included as covariates in the model.

Both high- and low-intensity exercise were significantly associated with slower APOE epsilon4-related cognitive decline.

There was no significant interaction between physical activity and APOE epsilon4 with changes in striatal DAT activities.

“Increased physical activity attenuated APOE epsilon4-related vulnerability to early cognitive decline in patients with Parkinson’s disease,” the authors noted, adding that the effect “did not appear to be mediated by striatal dopamine activity.”

They hypothesized that physical activity may “offer a greater protective effect” on cerebral amyloid accumulation in APOE epsilon4 carriers. It is also possible that physical activity will counteract the negative impact of the APOE epsilon4 allele through improved brain mechanism and decreased neuroinflammation.
 

‘The next blockbuster drug’

Commenting on the study in an interview, Bastiaan R. Bloem, MD, PhD, director of the center of expertise for Parkinson & movement disorders, Radboud University Medical Center, Nijmegen, Netherlands, said exercise might be seen as “the next blockbuster drug.”

Dr. Bloem, who was not involved in the study, noted there is “quite robust evidence now that exercise acts as symptomatic therapy, like a drug, alleviating sleep [disturbances], depression, constipation, and motor symptoms.”

The study “sheds new light on the idea of exercise as not only alleviating symptoms but actually as a potential disease modifier,” said Dr. Bloem, whose research has focused on the beneficial effects of a rigorous exercise program, combined with tablet-based gamificaton and a reward system in stabilizing motor symptoms in patients with Parkinson’s disease over time.

“The reward system created additional motivation for the patients with Parkinson’s disease who often experience depression and apathy that interfere with motivation,” he said.

The current study has important take-home messages for practicing clinicians. “Physicians should encourage exercise in patients, and patients should also take the lead themselves,” Dr. Bloem said. “It doesn’t matter what type of exercise you do, but it should have an aerobic component, should be safe so the patient doesn’t fall down, should have enough intensity to cause the patient to pant, and should be individualized and enjoyable so the patients stick to it,” he emphasized.

Dr. Bloem noted that yoga and mindfulness are also helpful. “If we’ve learned anything from the COVID-19 crisis, it’s that chronic stress is deleterious to all of us and particularly bad for people with PD, because you need dopamine to be able to handle stress, and the lack of dopamine in people with PD makes them deteriorate faster.”

The study was supported by a research grant of National Research Foundation by the Ministry of Science and ICT (MSIT) in Korea. The authors and Dr. Bloem have disclosed no relevant financial relationships.

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

Exercise may help prevent cognitive decline in high-risk patients with early Parkinson’s disease, new research suggests. Investigators found that patients with Parkinson’s disease who were APOE epsilon4 carriers had greater cognitive decline compared with non-APOE epsilon4 carriers, but the findings also revealed higher physical activity appeared to slow cognitive decline in this higher risk group.

“The main finding of the current study is that higher physical activity was related to slower APOE epsilon4-associated cognitive decline in patients with early Parkinson’s disease, which was shown to be robust in sensitivity analyses,” wrote the researchers, led by Ryul Kim, MD, Inha University Hospital, Incheon, Korea.

The study was published online March 31 in Neurology.
 

Unclear mechanism

The APOE epsilon4 allele is known to be a “major risk factor” for Alzheimer’s disease, but “accumulating evidence shows that this allele also has a potential role in cognitive impairment in Parkinson’s disease,” the authors noted.

Previous research shows physical activity has beneficial effects in patients with Parkinson’s disease, but the mechanisms underlying these effects are “not well understood.” Additional data suggest physical activity modifies the APOE epsilon4 effect on the development and progression of Alzheimer’s disease.

“These observations led us to hypothesize that physical activity also plays a role in modulating the association between APOE [epsilon4] and cognition in Parkinson’s disease,” but no studies have yet reported on this interaction in patients with Parkinson’s disease, the authors noted.

To investigate, they drew on data from the Parkinson’s Progression Markers Initiative (PPMI) – a cohort study conducted to identify Parkinson’s disease progression markers.

The current analysis included 173 patients recently diagnosed with Parkinson’s disease but not yet treated for the condition. The cohort’s mean age was 63.3 ± 10.0 years, age of Parkinson’s disease onset was 59.4 ± 10.0 years, and 68% were male. Of these participants, 46 were APOE epsilon4 carriers.

Dopamine transporter (DAT) activity was assessed using imaging at enrollment and again at years 2 and 4. Cognitive function was assessed at years 2, 3, and 4 using the Montreal Cognitive Assessment (MoCA) test.
 

Protective effect

Although APOE epsilon4 carriers tended to be younger than noncarriers, the age of Parkinson’s disease onset did not differ between the 2 groups, and there were also no significant differences between the groups in demographic and clinical variables.

There were larger declines in MoCA scores in the APOE epsilon4 carriers versus the noncarriers (0.21 ± 1.40 and 0.08 ± 1.15 respectively).

The APOE epsilon4 allele was associated with a “steeper” rate of cognitive decline, compared with the non-APOE epsilon4 allele (estimate −1.33 [95% confidence interval, −2.12 to −0.47, P = .002).

There was a significant interaction of physical activity, APOE epsilon4, and time: Higher physical activity was associated with slower APOE epsilon4-related cognitive decline (estimate 0.007 [0.003 to 0.011, P = .001).

However, the researchers found no significant main effects of the APOE epsilon4 allele or physical activity on the change in the MoCA score.

“Considering that dopaminergic treatment may affect cognitive function, particularly in the early stage of Parkinson’s disease, we additionally included the levodopa daily equivalent dose (LEDD) and its interaction with time as covariates in the model,” the investigators noted.

They found that the interactive association between physical activity and the APOE epsilon4 allele on cognitive decline remained significant, even when participants who had normal cognitive performance at year 2 were included in the study population or when LEDD variables were included as covariates in the model.

Both high- and low-intensity exercise were significantly associated with slower APOE epsilon4-related cognitive decline.

There was no significant interaction between physical activity and APOE epsilon4 with changes in striatal DAT activities.

“Increased physical activity attenuated APOE epsilon4-related vulnerability to early cognitive decline in patients with Parkinson’s disease,” the authors noted, adding that the effect “did not appear to be mediated by striatal dopamine activity.”

They hypothesized that physical activity may “offer a greater protective effect” on cerebral amyloid accumulation in APOE epsilon4 carriers. It is also possible that physical activity will counteract the negative impact of the APOE epsilon4 allele through improved brain mechanism and decreased neuroinflammation.
 

‘The next blockbuster drug’

Commenting on the study in an interview, Bastiaan R. Bloem, MD, PhD, director of the center of expertise for Parkinson & movement disorders, Radboud University Medical Center, Nijmegen, Netherlands, said exercise might be seen as “the next blockbuster drug.”

Dr. Bloem, who was not involved in the study, noted there is “quite robust evidence now that exercise acts as symptomatic therapy, like a drug, alleviating sleep [disturbances], depression, constipation, and motor symptoms.”

The study “sheds new light on the idea of exercise as not only alleviating symptoms but actually as a potential disease modifier,” said Dr. Bloem, whose research has focused on the beneficial effects of a rigorous exercise program, combined with tablet-based gamificaton and a reward system in stabilizing motor symptoms in patients with Parkinson’s disease over time.

“The reward system created additional motivation for the patients with Parkinson’s disease who often experience depression and apathy that interfere with motivation,” he said.

The current study has important take-home messages for practicing clinicians. “Physicians should encourage exercise in patients, and patients should also take the lead themselves,” Dr. Bloem said. “It doesn’t matter what type of exercise you do, but it should have an aerobic component, should be safe so the patient doesn’t fall down, should have enough intensity to cause the patient to pant, and should be individualized and enjoyable so the patients stick to it,” he emphasized.

Dr. Bloem noted that yoga and mindfulness are also helpful. “If we’ve learned anything from the COVID-19 crisis, it’s that chronic stress is deleterious to all of us and particularly bad for people with PD, because you need dopamine to be able to handle stress, and the lack of dopamine in people with PD makes them deteriorate faster.”

The study was supported by a research grant of National Research Foundation by the Ministry of Science and ICT (MSIT) in Korea. The authors and Dr. Bloem have disclosed no relevant financial relationships.

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

Patients with migraine experienced about a 60% reduction in pain intensity and number of headache days per month after exposure to green light therapy, according to results of a small study from the University of Arizona, Tucson.

“This is the first clinical study to evaluate green light exposure as a potential preventive therapy for patients with migraine, “ senior author Mohab M. Ibrahim, MD, PhD, said in a press release. “Now I have another tool in my toolbox to treat one of the most difficult neurologic conditions – migraine.”

“Given the safety, affordability, and efficacy of green light exposure, there is merit to conduct a larger study,” he and coauthors from the university wrote in their paper.

The study included 29 adult patients (average age 52.2 years), 22 with chronic migraine and the rest with episodic migraine who were recruited from the University of Arizona/Banner Medical Center chronic pain clinic. To be included, patients had to meet the International Headache Society diagnostic criteria for chronic or episodic migraine, have an average headache pain intensity of 5 out of 10 or greater on the numeric pain scale (NPS) over the 10 weeks prior to enrolling in the study, and be dissatisfied with their current migraine therapy.

The patients were free to start, continue, or discontinue any other migraine treatments as recommended by their physicians as long as this was reported to the study team.
 

White versus green

The one-way crossover design involved exposure to 10 weeks of white light emitting diodes, for 1-2 hours per day, followed by a 2-week washout period and then 10 weeks’ exposure to green light emitting diodes (GLED) for the same daily duration. The protocol involved use of a light strip emitting an intensity of between 4 and 100 lux measured at approximately 2 m and 1 m from a lux meter.

Patients were instructed to use the light in a dark room, without falling asleep, and to participate in activities that did not require external light sources, such as listening to music, reading books, doing exercises, or engaging in similar activities. The daily minimum exposure of 1 hour, up to a maximum of 2 hours, was to be completed in one sitting.

The primary outcome measure was the number of headache days per month, defined as days with moderate to severe headache pain for at least 4 hours. Secondary outcomes included perceived reduction in duration and intensity of the headache phase of the migraine episodes assessed every 2 weeks with the NPS, improved ability to fall and stay asleep, improved ability to perform work and daily activity, improved quality of life, and reduction of pain medications.

The researchers found that when the patients with chronic migraine and episodic migraine were examined as separate groups, white light exposure did not significantly reduce the number of headache days per month, but when the chronic migraine and episodic migraine groups were combined there was a significant reduction from 18.2 to 16.5 headache days per month.

On the other hand, green light did result in significantly reduced headache days both in the separate (from 7.9 to 2.4 days in the episodic migraine group and 22.3 to 9.4 days in the chronic migraine group) and combined groups (from 18.4 to 7.4 days).

“While some improvement in secondary outcomes was observed with white light emitting diodes, more secondary outcomes with significantly greater magnitude including assessments of quality of life, Short-Form McGill Pain Questionnaire, Headache Impact Test-6, and Five-level version of the EuroQol five-dimensional survey without reported side effects were observed with green light emitting diodes,” the authors reported.

“The use of a nonpharmacological therapy such as green light can be of tremendous help to a variety of patients that either do not want to be on medications or do not respond to them,” coauthor Amol M. Patwardhan, MD, PhD, said in the press release. “The beauty of this approach is the lack of associated side effects. If at all, it appears to improve sleep and other quality of life measures,” said Dr. Patwardhan, associate professor and vice chair of research in the University of Arizona’s department of anesthesiology.
 

Better than white light

Asked to comment on the findings, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, said research has shown for some time that exposure to green light has beneficial effects in migraine patients. This study, although small, does indicate that green light is more beneficial than is white light and reduces headache days and intensity. “I believe patients would be willing to spend 1-2 hours a day in green light to reduce and improve their migraine with few side effects. A larger randomized trial should be done,” he said.

The study was funded by support from the National Center for Complementary and Integrative Health (to Dr. Ibrahim), the Comprehensive Chronic Pain and Addiction Center–University of Arizona, and the University of Arizona CHiLLI initiative. Dr. Ibrahim and one coauthor have a patent pending through the University of Arizona for use of green light therapy for the management of chronic pain. Dr. Rapoport is a former president of the International Headache Society. He is an editor of Headache and CNS Drugs, and Editor-in-Chief of Neurology Reviews. He reviews for many peer-reviewed journals such as Cephalalgia, Neurology, New England Journal of Medicine, and Headache.

Patients with migraine experienced about a 60% reduction in pain intensity and number of headache days per month after exposure to green light therapy, according to results of a small study from the University of Arizona, Tucson.

“This is the first clinical study to evaluate green light exposure as a potential preventive therapy for patients with migraine, “ senior author Mohab M. Ibrahim, MD, PhD, said in a press release. “Now I have another tool in my toolbox to treat one of the most difficult neurologic conditions – migraine.”

“Given the safety, affordability, and efficacy of green light exposure, there is merit to conduct a larger study,” he and coauthors from the university wrote in their paper.

The study included 29 adult patients (average age 52.2 years), 22 with chronic migraine and the rest with episodic migraine who were recruited from the University of Arizona/Banner Medical Center chronic pain clinic. To be included, patients had to meet the International Headache Society diagnostic criteria for chronic or episodic migraine, have an average headache pain intensity of 5 out of 10 or greater on the numeric pain scale (NPS) over the 10 weeks prior to enrolling in the study, and be dissatisfied with their current migraine therapy.

The patients were free to start, continue, or discontinue any other migraine treatments as recommended by their physicians as long as this was reported to the study team.
 

White versus green

The one-way crossover design involved exposure to 10 weeks of white light emitting diodes, for 1-2 hours per day, followed by a 2-week washout period and then 10 weeks’ exposure to green light emitting diodes (GLED) for the same daily duration. The protocol involved use of a light strip emitting an intensity of between 4 and 100 lux measured at approximately 2 m and 1 m from a lux meter.

Patients were instructed to use the light in a dark room, without falling asleep, and to participate in activities that did not require external light sources, such as listening to music, reading books, doing exercises, or engaging in similar activities. The daily minimum exposure of 1 hour, up to a maximum of 2 hours, was to be completed in one sitting.

The primary outcome measure was the number of headache days per month, defined as days with moderate to severe headache pain for at least 4 hours. Secondary outcomes included perceived reduction in duration and intensity of the headache phase of the migraine episodes assessed every 2 weeks with the NPS, improved ability to fall and stay asleep, improved ability to perform work and daily activity, improved quality of life, and reduction of pain medications.

The researchers found that when the patients with chronic migraine and episodic migraine were examined as separate groups, white light exposure did not significantly reduce the number of headache days per month, but when the chronic migraine and episodic migraine groups were combined there was a significant reduction from 18.2 to 16.5 headache days per month.

On the other hand, green light did result in significantly reduced headache days both in the separate (from 7.9 to 2.4 days in the episodic migraine group and 22.3 to 9.4 days in the chronic migraine group) and combined groups (from 18.4 to 7.4 days).

“While some improvement in secondary outcomes was observed with white light emitting diodes, more secondary outcomes with significantly greater magnitude including assessments of quality of life, Short-Form McGill Pain Questionnaire, Headache Impact Test-6, and Five-level version of the EuroQol five-dimensional survey without reported side effects were observed with green light emitting diodes,” the authors reported.

“The use of a nonpharmacological therapy such as green light can be of tremendous help to a variety of patients that either do not want to be on medications or do not respond to them,” coauthor Amol M. Patwardhan, MD, PhD, said in the press release. “The beauty of this approach is the lack of associated side effects. If at all, it appears to improve sleep and other quality of life measures,” said Dr. Patwardhan, associate professor and vice chair of research in the University of Arizona’s department of anesthesiology.
 

Better than white light

Asked to comment on the findings, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, said research has shown for some time that exposure to green light has beneficial effects in migraine patients. This study, although small, does indicate that green light is more beneficial than is white light and reduces headache days and intensity. “I believe patients would be willing to spend 1-2 hours a day in green light to reduce and improve their migraine with few side effects. A larger randomized trial should be done,” he said.

The study was funded by support from the National Center for Complementary and Integrative Health (to Dr. Ibrahim), the Comprehensive Chronic Pain and Addiction Center–University of Arizona, and the University of Arizona CHiLLI initiative. Dr. Ibrahim and one coauthor have a patent pending through the University of Arizona for use of green light therapy for the management of chronic pain. Dr. Rapoport is a former president of the International Headache Society. He is an editor of Headache and CNS Drugs, and Editor-in-Chief of Neurology Reviews. He reviews for many peer-reviewed journals such as Cephalalgia, Neurology, New England Journal of Medicine, and Headache.

Patients with migraine experienced about a 60% reduction in pain intensity and number of headache days per month after exposure to green light therapy, according to results of a small study from the University of Arizona, Tucson.

“This is the first clinical study to evaluate green light exposure as a potential preventive therapy for patients with migraine, “ senior author Mohab M. Ibrahim, MD, PhD, said in a press release. “Now I have another tool in my toolbox to treat one of the most difficult neurologic conditions – migraine.”

“Given the safety, affordability, and efficacy of green light exposure, there is merit to conduct a larger study,” he and coauthors from the university wrote in their paper.

The study included 29 adult patients (average age 52.2 years), 22 with chronic migraine and the rest with episodic migraine who were recruited from the University of Arizona/Banner Medical Center chronic pain clinic. To be included, patients had to meet the International Headache Society diagnostic criteria for chronic or episodic migraine, have an average headache pain intensity of 5 out of 10 or greater on the numeric pain scale (NPS) over the 10 weeks prior to enrolling in the study, and be dissatisfied with their current migraine therapy.

The patients were free to start, continue, or discontinue any other migraine treatments as recommended by their physicians as long as this was reported to the study team.
 

White versus green

The one-way crossover design involved exposure to 10 weeks of white light emitting diodes, for 1-2 hours per day, followed by a 2-week washout period and then 10 weeks’ exposure to green light emitting diodes (GLED) for the same daily duration. The protocol involved use of a light strip emitting an intensity of between 4 and 100 lux measured at approximately 2 m and 1 m from a lux meter.

Patients were instructed to use the light in a dark room, without falling asleep, and to participate in activities that did not require external light sources, such as listening to music, reading books, doing exercises, or engaging in similar activities. The daily minimum exposure of 1 hour, up to a maximum of 2 hours, was to be completed in one sitting.

The primary outcome measure was the number of headache days per month, defined as days with moderate to severe headache pain for at least 4 hours. Secondary outcomes included perceived reduction in duration and intensity of the headache phase of the migraine episodes assessed every 2 weeks with the NPS, improved ability to fall and stay asleep, improved ability to perform work and daily activity, improved quality of life, and reduction of pain medications.

The researchers found that when the patients with chronic migraine and episodic migraine were examined as separate groups, white light exposure did not significantly reduce the number of headache days per month, but when the chronic migraine and episodic migraine groups were combined there was a significant reduction from 18.2 to 16.5 headache days per month.

On the other hand, green light did result in significantly reduced headache days both in the separate (from 7.9 to 2.4 days in the episodic migraine group and 22.3 to 9.4 days in the chronic migraine group) and combined groups (from 18.4 to 7.4 days).

“While some improvement in secondary outcomes was observed with white light emitting diodes, more secondary outcomes with significantly greater magnitude including assessments of quality of life, Short-Form McGill Pain Questionnaire, Headache Impact Test-6, and Five-level version of the EuroQol five-dimensional survey without reported side effects were observed with green light emitting diodes,” the authors reported.

“The use of a nonpharmacological therapy such as green light can be of tremendous help to a variety of patients that either do not want to be on medications or do not respond to them,” coauthor Amol M. Patwardhan, MD, PhD, said in the press release. “The beauty of this approach is the lack of associated side effects. If at all, it appears to improve sleep and other quality of life measures,” said Dr. Patwardhan, associate professor and vice chair of research in the University of Arizona’s department of anesthesiology.
 

Better than white light

Asked to comment on the findings, Alan M. Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles, said research has shown for some time that exposure to green light has beneficial effects in migraine patients. This study, although small, does indicate that green light is more beneficial than is white light and reduces headache days and intensity. “I believe patients would be willing to spend 1-2 hours a day in green light to reduce and improve their migraine with few side effects. A larger randomized trial should be done,” he said.

The study was funded by support from the National Center for Complementary and Integrative Health (to Dr. Ibrahim), the Comprehensive Chronic Pain and Addiction Center–University of Arizona, and the University of Arizona CHiLLI initiative. Dr. Ibrahim and one coauthor have a patent pending through the University of Arizona for use of green light therapy for the management of chronic pain. Dr. Rapoport is a former president of the International Headache Society. He is an editor of Headache and CNS Drugs, and Editor-in-Chief of Neurology Reviews. He reviews for many peer-reviewed journals such as Cephalalgia, Neurology, New England Journal of Medicine, and Headache.

A minimally invasive blood test along with artificial intelligence (AI) may flag early-stage Alzheimer’s disease, raising the prospect of early intervention when effective treatments become available.

In a study, investigators used six AI methodologies, including Deep Learning, to assess blood leukocyte epigenomic biomarkers. They found more than 150 genetic differences among study participants with Alzheimer’s disease in comparison with participants who did not have Alzheimer’s disease.

All of the AI platforms were effective in predicting Alzheimer’s disease. Deep Learning’s assessment of intragenic cytosine-phosphate-guanines (CpGs) had sensitivity and specificity rates of 97%.

“It’s almost as if the leukocytes have become a newspaper to tell us, ‘This is what is going on in the brain,’ “ lead author Ray Bahado-Singh, MD, chair of the department of obstetrics and gynecology, Oakland University, Auburn Hills, Mich., said in a news release.

The researchers noted that the findings, if replicated in future studies, may help in providing Alzheimer’s disease diagnoses “much earlier” in the disease process. “The holy grail is to identify patients in the preclinical stage so effective early interventions, including new medications, can be studied and ultimately used,” Dr. Bahado-Singh said.

“This certainly isn’t the final step in Alzheimer’s research, but I think this represents a significant change in direction,” he told attendees at a press briefing.

The findings were published online March 31 in PLOS ONE.
 

Silver tsunami

The investigators noted that Alzheimer’s disease is often diagnosed when the disease is in its later stages, after irreversible brain damage has occurred. “There is currently no cure for the disease, and the treatment is limited to drugs that attempt to treat symptoms and have little effect on the disease’s progression,” they noted.

Coinvestigator Khaled Imam, MD, director of geriatric medicine for Beaumont Health in Michigan, pointed out that although MRI and lumbar puncture can identify Alzheimer’s disease early on, the processes are expensive and/or invasive.

“Having biomarkers in the blood ... and being able to identify [Alzheimer’s disease] years before symptoms start, hopefully we’d be able to intervene early on in the process of the disease,” Dr. Imam said.

It is estimated that the number of Americans aged 85 and older will triple by 2050. This impending “silver tsunami,” which will come with a commensurate increase in Alzheimer’s disease cases, makes it even more important to be able to diagnose the disease early on, he noted.

The study included 24 individuals with late-onset Alzheimer’s disease (70.8% women; mean age, 83 years); 24 were deemed to be “cognitively healthy” (66.7% women; mean age, 80 years). About 500 ng of genomic DNA was extracted from whole-blood samples from each participant.

The researchers used the Infinium MethylationEPIC BeadChip array, and the samples were then examined for markers of methylation that would “indicate the disease process has started,” they noted.

In addition to Deep Learning, the five other AI platforms were the Support Vector Machine, Generalized Linear Model, Prediction Analysis for Microarrays, Random Forest, and Linear Discriminant Analysis.

These platforms were used to assess leukocyte genome changes. To predict Alzheimer’s disease, the researchers also used Ingenuity Pathway Analysis.
 

Significant “chemical changes”

Results showed that the Alzheimer’s disease group had 152 significantly differentially methylated CpGs in 171 genes in comparison with the non-Alzheimer’s disease group (false discovery rate P value < .05).

As a whole, using intragenic and intergenic/extragenic CpGs, the AI platforms were effective in predicting who had Alzheimer’s disease (area under the curve [AUC], ≥ 0.93). Using intragenic markers, the AUC for Deep Learning was 0.99.

“We looked at close to a million different sites, and we saw some chemical changes that we know are associated with alteration or change in gene function,” Dr. Bahado-Singh said.

Altered genes that were found in the Alzheimer’s disease group included CR1L, CTSV, S1PR1, and LTB4R – all of which “have been previously linked with Alzheimer’s disease and dementia,” the researchers noted. They also found the methylated genes CTSV and PRMT5, both of which have been previously associated with cardiovascular disease.

“A significant strength of our study is the novelty, i.e. the use of blood leukocytes to accurately detect Alzheimer’s disease and also for interrogating the pathogenesis of Alzheimer’s disease,” the investigators wrote.

Dr. Bahado-Singh said that the test let them identify changes in cells in the blood, “giving us a comprehensive account not only of the fact that the brain is being affected by Alzheimer’s disease but it’s telling us what kinds of processes are going on in the brain.

“Normally you don’t have access to the brain. This gives us a simple blood test to get an ongoing reading of the course of events in the brain – and potentially tell us very early on before the onset of symptoms,” he added.
 

Cautiously optimistic

During the question-and-answer session following his presentation at the briefing, Dr. Bahado-Singh reiterated that they are at a very early stage in the research and were not able to make clinical recommendations at this point. However, he added, “There was evidence that DNA methylation change could likely precede the onset of abnormalities in the cells that give rise to the disease.”

Coinvestigator Stewart Graham, PhD, director of Alzheimer’s research at Beaumont Health, added that although the initial study findings led to some excitement for the team, “we have to be very conservative with what we say.”

He noted that the findings need to be replicated in a more diverse population. Still, “we’re excited at the moment and looking forward to seeing what the future results hold,” Dr. Graham said.

Dr. Bahado-Singh said that if larger studies confirm the findings and the test is viable, it would make sense to use it as a screen for individuals older than 65. He noted that because of the aging of the population, “this subset of individuals will constitute a larger and larger fraction of the population globally.”
 

Still early days

Commenting on the findings, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, noted that the investigators used an “interesting” diagnostic process.

“It was a unique approach to looking at and trying to understand what might be some of the biological underpinnings and using these tools and technologies to determine if they’re able to differentiate individuals with Alzheimer’s disease” from those without Alzheimer’s disease, said Dr. Snyder, who was not involved with the research.

“Ultimately, we want to know who is at greater risk, who may have some of the changing biology at the earliest time point so that we can intervene to stop the progression of the disease,” she said.

She pointed out that a number of types of biomarker tests are currently under investigation, many of which are measuring different outcomes. “And that’s what we want to see going forward. We want to have as many tools in our toolbox that allow us to accurately diagnose at that earliest time point,” Dr. Snyder said.

“At this point, [the current study] is still pretty early, so it needs to be replicated and then expanded to larger groups to really understand what they may be seeing,” she added.

Dr. Bahado-Singh, Dr. Imam, Dr. Graham, and Dr. Snyder have reported no relevant financial relationships.

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

A minimally invasive blood test along with artificial intelligence (AI) may flag early-stage Alzheimer’s disease, raising the prospect of early intervention when effective treatments become available.

In a study, investigators used six AI methodologies, including Deep Learning, to assess blood leukocyte epigenomic biomarkers. They found more than 150 genetic differences among study participants with Alzheimer’s disease in comparison with participants who did not have Alzheimer’s disease.

All of the AI platforms were effective in predicting Alzheimer’s disease. Deep Learning’s assessment of intragenic cytosine-phosphate-guanines (CpGs) had sensitivity and specificity rates of 97%.

“It’s almost as if the leukocytes have become a newspaper to tell us, ‘This is what is going on in the brain,’ “ lead author Ray Bahado-Singh, MD, chair of the department of obstetrics and gynecology, Oakland University, Auburn Hills, Mich., said in a news release.

The researchers noted that the findings, if replicated in future studies, may help in providing Alzheimer’s disease diagnoses “much earlier” in the disease process. “The holy grail is to identify patients in the preclinical stage so effective early interventions, including new medications, can be studied and ultimately used,” Dr. Bahado-Singh said.

“This certainly isn’t the final step in Alzheimer’s research, but I think this represents a significant change in direction,” he told attendees at a press briefing.

The findings were published online March 31 in PLOS ONE.
 

Silver tsunami

The investigators noted that Alzheimer’s disease is often diagnosed when the disease is in its later stages, after irreversible brain damage has occurred. “There is currently no cure for the disease, and the treatment is limited to drugs that attempt to treat symptoms and have little effect on the disease’s progression,” they noted.

Coinvestigator Khaled Imam, MD, director of geriatric medicine for Beaumont Health in Michigan, pointed out that although MRI and lumbar puncture can identify Alzheimer’s disease early on, the processes are expensive and/or invasive.

“Having biomarkers in the blood ... and being able to identify [Alzheimer’s disease] years before symptoms start, hopefully we’d be able to intervene early on in the process of the disease,” Dr. Imam said.

It is estimated that the number of Americans aged 85 and older will triple by 2050. This impending “silver tsunami,” which will come with a commensurate increase in Alzheimer’s disease cases, makes it even more important to be able to diagnose the disease early on, he noted.

The study included 24 individuals with late-onset Alzheimer’s disease (70.8% women; mean age, 83 years); 24 were deemed to be “cognitively healthy” (66.7% women; mean age, 80 years). About 500 ng of genomic DNA was extracted from whole-blood samples from each participant.

The researchers used the Infinium MethylationEPIC BeadChip array, and the samples were then examined for markers of methylation that would “indicate the disease process has started,” they noted.

In addition to Deep Learning, the five other AI platforms were the Support Vector Machine, Generalized Linear Model, Prediction Analysis for Microarrays, Random Forest, and Linear Discriminant Analysis.

These platforms were used to assess leukocyte genome changes. To predict Alzheimer’s disease, the researchers also used Ingenuity Pathway Analysis.
 

Significant “chemical changes”

Results showed that the Alzheimer’s disease group had 152 significantly differentially methylated CpGs in 171 genes in comparison with the non-Alzheimer’s disease group (false discovery rate P value < .05).

As a whole, using intragenic and intergenic/extragenic CpGs, the AI platforms were effective in predicting who had Alzheimer’s disease (area under the curve [AUC], ≥ 0.93). Using intragenic markers, the AUC for Deep Learning was 0.99.

“We looked at close to a million different sites, and we saw some chemical changes that we know are associated with alteration or change in gene function,” Dr. Bahado-Singh said.

Altered genes that were found in the Alzheimer’s disease group included CR1L, CTSV, S1PR1, and LTB4R – all of which “have been previously linked with Alzheimer’s disease and dementia,” the researchers noted. They also found the methylated genes CTSV and PRMT5, both of which have been previously associated with cardiovascular disease.

“A significant strength of our study is the novelty, i.e. the use of blood leukocytes to accurately detect Alzheimer’s disease and also for interrogating the pathogenesis of Alzheimer’s disease,” the investigators wrote.

Dr. Bahado-Singh said that the test let them identify changes in cells in the blood, “giving us a comprehensive account not only of the fact that the brain is being affected by Alzheimer’s disease but it’s telling us what kinds of processes are going on in the brain.

“Normally you don’t have access to the brain. This gives us a simple blood test to get an ongoing reading of the course of events in the brain – and potentially tell us very early on before the onset of symptoms,” he added.
 

Cautiously optimistic

During the question-and-answer session following his presentation at the briefing, Dr. Bahado-Singh reiterated that they are at a very early stage in the research and were not able to make clinical recommendations at this point. However, he added, “There was evidence that DNA methylation change could likely precede the onset of abnormalities in the cells that give rise to the disease.”

Coinvestigator Stewart Graham, PhD, director of Alzheimer’s research at Beaumont Health, added that although the initial study findings led to some excitement for the team, “we have to be very conservative with what we say.”

He noted that the findings need to be replicated in a more diverse population. Still, “we’re excited at the moment and looking forward to seeing what the future results hold,” Dr. Graham said.

Dr. Bahado-Singh said that if larger studies confirm the findings and the test is viable, it would make sense to use it as a screen for individuals older than 65. He noted that because of the aging of the population, “this subset of individuals will constitute a larger and larger fraction of the population globally.”
 

Still early days

Commenting on the findings, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, noted that the investigators used an “interesting” diagnostic process.

“It was a unique approach to looking at and trying to understand what might be some of the biological underpinnings and using these tools and technologies to determine if they’re able to differentiate individuals with Alzheimer’s disease” from those without Alzheimer’s disease, said Dr. Snyder, who was not involved with the research.

“Ultimately, we want to know who is at greater risk, who may have some of the changing biology at the earliest time point so that we can intervene to stop the progression of the disease,” she said.

She pointed out that a number of types of biomarker tests are currently under investigation, many of which are measuring different outcomes. “And that’s what we want to see going forward. We want to have as many tools in our toolbox that allow us to accurately diagnose at that earliest time point,” Dr. Snyder said.

“At this point, [the current study] is still pretty early, so it needs to be replicated and then expanded to larger groups to really understand what they may be seeing,” she added.

Dr. Bahado-Singh, Dr. Imam, Dr. Graham, and Dr. Snyder have reported no relevant financial relationships.

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

A minimally invasive blood test along with artificial intelligence (AI) may flag early-stage Alzheimer’s disease, raising the prospect of early intervention when effective treatments become available.

In a study, investigators used six AI methodologies, including Deep Learning, to assess blood leukocyte epigenomic biomarkers. They found more than 150 genetic differences among study participants with Alzheimer’s disease in comparison with participants who did not have Alzheimer’s disease.

All of the AI platforms were effective in predicting Alzheimer’s disease. Deep Learning’s assessment of intragenic cytosine-phosphate-guanines (CpGs) had sensitivity and specificity rates of 97%.

“It’s almost as if the leukocytes have become a newspaper to tell us, ‘This is what is going on in the brain,’ “ lead author Ray Bahado-Singh, MD, chair of the department of obstetrics and gynecology, Oakland University, Auburn Hills, Mich., said in a news release.

The researchers noted that the findings, if replicated in future studies, may help in providing Alzheimer’s disease diagnoses “much earlier” in the disease process. “The holy grail is to identify patients in the preclinical stage so effective early interventions, including new medications, can be studied and ultimately used,” Dr. Bahado-Singh said.

“This certainly isn’t the final step in Alzheimer’s research, but I think this represents a significant change in direction,” he told attendees at a press briefing.

The findings were published online March 31 in PLOS ONE.
 

Silver tsunami

The investigators noted that Alzheimer’s disease is often diagnosed when the disease is in its later stages, after irreversible brain damage has occurred. “There is currently no cure for the disease, and the treatment is limited to drugs that attempt to treat symptoms and have little effect on the disease’s progression,” they noted.

Coinvestigator Khaled Imam, MD, director of geriatric medicine for Beaumont Health in Michigan, pointed out that although MRI and lumbar puncture can identify Alzheimer’s disease early on, the processes are expensive and/or invasive.

“Having biomarkers in the blood ... and being able to identify [Alzheimer’s disease] years before symptoms start, hopefully we’d be able to intervene early on in the process of the disease,” Dr. Imam said.

It is estimated that the number of Americans aged 85 and older will triple by 2050. This impending “silver tsunami,” which will come with a commensurate increase in Alzheimer’s disease cases, makes it even more important to be able to diagnose the disease early on, he noted.

The study included 24 individuals with late-onset Alzheimer’s disease (70.8% women; mean age, 83 years); 24 were deemed to be “cognitively healthy” (66.7% women; mean age, 80 years). About 500 ng of genomic DNA was extracted from whole-blood samples from each participant.

The researchers used the Infinium MethylationEPIC BeadChip array, and the samples were then examined for markers of methylation that would “indicate the disease process has started,” they noted.

In addition to Deep Learning, the five other AI platforms were the Support Vector Machine, Generalized Linear Model, Prediction Analysis for Microarrays, Random Forest, and Linear Discriminant Analysis.

These platforms were used to assess leukocyte genome changes. To predict Alzheimer’s disease, the researchers also used Ingenuity Pathway Analysis.
 

Significant “chemical changes”

Results showed that the Alzheimer’s disease group had 152 significantly differentially methylated CpGs in 171 genes in comparison with the non-Alzheimer’s disease group (false discovery rate P value < .05).

As a whole, using intragenic and intergenic/extragenic CpGs, the AI platforms were effective in predicting who had Alzheimer’s disease (area under the curve [AUC], ≥ 0.93). Using intragenic markers, the AUC for Deep Learning was 0.99.

“We looked at close to a million different sites, and we saw some chemical changes that we know are associated with alteration or change in gene function,” Dr. Bahado-Singh said.

Altered genes that were found in the Alzheimer’s disease group included CR1L, CTSV, S1PR1, and LTB4R – all of which “have been previously linked with Alzheimer’s disease and dementia,” the researchers noted. They also found the methylated genes CTSV and PRMT5, both of which have been previously associated with cardiovascular disease.

“A significant strength of our study is the novelty, i.e. the use of blood leukocytes to accurately detect Alzheimer’s disease and also for interrogating the pathogenesis of Alzheimer’s disease,” the investigators wrote.

Dr. Bahado-Singh said that the test let them identify changes in cells in the blood, “giving us a comprehensive account not only of the fact that the brain is being affected by Alzheimer’s disease but it’s telling us what kinds of processes are going on in the brain.

“Normally you don’t have access to the brain. This gives us a simple blood test to get an ongoing reading of the course of events in the brain – and potentially tell us very early on before the onset of symptoms,” he added.
 

Cautiously optimistic

During the question-and-answer session following his presentation at the briefing, Dr. Bahado-Singh reiterated that they are at a very early stage in the research and were not able to make clinical recommendations at this point. However, he added, “There was evidence that DNA methylation change could likely precede the onset of abnormalities in the cells that give rise to the disease.”

Coinvestigator Stewart Graham, PhD, director of Alzheimer’s research at Beaumont Health, added that although the initial study findings led to some excitement for the team, “we have to be very conservative with what we say.”

He noted that the findings need to be replicated in a more diverse population. Still, “we’re excited at the moment and looking forward to seeing what the future results hold,” Dr. Graham said.

Dr. Bahado-Singh said that if larger studies confirm the findings and the test is viable, it would make sense to use it as a screen for individuals older than 65. He noted that because of the aging of the population, “this subset of individuals will constitute a larger and larger fraction of the population globally.”
 

Still early days

Commenting on the findings, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, noted that the investigators used an “interesting” diagnostic process.

“It was a unique approach to looking at and trying to understand what might be some of the biological underpinnings and using these tools and technologies to determine if they’re able to differentiate individuals with Alzheimer’s disease” from those without Alzheimer’s disease, said Dr. Snyder, who was not involved with the research.

“Ultimately, we want to know who is at greater risk, who may have some of the changing biology at the earliest time point so that we can intervene to stop the progression of the disease,” she said.

She pointed out that a number of types of biomarker tests are currently under investigation, many of which are measuring different outcomes. “And that’s what we want to see going forward. We want to have as many tools in our toolbox that allow us to accurately diagnose at that earliest time point,” Dr. Snyder said.

“At this point, [the current study] is still pretty early, so it needs to be replicated and then expanded to larger groups to really understand what they may be seeing,” she added.

Dr. Bahado-Singh, Dr. Imam, Dr. Graham, and Dr. Snyder have reported no relevant financial relationships.

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

Toxic metabolic encephalopathy (TME) is common and often lethal in hospitalized patients with COVID-19, new research shows. Results of a retrospective study show that of almost 4,500 patients with COVID-19, 12% were diagnosed with TME. Of these, 78% developed encephalopathy immediately prior to hospital admission. Septic encephalopathy, hypoxic-ischemic encephalopathy (HIE), and uremia were the most common causes, although multiple causes were present in close to 80% of patients. TME was also associated with a 24% higher risk of in-hospital death.

“We found that close to one in eight patients who were hospitalized with COVID-19 had TME that was not attributed to the effects of sedatives, and that this is incredibly common among these patients who are critically ill” said lead author Jennifer A. Frontera, MD, New York University.

“The general principle of our findings is to be more aggressive in TME; and from a neurologist perspective, the way to do this is to eliminate the effects of sedation, which is a confounder,” she said.

The study was published online March 16 in Neurocritical Care.
 

Drilling down

“Many neurological complications of COVID-19 are sequelae of severe illness or secondary effects of multisystem organ failure, but our previous work identified TME as the most common neurological complication,” Dr. Frontera said.

Previous research investigating encephalopathy among patients with COVID-19 included patients who may have been sedated or have had a positive Confusion Assessment Method (CAM) result.

“A lot of the delirium literature is effectively heterogeneous because there are a number of patients who are on sedative medication that, if you could turn it off, these patients would return to normal. Some may have underlying neurological issues that can be addressed, but you can›t get to the bottom of this unless you turn off the sedation,” Dr. Frontera noted.

“We wanted to be specific and try to drill down to see what the underlying cause of the encephalopathy was,” she said.

The researchers retrospectively analyzed data on 4,491 patients (≥ 18 years old) with COVID-19 who were admitted to four New York City hospitals between March 1, 2020, and May 20, 2020. Of these, 559 (12%) with TME were compared with 3,932 patients without TME.

The researchers looked at index admissions and included patients who had:

• New changes in mental status or significant worsening of mental status (in patients with baseline abnormal mental status).
• Hyperglycemia or  with transient focal neurologic deficits that resolved with glucose correction.
• An adequate washout of sedating medications (when relevant) prior to mental status assessment.

Potential etiologies included electrolyte abnormalities, organ failure, hypertensive encephalopathy, sepsis or active infection, fever, nutritional deficiency, and environmental injury.
 

Foreign environment

Most (78%) of the 559 patients diagnosed with TME had already developed encephalopathy immediately prior to hospital admission, the authors report. The most common etiologies of TME among hospitalized patients with COVID-19 are listed below.

Compared with patients without TME, those with TME – (all Ps < .001):

• Were older (76 vs. 62 years).
• Had higher rates of dementia (27% vs. 3%).
• Had higher rates of psychiatric history (20% vs. 10%).
• Were more often intubated (37% vs. 20%).
• Had a longer length of hospital stay (7.9 vs. 6.0 days).
• Were less often discharged home (25% vs. 66%).

“It’s no surprise that older patients and people with dementia or psychiatric illness are predisposed to becoming encephalopathic,” said Dr. Frontera. “Being in a foreign environment, such as a hospital, or being sleep-deprived in the ICU is likely to make them more confused during their hospital stay.”
 

Delirium as a symptom

In-hospital mortality or discharge to hospice was considerably higher in the TME versus non-TME patients (44% vs. 18%, respectively).

When the researchers adjusted for confounders (age, sex, race, worse Sequential Organ Failure Assessment score during hospitalization, ventilator status, study week, hospital location, and ICU care level) and excluded patients receiving only comfort care, they found that TME was associated with a 24% increased risk of in-hospital death (30% in patients with TME vs. 16% in those without TME).

The highest mortality risk was associated with hypoxemia, with 42% of patients with HIE dying during hospitalization, compared with 16% of patients without HIE (adjusted hazard ratio 1.56; 95% confidence interval, 1.21-2.00; P = .001).

“Not all patients who are intubated require sedation, but there’s generally a lot of hesitation in reducing or stopping sedation in some patients,” Dr. Frontera observed.

She acknowledged there are “many extremely sick patients whom you can’t ventilate without sedation.”

Nevertheless, “delirium in and of itself does not cause death. It’s a symptom, not a disease, and we have to figure out what causes it. Delirium might not need to be sedated, and it’s more important to see what the causal problem is.”
 

Independent predictor of death

Commenting on the study, Panayiotis N. Varelas, MD, PhD, vice president of the Neurocritical Care Society, said the study “approached the TME issue better than previously, namely allowing time for sedatives to wear off to have a better sample of patients with this syndrome.”

Dr. Varelas, who is chairman of the department of neurology and professor of neurology at Albany (N.Y.) Medical College, emphasized that TME “is not benign and, in patients with COVID-19, it is an independent predictor of in-hospital mortality.”

“One should take all possible measures … to avoid desaturation and hypotensive episodes and also aggressively treat SAE and uremic encephalopathy in hopes of improving the outcomes,” added Dr. Varelas, who was not involved with the study.

Also commenting on the study, Mitchell Elkind, MD, professor of neurology and epidemiology at Columbia University in New York, who was not associated with the research, said it “nicely distinguishes among the different causes of encephalopathy, including sepsis, hypoxia, and kidney failure … emphasizing just how sick these patients are.”

The study received no direct funding. Individual investigators were supported by grants from the National Institute on Aging and the National Institute of Neurological Disorders and Stroke. The investigators, Dr. Varelas, and Dr. Elkind have disclosed no relevant financial relationships.

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

Toxic metabolic encephalopathy (TME) is common and often lethal in hospitalized patients with COVID-19, new research shows. Results of a retrospective study show that of almost 4,500 patients with COVID-19, 12% were diagnosed with TME. Of these, 78% developed encephalopathy immediately prior to hospital admission. Septic encephalopathy, hypoxic-ischemic encephalopathy (HIE), and uremia were the most common causes, although multiple causes were present in close to 80% of patients. TME was also associated with a 24% higher risk of in-hospital death.

“We found that close to one in eight patients who were hospitalized with COVID-19 had TME that was not attributed to the effects of sedatives, and that this is incredibly common among these patients who are critically ill” said lead author Jennifer A. Frontera, MD, New York University.

“The general principle of our findings is to be more aggressive in TME; and from a neurologist perspective, the way to do this is to eliminate the effects of sedation, which is a confounder,” she said.

The study was published online March 16 in Neurocritical Care.
 

Drilling down

“Many neurological complications of COVID-19 are sequelae of severe illness or secondary effects of multisystem organ failure, but our previous work identified TME as the most common neurological complication,” Dr. Frontera said.

Previous research investigating encephalopathy among patients with COVID-19 included patients who may have been sedated or have had a positive Confusion Assessment Method (CAM) result.

“A lot of the delirium literature is effectively heterogeneous because there are a number of patients who are on sedative medication that, if you could turn it off, these patients would return to normal. Some may have underlying neurological issues that can be addressed, but you can›t get to the bottom of this unless you turn off the sedation,” Dr. Frontera noted.

“We wanted to be specific and try to drill down to see what the underlying cause of the encephalopathy was,” she said.

The researchers retrospectively analyzed data on 4,491 patients (≥ 18 years old) with COVID-19 who were admitted to four New York City hospitals between March 1, 2020, and May 20, 2020. Of these, 559 (12%) with TME were compared with 3,932 patients without TME.

The researchers looked at index admissions and included patients who had:

• New changes in mental status or significant worsening of mental status (in patients with baseline abnormal mental status).
• Hyperglycemia or  with transient focal neurologic deficits that resolved with glucose correction.
• An adequate washout of sedating medications (when relevant) prior to mental status assessment.

Potential etiologies included electrolyte abnormalities, organ failure, hypertensive encephalopathy, sepsis or active infection, fever, nutritional deficiency, and environmental injury.
 

Foreign environment

Most (78%) of the 559 patients diagnosed with TME had already developed encephalopathy immediately prior to hospital admission, the authors report. The most common etiologies of TME among hospitalized patients with COVID-19 are listed below.

Compared with patients without TME, those with TME – (all Ps < .001):

• Were older (76 vs. 62 years).
• Had higher rates of dementia (27% vs. 3%).
• Had higher rates of psychiatric history (20% vs. 10%).
• Were more often intubated (37% vs. 20%).
• Had a longer length of hospital stay (7.9 vs. 6.0 days).
• Were less often discharged home (25% vs. 66%).

“It’s no surprise that older patients and people with dementia or psychiatric illness are predisposed to becoming encephalopathic,” said Dr. Frontera. “Being in a foreign environment, such as a hospital, or being sleep-deprived in the ICU is likely to make them more confused during their hospital stay.”
 

Delirium as a symptom

In-hospital mortality or discharge to hospice was considerably higher in the TME versus non-TME patients (44% vs. 18%, respectively).

When the researchers adjusted for confounders (age, sex, race, worse Sequential Organ Failure Assessment score during hospitalization, ventilator status, study week, hospital location, and ICU care level) and excluded patients receiving only comfort care, they found that TME was associated with a 24% increased risk of in-hospital death (30% in patients with TME vs. 16% in those without TME).

The highest mortality risk was associated with hypoxemia, with 42% of patients with HIE dying during hospitalization, compared with 16% of patients without HIE (adjusted hazard ratio 1.56; 95% confidence interval, 1.21-2.00; P = .001).

“Not all patients who are intubated require sedation, but there’s generally a lot of hesitation in reducing or stopping sedation in some patients,” Dr. Frontera observed.

She acknowledged there are “many extremely sick patients whom you can’t ventilate without sedation.”

Nevertheless, “delirium in and of itself does not cause death. It’s a symptom, not a disease, and we have to figure out what causes it. Delirium might not need to be sedated, and it’s more important to see what the causal problem is.”
 

Independent predictor of death

Commenting on the study, Panayiotis N. Varelas, MD, PhD, vice president of the Neurocritical Care Society, said the study “approached the TME issue better than previously, namely allowing time for sedatives to wear off to have a better sample of patients with this syndrome.”

Dr. Varelas, who is chairman of the department of neurology and professor of neurology at Albany (N.Y.) Medical College, emphasized that TME “is not benign and, in patients with COVID-19, it is an independent predictor of in-hospital mortality.”

“One should take all possible measures … to avoid desaturation and hypotensive episodes and also aggressively treat SAE and uremic encephalopathy in hopes of improving the outcomes,” added Dr. Varelas, who was not involved with the study.

Also commenting on the study, Mitchell Elkind, MD, professor of neurology and epidemiology at Columbia University in New York, who was not associated with the research, said it “nicely distinguishes among the different causes of encephalopathy, including sepsis, hypoxia, and kidney failure … emphasizing just how sick these patients are.”

The study received no direct funding. Individual investigators were supported by grants from the National Institute on Aging and the National Institute of Neurological Disorders and Stroke. The investigators, Dr. Varelas, and Dr. Elkind have disclosed no relevant financial relationships.

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

Toxic metabolic encephalopathy (TME) is common and often lethal in hospitalized patients with COVID-19, new research shows. Results of a retrospective study show that of almost 4,500 patients with COVID-19, 12% were diagnosed with TME. Of these, 78% developed encephalopathy immediately prior to hospital admission. Septic encephalopathy, hypoxic-ischemic encephalopathy (HIE), and uremia were the most common causes, although multiple causes were present in close to 80% of patients. TME was also associated with a 24% higher risk of in-hospital death.

“We found that close to one in eight patients who were hospitalized with COVID-19 had TME that was not attributed to the effects of sedatives, and that this is incredibly common among these patients who are critically ill” said lead author Jennifer A. Frontera, MD, New York University.

“The general principle of our findings is to be more aggressive in TME; and from a neurologist perspective, the way to do this is to eliminate the effects of sedation, which is a confounder,” she said.

The study was published online March 16 in Neurocritical Care.
 

Drilling down

“Many neurological complications of COVID-19 are sequelae of severe illness or secondary effects of multisystem organ failure, but our previous work identified TME as the most common neurological complication,” Dr. Frontera said.

Previous research investigating encephalopathy among patients with COVID-19 included patients who may have been sedated or have had a positive Confusion Assessment Method (CAM) result.

“A lot of the delirium literature is effectively heterogeneous because there are a number of patients who are on sedative medication that, if you could turn it off, these patients would return to normal. Some may have underlying neurological issues that can be addressed, but you can›t get to the bottom of this unless you turn off the sedation,” Dr. Frontera noted.

“We wanted to be specific and try to drill down to see what the underlying cause of the encephalopathy was,” she said.

The researchers retrospectively analyzed data on 4,491 patients (≥ 18 years old) with COVID-19 who were admitted to four New York City hospitals between March 1, 2020, and May 20, 2020. Of these, 559 (12%) with TME were compared with 3,932 patients without TME.

The researchers looked at index admissions and included patients who had:

• New changes in mental status or significant worsening of mental status (in patients with baseline abnormal mental status).
• Hyperglycemia or  with transient focal neurologic deficits that resolved with glucose correction.
• An adequate washout of sedating medications (when relevant) prior to mental status assessment.

Potential etiologies included electrolyte abnormalities, organ failure, hypertensive encephalopathy, sepsis or active infection, fever, nutritional deficiency, and environmental injury.
 

Foreign environment

Most (78%) of the 559 patients diagnosed with TME had already developed encephalopathy immediately prior to hospital admission, the authors report. The most common etiologies of TME among hospitalized patients with COVID-19 are listed below.

Compared with patients without TME, those with TME – (all Ps < .001):

• Were older (76 vs. 62 years).
• Had higher rates of dementia (27% vs. 3%).
• Had higher rates of psychiatric history (20% vs. 10%).
• Were more often intubated (37% vs. 20%).
• Had a longer length of hospital stay (7.9 vs. 6.0 days).
• Were less often discharged home (25% vs. 66%).

“It’s no surprise that older patients and people with dementia or psychiatric illness are predisposed to becoming encephalopathic,” said Dr. Frontera. “Being in a foreign environment, such as a hospital, or being sleep-deprived in the ICU is likely to make them more confused during their hospital stay.”
 

Delirium as a symptom

In-hospital mortality or discharge to hospice was considerably higher in the TME versus non-TME patients (44% vs. 18%, respectively).

When the researchers adjusted for confounders (age, sex, race, worse Sequential Organ Failure Assessment score during hospitalization, ventilator status, study week, hospital location, and ICU care level) and excluded patients receiving only comfort care, they found that TME was associated with a 24% increased risk of in-hospital death (30% in patients with TME vs. 16% in those without TME).

The highest mortality risk was associated with hypoxemia, with 42% of patients with HIE dying during hospitalization, compared with 16% of patients without HIE (adjusted hazard ratio 1.56; 95% confidence interval, 1.21-2.00; P = .001).

“Not all patients who are intubated require sedation, but there’s generally a lot of hesitation in reducing or stopping sedation in some patients,” Dr. Frontera observed.

She acknowledged there are “many extremely sick patients whom you can’t ventilate without sedation.”

Nevertheless, “delirium in and of itself does not cause death. It’s a symptom, not a disease, and we have to figure out what causes it. Delirium might not need to be sedated, and it’s more important to see what the causal problem is.”
 

Independent predictor of death

Commenting on the study, Panayiotis N. Varelas, MD, PhD, vice president of the Neurocritical Care Society, said the study “approached the TME issue better than previously, namely allowing time for sedatives to wear off to have a better sample of patients with this syndrome.”

Dr. Varelas, who is chairman of the department of neurology and professor of neurology at Albany (N.Y.) Medical College, emphasized that TME “is not benign and, in patients with COVID-19, it is an independent predictor of in-hospital mortality.”

“One should take all possible measures … to avoid desaturation and hypotensive episodes and also aggressively treat SAE and uremic encephalopathy in hopes of improving the outcomes,” added Dr. Varelas, who was not involved with the study.

Also commenting on the study, Mitchell Elkind, MD, professor of neurology and epidemiology at Columbia University in New York, who was not associated with the research, said it “nicely distinguishes among the different causes of encephalopathy, including sepsis, hypoxia, and kidney failure … emphasizing just how sick these patients are.”

The study received no direct funding. Individual investigators were supported by grants from the National Institute on Aging and the National Institute of Neurological Disorders and Stroke. The investigators, Dr. Varelas, and Dr. Elkind have disclosed no relevant financial relationships.

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

Medicare payments for branded neurologic drugs jumped 50% over a 5-year period, while claims for these medications increased by just 8%, new research shows. Results of the retrospective study also showed that most of the increased costs for these agents were due to rising costs for neuroimmunology drugs, mainly for those used to treat multiple sclerosis (MS).

“The same brand name medication in 2017 cost approximately 50% more than in 2013,” said Adam de Havenon, MD, assistant professor of neurology, University of Utah, Salt Lake City.

“An analogy would be if you bought an iPhone 5 in 2013 for $500, and then in 2017, you were asked to pay $750 for the exact same iPhone 5,” Dr. de Havenon added.

The study findings were published online March 10 in the journal Neurology.
 

$26 billion in payments

Both neurologists and patients are concerned about the high cost of prescription drugs for neurologic diseases, and Medicare Part D data indicate that these drugs are the most expensive component of neurologic care, the researchers noted. In addition, out-of-pocket costs have increased significantly for patients with neurologic disease such as Parkinson’s disease, epilepsy, and MS.

To understand trends in payments for neurologic drugs, Dr. de Havenon and colleagues analyzed Medicare Part D claims filed from 2013 to 2017. The payments include costs paid by Medicare, the patient, government subsidies, and other third-party payers.

In addition to examining more current Medicare Part D data than previous studies, the current analysis examined all medications prescribed by neurologists that consistently remained branded or generic during the 5-year study period, said Dr. de Havenon. This approach resulted in a large number of claims and a large total cost.

To calculate the percentage change in annual payment claims, the researchers used 2013 prices as a reference point. They identified drugs named in 2013 claims and classified them as generic, brand-name only, or brand-name with generic equivalent. Researchers also divided the drugs by neurologic subspecialty.

The analysis included 520 drugs, all of which were available in each year of the study period. Of these drugs, 322 were generic, 61 were brand-name only, and 137 were brand-name with a generic equivalent. There were 90.7 million total claims.

Results showed total payments amounted to $26.65 billion. Yearly total payments increased from $4.05 billion in 2013 to $6.09 billion in 2017, representing a 50.4% increase, even after adjusting for inflation. Total claims increased by 7.6% – from 17.1 million in 2013 to 18.4 million in 2017.

From 2013 to 2017, claim payments increased by 0.6% for generic drugs, 42.4% for brand-name only drugs, and 45% for brand-name drugs with generic equivalents. The proportion of claims increased from 81.9% to 88% for generic drugs and from 4.9% to 6.2% for brand-name only drugs.

However, the proportion of claims for brand-name drugs with generic equivalents decreased from 13.3% to 5.8%.
 

Treatment barrier

Neuroimmunologic drugs, most of which were prescribed for MS, had exceptional cost, the researchers noted. These drugs accounted for more than 50% of payments but only 4.3% of claims. Claim payment for these drugs increased by 46.9% during the study period, from $3,337 to $4,902.

When neuroimmunologic drugs were removed from the analysis there was still significant increase in claim payments for brand-name only drugs (50.4%) and brand-name drugs with generic equivalents (45.6%).

Although neuroimmunologic medicines, including monoclonal antibodies, are more expensive to produce, this factor alone does not explain their exceptional cost, said Dr. de Havenon. “The high cost of brand-name drugs in this speciality is likely because the market bears it,” he added. “In other words, MS is a disabling disease and the medications work, so historically the Centers for Medicare & Medicaid Services have been willing to tolerate the high cost of these primarily brand-name medications.”

Several countries have controlled drug costs by negotiating with pharmaceutical companies and through legislation, Dr. de Havenon noted.

“My intent with this article was to raise awareness on the topic, which I struggle with frequently as a clinician. I know I want my patients to have a medication, but the cost prevents it,” he said.
 

‘Unfettered’ price-setting

Commenting on the findings, Robert J. Fox, MD, vice chair for research at the Neurological Institute of the Cleveland Clinic, said the study “brings into clear light” what neurologists, particularly those who treat MS, have long suspected but did not really know. These neurologists “are typically distanced from the payment aspects of the medications they prescribe,” said Dr. Fox, who was not involved with the research.

Although a particular strength of the study was its comprehensiveness, the researchers excluded infusion claims – which account for a large portion of total patient care costs for many disorders, he noted.

Drugs for MS historically have been expensive, ostensibly because of their high cost of development. In addition, the large and continued price increase that occurs long after these drugs have been approved remains unexplained, said Dr. Fox.

He noted that the study findings might not directly affect clinical practice because neurologists will continue prescribing medications they think are best for their patients. “Instead, I think this is a lesson to lawmakers about the massive error in the Medicare Modernization Act of 2003, where the federal government was prohibited from negotiating drug prices. If the seller is unfettered in setting a price, then no one should be surprised when the price rises,” Dr. Fox said.

Because many new drugs and new generic formulations for treating MS have become available during the past year, “repeating these types of economic studies for the period 2020-2025 will help us understand if generic competition – as well as new laws if they are passed – alter price,” he concluded.

The study was funded by the American Academy of Neurology, which publishes Neurology. Dr. de Havenon has received clinical research funding from AMAG Pharmaceuticals and Regeneron Pharmaceuticals. Dr. Fox receives consulting fees from many pharmaceutical companies involved in the development of therapies for MS.

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

Medicare payments for branded neurologic drugs jumped 50% over a 5-year period, while claims for these medications increased by just 8%, new research shows. Results of the retrospective study also showed that most of the increased costs for these agents were due to rising costs for neuroimmunology drugs, mainly for those used to treat multiple sclerosis (MS).

“The same brand name medication in 2017 cost approximately 50% more than in 2013,” said Adam de Havenon, MD, assistant professor of neurology, University of Utah, Salt Lake City.

“An analogy would be if you bought an iPhone 5 in 2013 for $500, and then in 2017, you were asked to pay $750 for the exact same iPhone 5,” Dr. de Havenon added.

The study findings were published online March 10 in the journal Neurology.
 

$26 billion in payments

Both neurologists and patients are concerned about the high cost of prescription drugs for neurologic diseases, and Medicare Part D data indicate that these drugs are the most expensive component of neurologic care, the researchers noted. In addition, out-of-pocket costs have increased significantly for patients with neurologic disease such as Parkinson’s disease, epilepsy, and MS.

To understand trends in payments for neurologic drugs, Dr. de Havenon and colleagues analyzed Medicare Part D claims filed from 2013 to 2017. The payments include costs paid by Medicare, the patient, government subsidies, and other third-party payers.

In addition to examining more current Medicare Part D data than previous studies, the current analysis examined all medications prescribed by neurologists that consistently remained branded or generic during the 5-year study period, said Dr. de Havenon. This approach resulted in a large number of claims and a large total cost.

To calculate the percentage change in annual payment claims, the researchers used 2013 prices as a reference point. They identified drugs named in 2013 claims and classified them as generic, brand-name only, or brand-name with generic equivalent. Researchers also divided the drugs by neurologic subspecialty.

The analysis included 520 drugs, all of which were available in each year of the study period. Of these drugs, 322 were generic, 61 were brand-name only, and 137 were brand-name with a generic equivalent. There were 90.7 million total claims.

Results showed total payments amounted to $26.65 billion. Yearly total payments increased from $4.05 billion in 2013 to $6.09 billion in 2017, representing a 50.4% increase, even after adjusting for inflation. Total claims increased by 7.6% – from 17.1 million in 2013 to 18.4 million in 2017.

From 2013 to 2017, claim payments increased by 0.6% for generic drugs, 42.4% for brand-name only drugs, and 45% for brand-name drugs with generic equivalents. The proportion of claims increased from 81.9% to 88% for generic drugs and from 4.9% to 6.2% for brand-name only drugs.

However, the proportion of claims for brand-name drugs with generic equivalents decreased from 13.3% to 5.8%.
 

Treatment barrier

Neuroimmunologic drugs, most of which were prescribed for MS, had exceptional cost, the researchers noted. These drugs accounted for more than 50% of payments but only 4.3% of claims. Claim payment for these drugs increased by 46.9% during the study period, from $3,337 to $4,902.

When neuroimmunologic drugs were removed from the analysis there was still significant increase in claim payments for brand-name only drugs (50.4%) and brand-name drugs with generic equivalents (45.6%).

Although neuroimmunologic medicines, including monoclonal antibodies, are more expensive to produce, this factor alone does not explain their exceptional cost, said Dr. de Havenon. “The high cost of brand-name drugs in this speciality is likely because the market bears it,” he added. “In other words, MS is a disabling disease and the medications work, so historically the Centers for Medicare & Medicaid Services have been willing to tolerate the high cost of these primarily brand-name medications.”

Several countries have controlled drug costs by negotiating with pharmaceutical companies and through legislation, Dr. de Havenon noted.

“My intent with this article was to raise awareness on the topic, which I struggle with frequently as a clinician. I know I want my patients to have a medication, but the cost prevents it,” he said.
 

‘Unfettered’ price-setting

Commenting on the findings, Robert J. Fox, MD, vice chair for research at the Neurological Institute of the Cleveland Clinic, said the study “brings into clear light” what neurologists, particularly those who treat MS, have long suspected but did not really know. These neurologists “are typically distanced from the payment aspects of the medications they prescribe,” said Dr. Fox, who was not involved with the research.

Although a particular strength of the study was its comprehensiveness, the researchers excluded infusion claims – which account for a large portion of total patient care costs for many disorders, he noted.

Drugs for MS historically have been expensive, ostensibly because of their high cost of development. In addition, the large and continued price increase that occurs long after these drugs have been approved remains unexplained, said Dr. Fox.

He noted that the study findings might not directly affect clinical practice because neurologists will continue prescribing medications they think are best for their patients. “Instead, I think this is a lesson to lawmakers about the massive error in the Medicare Modernization Act of 2003, where the federal government was prohibited from negotiating drug prices. If the seller is unfettered in setting a price, then no one should be surprised when the price rises,” Dr. Fox said.

Because many new drugs and new generic formulations for treating MS have become available during the past year, “repeating these types of economic studies for the period 2020-2025 will help us understand if generic competition – as well as new laws if they are passed – alter price,” he concluded.

The study was funded by the American Academy of Neurology, which publishes Neurology. Dr. de Havenon has received clinical research funding from AMAG Pharmaceuticals and Regeneron Pharmaceuticals. Dr. Fox receives consulting fees from many pharmaceutical companies involved in the development of therapies for MS.

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

Medicare payments for branded neurologic drugs jumped 50% over a 5-year period, while claims for these medications increased by just 8%, new research shows. Results of the retrospective study also showed that most of the increased costs for these agents were due to rising costs for neuroimmunology drugs, mainly for those used to treat multiple sclerosis (MS).

“The same brand name medication in 2017 cost approximately 50% more than in 2013,” said Adam de Havenon, MD, assistant professor of neurology, University of Utah, Salt Lake City.

“An analogy would be if you bought an iPhone 5 in 2013 for $500, and then in 2017, you were asked to pay $750 for the exact same iPhone 5,” Dr. de Havenon added.

The study findings were published online March 10 in the journal Neurology.
 

$26 billion in payments

Both neurologists and patients are concerned about the high cost of prescription drugs for neurologic diseases, and Medicare Part D data indicate that these drugs are the most expensive component of neurologic care, the researchers noted. In addition, out-of-pocket costs have increased significantly for patients with neurologic disease such as Parkinson’s disease, epilepsy, and MS.

To understand trends in payments for neurologic drugs, Dr. de Havenon and colleagues analyzed Medicare Part D claims filed from 2013 to 2017. The payments include costs paid by Medicare, the patient, government subsidies, and other third-party payers.

In addition to examining more current Medicare Part D data than previous studies, the current analysis examined all medications prescribed by neurologists that consistently remained branded or generic during the 5-year study period, said Dr. de Havenon. This approach resulted in a large number of claims and a large total cost.

To calculate the percentage change in annual payment claims, the researchers used 2013 prices as a reference point. They identified drugs named in 2013 claims and classified them as generic, brand-name only, or brand-name with generic equivalent. Researchers also divided the drugs by neurologic subspecialty.

The analysis included 520 drugs, all of which were available in each year of the study period. Of these drugs, 322 were generic, 61 were brand-name only, and 137 were brand-name with a generic equivalent. There were 90.7 million total claims.

Results showed total payments amounted to $26.65 billion. Yearly total payments increased from $4.05 billion in 2013 to $6.09 billion in 2017, representing a 50.4% increase, even after adjusting for inflation. Total claims increased by 7.6% – from 17.1 million in 2013 to 18.4 million in 2017.

From 2013 to 2017, claim payments increased by 0.6% for generic drugs, 42.4% for brand-name only drugs, and 45% for brand-name drugs with generic equivalents. The proportion of claims increased from 81.9% to 88% for generic drugs and from 4.9% to 6.2% for brand-name only drugs.

However, the proportion of claims for brand-name drugs with generic equivalents decreased from 13.3% to 5.8%.
 

Treatment barrier

Neuroimmunologic drugs, most of which were prescribed for MS, had exceptional cost, the researchers noted. These drugs accounted for more than 50% of payments but only 4.3% of claims. Claim payment for these drugs increased by 46.9% during the study period, from $3,337 to $4,902.

When neuroimmunologic drugs were removed from the analysis there was still significant increase in claim payments for brand-name only drugs (50.4%) and brand-name drugs with generic equivalents (45.6%).

Although neuroimmunologic medicines, including monoclonal antibodies, are more expensive to produce, this factor alone does not explain their exceptional cost, said Dr. de Havenon. “The high cost of brand-name drugs in this speciality is likely because the market bears it,” he added. “In other words, MS is a disabling disease and the medications work, so historically the Centers for Medicare & Medicaid Services have been willing to tolerate the high cost of these primarily brand-name medications.”

Several countries have controlled drug costs by negotiating with pharmaceutical companies and through legislation, Dr. de Havenon noted.

“My intent with this article was to raise awareness on the topic, which I struggle with frequently as a clinician. I know I want my patients to have a medication, but the cost prevents it,” he said.
 

‘Unfettered’ price-setting

Commenting on the findings, Robert J. Fox, MD, vice chair for research at the Neurological Institute of the Cleveland Clinic, said the study “brings into clear light” what neurologists, particularly those who treat MS, have long suspected but did not really know. These neurologists “are typically distanced from the payment aspects of the medications they prescribe,” said Dr. Fox, who was not involved with the research.

Although a particular strength of the study was its comprehensiveness, the researchers excluded infusion claims – which account for a large portion of total patient care costs for many disorders, he noted.

Drugs for MS historically have been expensive, ostensibly because of their high cost of development. In addition, the large and continued price increase that occurs long after these drugs have been approved remains unexplained, said Dr. Fox.

He noted that the study findings might not directly affect clinical practice because neurologists will continue prescribing medications they think are best for their patients. “Instead, I think this is a lesson to lawmakers about the massive error in the Medicare Modernization Act of 2003, where the federal government was prohibited from negotiating drug prices. If the seller is unfettered in setting a price, then no one should be surprised when the price rises,” Dr. Fox said.

Because many new drugs and new generic formulations for treating MS have become available during the past year, “repeating these types of economic studies for the period 2020-2025 will help us understand if generic competition – as well as new laws if they are passed – alter price,” he concluded.

The study was funded by the American Academy of Neurology, which publishes Neurology. Dr. de Havenon has received clinical research funding from AMAG Pharmaceuticals and Regeneron Pharmaceuticals. Dr. Fox receives consulting fees from many pharmaceutical companies involved in the development of therapies for MS.

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

A significant proportion of community-dwelling older adults with dementia take three or more central nervous system medications despite guidelines that say to avoid this dangerous practice, new research suggests.

Investigators found that 14% of these individuals were receiving CNS-active polypharmacy, defined as combinations of multiple psychotropic and opioid medications taken for more than 30 days.

“For most patients, the risks of these medications, particularly in combination, are almost certainly greater than the potential benefits,” said Donovan Maust, MD, associate director of the geriatric psychiatry program, University of Michigan, Ann Arbor.

The study was published online March 9 in JAMA.
 

Serious risks

Memory impairment is the cardinal feature of dementia, but behavioral and psychological symptoms, which can include apathy, delusions, and agitation, are common during all stages of illness and cause significant caregiver distress, the researchers noted.

They noted that there is a dearth of high-quality evidence to support prescribing these medications in this patient population, yet “clinicians regularly prescribe psychotropic medications to community-dwelling persons with dementia in rates that far exceed use in the general older adult population.”

The Beers Criteria, from the American Geriatrics Society, advise against the practice of CNS polypharmacy because of the significant increase in risk for falls as well as impaired cognition, cardiac conduction abnormalities, respiratory suppression, and death when polypharmacy involves opioids.

They note that previous studies from Europe of polypharmacy for patients with dementia have not included antiepileptic medications or opioids, so the true extent of CNS-active polypharmacy may be “significantly” underestimated.

To determine the prevalence of polypharmacy with CNS-active medications among community-dwelling older adults with dementia, the researchers analyzed data on prescription fills for nearly 1.2 million community-dwelling Medicare patients with dementia.

The primary outcome was the prevalence of CNS-active polypharmacy in 2018. They defined CNS-active polypharmacy as exposure to three or more medications for more than 30 consecutive days from the following drug classes: antidepressants, antipsychotics, antiepileptics, benzodiazepines, nonbenzodiazepines, benzodiazepine receptor agonist hypnotics, and opioids.

They found that roughly one in seven (13.9%) patients met criteria for CNS-active polypharmacy. Of those receiving a CNS-active polypharmacy regimen, 57.8% had been doing so for longer than 180 days, and 6.8% had been doing so for a year. Nearly 30% of patients were exposed to five or more medications, and 5.2% were exposed to five or more medication classes.
 

Conservative approach warranted

Nearly all (92%) patients taking three or more CNS-active medications were taking an antidepressant, “consistent with their place as the psychotropic class most commonly prescribed both to older adults overall and those with dementia,” the investigators noted.

There is minimal high-quality evidence to support the efficacy of antidepressants for the treatment of depression for patients with dementia, they pointed out.

Nearly half (47%) of patients who were taking three or more CNS-active medications received at least one antipsychotic, most often quetiapine. Antipsychotics are not approved for people with dementia but are often prescribed off label for agitation, anxiety, and sleep problems, the researchers noted.

Nearly two thirds (62%) of patients with dementia who were taking three or more CNS drugs were taking an antiepileptic (most commonly, gabapentin); 41%, benzodiazepines; 32%, opioids; and 6%, Z-drugs.

The most common polypharmacy class combination included at least one antidepressant, one antiepileptic, and one antipsychotic. These accounted for 12.9% of polypharmacy days.

Despite limited high-quality evidence of efficacy, the prescribing of psychotropic medications and opioids is “pervasive” for adults with dementia in the United States, the investigators noted.

“Especially given that older adults with dementia might not be able to convey side effects they are experiencing, I think clinicians should be more conservative in how they are prescribing these medications and skeptical about the potential for benefit,” said Dr. Maust.

Regarding study limitations, the researchers noted that prescription medication claims may have led to an overestimation of the exposure to polypharmacy, insofar as the prescriptions may have been filled but not taken or were taken only on an as-needed basis.

In addition, the investigators were unable to determine the appropriateness of the particular combinations used or to examine the specific harms associated with CNS-active polypharmacy.
 

A major clinical challenge

Weighing in on the results, Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation, said the study is important because polypharmacy is one of the “geriatric giants, and the question is, what do you do about it?”

Dr. Fillit said it is important to conduct a careful medication review for all older patients, “making sure that the use of each drug is appropriate. The most important thing is to define what is the appropriate utilization of these kinds of drugs. That goes for both overutilization or misuse of these drugs and underutilization, where people are undertreated for symptoms that can’t be managed by behavioral management, for example,” Dr. Fillit said.

Dr. Fillit also said the finding that about 14% of dementia patients were receiving three or more of these drugs “may not be an outrageous number, because these patients, especially as they get into moderate and severe stages of disease, can be incredibly difficult to manage.

“Very often, dementia patients have depression, and up to 90% will have agitation and even psychosis during the course of dementia. And many of these patients need these types of drugs,” said Dr. Fillit.

Echoing the authors, Dr. Fillit said a key limitation of the study is not knowing whether the prescribing was appropriate or not.

The study was supported by a grant from the National Institute on Aging. Dr. Maust and Dr. Fillit have disclosed no relevant financial relationships.

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

A significant proportion of community-dwelling older adults with dementia take three or more central nervous system medications despite guidelines that say to avoid this dangerous practice, new research suggests.

Investigators found that 14% of these individuals were receiving CNS-active polypharmacy, defined as combinations of multiple psychotropic and opioid medications taken for more than 30 days.

“For most patients, the risks of these medications, particularly in combination, are almost certainly greater than the potential benefits,” said Donovan Maust, MD, associate director of the geriatric psychiatry program, University of Michigan, Ann Arbor.

The study was published online March 9 in JAMA.
 

Serious risks

Memory impairment is the cardinal feature of dementia, but behavioral and psychological symptoms, which can include apathy, delusions, and agitation, are common during all stages of illness and cause significant caregiver distress, the researchers noted.

They noted that there is a dearth of high-quality evidence to support prescribing these medications in this patient population, yet “clinicians regularly prescribe psychotropic medications to community-dwelling persons with dementia in rates that far exceed use in the general older adult population.”

The Beers Criteria, from the American Geriatrics Society, advise against the practice of CNS polypharmacy because of the significant increase in risk for falls as well as impaired cognition, cardiac conduction abnormalities, respiratory suppression, and death when polypharmacy involves opioids.

They note that previous studies from Europe of polypharmacy for patients with dementia have not included antiepileptic medications or opioids, so the true extent of CNS-active polypharmacy may be “significantly” underestimated.

To determine the prevalence of polypharmacy with CNS-active medications among community-dwelling older adults with dementia, the researchers analyzed data on prescription fills for nearly 1.2 million community-dwelling Medicare patients with dementia.

The primary outcome was the prevalence of CNS-active polypharmacy in 2018. They defined CNS-active polypharmacy as exposure to three or more medications for more than 30 consecutive days from the following drug classes: antidepressants, antipsychotics, antiepileptics, benzodiazepines, nonbenzodiazepines, benzodiazepine receptor agonist hypnotics, and opioids.

They found that roughly one in seven (13.9%) patients met criteria for CNS-active polypharmacy. Of those receiving a CNS-active polypharmacy regimen, 57.8% had been doing so for longer than 180 days, and 6.8% had been doing so for a year. Nearly 30% of patients were exposed to five or more medications, and 5.2% were exposed to five or more medication classes.
 

Conservative approach warranted

Nearly all (92%) patients taking three or more CNS-active medications were taking an antidepressant, “consistent with their place as the psychotropic class most commonly prescribed both to older adults overall and those with dementia,” the investigators noted.

There is minimal high-quality evidence to support the efficacy of antidepressants for the treatment of depression for patients with dementia, they pointed out.

Nearly half (47%) of patients who were taking three or more CNS-active medications received at least one antipsychotic, most often quetiapine. Antipsychotics are not approved for people with dementia but are often prescribed off label for agitation, anxiety, and sleep problems, the researchers noted.

Nearly two thirds (62%) of patients with dementia who were taking three or more CNS drugs were taking an antiepileptic (most commonly, gabapentin); 41%, benzodiazepines; 32%, opioids; and 6%, Z-drugs.

The most common polypharmacy class combination included at least one antidepressant, one antiepileptic, and one antipsychotic. These accounted for 12.9% of polypharmacy days.

Despite limited high-quality evidence of efficacy, the prescribing of psychotropic medications and opioids is “pervasive” for adults with dementia in the United States, the investigators noted.

“Especially given that older adults with dementia might not be able to convey side effects they are experiencing, I think clinicians should be more conservative in how they are prescribing these medications and skeptical about the potential for benefit,” said Dr. Maust.

Regarding study limitations, the researchers noted that prescription medication claims may have led to an overestimation of the exposure to polypharmacy, insofar as the prescriptions may have been filled but not taken or were taken only on an as-needed basis.

In addition, the investigators were unable to determine the appropriateness of the particular combinations used or to examine the specific harms associated with CNS-active polypharmacy.
 

A major clinical challenge

Weighing in on the results, Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation, said the study is important because polypharmacy is one of the “geriatric giants, and the question is, what do you do about it?”

Dr. Fillit said it is important to conduct a careful medication review for all older patients, “making sure that the use of each drug is appropriate. The most important thing is to define what is the appropriate utilization of these kinds of drugs. That goes for both overutilization or misuse of these drugs and underutilization, where people are undertreated for symptoms that can’t be managed by behavioral management, for example,” Dr. Fillit said.

Dr. Fillit also said the finding that about 14% of dementia patients were receiving three or more of these drugs “may not be an outrageous number, because these patients, especially as they get into moderate and severe stages of disease, can be incredibly difficult to manage.

“Very often, dementia patients have depression, and up to 90% will have agitation and even psychosis during the course of dementia. And many of these patients need these types of drugs,” said Dr. Fillit.

Echoing the authors, Dr. Fillit said a key limitation of the study is not knowing whether the prescribing was appropriate or not.

The study was supported by a grant from the National Institute on Aging. Dr. Maust and Dr. Fillit have disclosed no relevant financial relationships.

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

A significant proportion of community-dwelling older adults with dementia take three or more central nervous system medications despite guidelines that say to avoid this dangerous practice, new research suggests.

Investigators found that 14% of these individuals were receiving CNS-active polypharmacy, defined as combinations of multiple psychotropic and opioid medications taken for more than 30 days.

“For most patients, the risks of these medications, particularly in combination, are almost certainly greater than the potential benefits,” said Donovan Maust, MD, associate director of the geriatric psychiatry program, University of Michigan, Ann Arbor.

The study was published online March 9 in JAMA.
 

Serious risks

Memory impairment is the cardinal feature of dementia, but behavioral and psychological symptoms, which can include apathy, delusions, and agitation, are common during all stages of illness and cause significant caregiver distress, the researchers noted.

They noted that there is a dearth of high-quality evidence to support prescribing these medications in this patient population, yet “clinicians regularly prescribe psychotropic medications to community-dwelling persons with dementia in rates that far exceed use in the general older adult population.”

The Beers Criteria, from the American Geriatrics Society, advise against the practice of CNS polypharmacy because of the significant increase in risk for falls as well as impaired cognition, cardiac conduction abnormalities, respiratory suppression, and death when polypharmacy involves opioids.

They note that previous studies from Europe of polypharmacy for patients with dementia have not included antiepileptic medications or opioids, so the true extent of CNS-active polypharmacy may be “significantly” underestimated.

To determine the prevalence of polypharmacy with CNS-active medications among community-dwelling older adults with dementia, the researchers analyzed data on prescription fills for nearly 1.2 million community-dwelling Medicare patients with dementia.

The primary outcome was the prevalence of CNS-active polypharmacy in 2018. They defined CNS-active polypharmacy as exposure to three or more medications for more than 30 consecutive days from the following drug classes: antidepressants, antipsychotics, antiepileptics, benzodiazepines, nonbenzodiazepines, benzodiazepine receptor agonist hypnotics, and opioids.

They found that roughly one in seven (13.9%) patients met criteria for CNS-active polypharmacy. Of those receiving a CNS-active polypharmacy regimen, 57.8% had been doing so for longer than 180 days, and 6.8% had been doing so for a year. Nearly 30% of patients were exposed to five or more medications, and 5.2% were exposed to five or more medication classes.
 

Conservative approach warranted

Nearly all (92%) patients taking three or more CNS-active medications were taking an antidepressant, “consistent with their place as the psychotropic class most commonly prescribed both to older adults overall and those with dementia,” the investigators noted.

There is minimal high-quality evidence to support the efficacy of antidepressants for the treatment of depression for patients with dementia, they pointed out.

Nearly half (47%) of patients who were taking three or more CNS-active medications received at least one antipsychotic, most often quetiapine. Antipsychotics are not approved for people with dementia but are often prescribed off label for agitation, anxiety, and sleep problems, the researchers noted.

Nearly two thirds (62%) of patients with dementia who were taking three or more CNS drugs were taking an antiepileptic (most commonly, gabapentin); 41%, benzodiazepines; 32%, opioids; and 6%, Z-drugs.

The most common polypharmacy class combination included at least one antidepressant, one antiepileptic, and one antipsychotic. These accounted for 12.9% of polypharmacy days.

Despite limited high-quality evidence of efficacy, the prescribing of psychotropic medications and opioids is “pervasive” for adults with dementia in the United States, the investigators noted.

“Especially given that older adults with dementia might not be able to convey side effects they are experiencing, I think clinicians should be more conservative in how they are prescribing these medications and skeptical about the potential for benefit,” said Dr. Maust.

Regarding study limitations, the researchers noted that prescription medication claims may have led to an overestimation of the exposure to polypharmacy, insofar as the prescriptions may have been filled but not taken or were taken only on an as-needed basis.

In addition, the investigators were unable to determine the appropriateness of the particular combinations used or to examine the specific harms associated with CNS-active polypharmacy.
 

A major clinical challenge

Weighing in on the results, Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation, said the study is important because polypharmacy is one of the “geriatric giants, and the question is, what do you do about it?”

Dr. Fillit said it is important to conduct a careful medication review for all older patients, “making sure that the use of each drug is appropriate. The most important thing is to define what is the appropriate utilization of these kinds of drugs. That goes for both overutilization or misuse of these drugs and underutilization, where people are undertreated for symptoms that can’t be managed by behavioral management, for example,” Dr. Fillit said.

Dr. Fillit also said the finding that about 14% of dementia patients were receiving three or more of these drugs “may not be an outrageous number, because these patients, especially as they get into moderate and severe stages of disease, can be incredibly difficult to manage.

“Very often, dementia patients have depression, and up to 90% will have agitation and even psychosis during the course of dementia. And many of these patients need these types of drugs,” said Dr. Fillit.

Echoing the authors, Dr. Fillit said a key limitation of the study is not knowing whether the prescribing was appropriate or not.

The study was supported by a grant from the National Institute on Aging. Dr. Maust and Dr. Fillit have disclosed no relevant financial relationships.

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