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Functional MRI detects consciousness after brain damage
Functional MRI can measure patterns of connectivity to determine levels of consciousness in nonresponsive patients with brain injury, according to results from a multicenter, cross-sectional, observational study.
Blood oxygen level–dependent (BOLD) fMRI showed that brain-wide coordination patterns of high complexity became increasingly common moving from unresponsive patients to those with minimal consciousness to healthy individuals, reported lead author Athena Demertzi, PhD, of GIGA Research Institute at the University of Liège in Belgium, and her colleagues.
“Finding reliable markers indicating the presence or absence of consciousness represents an outstanding open problem for science,” the investigators wrote in Science Advances.
In medicine, an fMRI-based measure of consciousness could supplement behavioral assessments of awareness and guide therapeutic strategies; more broadly, image-based markers could help elucidate the nature of consciousness itself.
“We postulate that consciousness has specific characteristics that are based on the temporal dynamics of ongoing brain activity and its coordination over distant cortical regions,” the investigators wrote. “Our hypothesis stems from the common stance of various contemporary theories which propose that consciousness relates to a dynamic process of self-sustained, coordinated brain-scale activity assisting the tuning to a constantly evolving environment, rather than in static descriptions of brain function.”
There is a need for a reliable way of distinguishing consciousness from unconscious states, the investigators said. “Given that nonresponsiveness can be associated with a variety of brain lesions, varying levels of vigilance, and covert cognition, we highlight the need to determine a common set of features capable of accounting for the capacity to sustain conscious experience.”
To search for patterns of brain signal coordination that correlate with consciousness, four independent research centers performed BOLD fMRI scans of participants at rest or under anesthesia with propofol. Of 159 total participants, 47 were healthy individuals and 112 were patients in a vegetative state/with unresponsive wakefulness syndrome (UWS) or in a minimally conscious state (MCS), based on standardized behavioral assessments. The main data analysis, which included 125 participants, assessed BOLD fMRI signal coordination between six brain networks known to have roles in cognitive and functional processes.
The researchers’ analysis revealed four distinct and recurring brain-wide coordination patterns ranging on a scale from highest activity (pattern 1) to lowest activity (pattern 4). Pattern 1, which exhibited most long-distance edges, spatial complexity, efficiency, and community structure, became increasingly common when moving from UWS patients to MCS patients to healthy control individuals (UWS < MCS < HC, rho = 0.7, Spearman rank correlation between rate and group, P less than 1 x 10-16).
In contrast, pattern 4, characterized by low interareal coordination, showed an inverse trend; it became less common when moving from vegetative patients to healthy individuals (UWS > MCS > HC, Spearman rank correlation between rate and group, rho = –0.6, P less than 1 x 10-11). Although patterns 2 and 3 occurred with equal frequency across all groups, the investigators noted that switching between patterns was most common and predictably sequential in healthy individuals, versus patients with UWS, who were least likely to switch patterns. A total of 23 patients who were scanned under propofol anesthesia were equally likely to exhibit pattern 4, regardless of health status, suggesting that pattern 4 depends upon fixed anatomical pathways. Results were not affected by scanning site or other patient characteristics, such as age, gender, etiology, or chronicity.
“We conclude that these patterns of transient brain signal coordination are characteristic of conscious and unconscious brain states,” the investigators wrote, “warranting future research concerning their relationship to ongoing conscious content, and the possibility of modifying their prevalence by external perturbations, both in healthy and pathological individuals, as well as across species.”
The study was funded by a James S. McDonnell Foundation Collaborative Activity Award, INSERM, the Belgian National Funds for Scientific Research, the Canada Excellence Research Chairs program, and others. The authors declared having no conflicts of interest.
SOURCE: Demertzi A et al. Sci Adv. 2019 Feb 6. doi: 10.1126/sciadv.aat7603.
Functional MRI can measure patterns of connectivity to determine levels of consciousness in nonresponsive patients with brain injury, according to results from a multicenter, cross-sectional, observational study.
Blood oxygen level–dependent (BOLD) fMRI showed that brain-wide coordination patterns of high complexity became increasingly common moving from unresponsive patients to those with minimal consciousness to healthy individuals, reported lead author Athena Demertzi, PhD, of GIGA Research Institute at the University of Liège in Belgium, and her colleagues.
“Finding reliable markers indicating the presence or absence of consciousness represents an outstanding open problem for science,” the investigators wrote in Science Advances.
In medicine, an fMRI-based measure of consciousness could supplement behavioral assessments of awareness and guide therapeutic strategies; more broadly, image-based markers could help elucidate the nature of consciousness itself.
“We postulate that consciousness has specific characteristics that are based on the temporal dynamics of ongoing brain activity and its coordination over distant cortical regions,” the investigators wrote. “Our hypothesis stems from the common stance of various contemporary theories which propose that consciousness relates to a dynamic process of self-sustained, coordinated brain-scale activity assisting the tuning to a constantly evolving environment, rather than in static descriptions of brain function.”
There is a need for a reliable way of distinguishing consciousness from unconscious states, the investigators said. “Given that nonresponsiveness can be associated with a variety of brain lesions, varying levels of vigilance, and covert cognition, we highlight the need to determine a common set of features capable of accounting for the capacity to sustain conscious experience.”
To search for patterns of brain signal coordination that correlate with consciousness, four independent research centers performed BOLD fMRI scans of participants at rest or under anesthesia with propofol. Of 159 total participants, 47 were healthy individuals and 112 were patients in a vegetative state/with unresponsive wakefulness syndrome (UWS) or in a minimally conscious state (MCS), based on standardized behavioral assessments. The main data analysis, which included 125 participants, assessed BOLD fMRI signal coordination between six brain networks known to have roles in cognitive and functional processes.
The researchers’ analysis revealed four distinct and recurring brain-wide coordination patterns ranging on a scale from highest activity (pattern 1) to lowest activity (pattern 4). Pattern 1, which exhibited most long-distance edges, spatial complexity, efficiency, and community structure, became increasingly common when moving from UWS patients to MCS patients to healthy control individuals (UWS < MCS < HC, rho = 0.7, Spearman rank correlation between rate and group, P less than 1 x 10-16).
In contrast, pattern 4, characterized by low interareal coordination, showed an inverse trend; it became less common when moving from vegetative patients to healthy individuals (UWS > MCS > HC, Spearman rank correlation between rate and group, rho = –0.6, P less than 1 x 10-11). Although patterns 2 and 3 occurred with equal frequency across all groups, the investigators noted that switching between patterns was most common and predictably sequential in healthy individuals, versus patients with UWS, who were least likely to switch patterns. A total of 23 patients who were scanned under propofol anesthesia were equally likely to exhibit pattern 4, regardless of health status, suggesting that pattern 4 depends upon fixed anatomical pathways. Results were not affected by scanning site or other patient characteristics, such as age, gender, etiology, or chronicity.
“We conclude that these patterns of transient brain signal coordination are characteristic of conscious and unconscious brain states,” the investigators wrote, “warranting future research concerning their relationship to ongoing conscious content, and the possibility of modifying their prevalence by external perturbations, both in healthy and pathological individuals, as well as across species.”
The study was funded by a James S. McDonnell Foundation Collaborative Activity Award, INSERM, the Belgian National Funds for Scientific Research, the Canada Excellence Research Chairs program, and others. The authors declared having no conflicts of interest.
SOURCE: Demertzi A et al. Sci Adv. 2019 Feb 6. doi: 10.1126/sciadv.aat7603.
Functional MRI can measure patterns of connectivity to determine levels of consciousness in nonresponsive patients with brain injury, according to results from a multicenter, cross-sectional, observational study.
Blood oxygen level–dependent (BOLD) fMRI showed that brain-wide coordination patterns of high complexity became increasingly common moving from unresponsive patients to those with minimal consciousness to healthy individuals, reported lead author Athena Demertzi, PhD, of GIGA Research Institute at the University of Liège in Belgium, and her colleagues.
“Finding reliable markers indicating the presence or absence of consciousness represents an outstanding open problem for science,” the investigators wrote in Science Advances.
In medicine, an fMRI-based measure of consciousness could supplement behavioral assessments of awareness and guide therapeutic strategies; more broadly, image-based markers could help elucidate the nature of consciousness itself.
“We postulate that consciousness has specific characteristics that are based on the temporal dynamics of ongoing brain activity and its coordination over distant cortical regions,” the investigators wrote. “Our hypothesis stems from the common stance of various contemporary theories which propose that consciousness relates to a dynamic process of self-sustained, coordinated brain-scale activity assisting the tuning to a constantly evolving environment, rather than in static descriptions of brain function.”
There is a need for a reliable way of distinguishing consciousness from unconscious states, the investigators said. “Given that nonresponsiveness can be associated with a variety of brain lesions, varying levels of vigilance, and covert cognition, we highlight the need to determine a common set of features capable of accounting for the capacity to sustain conscious experience.”
To search for patterns of brain signal coordination that correlate with consciousness, four independent research centers performed BOLD fMRI scans of participants at rest or under anesthesia with propofol. Of 159 total participants, 47 were healthy individuals and 112 were patients in a vegetative state/with unresponsive wakefulness syndrome (UWS) or in a minimally conscious state (MCS), based on standardized behavioral assessments. The main data analysis, which included 125 participants, assessed BOLD fMRI signal coordination between six brain networks known to have roles in cognitive and functional processes.
The researchers’ analysis revealed four distinct and recurring brain-wide coordination patterns ranging on a scale from highest activity (pattern 1) to lowest activity (pattern 4). Pattern 1, which exhibited most long-distance edges, spatial complexity, efficiency, and community structure, became increasingly common when moving from UWS patients to MCS patients to healthy control individuals (UWS < MCS < HC, rho = 0.7, Spearman rank correlation between rate and group, P less than 1 x 10-16).
In contrast, pattern 4, characterized by low interareal coordination, showed an inverse trend; it became less common when moving from vegetative patients to healthy individuals (UWS > MCS > HC, Spearman rank correlation between rate and group, rho = –0.6, P less than 1 x 10-11). Although patterns 2 and 3 occurred with equal frequency across all groups, the investigators noted that switching between patterns was most common and predictably sequential in healthy individuals, versus patients with UWS, who were least likely to switch patterns. A total of 23 patients who were scanned under propofol anesthesia were equally likely to exhibit pattern 4, regardless of health status, suggesting that pattern 4 depends upon fixed anatomical pathways. Results were not affected by scanning site or other patient characteristics, such as age, gender, etiology, or chronicity.
“We conclude that these patterns of transient brain signal coordination are characteristic of conscious and unconscious brain states,” the investigators wrote, “warranting future research concerning their relationship to ongoing conscious content, and the possibility of modifying their prevalence by external perturbations, both in healthy and pathological individuals, as well as across species.”
The study was funded by a James S. McDonnell Foundation Collaborative Activity Award, INSERM, the Belgian National Funds for Scientific Research, the Canada Excellence Research Chairs program, and others. The authors declared having no conflicts of interest.
SOURCE: Demertzi A et al. Sci Adv. 2019 Feb 6. doi: 10.1126/sciadv.aat7603.
FROM SCIENCE ADVANCES
Key clinical point:
Major finding: A brain-wide coordination pattern of high complexity became increasingly common when moving from patients with unresponsive wakefulness syndrome (UWS) to patients in a minimally conscious state (MCS) to healthy control individuals.
Study details: A study involving blood oxygen level–dependent (BOLD) fMRI scans at rest or under anesthesia in 159 participants at four independent research facilities.
Disclosures: The study was funded by a James S. McDonnell Foundation Collaborative Activity Award, INSERM, the Belgian National Funds for Scientific Research, the Canada Excellence Research Chairs program, and others. The authors declared having no conflicts of interest.
Source: Demertzi A et al. Sci Adv. 2019 Feb 6. doi: 10.1126/sciadv.aat7603.
American football and CTE: Is a racial divide inevitable?
Evidence that American football can lead to chronic traumatic encephalopathy (CTE), continues to grow. As a result, some parents are opting to sign their sons up for other sports.
In the 2017-2018 school year, 6.6% fewer high school athletes participated in tackle football than did 8 years before according to the National Federation of State High School Associations.
Many black parents encourage their sons to play football as a way to protect them gang activity. In addition, the sport can be their sole option for securing a college education for their children, an article in the Atlantic said. A recent survey of 50,000 8th-, 10th-, and 12th-grade students found that tackle football is predominantly the domain of black youth.
“This divergence paints a troubling picture of how economic opportunity – or a lack thereof – governs which boys are incentivized to put their body and brain at risk to play. Depending on where families live, and what other options are available to them, they see either a game that is too violent to consider or one that is necessary and important, if risky. Millions of Americans still watch football; NFL ratings were up this season,” Alana Semuels wrote in the article. “That a distinct portion of families won’t let their children play creates a disturbing future for the country’s most popular game.”
“Without a reversal in economic fortunes for poor communities across the country, football could one day become a sport played almost exclusively by black athletes, while still enjoyed by everyone. Black athletes – who already make up the majority of players in the most dangerous on-field positions – would continue to suffer from long-term brain damage, their life cut short by dementia and the scourge of CTE,” she wrote.
Meanwhile, numerous outlets reported that Super Bowl LIII garnered the lowest ratings since 2008.
Psychiatric hospital set to close
In both Kansas and Missouri, a shortage in mental health care has become evident, according to an article in the Kansas City Star. And now the Two Rivers Behavioral Health System, a private psychiatric hospital in southeast Kansas City, Mo., is closing its doors. The result will be a loss of 129 jobs and 105 fewer mental health beds in the city.
Patients currently in the facility will be relocated, and their care will continue. But for those who come after, care will now be tougher to find.
Two Rivers, owned by Pennsylvania-based Universal Health Services, treats children and adults. It had 2,347 discharges in 2017 and almost $28 million in revenue but had a net loss of about $3.4 million. The facility has been under scrutiny in the past two decades over its treatment of patients, with accusations about the bolstering of false memories concerning involvements in satanic cults and the treatment of a convicted sex offender who assaulted another patient. The most recent state inspection showed that Two Rivers had failed to provide a safe environment for six patients who were considered suicide risks. The patients had unsupervised access to the nurses’ station, as well as access to pens that could have been used for stabbing and a charging cord that could have been used for strangulation.
In an interview with the Star, Mark Stringer, director of the Missouri Department of Mental Health, said private psychiatric hospitals like Two Rivers are finding it harder to keep functioning, partly because of nursing shortages. Private facilities are not subsidized like state mental hospitals and are unable to secure staff from other facilities.
“There is a general worry about the availability of psychiatric services for people in crisis; there’s just no doubt about that,” Mr. Stringer said. “The loss of beds certainly hurts.”
New center offers ‘kind patient care’
In Nashville, Tenn., a new mental illness crisis treatment center is open. The center offers a 24/7 option for those with mental health issues who have run afoul of the law. Instead of incarceration, they can receive treatment, the Tennessean reported.
Estimates are that more than 1 million residents of Tennessee aged 18 years and older have a mental health or substance use disorder. About 25% of those residents having a serious mental health illness.
The new facility includes a crisis walk-in center and a unit where those in the throes of a mental health crisis can seek care. A goal is to get people suffering from an urgent mental illness crisis connected to help faster, especially when they come into contact with police.
“It’s very important to come to a place that’s going to get you help,” Bonnie Kelly said in the article. Ms. Kelly, who reportedly has bipolar disorder, has been arrested several times for disorderly conduct tied to her condition. “It means everything. It is good, kind patient care, rather than just getting you out of the way.”
Aside from benefiting those in need of mental health care, the center will ease the strain on Nashville police, who currently spend more than 5,000 hours each year responding to mental health–related calls. The officers must remain with the person until transfer to a jail or mental health facility is done.
“As a city, we are recognizing that there is a need, and we are investing in that,” East Precinct Commander David Imhof said in the article. “We are helping a population that has had no voice in the past.” Right now, fewer than 60% of patients discharged from state mental health facilities receive any sort of coverage. The result can be cycles of release, arrest, and incarceration.
Agency aims to protect patients
The Oregon Health Authority has stepped in to prevent numerous state-funded mental health facilities run by the same contractor from booting out patients with severe mental health problems.
The contractor is Kepro, a Pennsylvania-based company. Since December, the health authority has reversed decisions to release 17 patients, according to an article in the Oregonian. The harder line follows revelations by the newspaper of serious harm to patients who had been released before they were capable of caring for themselves.
Kepro was hired by the health authority and paid $27 million to evaluate the medical needs of mental health patients in Oregon. As part of the evaluation, 215 of 250 patients were deemed unqualified to remain in care.
One was Ruane Oliverio, who has schizophrenia, who was kicked out of a locked facility in Portland last June. Clinicians had warned against her release, insisting that her mental state remained too vulnerable. After being hospitalized multiple times, she was sent to the Oregon State Hospital, the highest and most expensive level of care. She was one of those targeted for release. This decision was reversed, and she continues to receive care.
Coalition seeks mental health care for refugees
A new coalition called Matters Involving Neuro-Disorders, or MIND, is trying to help refugees with mental health conditions. The effort is a response to several mental health-related deaths of refugees during 2014-2016, a video produced by the San Diego Union-Tribune said.
“Refugees are brought to this country to help them rebuild their lives,” said Justin Mudekereza, executive director of New Neighbor Relief, a nonprofit organization dedicated to helping refugees adjust to their new lives in the United States. “They have gone through a lot in their countries, then from there, they went to refugee camps, where they spend 15-20 years or more before they got a chance to come to this country.”
Sheila S. Mitra-Sarkar, PhD, of the Institute of Public Urban Affairs at San Diego State University, described the need for a “comprehensive solution” to help refugees adapt to their new society, learn English, find housing and employment, and thrive.
“When I see a patient or someone who seems to have a psychological issue ... I look at everything that goes around them,” said John C. Kuek, PhD, of La Maestra Community Health Centers in San Diego. “I’m looking at the housing issue, the employment issue, and translational issue – meaning they have some family back home and they have a live family here to care for.”
Evidence that American football can lead to chronic traumatic encephalopathy (CTE), continues to grow. As a result, some parents are opting to sign their sons up for other sports.
In the 2017-2018 school year, 6.6% fewer high school athletes participated in tackle football than did 8 years before according to the National Federation of State High School Associations.
Many black parents encourage their sons to play football as a way to protect them gang activity. In addition, the sport can be their sole option for securing a college education for their children, an article in the Atlantic said. A recent survey of 50,000 8th-, 10th-, and 12th-grade students found that tackle football is predominantly the domain of black youth.
“This divergence paints a troubling picture of how economic opportunity – or a lack thereof – governs which boys are incentivized to put their body and brain at risk to play. Depending on where families live, and what other options are available to them, they see either a game that is too violent to consider or one that is necessary and important, if risky. Millions of Americans still watch football; NFL ratings were up this season,” Alana Semuels wrote in the article. “That a distinct portion of families won’t let their children play creates a disturbing future for the country’s most popular game.”
“Without a reversal in economic fortunes for poor communities across the country, football could one day become a sport played almost exclusively by black athletes, while still enjoyed by everyone. Black athletes – who already make up the majority of players in the most dangerous on-field positions – would continue to suffer from long-term brain damage, their life cut short by dementia and the scourge of CTE,” she wrote.
Meanwhile, numerous outlets reported that Super Bowl LIII garnered the lowest ratings since 2008.
Psychiatric hospital set to close
In both Kansas and Missouri, a shortage in mental health care has become evident, according to an article in the Kansas City Star. And now the Two Rivers Behavioral Health System, a private psychiatric hospital in southeast Kansas City, Mo., is closing its doors. The result will be a loss of 129 jobs and 105 fewer mental health beds in the city.
Patients currently in the facility will be relocated, and their care will continue. But for those who come after, care will now be tougher to find.
Two Rivers, owned by Pennsylvania-based Universal Health Services, treats children and adults. It had 2,347 discharges in 2017 and almost $28 million in revenue but had a net loss of about $3.4 million. The facility has been under scrutiny in the past two decades over its treatment of patients, with accusations about the bolstering of false memories concerning involvements in satanic cults and the treatment of a convicted sex offender who assaulted another patient. The most recent state inspection showed that Two Rivers had failed to provide a safe environment for six patients who were considered suicide risks. The patients had unsupervised access to the nurses’ station, as well as access to pens that could have been used for stabbing and a charging cord that could have been used for strangulation.
In an interview with the Star, Mark Stringer, director of the Missouri Department of Mental Health, said private psychiatric hospitals like Two Rivers are finding it harder to keep functioning, partly because of nursing shortages. Private facilities are not subsidized like state mental hospitals and are unable to secure staff from other facilities.
“There is a general worry about the availability of psychiatric services for people in crisis; there’s just no doubt about that,” Mr. Stringer said. “The loss of beds certainly hurts.”
New center offers ‘kind patient care’
In Nashville, Tenn., a new mental illness crisis treatment center is open. The center offers a 24/7 option for those with mental health issues who have run afoul of the law. Instead of incarceration, they can receive treatment, the Tennessean reported.
Estimates are that more than 1 million residents of Tennessee aged 18 years and older have a mental health or substance use disorder. About 25% of those residents having a serious mental health illness.
The new facility includes a crisis walk-in center and a unit where those in the throes of a mental health crisis can seek care. A goal is to get people suffering from an urgent mental illness crisis connected to help faster, especially when they come into contact with police.
“It’s very important to come to a place that’s going to get you help,” Bonnie Kelly said in the article. Ms. Kelly, who reportedly has bipolar disorder, has been arrested several times for disorderly conduct tied to her condition. “It means everything. It is good, kind patient care, rather than just getting you out of the way.”
Aside from benefiting those in need of mental health care, the center will ease the strain on Nashville police, who currently spend more than 5,000 hours each year responding to mental health–related calls. The officers must remain with the person until transfer to a jail or mental health facility is done.
“As a city, we are recognizing that there is a need, and we are investing in that,” East Precinct Commander David Imhof said in the article. “We are helping a population that has had no voice in the past.” Right now, fewer than 60% of patients discharged from state mental health facilities receive any sort of coverage. The result can be cycles of release, arrest, and incarceration.
Agency aims to protect patients
The Oregon Health Authority has stepped in to prevent numerous state-funded mental health facilities run by the same contractor from booting out patients with severe mental health problems.
The contractor is Kepro, a Pennsylvania-based company. Since December, the health authority has reversed decisions to release 17 patients, according to an article in the Oregonian. The harder line follows revelations by the newspaper of serious harm to patients who had been released before they were capable of caring for themselves.
Kepro was hired by the health authority and paid $27 million to evaluate the medical needs of mental health patients in Oregon. As part of the evaluation, 215 of 250 patients were deemed unqualified to remain in care.
One was Ruane Oliverio, who has schizophrenia, who was kicked out of a locked facility in Portland last June. Clinicians had warned against her release, insisting that her mental state remained too vulnerable. After being hospitalized multiple times, she was sent to the Oregon State Hospital, the highest and most expensive level of care. She was one of those targeted for release. This decision was reversed, and she continues to receive care.
Coalition seeks mental health care for refugees
A new coalition called Matters Involving Neuro-Disorders, or MIND, is trying to help refugees with mental health conditions. The effort is a response to several mental health-related deaths of refugees during 2014-2016, a video produced by the San Diego Union-Tribune said.
“Refugees are brought to this country to help them rebuild their lives,” said Justin Mudekereza, executive director of New Neighbor Relief, a nonprofit organization dedicated to helping refugees adjust to their new lives in the United States. “They have gone through a lot in their countries, then from there, they went to refugee camps, where they spend 15-20 years or more before they got a chance to come to this country.”
Sheila S. Mitra-Sarkar, PhD, of the Institute of Public Urban Affairs at San Diego State University, described the need for a “comprehensive solution” to help refugees adapt to their new society, learn English, find housing and employment, and thrive.
“When I see a patient or someone who seems to have a psychological issue ... I look at everything that goes around them,” said John C. Kuek, PhD, of La Maestra Community Health Centers in San Diego. “I’m looking at the housing issue, the employment issue, and translational issue – meaning they have some family back home and they have a live family here to care for.”
Evidence that American football can lead to chronic traumatic encephalopathy (CTE), continues to grow. As a result, some parents are opting to sign their sons up for other sports.
In the 2017-2018 school year, 6.6% fewer high school athletes participated in tackle football than did 8 years before according to the National Federation of State High School Associations.
Many black parents encourage their sons to play football as a way to protect them gang activity. In addition, the sport can be their sole option for securing a college education for their children, an article in the Atlantic said. A recent survey of 50,000 8th-, 10th-, and 12th-grade students found that tackle football is predominantly the domain of black youth.
“This divergence paints a troubling picture of how economic opportunity – or a lack thereof – governs which boys are incentivized to put their body and brain at risk to play. Depending on where families live, and what other options are available to them, they see either a game that is too violent to consider or one that is necessary and important, if risky. Millions of Americans still watch football; NFL ratings were up this season,” Alana Semuels wrote in the article. “That a distinct portion of families won’t let their children play creates a disturbing future for the country’s most popular game.”
“Without a reversal in economic fortunes for poor communities across the country, football could one day become a sport played almost exclusively by black athletes, while still enjoyed by everyone. Black athletes – who already make up the majority of players in the most dangerous on-field positions – would continue to suffer from long-term brain damage, their life cut short by dementia and the scourge of CTE,” she wrote.
Meanwhile, numerous outlets reported that Super Bowl LIII garnered the lowest ratings since 2008.
Psychiatric hospital set to close
In both Kansas and Missouri, a shortage in mental health care has become evident, according to an article in the Kansas City Star. And now the Two Rivers Behavioral Health System, a private psychiatric hospital in southeast Kansas City, Mo., is closing its doors. The result will be a loss of 129 jobs and 105 fewer mental health beds in the city.
Patients currently in the facility will be relocated, and their care will continue. But for those who come after, care will now be tougher to find.
Two Rivers, owned by Pennsylvania-based Universal Health Services, treats children and adults. It had 2,347 discharges in 2017 and almost $28 million in revenue but had a net loss of about $3.4 million. The facility has been under scrutiny in the past two decades over its treatment of patients, with accusations about the bolstering of false memories concerning involvements in satanic cults and the treatment of a convicted sex offender who assaulted another patient. The most recent state inspection showed that Two Rivers had failed to provide a safe environment for six patients who were considered suicide risks. The patients had unsupervised access to the nurses’ station, as well as access to pens that could have been used for stabbing and a charging cord that could have been used for strangulation.
In an interview with the Star, Mark Stringer, director of the Missouri Department of Mental Health, said private psychiatric hospitals like Two Rivers are finding it harder to keep functioning, partly because of nursing shortages. Private facilities are not subsidized like state mental hospitals and are unable to secure staff from other facilities.
“There is a general worry about the availability of psychiatric services for people in crisis; there’s just no doubt about that,” Mr. Stringer said. “The loss of beds certainly hurts.”
New center offers ‘kind patient care’
In Nashville, Tenn., a new mental illness crisis treatment center is open. The center offers a 24/7 option for those with mental health issues who have run afoul of the law. Instead of incarceration, they can receive treatment, the Tennessean reported.
Estimates are that more than 1 million residents of Tennessee aged 18 years and older have a mental health or substance use disorder. About 25% of those residents having a serious mental health illness.
The new facility includes a crisis walk-in center and a unit where those in the throes of a mental health crisis can seek care. A goal is to get people suffering from an urgent mental illness crisis connected to help faster, especially when they come into contact with police.
“It’s very important to come to a place that’s going to get you help,” Bonnie Kelly said in the article. Ms. Kelly, who reportedly has bipolar disorder, has been arrested several times for disorderly conduct tied to her condition. “It means everything. It is good, kind patient care, rather than just getting you out of the way.”
Aside from benefiting those in need of mental health care, the center will ease the strain on Nashville police, who currently spend more than 5,000 hours each year responding to mental health–related calls. The officers must remain with the person until transfer to a jail or mental health facility is done.
“As a city, we are recognizing that there is a need, and we are investing in that,” East Precinct Commander David Imhof said in the article. “We are helping a population that has had no voice in the past.” Right now, fewer than 60% of patients discharged from state mental health facilities receive any sort of coverage. The result can be cycles of release, arrest, and incarceration.
Agency aims to protect patients
The Oregon Health Authority has stepped in to prevent numerous state-funded mental health facilities run by the same contractor from booting out patients with severe mental health problems.
The contractor is Kepro, a Pennsylvania-based company. Since December, the health authority has reversed decisions to release 17 patients, according to an article in the Oregonian. The harder line follows revelations by the newspaper of serious harm to patients who had been released before they were capable of caring for themselves.
Kepro was hired by the health authority and paid $27 million to evaluate the medical needs of mental health patients in Oregon. As part of the evaluation, 215 of 250 patients were deemed unqualified to remain in care.
One was Ruane Oliverio, who has schizophrenia, who was kicked out of a locked facility in Portland last June. Clinicians had warned against her release, insisting that her mental state remained too vulnerable. After being hospitalized multiple times, she was sent to the Oregon State Hospital, the highest and most expensive level of care. She was one of those targeted for release. This decision was reversed, and she continues to receive care.
Coalition seeks mental health care for refugees
A new coalition called Matters Involving Neuro-Disorders, or MIND, is trying to help refugees with mental health conditions. The effort is a response to several mental health-related deaths of refugees during 2014-2016, a video produced by the San Diego Union-Tribune said.
“Refugees are brought to this country to help them rebuild their lives,” said Justin Mudekereza, executive director of New Neighbor Relief, a nonprofit organization dedicated to helping refugees adjust to their new lives in the United States. “They have gone through a lot in their countries, then from there, they went to refugee camps, where they spend 15-20 years or more before they got a chance to come to this country.”
Sheila S. Mitra-Sarkar, PhD, of the Institute of Public Urban Affairs at San Diego State University, described the need for a “comprehensive solution” to help refugees adapt to their new society, learn English, find housing and employment, and thrive.
“When I see a patient or someone who seems to have a psychological issue ... I look at everything that goes around them,” said John C. Kuek, PhD, of La Maestra Community Health Centers in San Diego. “I’m looking at the housing issue, the employment issue, and translational issue – meaning they have some family back home and they have a live family here to care for.”
Researchers compare focused ultrasound and DBS for essential tremor
LAS VEGAS – according to two presentations delivered at the annual meeting of the North American Neuromodulation Society. The techniques’ surgical procedures, associated risks, and adverse event profiles may influence neurologists and patients in their choice of treatment.
FUS allows neurosurgeons to apply thermal ablation to create a lesion on the thalamus. MRI guidance enables precise control of the lesion location (within approximately 1 mm) and of the treatment intensity. The surgery can be performed with high-resolution stereotactic framing.
DBS entails the surgical implantation of a neurostimulator and attached leads and electrodes. The neurosurgeon drills a hole of approximately 14 mm in diameter into the skull so that the electrode can be inserted stereotactically while the patient is awake or asleep. The neurostimulator is installed separately.
Both treatments provide functional benefits
In 2016, W. Jeff Elias, MD, director of stereotactic and functional neurosurgery at the University of Virginia in Charlottesville, and his colleagues published the results of a randomized controlled trial that compared FUS with sham treatment in 76 patients with essential tremor. At three months, hand tremor had improved by approximately 50% among treated patients, but controls had no significant benefit(N Engl J Med. 2016 Aug 25;375[8]:730-9). The improvement among treated patients was maintained for 12 months. Disability and quality of life also improved after FUS.
A study by Schuurman et al. published in 2000 (N Engl J Med. 2000 Feb 17;342[7]:461-8) showed that DBS and FUS had similar efficacy at 1 year, said Kathryn L. Holloway, MD, professor of neurosurgery at Virginia Commonwealth University in Richmond. It included 45 patients with Parkinson’s disease, 13 with essential tremor, and 10 with multiple sclerosis who were randomized 1:1 to FUS or DBS. The primary outcome was activities of daily living, and blinded physicians assessed patient videos. Most of the patients who improved had received DBS, and most of the ones who worsened had received FUS, said Dr. Holloway. Among patients with essential tremor, tremor improved by between 94% and 100% with either treatment.
To find more recent data about these treatments, Dr. Holloway searched the literature for studies of FUS or DBS for essential tremor. She analyzed only studies that included unselected populations, blinded evaluations within 1 or 2 years of surgery, and tremor scores for the treated side. She found two studies of FUS, including Dr. Elias’s 2016 trial and a 2018 follow-up (Ann Neurol. 2018 Jan;83[1]:107-14). Dr. Holloway also identified three trials of DBS.
In these studies, reduction of hand tremor was 55% with FUS and between 63% and 69% with DBS. Reduction of postural tremor was approximately 72% with FUS and approximately 67% with DBS. Reduction of action tremor was about 52% with FUS and between 65% and 71% with DBS. Overall, DBS appears to be more effective, said Dr. Holloway.
A 2015 study (Mov Disord. 2015 Dec;30[14]:1937-43) that compared bilateral DBS, unilateral DBS, and unilateral FUS for essential tremor indicated that the treatments provide similar benefits on hand tremor, disability, and quality of life, said Dr. Elias. FUS is inferior to DBS, however, for total tremor and axial tremor.
Furthermore, the efficacy of FUS wanes over time, said Dr. Elias. He and his colleagues conducted a pilot study of 15 patients with essential tremor who received FUS (N Engl J Med. 2013 Aug 15;369[7]:640-8). At 6 years, 6 of 13 patients whose data were available still had a 50% improvement in tremor. “Some went on to [receive] DBS,” said Dr. Elias. “Functional improvements persisted more than the tremor improvement.”
Adverse events
In their 2016 trial of FUS, Dr. Elias and his colleagues observed 210 adverse events, which is approximately “what you would expect with a modern day, FDA-monitored clinical trial.” Sensory effects and gait disturbance accounted for most of the thalamotomy-related adverse events. Sensory problems such as numbness or parestheisa persisted at 1 year in 14% of treated patients, and gait disturbance persisted at 1 year in 9%. The investigators did not observe any hemorrhages, infections, or cavitation-related effects from FUS.
In a 2018 analysis of five clinical trials of FUS for essential tremor, Fishman et al. found that 79% of adverse events were mild and 1% were severe (Mov Disord. 2018 May;33[5]:843-7). The risk of a severe adverse event therefore can be considered low, and it may decrease as neurosurgeons gain experience with the procedure, said Dr. Elias.
In the 2000 Schuurman et al. study, the researchers observed significantly fewer adverse events overall among patients with Parkinson’s disease or essential tremor who received DBS, compared with patients who received FUS. Cognitive deterioration, severe dysarthria, and severe ataxia were more common in the FUS group than in the DBS group. Dr. Holloway’s analysis of adverse events in the five more recent trials that she identified yielded similar results.
Although MRI-guided FUS is a precise way to make lesions, functional areas in the thalamus overlap, which makes it more difficult to target only the intended region, said Dr. Holloway. The functional overlap thus increases the risk of adverse events (e.g., sensory impairments, dysarthria, or ataxia). The adverse events that result from FUS may last as long as a year. “Patients will put up anything for about a month after surgery, and then they start to get annoyed,” said Dr. Holloway.
In addition, Schuurman et al. found that FUS entailed a greater risk of permanent side effects, compared with DBS. “That’s the key point here,” said Dr. Holloway. Most of the adverse effects in the DBS group were resolved by adjusting or turning off the stimulator. Hardware issues resulting from DBS are frustrating, but reversible, but a patient with an adverse event after FUS often is “stuck with it,” said Dr. Holloway. The Schuurman et al. data indicated that, in terms of adverse events, “thalamotomy was inferior to DBS,” she added.
Implantation of DBS entails the risks inherent to surgeries that open the skull (such as seizures, air embolism, and hemorrhage). DBS entails a 2% risk of hemorrhage or infection, said Dr. Elias. Furthermore, as much as 15% of patients who undergo DBS implantation require additional surgery.
“FUS is not going to cause a life-threatening hemorrhage, but DBS certainly can,” said Dr. Holloway.
Managing disease progression
Essential tremor is a progressive disease, and older patients are more likely to have exponential progression than linear progression. Data, such as those published by Zhang et al. (J Neurosurg. 2010 Jun;112[6]:1271-6), indicate that DBS can “keep up with the progression of the disease,” said Dr. Holloway. The authors found that tremor scores did not change significantly over approximately 5 years when patients with essential tremor who had received DBS implantation had periodic assessments and increases in stimulation parameters when appropriate.
If a patient with essential tremor undergoes FUS thalamotomy and has subsequent disease progression, DBS may be considered for reducing tremor, said Dr. Holloway. Most adverse events resulting from DBS implantation are reversible with adjustment of the stimulation parameters. A second thalamotomy, however, could cause severe dysarthria and other irreversible adverse events. “Only DBS can safely address tremor progression,” said Dr. Holloway.
LAS VEGAS – according to two presentations delivered at the annual meeting of the North American Neuromodulation Society. The techniques’ surgical procedures, associated risks, and adverse event profiles may influence neurologists and patients in their choice of treatment.
FUS allows neurosurgeons to apply thermal ablation to create a lesion on the thalamus. MRI guidance enables precise control of the lesion location (within approximately 1 mm) and of the treatment intensity. The surgery can be performed with high-resolution stereotactic framing.
DBS entails the surgical implantation of a neurostimulator and attached leads and electrodes. The neurosurgeon drills a hole of approximately 14 mm in diameter into the skull so that the electrode can be inserted stereotactically while the patient is awake or asleep. The neurostimulator is installed separately.
Both treatments provide functional benefits
In 2016, W. Jeff Elias, MD, director of stereotactic and functional neurosurgery at the University of Virginia in Charlottesville, and his colleagues published the results of a randomized controlled trial that compared FUS with sham treatment in 76 patients with essential tremor. At three months, hand tremor had improved by approximately 50% among treated patients, but controls had no significant benefit(N Engl J Med. 2016 Aug 25;375[8]:730-9). The improvement among treated patients was maintained for 12 months. Disability and quality of life also improved after FUS.
A study by Schuurman et al. published in 2000 (N Engl J Med. 2000 Feb 17;342[7]:461-8) showed that DBS and FUS had similar efficacy at 1 year, said Kathryn L. Holloway, MD, professor of neurosurgery at Virginia Commonwealth University in Richmond. It included 45 patients with Parkinson’s disease, 13 with essential tremor, and 10 with multiple sclerosis who were randomized 1:1 to FUS or DBS. The primary outcome was activities of daily living, and blinded physicians assessed patient videos. Most of the patients who improved had received DBS, and most of the ones who worsened had received FUS, said Dr. Holloway. Among patients with essential tremor, tremor improved by between 94% and 100% with either treatment.
To find more recent data about these treatments, Dr. Holloway searched the literature for studies of FUS or DBS for essential tremor. She analyzed only studies that included unselected populations, blinded evaluations within 1 or 2 years of surgery, and tremor scores for the treated side. She found two studies of FUS, including Dr. Elias’s 2016 trial and a 2018 follow-up (Ann Neurol. 2018 Jan;83[1]:107-14). Dr. Holloway also identified three trials of DBS.
In these studies, reduction of hand tremor was 55% with FUS and between 63% and 69% with DBS. Reduction of postural tremor was approximately 72% with FUS and approximately 67% with DBS. Reduction of action tremor was about 52% with FUS and between 65% and 71% with DBS. Overall, DBS appears to be more effective, said Dr. Holloway.
A 2015 study (Mov Disord. 2015 Dec;30[14]:1937-43) that compared bilateral DBS, unilateral DBS, and unilateral FUS for essential tremor indicated that the treatments provide similar benefits on hand tremor, disability, and quality of life, said Dr. Elias. FUS is inferior to DBS, however, for total tremor and axial tremor.
Furthermore, the efficacy of FUS wanes over time, said Dr. Elias. He and his colleagues conducted a pilot study of 15 patients with essential tremor who received FUS (N Engl J Med. 2013 Aug 15;369[7]:640-8). At 6 years, 6 of 13 patients whose data were available still had a 50% improvement in tremor. “Some went on to [receive] DBS,” said Dr. Elias. “Functional improvements persisted more than the tremor improvement.”
Adverse events
In their 2016 trial of FUS, Dr. Elias and his colleagues observed 210 adverse events, which is approximately “what you would expect with a modern day, FDA-monitored clinical trial.” Sensory effects and gait disturbance accounted for most of the thalamotomy-related adverse events. Sensory problems such as numbness or parestheisa persisted at 1 year in 14% of treated patients, and gait disturbance persisted at 1 year in 9%. The investigators did not observe any hemorrhages, infections, or cavitation-related effects from FUS.
In a 2018 analysis of five clinical trials of FUS for essential tremor, Fishman et al. found that 79% of adverse events were mild and 1% were severe (Mov Disord. 2018 May;33[5]:843-7). The risk of a severe adverse event therefore can be considered low, and it may decrease as neurosurgeons gain experience with the procedure, said Dr. Elias.
In the 2000 Schuurman et al. study, the researchers observed significantly fewer adverse events overall among patients with Parkinson’s disease or essential tremor who received DBS, compared with patients who received FUS. Cognitive deterioration, severe dysarthria, and severe ataxia were more common in the FUS group than in the DBS group. Dr. Holloway’s analysis of adverse events in the five more recent trials that she identified yielded similar results.
Although MRI-guided FUS is a precise way to make lesions, functional areas in the thalamus overlap, which makes it more difficult to target only the intended region, said Dr. Holloway. The functional overlap thus increases the risk of adverse events (e.g., sensory impairments, dysarthria, or ataxia). The adverse events that result from FUS may last as long as a year. “Patients will put up anything for about a month after surgery, and then they start to get annoyed,” said Dr. Holloway.
In addition, Schuurman et al. found that FUS entailed a greater risk of permanent side effects, compared with DBS. “That’s the key point here,” said Dr. Holloway. Most of the adverse effects in the DBS group were resolved by adjusting or turning off the stimulator. Hardware issues resulting from DBS are frustrating, but reversible, but a patient with an adverse event after FUS often is “stuck with it,” said Dr. Holloway. The Schuurman et al. data indicated that, in terms of adverse events, “thalamotomy was inferior to DBS,” she added.
Implantation of DBS entails the risks inherent to surgeries that open the skull (such as seizures, air embolism, and hemorrhage). DBS entails a 2% risk of hemorrhage or infection, said Dr. Elias. Furthermore, as much as 15% of patients who undergo DBS implantation require additional surgery.
“FUS is not going to cause a life-threatening hemorrhage, but DBS certainly can,” said Dr. Holloway.
Managing disease progression
Essential tremor is a progressive disease, and older patients are more likely to have exponential progression than linear progression. Data, such as those published by Zhang et al. (J Neurosurg. 2010 Jun;112[6]:1271-6), indicate that DBS can “keep up with the progression of the disease,” said Dr. Holloway. The authors found that tremor scores did not change significantly over approximately 5 years when patients with essential tremor who had received DBS implantation had periodic assessments and increases in stimulation parameters when appropriate.
If a patient with essential tremor undergoes FUS thalamotomy and has subsequent disease progression, DBS may be considered for reducing tremor, said Dr. Holloway. Most adverse events resulting from DBS implantation are reversible with adjustment of the stimulation parameters. A second thalamotomy, however, could cause severe dysarthria and other irreversible adverse events. “Only DBS can safely address tremor progression,” said Dr. Holloway.
LAS VEGAS – according to two presentations delivered at the annual meeting of the North American Neuromodulation Society. The techniques’ surgical procedures, associated risks, and adverse event profiles may influence neurologists and patients in their choice of treatment.
FUS allows neurosurgeons to apply thermal ablation to create a lesion on the thalamus. MRI guidance enables precise control of the lesion location (within approximately 1 mm) and of the treatment intensity. The surgery can be performed with high-resolution stereotactic framing.
DBS entails the surgical implantation of a neurostimulator and attached leads and electrodes. The neurosurgeon drills a hole of approximately 14 mm in diameter into the skull so that the electrode can be inserted stereotactically while the patient is awake or asleep. The neurostimulator is installed separately.
Both treatments provide functional benefits
In 2016, W. Jeff Elias, MD, director of stereotactic and functional neurosurgery at the University of Virginia in Charlottesville, and his colleagues published the results of a randomized controlled trial that compared FUS with sham treatment in 76 patients with essential tremor. At three months, hand tremor had improved by approximately 50% among treated patients, but controls had no significant benefit(N Engl J Med. 2016 Aug 25;375[8]:730-9). The improvement among treated patients was maintained for 12 months. Disability and quality of life also improved after FUS.
A study by Schuurman et al. published in 2000 (N Engl J Med. 2000 Feb 17;342[7]:461-8) showed that DBS and FUS had similar efficacy at 1 year, said Kathryn L. Holloway, MD, professor of neurosurgery at Virginia Commonwealth University in Richmond. It included 45 patients with Parkinson’s disease, 13 with essential tremor, and 10 with multiple sclerosis who were randomized 1:1 to FUS or DBS. The primary outcome was activities of daily living, and blinded physicians assessed patient videos. Most of the patients who improved had received DBS, and most of the ones who worsened had received FUS, said Dr. Holloway. Among patients with essential tremor, tremor improved by between 94% and 100% with either treatment.
To find more recent data about these treatments, Dr. Holloway searched the literature for studies of FUS or DBS for essential tremor. She analyzed only studies that included unselected populations, blinded evaluations within 1 or 2 years of surgery, and tremor scores for the treated side. She found two studies of FUS, including Dr. Elias’s 2016 trial and a 2018 follow-up (Ann Neurol. 2018 Jan;83[1]:107-14). Dr. Holloway also identified three trials of DBS.
In these studies, reduction of hand tremor was 55% with FUS and between 63% and 69% with DBS. Reduction of postural tremor was approximately 72% with FUS and approximately 67% with DBS. Reduction of action tremor was about 52% with FUS and between 65% and 71% with DBS. Overall, DBS appears to be more effective, said Dr. Holloway.
A 2015 study (Mov Disord. 2015 Dec;30[14]:1937-43) that compared bilateral DBS, unilateral DBS, and unilateral FUS for essential tremor indicated that the treatments provide similar benefits on hand tremor, disability, and quality of life, said Dr. Elias. FUS is inferior to DBS, however, for total tremor and axial tremor.
Furthermore, the efficacy of FUS wanes over time, said Dr. Elias. He and his colleagues conducted a pilot study of 15 patients with essential tremor who received FUS (N Engl J Med. 2013 Aug 15;369[7]:640-8). At 6 years, 6 of 13 patients whose data were available still had a 50% improvement in tremor. “Some went on to [receive] DBS,” said Dr. Elias. “Functional improvements persisted more than the tremor improvement.”
Adverse events
In their 2016 trial of FUS, Dr. Elias and his colleagues observed 210 adverse events, which is approximately “what you would expect with a modern day, FDA-monitored clinical trial.” Sensory effects and gait disturbance accounted for most of the thalamotomy-related adverse events. Sensory problems such as numbness or parestheisa persisted at 1 year in 14% of treated patients, and gait disturbance persisted at 1 year in 9%. The investigators did not observe any hemorrhages, infections, or cavitation-related effects from FUS.
In a 2018 analysis of five clinical trials of FUS for essential tremor, Fishman et al. found that 79% of adverse events were mild and 1% were severe (Mov Disord. 2018 May;33[5]:843-7). The risk of a severe adverse event therefore can be considered low, and it may decrease as neurosurgeons gain experience with the procedure, said Dr. Elias.
In the 2000 Schuurman et al. study, the researchers observed significantly fewer adverse events overall among patients with Parkinson’s disease or essential tremor who received DBS, compared with patients who received FUS. Cognitive deterioration, severe dysarthria, and severe ataxia were more common in the FUS group than in the DBS group. Dr. Holloway’s analysis of adverse events in the five more recent trials that she identified yielded similar results.
Although MRI-guided FUS is a precise way to make lesions, functional areas in the thalamus overlap, which makes it more difficult to target only the intended region, said Dr. Holloway. The functional overlap thus increases the risk of adverse events (e.g., sensory impairments, dysarthria, or ataxia). The adverse events that result from FUS may last as long as a year. “Patients will put up anything for about a month after surgery, and then they start to get annoyed,” said Dr. Holloway.
In addition, Schuurman et al. found that FUS entailed a greater risk of permanent side effects, compared with DBS. “That’s the key point here,” said Dr. Holloway. Most of the adverse effects in the DBS group were resolved by adjusting or turning off the stimulator. Hardware issues resulting from DBS are frustrating, but reversible, but a patient with an adverse event after FUS often is “stuck with it,” said Dr. Holloway. The Schuurman et al. data indicated that, in terms of adverse events, “thalamotomy was inferior to DBS,” she added.
Implantation of DBS entails the risks inherent to surgeries that open the skull (such as seizures, air embolism, and hemorrhage). DBS entails a 2% risk of hemorrhage or infection, said Dr. Elias. Furthermore, as much as 15% of patients who undergo DBS implantation require additional surgery.
“FUS is not going to cause a life-threatening hemorrhage, but DBS certainly can,” said Dr. Holloway.
Managing disease progression
Essential tremor is a progressive disease, and older patients are more likely to have exponential progression than linear progression. Data, such as those published by Zhang et al. (J Neurosurg. 2010 Jun;112[6]:1271-6), indicate that DBS can “keep up with the progression of the disease,” said Dr. Holloway. The authors found that tremor scores did not change significantly over approximately 5 years when patients with essential tremor who had received DBS implantation had periodic assessments and increases in stimulation parameters when appropriate.
If a patient with essential tremor undergoes FUS thalamotomy and has subsequent disease progression, DBS may be considered for reducing tremor, said Dr. Holloway. Most adverse events resulting from DBS implantation are reversible with adjustment of the stimulation parameters. A second thalamotomy, however, could cause severe dysarthria and other irreversible adverse events. “Only DBS can safely address tremor progression,” said Dr. Holloway.
REPORTING FROM NANS 2019
Statins cut vascular events in elderly patients
Statin therapy appears to reduce the risk of major vascular events for patients of all age groups, but there is less evidence that older patients with evidence of occlusive vascular disease benefit from the treatment, according to a recent meta-analysis of 28 trials from the Cholesterol Treatment Trialists’ Collaboration published in The Lancet.
Statins are “useful and affordable drug[s] that reduce heart attacks and strokes in older patients. Until now there has been an evidence gap and we wanted to look at their efficacy and safety in older people,” Jordan Fulcher, BSc (Med), MBBS, from the Cholesterol Treatment Trialists’ (CTT) Collaboration and the University of Sydney stated in a press release. “Our analysis indicates that major cardiovascular events were reduced by about a fifth, per mmol/L lower LDL cholesterol, by statin therapy across all age groups. Despite previous concerns, we found no adverse effect on cancer or nonvascular mortality in any age group.”
The researchers examined 186,854 participants from 28 CTT trials undergoing statin therapy, of whom 14,483 (8%) were older than 75 years. Patients were divided into six groups based on age and examined the risk of major cardiovascular events such as stroke, coronary revascularization and major coronary events, as well as the incidence of cancer and vascular mortality.
Among all age groups, there was a significant reduction in major vascular events, with a 21% proportional per 1.0-mmol/L reduction in LDL cholesterol (risk ratio, 0.79; 95% confidence interval, 0.77-0.81) among patients receiving statin therapy or a more intensive statin regimen, and there was a 24% proportional reduction (RR, 0.76; 95% CI, 0.73-0.79) of major coronary events per 1.0-mmol/L reduction in LDL cholesterol, with older age resulting in a lower proportional reduction of major coronary events (P = .009). The researchers also found a proportional reduction of coronary revascularization procedures by 25% (RR, 0.75; 95% CI, 0.73-0.78) and stroke by 16% (RR, 0.84; 95% CI, 0.80-0.89) among patients of any age group receiving statin therapy or more intensive statin regimen, with no significant differences between age groups.
There was a 12% proportional reduction in vascular mortality per 1.0-mmol/L reduction in LDL cholesterol (RR, 0.88; 95% CI, 0.85-0.91), but this statistic did not remain significant after the researchers excluded four trials that included patients with heart failure or who were receiving renal dialysis. After excluding these trials from the overall analysis, the researchers found the smaller proportional reductions persisted for older patients for major coronary events (P = .01) but was no longer significant for major vascular events.
The researchers noted their study was limited by the highly selected patient population, low percentage of patients older than 75 years, including trials with efficacy endpoints where some nonserious adverse events may not have been recorded, and not including some trials in the meta-analysis if they were not part of the CTT.
This study was funded by Australian National Health and Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, and British Heart Foundation. The authors have reported personal fees, grants, and consulting fees from Abbott, Aegerion, Amgen, Arisaph, AstraZeneca, Bayer, Beckmann, Berlin-Chemie, Boehringer Ingelheim, Daiichi Sankyo, Dalcor, DuPont, Esperion, GlaxoSmithKline, ISIS Pharmaceuticals, Kowa, Mylan, Pfizer, Roche, Sanofi, Singulex, The Medicines Company, and Vatera Capital, as well as the British Heart Foundation, Cancer Research UK, National Institute for Health Research Oxford Biomedical Research Centre, Medical Research Council, Nuffield Department of Population Health, Weill Cornell Medicine, and UK Biobank.
SOURCE: Fulcher J et al. Lancet. 2019;393:407-15.
Statin therapy is often discontinued for older patients who have concomitant disease or other considerations, but it should still be considered in older patients when the benefits outweigh the risks, Bernard M.Y. Cheung, PhD, and Karen S.L. Lam, MD, wrote in a related editorial.
“Even if the relative risk reduction in people older than 75 years is less than expected, statin therapy might still be justified by a high baseline cardiovascular risk, which is usually present in older people,” they said.
One explanation for the decreased relative risk reduction among older patients from the results by Fulcher et al. in the Cholesterol Treatment Trialists’ (CTT) Collaboration trial could have been the inclusion of older patients with cardiac and renal failure, and treating patients with lower cardiac risk or lowering LDL cholesterol in patients at risk of cardiovascular events can help prevent major vascular events later.
Ultimately, no drug is harmless and the risk and benefits must be weighed before making a decision to use statins with older patients just as they would in any other patient population. “The challenge for the health-care profession and the media is to convey risks and benefits in ways that patients can understand, enabling them to make an informed choice,” the authors wrote.
Dr. Cheung and Dr. Lam are from the department of medicine at Queen Mary Hospital, University of Hong Kong in Hong Kong Special Administrative Region, China. They had no relevant disclosures.
Statin therapy is often discontinued for older patients who have concomitant disease or other considerations, but it should still be considered in older patients when the benefits outweigh the risks, Bernard M.Y. Cheung, PhD, and Karen S.L. Lam, MD, wrote in a related editorial.
“Even if the relative risk reduction in people older than 75 years is less than expected, statin therapy might still be justified by a high baseline cardiovascular risk, which is usually present in older people,” they said.
One explanation for the decreased relative risk reduction among older patients from the results by Fulcher et al. in the Cholesterol Treatment Trialists’ (CTT) Collaboration trial could have been the inclusion of older patients with cardiac and renal failure, and treating patients with lower cardiac risk or lowering LDL cholesterol in patients at risk of cardiovascular events can help prevent major vascular events later.
Ultimately, no drug is harmless and the risk and benefits must be weighed before making a decision to use statins with older patients just as they would in any other patient population. “The challenge for the health-care profession and the media is to convey risks and benefits in ways that patients can understand, enabling them to make an informed choice,” the authors wrote.
Dr. Cheung and Dr. Lam are from the department of medicine at Queen Mary Hospital, University of Hong Kong in Hong Kong Special Administrative Region, China. They had no relevant disclosures.
Statin therapy is often discontinued for older patients who have concomitant disease or other considerations, but it should still be considered in older patients when the benefits outweigh the risks, Bernard M.Y. Cheung, PhD, and Karen S.L. Lam, MD, wrote in a related editorial.
“Even if the relative risk reduction in people older than 75 years is less than expected, statin therapy might still be justified by a high baseline cardiovascular risk, which is usually present in older people,” they said.
One explanation for the decreased relative risk reduction among older patients from the results by Fulcher et al. in the Cholesterol Treatment Trialists’ (CTT) Collaboration trial could have been the inclusion of older patients with cardiac and renal failure, and treating patients with lower cardiac risk or lowering LDL cholesterol in patients at risk of cardiovascular events can help prevent major vascular events later.
Ultimately, no drug is harmless and the risk and benefits must be weighed before making a decision to use statins with older patients just as they would in any other patient population. “The challenge for the health-care profession and the media is to convey risks and benefits in ways that patients can understand, enabling them to make an informed choice,” the authors wrote.
Dr. Cheung and Dr. Lam are from the department of medicine at Queen Mary Hospital, University of Hong Kong in Hong Kong Special Administrative Region, China. They had no relevant disclosures.
Statin therapy appears to reduce the risk of major vascular events for patients of all age groups, but there is less evidence that older patients with evidence of occlusive vascular disease benefit from the treatment, according to a recent meta-analysis of 28 trials from the Cholesterol Treatment Trialists’ Collaboration published in The Lancet.
Statins are “useful and affordable drug[s] that reduce heart attacks and strokes in older patients. Until now there has been an evidence gap and we wanted to look at their efficacy and safety in older people,” Jordan Fulcher, BSc (Med), MBBS, from the Cholesterol Treatment Trialists’ (CTT) Collaboration and the University of Sydney stated in a press release. “Our analysis indicates that major cardiovascular events were reduced by about a fifth, per mmol/L lower LDL cholesterol, by statin therapy across all age groups. Despite previous concerns, we found no adverse effect on cancer or nonvascular mortality in any age group.”
The researchers examined 186,854 participants from 28 CTT trials undergoing statin therapy, of whom 14,483 (8%) were older than 75 years. Patients were divided into six groups based on age and examined the risk of major cardiovascular events such as stroke, coronary revascularization and major coronary events, as well as the incidence of cancer and vascular mortality.
Among all age groups, there was a significant reduction in major vascular events, with a 21% proportional per 1.0-mmol/L reduction in LDL cholesterol (risk ratio, 0.79; 95% confidence interval, 0.77-0.81) among patients receiving statin therapy or a more intensive statin regimen, and there was a 24% proportional reduction (RR, 0.76; 95% CI, 0.73-0.79) of major coronary events per 1.0-mmol/L reduction in LDL cholesterol, with older age resulting in a lower proportional reduction of major coronary events (P = .009). The researchers also found a proportional reduction of coronary revascularization procedures by 25% (RR, 0.75; 95% CI, 0.73-0.78) and stroke by 16% (RR, 0.84; 95% CI, 0.80-0.89) among patients of any age group receiving statin therapy or more intensive statin regimen, with no significant differences between age groups.
There was a 12% proportional reduction in vascular mortality per 1.0-mmol/L reduction in LDL cholesterol (RR, 0.88; 95% CI, 0.85-0.91), but this statistic did not remain significant after the researchers excluded four trials that included patients with heart failure or who were receiving renal dialysis. After excluding these trials from the overall analysis, the researchers found the smaller proportional reductions persisted for older patients for major coronary events (P = .01) but was no longer significant for major vascular events.
The researchers noted their study was limited by the highly selected patient population, low percentage of patients older than 75 years, including trials with efficacy endpoints where some nonserious adverse events may not have been recorded, and not including some trials in the meta-analysis if they were not part of the CTT.
This study was funded by Australian National Health and Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, and British Heart Foundation. The authors have reported personal fees, grants, and consulting fees from Abbott, Aegerion, Amgen, Arisaph, AstraZeneca, Bayer, Beckmann, Berlin-Chemie, Boehringer Ingelheim, Daiichi Sankyo, Dalcor, DuPont, Esperion, GlaxoSmithKline, ISIS Pharmaceuticals, Kowa, Mylan, Pfizer, Roche, Sanofi, Singulex, The Medicines Company, and Vatera Capital, as well as the British Heart Foundation, Cancer Research UK, National Institute for Health Research Oxford Biomedical Research Centre, Medical Research Council, Nuffield Department of Population Health, Weill Cornell Medicine, and UK Biobank.
SOURCE: Fulcher J et al. Lancet. 2019;393:407-15.
Statin therapy appears to reduce the risk of major vascular events for patients of all age groups, but there is less evidence that older patients with evidence of occlusive vascular disease benefit from the treatment, according to a recent meta-analysis of 28 trials from the Cholesterol Treatment Trialists’ Collaboration published in The Lancet.
Statins are “useful and affordable drug[s] that reduce heart attacks and strokes in older patients. Until now there has been an evidence gap and we wanted to look at their efficacy and safety in older people,” Jordan Fulcher, BSc (Med), MBBS, from the Cholesterol Treatment Trialists’ (CTT) Collaboration and the University of Sydney stated in a press release. “Our analysis indicates that major cardiovascular events were reduced by about a fifth, per mmol/L lower LDL cholesterol, by statin therapy across all age groups. Despite previous concerns, we found no adverse effect on cancer or nonvascular mortality in any age group.”
The researchers examined 186,854 participants from 28 CTT trials undergoing statin therapy, of whom 14,483 (8%) were older than 75 years. Patients were divided into six groups based on age and examined the risk of major cardiovascular events such as stroke, coronary revascularization and major coronary events, as well as the incidence of cancer and vascular mortality.
Among all age groups, there was a significant reduction in major vascular events, with a 21% proportional per 1.0-mmol/L reduction in LDL cholesterol (risk ratio, 0.79; 95% confidence interval, 0.77-0.81) among patients receiving statin therapy or a more intensive statin regimen, and there was a 24% proportional reduction (RR, 0.76; 95% CI, 0.73-0.79) of major coronary events per 1.0-mmol/L reduction in LDL cholesterol, with older age resulting in a lower proportional reduction of major coronary events (P = .009). The researchers also found a proportional reduction of coronary revascularization procedures by 25% (RR, 0.75; 95% CI, 0.73-0.78) and stroke by 16% (RR, 0.84; 95% CI, 0.80-0.89) among patients of any age group receiving statin therapy or more intensive statin regimen, with no significant differences between age groups.
There was a 12% proportional reduction in vascular mortality per 1.0-mmol/L reduction in LDL cholesterol (RR, 0.88; 95% CI, 0.85-0.91), but this statistic did not remain significant after the researchers excluded four trials that included patients with heart failure or who were receiving renal dialysis. After excluding these trials from the overall analysis, the researchers found the smaller proportional reductions persisted for older patients for major coronary events (P = .01) but was no longer significant for major vascular events.
The researchers noted their study was limited by the highly selected patient population, low percentage of patients older than 75 years, including trials with efficacy endpoints where some nonserious adverse events may not have been recorded, and not including some trials in the meta-analysis if they were not part of the CTT.
This study was funded by Australian National Health and Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, and British Heart Foundation. The authors have reported personal fees, grants, and consulting fees from Abbott, Aegerion, Amgen, Arisaph, AstraZeneca, Bayer, Beckmann, Berlin-Chemie, Boehringer Ingelheim, Daiichi Sankyo, Dalcor, DuPont, Esperion, GlaxoSmithKline, ISIS Pharmaceuticals, Kowa, Mylan, Pfizer, Roche, Sanofi, Singulex, The Medicines Company, and Vatera Capital, as well as the British Heart Foundation, Cancer Research UK, National Institute for Health Research Oxford Biomedical Research Centre, Medical Research Council, Nuffield Department of Population Health, Weill Cornell Medicine, and UK Biobank.
SOURCE: Fulcher J et al. Lancet. 2019;393:407-15.
FROM THE LANCET
Key clinical point: but patients older than 75 years with occlusive vascular disease have a smaller reduction in major coronary events.
Major finding: Major vascular coronary events were reduced by 24% (risk ratio, 0.76; 95% confidence interval, 0.73-0.79) with a decrease in the reduction of coronary events among patients older than 75 years. Study details: A meta-analysis of 28 trials with 186,854 individuals undergoing statin therapy from the Cholesterol Treatment Trialists’ Collaboration.
Disclosures: This study was funded by Australian National Health and Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, and British Heart Foundation. The authors have reported personal fees, grants, and consulting fees from Abbott, Aegerion, Amgen, Arisaph, AstraZeneca, Bayer, Beckmann, Berlin-Chemie, Boehringer Ingelheim, Daiichi Sankyo, Dalcor, DuPont, Esperion, GlaxoSmithKline, ISIS Pharmaceuticals, Kowa, Mylan, Pfizer, Roche, Sanofi, Singulex, The Medicines Company, and Vatera Capital, as well as the British Heart Foundation, Cancer Research UK, National Institute for Health Research Oxford Biomedical Research Centre, Medical Research Council, Nuffield Department of Population Health, Weill Cornell Medicine, and UK Biobank.
Source: Fulcher J et al. Lancet. 2019;393:407-15.
When is it safe to resume anticoagulation in my patient with hemorrhagic stroke?
Balancing risk is critical to decision making
Department of Medicine, Massachusetts General Hospital, Boston
Case
A 75 year-old woman with a history of hypertension, diabetes mellitus, heart failure and nonvalvular atrial fibrillation (CHA2DS2-VASc score, 8) on anticoagulation is admitted with weakness and dysarthria. Exam is notable for hypertension and right-sided hemiparesis. CT of the head shows an intraparenchymal hemorrhage in the left putamen. Her anticoagulation is reversed and blood pressure well controlled. She is discharged 12 days later.
Brief overview of the issue
Intracranial hemorrhage (ICH) is the second most common cause of stroke and is associated with high morbidity and mortality.1 It is estimated that 10%-15% of spontaneous ICH cases occur in patients on therapeutic anticoagulation for atrial fibrillation.2 As our population ages and more people develop atrial fibrillation, anticoagulation for primary or secondary prevention of embolic stroke also will likely increase, placing more people at risk for ICH. Even stringently controlled therapeutic international normalized ratios (INRs) between 2 and 3 may double the risk of ICH.3
Patients with ICH require close monitoring and treatment, including blood pressure control, reversal of anticoagulation, reduction of intracranial pressure and, at times, neurosurgery.4 Although anticoagulation is discontinued and reversed at the onset of ICH, no clear consensus exists as to when it is safe to resume it. Although anticoagulation decreases the risk of stroke/thromboembolism, it may also increase the amount of bleeding associated with the initial ICH or lead to its recurrence.
Factors that may contribute to rebleeding include uncontrolled hypertension, advanced age, time to resumption of anticoagulation, and lobar location of ICH (i.e., in cerebral cortex and/or underlying white matter).5 Traditionally, lobar ICH has high incidence of cerebral amyloid angiopathy and has been associated with higher bleeding rates than has deep ICH (i.e., involving the thalami, basal ganglia, cerebellum, or brainstem) where cerebral amyloid angiopathy is rare and ICH is usually from hypertensive vessel disease. However, in patients with active thromboembolic disease, high-risk atrial fibrillation, and mechanical valves, withholding anticoagulation could place them at high risk of stroke.
Two questions should be addressed in the case presented: Is it safe to restart therapeutic anticoagulation; and if so, what is the optimal time interval between ICH and reinitiation of anticoagulation?
Overview of the data
There is limited guidance from major professional societies regarding the reinitiation of anticoagulation and the optimal timing of safely resuming anticoagulation in patients with prior ICH.
Current European Stroke Organization guidelines provide no specific recommendations for anticoagulation resumption after ICH.7 The American Heart Association/American Stroke Association guideline has a class IIA (weak) recommendation to avoid anticoagulation in spontaneous lobar ICH and a class IIB (very weak) recommendation to consider resuming anticoagulation in nonlobar ICH on a case-by-case basis.4
Two recent meta-analyses have examined outcomes of resuming anticoagulation after ICH. In a meta-analysis of 5,300 patients with nonlobar ICH involving eight retrospective studies, Murthy et al. evaluated the risk of thromboembolic events (described as a composite outcome of MI and stroke) and the risk of recurrent ICH.8 They reported that resumption of therapeutic anticoagulation was associated with a decrease in the rate of thromboembolic events (6.7% vs. 17.6%; risk ratio, 0.35; 95% confidence interval, 0.25-0.45) with no significant change in the rate of repeat ICH (8.7% vs. 7.8%).
A second meta-analysis of three retrospective trials conducted by Biffi et al. examined anticoagulation resumption in 1,012 patients with ICH solely in the setting of thromboprophylaxis for nonvalvular atrial fibrillation.9 Reinitiation of anticoagulation after ICH was associated with decreased mortality (hazard ratio, 0.27; 95% CI, 0.19-0.40; P less than .0001), improved functional outcome (HR, 4.15; 95% CI, 2.92-5.90; P less than .0001), and reduction in all-cause stroke recurrence (HR 0.47; 95% CI, 0.36-0.64; P less than .0001). There was no significant difference in the rate of recurrent ICH when anticoagulation was resumed. Despite the notion that patients with cerebral amyloid angiopathy are at high risk of rebleeding, this positive association still held irrespective of lobar vs. nonlobar location of ICH.
Collectively, these studies suggest that resumption of anticoagulation may be effective in decreasing the rates of thromboembolism, as well as provide a functional and mortality benefit without increasing the risk of rebleeding, irrespective of the location of the bleed.
Less is known about the optimal timing of resumption of therapeutic anticoagulation, with data ranging from 72 hours to 30 weeks.10 The American Heart Association/American Stroke Association has a class IIB (very weak) recommendation to avoid anticoagulation for at least 4 weeks in patients without mechanical heart valves.4 The median time to resumption of therapeutic anticoagulation in aforementioned meta-analyses ranged from 10 to 44 days.8,9
A recent observational study of 2,619 ICH survivors explored the relationship between the timing of reinitiation of anticoagulation and the incidence of thrombotic events (defined as ischemic stroke or death because of MI or systemic arterial thromboembolism) and hemorrhagic events (defined as recurrent ICH or bleeding event leading to death) occurring at least 28 days after initial ICH in patients with atrial fibrillation.11
A decrease in thrombotic events was demonstrated if anticoagulation was started 4-16 weeks after ICH. However, when anticoagulation was started more than 16 weeks after ICH, no benefit was seen. Additionally, there was no significant difference in hemorrhagic events between men and women who resumed anticoagulation. In patients with high venous thromboembolism risk based on CHA2DS2-VASc score, resumption of anticoagulation was associated with a decreased predicted incidence of vascular death and nonfatal stroke, with the greatest benefit observed when anticoagulation was started at 7-8 weeks after ICH.
Unfortunately, published literature to date on anticoagulation after ICH is based entirely on retrospective studies – not randomized, controlled studies – making it more likely that anticoagulation would have been resumed in healthier patients, not those left debilitated by the ICH.
Furthermore, information on the location and size of the hemorrhages – which may serve as another confounding factor – often has not been reported. This is important since patients with smaller hemorrhages in less precarious areas also may be more likely to have resumption of anticoagulation. Another limitation of the current literature is that warfarin is the most common anticoagulant studied, with few studies involving the increasingly prescribed newer direct oral anticoagulants. It is also important to stress that a causal relationship between use of anticoagulants and certain outcomes or adverse effects following ICH may be more difficult to invoke in the absence of randomized controlled study designs.
Application of the data to our patient
Resumption of anticoagulation in our patient with ICH requires balancing the risk of hemorrhage expansion and recurrent ICH with the risk of thromboembolic disease.
Our patient is at higher risk of bleeding because of her advanced age, but adequate control of her blood pressure and nonlobar location of her ICH in the basal ganglia also may decrease her risk of recurrent ICH. Her high CHA2DS2-VASc score places her at high risk of thromboembolic event and stroke, making it more likely for reinitiation of anticoagulation to confer a mortality benefit.
Based on AHA guidelines,4 we should wait at least 4 weeks, or possibly wait until weeks 7-8 after ICH when the greatest benefit may be expected based on prediction models.11
Bottom line
It would likely be safe to resume anticoagulation 4-8 weeks after ICH in our patient.
Dr. Gibson, Dr. Restrepo, Dr. Sasidhara, and Dr. Manian are hospitalists at Massachusetts General Hospital, Boston.
References
1. An SJ et al. Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: An update. J Stroke. 2017 Jan;19:3-10.
2. Horstmann S et al. Intracerebral hemorrhage during anticoagulation with vitamin K antagonists: a consecutive observational study. J Neurol. 2013 Aug;260:2046-51.
3. Rosand J et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med. 2004 Apr 26;164:880-4.
4. Hemphill JC et al. Guidelines for the management of spontaneous intracerebral hemorrhage. Stroke. 2015 Jul;46:2032-60.
5. Aguillar MI et al. Update in intracerebral hemorrhage. Neurohospitalist. 2011;1:148-59.
6. Hill MD et al. Rate of stroke recurrence in patients with primary intracerebral hemorrhage. Stroke. 2000;31:123-7.
7. Steiner T et al. European Stroke Organization (ESO) guidelines for the management of spontaneous cerebral hemorrhage. Int J Stroke. 2014;9:840-55.
8. Murthy SB et al. Restarting anticoagulation therapy after intracranial hemorrhage: A systematic review and meta-analysis. Stroke. 2017 Jun;48:1594-600.
9. Biffi A et al. Oral anticoagulation and functional outcome after intracerebral hemorrhage. Ann Neurol. 2017 Nov;82:755-65.
10. Witt DM. What to do after the bleed: Resuming anticoagulation after major bleeding. Hematology Am Soc Hematol Educ Program. 2016 Dec 2;206:620-4.
11. Pennlert J et al. Optimal timing of anticoagulant treatment after intracerebral hemorrhage in patients with atrial fibrillation. Stroke. 2017 Feb;48:314-20.
Key Points
- Robust scientific data on when to resume anticoagulation after ICH does not exist.
- Retrospective studies have shown that anticoagulation resumption after 4-8 weeks decreases the risk of thromboembolic events, decreases mortality, and improves functional status following ICH with no significant change in the risk of its recurrence.
- Prospective, randomized controlled trials are needed to explore risks/benefits of anticoagulation resumption and better define its optimal timing in relation to ICH.
Quiz
Which of the following is false regarding ICH?
A. Lobar ICHs are usually associated with cerebral amyloid angiopathy which are prone to bleeding.
B. Randomized, controlled studies have helped guide the decision as to when to resume anticoagulation in patients with ICH.
C. Current guidelines suggest deferring therapeutic anticoagulation for at least 4 weeks following ICH.
D. Resumption of anticoagulation after 4-8 weeks does not lead to increased risk of rebleeding in patients with prior ICH.
The false answer is B: Current recommendations regarding resumption of anticoagulation in patients with ICH are based solely on retrospective observational studies; there are no randomized, control trials to date.
A is true: In contrast to hypertensive vessel disease associated with deep ICH, lobar hemorrhages are usually associated with cerebral amyloid angiopathy, which are more prone to bleeding.
C is true: The AHA/ASA has a class IIB recommendation to avoid anticoagulation for at least 4 weeks after ICH in patients without mechanical heart valves.
D is true: Several studies have shown that resumption of anticoagulation 4-8 weeks after ICH does not increase the risk of rebleeding.
Balancing risk is critical to decision making
Balancing risk is critical to decision making
Department of Medicine, Massachusetts General Hospital, Boston
Case
A 75 year-old woman with a history of hypertension, diabetes mellitus, heart failure and nonvalvular atrial fibrillation (CHA2DS2-VASc score, 8) on anticoagulation is admitted with weakness and dysarthria. Exam is notable for hypertension and right-sided hemiparesis. CT of the head shows an intraparenchymal hemorrhage in the left putamen. Her anticoagulation is reversed and blood pressure well controlled. She is discharged 12 days later.
Brief overview of the issue
Intracranial hemorrhage (ICH) is the second most common cause of stroke and is associated with high morbidity and mortality.1 It is estimated that 10%-15% of spontaneous ICH cases occur in patients on therapeutic anticoagulation for atrial fibrillation.2 As our population ages and more people develop atrial fibrillation, anticoagulation for primary or secondary prevention of embolic stroke also will likely increase, placing more people at risk for ICH. Even stringently controlled therapeutic international normalized ratios (INRs) between 2 and 3 may double the risk of ICH.3
Patients with ICH require close monitoring and treatment, including blood pressure control, reversal of anticoagulation, reduction of intracranial pressure and, at times, neurosurgery.4 Although anticoagulation is discontinued and reversed at the onset of ICH, no clear consensus exists as to when it is safe to resume it. Although anticoagulation decreases the risk of stroke/thromboembolism, it may also increase the amount of bleeding associated with the initial ICH or lead to its recurrence.
Factors that may contribute to rebleeding include uncontrolled hypertension, advanced age, time to resumption of anticoagulation, and lobar location of ICH (i.e., in cerebral cortex and/or underlying white matter).5 Traditionally, lobar ICH has high incidence of cerebral amyloid angiopathy and has been associated with higher bleeding rates than has deep ICH (i.e., involving the thalami, basal ganglia, cerebellum, or brainstem) where cerebral amyloid angiopathy is rare and ICH is usually from hypertensive vessel disease. However, in patients with active thromboembolic disease, high-risk atrial fibrillation, and mechanical valves, withholding anticoagulation could place them at high risk of stroke.
Two questions should be addressed in the case presented: Is it safe to restart therapeutic anticoagulation; and if so, what is the optimal time interval between ICH and reinitiation of anticoagulation?
Overview of the data
There is limited guidance from major professional societies regarding the reinitiation of anticoagulation and the optimal timing of safely resuming anticoagulation in patients with prior ICH.
Current European Stroke Organization guidelines provide no specific recommendations for anticoagulation resumption after ICH.7 The American Heart Association/American Stroke Association guideline has a class IIA (weak) recommendation to avoid anticoagulation in spontaneous lobar ICH and a class IIB (very weak) recommendation to consider resuming anticoagulation in nonlobar ICH on a case-by-case basis.4
Two recent meta-analyses have examined outcomes of resuming anticoagulation after ICH. In a meta-analysis of 5,300 patients with nonlobar ICH involving eight retrospective studies, Murthy et al. evaluated the risk of thromboembolic events (described as a composite outcome of MI and stroke) and the risk of recurrent ICH.8 They reported that resumption of therapeutic anticoagulation was associated with a decrease in the rate of thromboembolic events (6.7% vs. 17.6%; risk ratio, 0.35; 95% confidence interval, 0.25-0.45) with no significant change in the rate of repeat ICH (8.7% vs. 7.8%).
A second meta-analysis of three retrospective trials conducted by Biffi et al. examined anticoagulation resumption in 1,012 patients with ICH solely in the setting of thromboprophylaxis for nonvalvular atrial fibrillation.9 Reinitiation of anticoagulation after ICH was associated with decreased mortality (hazard ratio, 0.27; 95% CI, 0.19-0.40; P less than .0001), improved functional outcome (HR, 4.15; 95% CI, 2.92-5.90; P less than .0001), and reduction in all-cause stroke recurrence (HR 0.47; 95% CI, 0.36-0.64; P less than .0001). There was no significant difference in the rate of recurrent ICH when anticoagulation was resumed. Despite the notion that patients with cerebral amyloid angiopathy are at high risk of rebleeding, this positive association still held irrespective of lobar vs. nonlobar location of ICH.
Collectively, these studies suggest that resumption of anticoagulation may be effective in decreasing the rates of thromboembolism, as well as provide a functional and mortality benefit without increasing the risk of rebleeding, irrespective of the location of the bleed.
Less is known about the optimal timing of resumption of therapeutic anticoagulation, with data ranging from 72 hours to 30 weeks.10 The American Heart Association/American Stroke Association has a class IIB (very weak) recommendation to avoid anticoagulation for at least 4 weeks in patients without mechanical heart valves.4 The median time to resumption of therapeutic anticoagulation in aforementioned meta-analyses ranged from 10 to 44 days.8,9
A recent observational study of 2,619 ICH survivors explored the relationship between the timing of reinitiation of anticoagulation and the incidence of thrombotic events (defined as ischemic stroke or death because of MI or systemic arterial thromboembolism) and hemorrhagic events (defined as recurrent ICH or bleeding event leading to death) occurring at least 28 days after initial ICH in patients with atrial fibrillation.11
A decrease in thrombotic events was demonstrated if anticoagulation was started 4-16 weeks after ICH. However, when anticoagulation was started more than 16 weeks after ICH, no benefit was seen. Additionally, there was no significant difference in hemorrhagic events between men and women who resumed anticoagulation. In patients with high venous thromboembolism risk based on CHA2DS2-VASc score, resumption of anticoagulation was associated with a decreased predicted incidence of vascular death and nonfatal stroke, with the greatest benefit observed when anticoagulation was started at 7-8 weeks after ICH.
Unfortunately, published literature to date on anticoagulation after ICH is based entirely on retrospective studies – not randomized, controlled studies – making it more likely that anticoagulation would have been resumed in healthier patients, not those left debilitated by the ICH.
Furthermore, information on the location and size of the hemorrhages – which may serve as another confounding factor – often has not been reported. This is important since patients with smaller hemorrhages in less precarious areas also may be more likely to have resumption of anticoagulation. Another limitation of the current literature is that warfarin is the most common anticoagulant studied, with few studies involving the increasingly prescribed newer direct oral anticoagulants. It is also important to stress that a causal relationship between use of anticoagulants and certain outcomes or adverse effects following ICH may be more difficult to invoke in the absence of randomized controlled study designs.
Application of the data to our patient
Resumption of anticoagulation in our patient with ICH requires balancing the risk of hemorrhage expansion and recurrent ICH with the risk of thromboembolic disease.
Our patient is at higher risk of bleeding because of her advanced age, but adequate control of her blood pressure and nonlobar location of her ICH in the basal ganglia also may decrease her risk of recurrent ICH. Her high CHA2DS2-VASc score places her at high risk of thromboembolic event and stroke, making it more likely for reinitiation of anticoagulation to confer a mortality benefit.
Based on AHA guidelines,4 we should wait at least 4 weeks, or possibly wait until weeks 7-8 after ICH when the greatest benefit may be expected based on prediction models.11
Bottom line
It would likely be safe to resume anticoagulation 4-8 weeks after ICH in our patient.
Dr. Gibson, Dr. Restrepo, Dr. Sasidhara, and Dr. Manian are hospitalists at Massachusetts General Hospital, Boston.
References
1. An SJ et al. Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: An update. J Stroke. 2017 Jan;19:3-10.
2. Horstmann S et al. Intracerebral hemorrhage during anticoagulation with vitamin K antagonists: a consecutive observational study. J Neurol. 2013 Aug;260:2046-51.
3. Rosand J et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med. 2004 Apr 26;164:880-4.
4. Hemphill JC et al. Guidelines for the management of spontaneous intracerebral hemorrhage. Stroke. 2015 Jul;46:2032-60.
5. Aguillar MI et al. Update in intracerebral hemorrhage. Neurohospitalist. 2011;1:148-59.
6. Hill MD et al. Rate of stroke recurrence in patients with primary intracerebral hemorrhage. Stroke. 2000;31:123-7.
7. Steiner T et al. European Stroke Organization (ESO) guidelines for the management of spontaneous cerebral hemorrhage. Int J Stroke. 2014;9:840-55.
8. Murthy SB et al. Restarting anticoagulation therapy after intracranial hemorrhage: A systematic review and meta-analysis. Stroke. 2017 Jun;48:1594-600.
9. Biffi A et al. Oral anticoagulation and functional outcome after intracerebral hemorrhage. Ann Neurol. 2017 Nov;82:755-65.
10. Witt DM. What to do after the bleed: Resuming anticoagulation after major bleeding. Hematology Am Soc Hematol Educ Program. 2016 Dec 2;206:620-4.
11. Pennlert J et al. Optimal timing of anticoagulant treatment after intracerebral hemorrhage in patients with atrial fibrillation. Stroke. 2017 Feb;48:314-20.
Key Points
- Robust scientific data on when to resume anticoagulation after ICH does not exist.
- Retrospective studies have shown that anticoagulation resumption after 4-8 weeks decreases the risk of thromboembolic events, decreases mortality, and improves functional status following ICH with no significant change in the risk of its recurrence.
- Prospective, randomized controlled trials are needed to explore risks/benefits of anticoagulation resumption and better define its optimal timing in relation to ICH.
Quiz
Which of the following is false regarding ICH?
A. Lobar ICHs are usually associated with cerebral amyloid angiopathy which are prone to bleeding.
B. Randomized, controlled studies have helped guide the decision as to when to resume anticoagulation in patients with ICH.
C. Current guidelines suggest deferring therapeutic anticoagulation for at least 4 weeks following ICH.
D. Resumption of anticoagulation after 4-8 weeks does not lead to increased risk of rebleeding in patients with prior ICH.
The false answer is B: Current recommendations regarding resumption of anticoagulation in patients with ICH are based solely on retrospective observational studies; there are no randomized, control trials to date.
A is true: In contrast to hypertensive vessel disease associated with deep ICH, lobar hemorrhages are usually associated with cerebral amyloid angiopathy, which are more prone to bleeding.
C is true: The AHA/ASA has a class IIB recommendation to avoid anticoagulation for at least 4 weeks after ICH in patients without mechanical heart valves.
D is true: Several studies have shown that resumption of anticoagulation 4-8 weeks after ICH does not increase the risk of rebleeding.
Department of Medicine, Massachusetts General Hospital, Boston
Case
A 75 year-old woman with a history of hypertension, diabetes mellitus, heart failure and nonvalvular atrial fibrillation (CHA2DS2-VASc score, 8) on anticoagulation is admitted with weakness and dysarthria. Exam is notable for hypertension and right-sided hemiparesis. CT of the head shows an intraparenchymal hemorrhage in the left putamen. Her anticoagulation is reversed and blood pressure well controlled. She is discharged 12 days later.
Brief overview of the issue
Intracranial hemorrhage (ICH) is the second most common cause of stroke and is associated with high morbidity and mortality.1 It is estimated that 10%-15% of spontaneous ICH cases occur in patients on therapeutic anticoagulation for atrial fibrillation.2 As our population ages and more people develop atrial fibrillation, anticoagulation for primary or secondary prevention of embolic stroke also will likely increase, placing more people at risk for ICH. Even stringently controlled therapeutic international normalized ratios (INRs) between 2 and 3 may double the risk of ICH.3
Patients with ICH require close monitoring and treatment, including blood pressure control, reversal of anticoagulation, reduction of intracranial pressure and, at times, neurosurgery.4 Although anticoagulation is discontinued and reversed at the onset of ICH, no clear consensus exists as to when it is safe to resume it. Although anticoagulation decreases the risk of stroke/thromboembolism, it may also increase the amount of bleeding associated with the initial ICH or lead to its recurrence.
Factors that may contribute to rebleeding include uncontrolled hypertension, advanced age, time to resumption of anticoagulation, and lobar location of ICH (i.e., in cerebral cortex and/or underlying white matter).5 Traditionally, lobar ICH has high incidence of cerebral amyloid angiopathy and has been associated with higher bleeding rates than has deep ICH (i.e., involving the thalami, basal ganglia, cerebellum, or brainstem) where cerebral amyloid angiopathy is rare and ICH is usually from hypertensive vessel disease. However, in patients with active thromboembolic disease, high-risk atrial fibrillation, and mechanical valves, withholding anticoagulation could place them at high risk of stroke.
Two questions should be addressed in the case presented: Is it safe to restart therapeutic anticoagulation; and if so, what is the optimal time interval between ICH and reinitiation of anticoagulation?
Overview of the data
There is limited guidance from major professional societies regarding the reinitiation of anticoagulation and the optimal timing of safely resuming anticoagulation in patients with prior ICH.
Current European Stroke Organization guidelines provide no specific recommendations for anticoagulation resumption after ICH.7 The American Heart Association/American Stroke Association guideline has a class IIA (weak) recommendation to avoid anticoagulation in spontaneous lobar ICH and a class IIB (very weak) recommendation to consider resuming anticoagulation in nonlobar ICH on a case-by-case basis.4
Two recent meta-analyses have examined outcomes of resuming anticoagulation after ICH. In a meta-analysis of 5,300 patients with nonlobar ICH involving eight retrospective studies, Murthy et al. evaluated the risk of thromboembolic events (described as a composite outcome of MI and stroke) and the risk of recurrent ICH.8 They reported that resumption of therapeutic anticoagulation was associated with a decrease in the rate of thromboembolic events (6.7% vs. 17.6%; risk ratio, 0.35; 95% confidence interval, 0.25-0.45) with no significant change in the rate of repeat ICH (8.7% vs. 7.8%).
A second meta-analysis of three retrospective trials conducted by Biffi et al. examined anticoagulation resumption in 1,012 patients with ICH solely in the setting of thromboprophylaxis for nonvalvular atrial fibrillation.9 Reinitiation of anticoagulation after ICH was associated with decreased mortality (hazard ratio, 0.27; 95% CI, 0.19-0.40; P less than .0001), improved functional outcome (HR, 4.15; 95% CI, 2.92-5.90; P less than .0001), and reduction in all-cause stroke recurrence (HR 0.47; 95% CI, 0.36-0.64; P less than .0001). There was no significant difference in the rate of recurrent ICH when anticoagulation was resumed. Despite the notion that patients with cerebral amyloid angiopathy are at high risk of rebleeding, this positive association still held irrespective of lobar vs. nonlobar location of ICH.
Collectively, these studies suggest that resumption of anticoagulation may be effective in decreasing the rates of thromboembolism, as well as provide a functional and mortality benefit without increasing the risk of rebleeding, irrespective of the location of the bleed.
Less is known about the optimal timing of resumption of therapeutic anticoagulation, with data ranging from 72 hours to 30 weeks.10 The American Heart Association/American Stroke Association has a class IIB (very weak) recommendation to avoid anticoagulation for at least 4 weeks in patients without mechanical heart valves.4 The median time to resumption of therapeutic anticoagulation in aforementioned meta-analyses ranged from 10 to 44 days.8,9
A recent observational study of 2,619 ICH survivors explored the relationship between the timing of reinitiation of anticoagulation and the incidence of thrombotic events (defined as ischemic stroke or death because of MI or systemic arterial thromboembolism) and hemorrhagic events (defined as recurrent ICH or bleeding event leading to death) occurring at least 28 days after initial ICH in patients with atrial fibrillation.11
A decrease in thrombotic events was demonstrated if anticoagulation was started 4-16 weeks after ICH. However, when anticoagulation was started more than 16 weeks after ICH, no benefit was seen. Additionally, there was no significant difference in hemorrhagic events between men and women who resumed anticoagulation. In patients with high venous thromboembolism risk based on CHA2DS2-VASc score, resumption of anticoagulation was associated with a decreased predicted incidence of vascular death and nonfatal stroke, with the greatest benefit observed when anticoagulation was started at 7-8 weeks after ICH.
Unfortunately, published literature to date on anticoagulation after ICH is based entirely on retrospective studies – not randomized, controlled studies – making it more likely that anticoagulation would have been resumed in healthier patients, not those left debilitated by the ICH.
Furthermore, information on the location and size of the hemorrhages – which may serve as another confounding factor – often has not been reported. This is important since patients with smaller hemorrhages in less precarious areas also may be more likely to have resumption of anticoagulation. Another limitation of the current literature is that warfarin is the most common anticoagulant studied, with few studies involving the increasingly prescribed newer direct oral anticoagulants. It is also important to stress that a causal relationship between use of anticoagulants and certain outcomes or adverse effects following ICH may be more difficult to invoke in the absence of randomized controlled study designs.
Application of the data to our patient
Resumption of anticoagulation in our patient with ICH requires balancing the risk of hemorrhage expansion and recurrent ICH with the risk of thromboembolic disease.
Our patient is at higher risk of bleeding because of her advanced age, but adequate control of her blood pressure and nonlobar location of her ICH in the basal ganglia also may decrease her risk of recurrent ICH. Her high CHA2DS2-VASc score places her at high risk of thromboembolic event and stroke, making it more likely for reinitiation of anticoagulation to confer a mortality benefit.
Based on AHA guidelines,4 we should wait at least 4 weeks, or possibly wait until weeks 7-8 after ICH when the greatest benefit may be expected based on prediction models.11
Bottom line
It would likely be safe to resume anticoagulation 4-8 weeks after ICH in our patient.
Dr. Gibson, Dr. Restrepo, Dr. Sasidhara, and Dr. Manian are hospitalists at Massachusetts General Hospital, Boston.
References
1. An SJ et al. Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: An update. J Stroke. 2017 Jan;19:3-10.
2. Horstmann S et al. Intracerebral hemorrhage during anticoagulation with vitamin K antagonists: a consecutive observational study. J Neurol. 2013 Aug;260:2046-51.
3. Rosand J et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med. 2004 Apr 26;164:880-4.
4. Hemphill JC et al. Guidelines for the management of spontaneous intracerebral hemorrhage. Stroke. 2015 Jul;46:2032-60.
5. Aguillar MI et al. Update in intracerebral hemorrhage. Neurohospitalist. 2011;1:148-59.
6. Hill MD et al. Rate of stroke recurrence in patients with primary intracerebral hemorrhage. Stroke. 2000;31:123-7.
7. Steiner T et al. European Stroke Organization (ESO) guidelines for the management of spontaneous cerebral hemorrhage. Int J Stroke. 2014;9:840-55.
8. Murthy SB et al. Restarting anticoagulation therapy after intracranial hemorrhage: A systematic review and meta-analysis. Stroke. 2017 Jun;48:1594-600.
9. Biffi A et al. Oral anticoagulation and functional outcome after intracerebral hemorrhage. Ann Neurol. 2017 Nov;82:755-65.
10. Witt DM. What to do after the bleed: Resuming anticoagulation after major bleeding. Hematology Am Soc Hematol Educ Program. 2016 Dec 2;206:620-4.
11. Pennlert J et al. Optimal timing of anticoagulant treatment after intracerebral hemorrhage in patients with atrial fibrillation. Stroke. 2017 Feb;48:314-20.
Key Points
- Robust scientific data on when to resume anticoagulation after ICH does not exist.
- Retrospective studies have shown that anticoagulation resumption after 4-8 weeks decreases the risk of thromboembolic events, decreases mortality, and improves functional status following ICH with no significant change in the risk of its recurrence.
- Prospective, randomized controlled trials are needed to explore risks/benefits of anticoagulation resumption and better define its optimal timing in relation to ICH.
Quiz
Which of the following is false regarding ICH?
A. Lobar ICHs are usually associated with cerebral amyloid angiopathy which are prone to bleeding.
B. Randomized, controlled studies have helped guide the decision as to when to resume anticoagulation in patients with ICH.
C. Current guidelines suggest deferring therapeutic anticoagulation for at least 4 weeks following ICH.
D. Resumption of anticoagulation after 4-8 weeks does not lead to increased risk of rebleeding in patients with prior ICH.
The false answer is B: Current recommendations regarding resumption of anticoagulation in patients with ICH are based solely on retrospective observational studies; there are no randomized, control trials to date.
A is true: In contrast to hypertensive vessel disease associated with deep ICH, lobar hemorrhages are usually associated with cerebral amyloid angiopathy, which are more prone to bleeding.
C is true: The AHA/ASA has a class IIB recommendation to avoid anticoagulation for at least 4 weeks after ICH in patients without mechanical heart valves.
D is true: Several studies have shown that resumption of anticoagulation 4-8 weeks after ICH does not increase the risk of rebleeding.
Mild aerobic exercise speeds sports concussion recovery
Mild aerobic exercise significantly shortened recovery time from sports-related concussion in adolescent athletes, compared with a stretching program in a randomized trial of 103 participants.
Sports-related concussion (SRC) remains a major public health problem with no effective treatment, wrote John J. Leddy, MD, of the State University of New York at Buffalo, and his colleagues.
Exercise tolerance after SRC has not been well studied. However, given the demonstrated benefits of aerobic exercise training on autonomic nervous system regulation, cerebral blood flow regulation, cardiovascular physiology, and brain neuroplasticity, the researchers hypothesized that exercise at a level that does not exacerbate symptoms might facilitate recovery in concussion patients.
In a study published in JAMA Pediatrics, the researchers randomized 103 adolescent athletes aged 13-18 years to a program of subsymptom aerobic exercise or a placebo stretching program. The participants were enrolled in the study within 10 days of an SRC, and were followed for 30 days or until recovery.
Athletes in the aerobic exercise group recovered in a median of 13 days, compared with 17 days for those in the stretching group (P = .009). Recovery was defined as “symptom resolution to normal,” based on normal physical and neurological examinations, “further confirmed by demonstration of the ability to exercise to exhaustion without exacerbation of symptoms” according to the Buffalo Concussion Treadmill Test, the researchers wrote.
No demographic differences or difference in previous concussions, time from injury until treatment, initial symptom severity score, initial exercise treadmill test, or physical exam were noted between the groups.
The average age of the participants was 15 years, 47% were female. The athletes performed the aerobic exercise or stretching programs approximately 20 minutes per day, and reported their daily symptoms and compliance via a website. The aerobic exercise consisted of walking or jogging on a treadmill or outdoors, or riding a stationary bike while wearing a heart rate monitor to maintain a target heart rate. The target heart rate was calculated as 80% of the heart rate at symptom exacerbation during the Buffalo Concussion Treadmill Test at each participant’s initial visit.
No adverse events related to the exercise intervention were reported, which supports the safety of subsymptom threshhold exercise, in the study population, Dr. Leddy and his associates noted.
The researchers also found lower rates of persistent symptoms at 1 month in the exercise group, compared with the stretching group (two participants vs. seven participants), but this difference was not statistically significant.
The study findings were limited by several factors, including the unblinded design and failure to address the mechanism of action for the effects of exercise. In addition, the results are not generalizable to younger children or other demographic groups, including those with concussions from causes other than sports and adults with heart conditions, the researchers noted.
However, “the results of this study should give clinicians confidence that moderate levels of physical activity, including prescribed subsymptom threshold aerobic exercise, after the first 48 hours following SRC can safely and significantly speed recovery,” Dr. Leddy and his associates concluded.
The study was supported by grants from the National Institutes of Health. The researchers had no financial conflicts to disclose.
SOURCE: Leddy JJ et al. JAMA Pediatr. 2019 Feb 4. doi: 10.1001/jamapediatrics.2018.4397.
In 2009 and 2010, the culture of sports concussion care began to shift with the publication of an initial study by Leddy et al. on the use of exercise at subsymptom levels as part of concussion rehabilitation, Sara P. D. Chrisman, MD, MPH, wrote in an accompanying editorial. Previous guidelines had emphasized total avoidance of physical activity, as well as avoidance of screen time and social activity, until patients were asymptomatic; however, “no definition was provided for the term asymptomatic, and no time limits were placed on rest, and as a result, rest often continued for weeks or months,” Dr. Chrisman said. Additional research over the past decade supported the potential value of moderate exercise, and the 2016 meeting of the Concussion in Sport Group resulted in recommendations limiting rest to 24-48 hours, which prompted further studies of exercise intervention.
The current study by Leddy et al. is a clinical trial using exercise “to treat acute concussion with a goal of reducing symptom duration,” she said. Despite the study’s limitations, including the inability to estimate how much exercise was needed to achieve the treatment outcome, “this is a landmark study that may shift the standard of care toward the use of rehabilitative exercise to decrease the duration of concussion symptoms.
“Future studies will need to explore the limits of exercise treatment for concussion,” and should address questions including the timing, intensity, and duration of exercise and whether the strategy is appropriate for other populations, such as those with mental health comorbidities, Dr. Chrisman concluded.
Dr. Chrisman is at the Center for Child Health, Behavior, and Development, Seattle Children’s Research Institute. These comments are from her editorial accompanying the article by Leddy et al. (JAMA Pedatr. 2019 Feb 4. doi: 10.1001/jamapediatrics.2018.5281). She had no financial conflicts to disclose.
In 2009 and 2010, the culture of sports concussion care began to shift with the publication of an initial study by Leddy et al. on the use of exercise at subsymptom levels as part of concussion rehabilitation, Sara P. D. Chrisman, MD, MPH, wrote in an accompanying editorial. Previous guidelines had emphasized total avoidance of physical activity, as well as avoidance of screen time and social activity, until patients were asymptomatic; however, “no definition was provided for the term asymptomatic, and no time limits were placed on rest, and as a result, rest often continued for weeks or months,” Dr. Chrisman said. Additional research over the past decade supported the potential value of moderate exercise, and the 2016 meeting of the Concussion in Sport Group resulted in recommendations limiting rest to 24-48 hours, which prompted further studies of exercise intervention.
The current study by Leddy et al. is a clinical trial using exercise “to treat acute concussion with a goal of reducing symptom duration,” she said. Despite the study’s limitations, including the inability to estimate how much exercise was needed to achieve the treatment outcome, “this is a landmark study that may shift the standard of care toward the use of rehabilitative exercise to decrease the duration of concussion symptoms.
“Future studies will need to explore the limits of exercise treatment for concussion,” and should address questions including the timing, intensity, and duration of exercise and whether the strategy is appropriate for other populations, such as those with mental health comorbidities, Dr. Chrisman concluded.
Dr. Chrisman is at the Center for Child Health, Behavior, and Development, Seattle Children’s Research Institute. These comments are from her editorial accompanying the article by Leddy et al. (JAMA Pedatr. 2019 Feb 4. doi: 10.1001/jamapediatrics.2018.5281). She had no financial conflicts to disclose.
In 2009 and 2010, the culture of sports concussion care began to shift with the publication of an initial study by Leddy et al. on the use of exercise at subsymptom levels as part of concussion rehabilitation, Sara P. D. Chrisman, MD, MPH, wrote in an accompanying editorial. Previous guidelines had emphasized total avoidance of physical activity, as well as avoidance of screen time and social activity, until patients were asymptomatic; however, “no definition was provided for the term asymptomatic, and no time limits were placed on rest, and as a result, rest often continued for weeks or months,” Dr. Chrisman said. Additional research over the past decade supported the potential value of moderate exercise, and the 2016 meeting of the Concussion in Sport Group resulted in recommendations limiting rest to 24-48 hours, which prompted further studies of exercise intervention.
The current study by Leddy et al. is a clinical trial using exercise “to treat acute concussion with a goal of reducing symptom duration,” she said. Despite the study’s limitations, including the inability to estimate how much exercise was needed to achieve the treatment outcome, “this is a landmark study that may shift the standard of care toward the use of rehabilitative exercise to decrease the duration of concussion symptoms.
“Future studies will need to explore the limits of exercise treatment for concussion,” and should address questions including the timing, intensity, and duration of exercise and whether the strategy is appropriate for other populations, such as those with mental health comorbidities, Dr. Chrisman concluded.
Dr. Chrisman is at the Center for Child Health, Behavior, and Development, Seattle Children’s Research Institute. These comments are from her editorial accompanying the article by Leddy et al. (JAMA Pedatr. 2019 Feb 4. doi: 10.1001/jamapediatrics.2018.5281). She had no financial conflicts to disclose.
Mild aerobic exercise significantly shortened recovery time from sports-related concussion in adolescent athletes, compared with a stretching program in a randomized trial of 103 participants.
Sports-related concussion (SRC) remains a major public health problem with no effective treatment, wrote John J. Leddy, MD, of the State University of New York at Buffalo, and his colleagues.
Exercise tolerance after SRC has not been well studied. However, given the demonstrated benefits of aerobic exercise training on autonomic nervous system regulation, cerebral blood flow regulation, cardiovascular physiology, and brain neuroplasticity, the researchers hypothesized that exercise at a level that does not exacerbate symptoms might facilitate recovery in concussion patients.
In a study published in JAMA Pediatrics, the researchers randomized 103 adolescent athletes aged 13-18 years to a program of subsymptom aerobic exercise or a placebo stretching program. The participants were enrolled in the study within 10 days of an SRC, and were followed for 30 days or until recovery.
Athletes in the aerobic exercise group recovered in a median of 13 days, compared with 17 days for those in the stretching group (P = .009). Recovery was defined as “symptom resolution to normal,” based on normal physical and neurological examinations, “further confirmed by demonstration of the ability to exercise to exhaustion without exacerbation of symptoms” according to the Buffalo Concussion Treadmill Test, the researchers wrote.
No demographic differences or difference in previous concussions, time from injury until treatment, initial symptom severity score, initial exercise treadmill test, or physical exam were noted between the groups.
The average age of the participants was 15 years, 47% were female. The athletes performed the aerobic exercise or stretching programs approximately 20 minutes per day, and reported their daily symptoms and compliance via a website. The aerobic exercise consisted of walking or jogging on a treadmill or outdoors, or riding a stationary bike while wearing a heart rate monitor to maintain a target heart rate. The target heart rate was calculated as 80% of the heart rate at symptom exacerbation during the Buffalo Concussion Treadmill Test at each participant’s initial visit.
No adverse events related to the exercise intervention were reported, which supports the safety of subsymptom threshhold exercise, in the study population, Dr. Leddy and his associates noted.
The researchers also found lower rates of persistent symptoms at 1 month in the exercise group, compared with the stretching group (two participants vs. seven participants), but this difference was not statistically significant.
The study findings were limited by several factors, including the unblinded design and failure to address the mechanism of action for the effects of exercise. In addition, the results are not generalizable to younger children or other demographic groups, including those with concussions from causes other than sports and adults with heart conditions, the researchers noted.
However, “the results of this study should give clinicians confidence that moderate levels of physical activity, including prescribed subsymptom threshold aerobic exercise, after the first 48 hours following SRC can safely and significantly speed recovery,” Dr. Leddy and his associates concluded.
The study was supported by grants from the National Institutes of Health. The researchers had no financial conflicts to disclose.
SOURCE: Leddy JJ et al. JAMA Pediatr. 2019 Feb 4. doi: 10.1001/jamapediatrics.2018.4397.
Mild aerobic exercise significantly shortened recovery time from sports-related concussion in adolescent athletes, compared with a stretching program in a randomized trial of 103 participants.
Sports-related concussion (SRC) remains a major public health problem with no effective treatment, wrote John J. Leddy, MD, of the State University of New York at Buffalo, and his colleagues.
Exercise tolerance after SRC has not been well studied. However, given the demonstrated benefits of aerobic exercise training on autonomic nervous system regulation, cerebral blood flow regulation, cardiovascular physiology, and brain neuroplasticity, the researchers hypothesized that exercise at a level that does not exacerbate symptoms might facilitate recovery in concussion patients.
In a study published in JAMA Pediatrics, the researchers randomized 103 adolescent athletes aged 13-18 years to a program of subsymptom aerobic exercise or a placebo stretching program. The participants were enrolled in the study within 10 days of an SRC, and were followed for 30 days or until recovery.
Athletes in the aerobic exercise group recovered in a median of 13 days, compared with 17 days for those in the stretching group (P = .009). Recovery was defined as “symptom resolution to normal,” based on normal physical and neurological examinations, “further confirmed by demonstration of the ability to exercise to exhaustion without exacerbation of symptoms” according to the Buffalo Concussion Treadmill Test, the researchers wrote.
No demographic differences or difference in previous concussions, time from injury until treatment, initial symptom severity score, initial exercise treadmill test, or physical exam were noted between the groups.
The average age of the participants was 15 years, 47% were female. The athletes performed the aerobic exercise or stretching programs approximately 20 minutes per day, and reported their daily symptoms and compliance via a website. The aerobic exercise consisted of walking or jogging on a treadmill or outdoors, or riding a stationary bike while wearing a heart rate monitor to maintain a target heart rate. The target heart rate was calculated as 80% of the heart rate at symptom exacerbation during the Buffalo Concussion Treadmill Test at each participant’s initial visit.
No adverse events related to the exercise intervention were reported, which supports the safety of subsymptom threshhold exercise, in the study population, Dr. Leddy and his associates noted.
The researchers also found lower rates of persistent symptoms at 1 month in the exercise group, compared with the stretching group (two participants vs. seven participants), but this difference was not statistically significant.
The study findings were limited by several factors, including the unblinded design and failure to address the mechanism of action for the effects of exercise. In addition, the results are not generalizable to younger children or other demographic groups, including those with concussions from causes other than sports and adults with heart conditions, the researchers noted.
However, “the results of this study should give clinicians confidence that moderate levels of physical activity, including prescribed subsymptom threshold aerobic exercise, after the first 48 hours following SRC can safely and significantly speed recovery,” Dr. Leddy and his associates concluded.
The study was supported by grants from the National Institutes of Health. The researchers had no financial conflicts to disclose.
SOURCE: Leddy JJ et al. JAMA Pediatr. 2019 Feb 4. doi: 10.1001/jamapediatrics.2018.4397.
FROM JAMA PEDIATRICS
Key clinical point:
Major finding: Teen athletes who performed aerobic exercise recovered from sports-related concussions in 13 days, compared with 17 days for those in a placebo-stretching group.
Study details: The data come from a randomized trial of 103 athletes aged 13-18 years.
Disclosures: The study was supported by grants from the National Institutes of Health. The researchers had no financial conflicts to disclose.
Source: Leddy JJ et al. JAMA Pediatr. 2019 Feb 4. doi: 10.1001/jamapediatrics.2018.4397.
Click for Credit: Missed HIV screening opps; aspirin & preeclampsia; more
Here are 5 articles from the February issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. Short-term lung function better predicts mortality risk in SSc
To take the posttest, go to: https://bit.ly/2RrRuIY
Expires November 26, 2019
2. Healthier lifestyle in midlife women reduces subclinical carotid atherosclerosis
To take the posttest, go to: https://bit.ly/2TvDH5G
Expires November 28, 2019
3. Three commonly used quick cognitive assessments often yield flawed results
To take the posttest, go to: https://bit.ly/2G1qkHn
Expires November 28, 2019
4. Missed HIV screening opportunities found among subsequently infected youth
To take the posttest, go to: https://bit.ly/2HGa8Nm
Expires November 29, 2019
5. Aspirin appears underused to prevent preeclampsia in SLE patients
To take the posttest, go to: https://bit.ly/2G0dU2v
Expires January 2, 2019
Here are 5 articles from the February issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. Short-term lung function better predicts mortality risk in SSc
To take the posttest, go to: https://bit.ly/2RrRuIY
Expires November 26, 2019
2. Healthier lifestyle in midlife women reduces subclinical carotid atherosclerosis
To take the posttest, go to: https://bit.ly/2TvDH5G
Expires November 28, 2019
3. Three commonly used quick cognitive assessments often yield flawed results
To take the posttest, go to: https://bit.ly/2G1qkHn
Expires November 28, 2019
4. Missed HIV screening opportunities found among subsequently infected youth
To take the posttest, go to: https://bit.ly/2HGa8Nm
Expires November 29, 2019
5. Aspirin appears underused to prevent preeclampsia in SLE patients
To take the posttest, go to: https://bit.ly/2G0dU2v
Expires January 2, 2019
Here are 5 articles from the February issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. Short-term lung function better predicts mortality risk in SSc
To take the posttest, go to: https://bit.ly/2RrRuIY
Expires November 26, 2019
2. Healthier lifestyle in midlife women reduces subclinical carotid atherosclerosis
To take the posttest, go to: https://bit.ly/2TvDH5G
Expires November 28, 2019
3. Three commonly used quick cognitive assessments often yield flawed results
To take the posttest, go to: https://bit.ly/2G1qkHn
Expires November 28, 2019
4. Missed HIV screening opportunities found among subsequently infected youth
To take the posttest, go to: https://bit.ly/2HGa8Nm
Expires November 29, 2019
5. Aspirin appears underused to prevent preeclampsia in SLE patients
To take the posttest, go to: https://bit.ly/2G0dU2v
Expires January 2, 2019
Mapping the Pathway of Pain
What makes us pull a hand away from a hot stove or flinch at a pinprick? Researchers from the National Center for Complementary and Integrative Health say they have identified activity in the brain that governs these reactions.
Alexander Chesler, PhD, senior author of the study, says we already know a lot about local spinal cord circuits for simple reflexive responses, but “the mechanisms underlying more complex behaviors remain poorly understood.”
Using heat as the source of discomfort in their experiments, the researchers found a predictable sequence of behaviors—likened to the sequence of responding to walking cautiously on a hot beach, then hopping as the heat intensifies, then running to a water source. “This kind of ‘feed-forward’ circuitry is unique because it is an upward spiral,” says Arnab Barik, PhD, one of the study authors. “The more this pathway is activated by harmful activity, the more it reacts, leading to dramatic behavioral responses.”
The experiments showed that the parts of the brainstem involved in this circuit are the parabrachial nucleus (PBNI) and the dorsal reticular formation in the medulla (MdD). Standing on a hot surface activated a group of nerve cells in the PBNI, triggering escape responses through connections to the MdD. Interestingly, the PBNI cells express a gene that codes for substances that also contribute to multiple disease processes.
“Our data provide evidence that the PBNI produces streams of information with distinct functional significance,” says Arnab Barik, PhD, one of the study authors. “The brainstem-spinal cord pathway identified in this study selectively controls pain response and elicits appropriate behaviors based on sensory input.”
Further investigation, the researchers say, can help us understand how pain is encoded in the brain. The study findings may also offer opportunities to understand how the body becomes dysregulated during chronic pain.
What makes us pull a hand away from a hot stove or flinch at a pinprick? Researchers from the National Center for Complementary and Integrative Health say they have identified activity in the brain that governs these reactions.
Alexander Chesler, PhD, senior author of the study, says we already know a lot about local spinal cord circuits for simple reflexive responses, but “the mechanisms underlying more complex behaviors remain poorly understood.”
Using heat as the source of discomfort in their experiments, the researchers found a predictable sequence of behaviors—likened to the sequence of responding to walking cautiously on a hot beach, then hopping as the heat intensifies, then running to a water source. “This kind of ‘feed-forward’ circuitry is unique because it is an upward spiral,” says Arnab Barik, PhD, one of the study authors. “The more this pathway is activated by harmful activity, the more it reacts, leading to dramatic behavioral responses.”
The experiments showed that the parts of the brainstem involved in this circuit are the parabrachial nucleus (PBNI) and the dorsal reticular formation in the medulla (MdD). Standing on a hot surface activated a group of nerve cells in the PBNI, triggering escape responses through connections to the MdD. Interestingly, the PBNI cells express a gene that codes for substances that also contribute to multiple disease processes.
“Our data provide evidence that the PBNI produces streams of information with distinct functional significance,” says Arnab Barik, PhD, one of the study authors. “The brainstem-spinal cord pathway identified in this study selectively controls pain response and elicits appropriate behaviors based on sensory input.”
Further investigation, the researchers say, can help us understand how pain is encoded in the brain. The study findings may also offer opportunities to understand how the body becomes dysregulated during chronic pain.
What makes us pull a hand away from a hot stove or flinch at a pinprick? Researchers from the National Center for Complementary and Integrative Health say they have identified activity in the brain that governs these reactions.
Alexander Chesler, PhD, senior author of the study, says we already know a lot about local spinal cord circuits for simple reflexive responses, but “the mechanisms underlying more complex behaviors remain poorly understood.”
Using heat as the source of discomfort in their experiments, the researchers found a predictable sequence of behaviors—likened to the sequence of responding to walking cautiously on a hot beach, then hopping as the heat intensifies, then running to a water source. “This kind of ‘feed-forward’ circuitry is unique because it is an upward spiral,” says Arnab Barik, PhD, one of the study authors. “The more this pathway is activated by harmful activity, the more it reacts, leading to dramatic behavioral responses.”
The experiments showed that the parts of the brainstem involved in this circuit are the parabrachial nucleus (PBNI) and the dorsal reticular formation in the medulla (MdD). Standing on a hot surface activated a group of nerve cells in the PBNI, triggering escape responses through connections to the MdD. Interestingly, the PBNI cells express a gene that codes for substances that also contribute to multiple disease processes.
“Our data provide evidence that the PBNI produces streams of information with distinct functional significance,” says Arnab Barik, PhD, one of the study authors. “The brainstem-spinal cord pathway identified in this study selectively controls pain response and elicits appropriate behaviors based on sensory input.”
Further investigation, the researchers say, can help us understand how pain is encoded in the brain. The study findings may also offer opportunities to understand how the body becomes dysregulated during chronic pain.
Aerobic exercise may mitigate age-related cognitive decline
published in Neurology.
“The effect of aerobic exercise on executive function was more pronounced as age increased, suggesting that it may mitigate age-related declines,” wrote Yaakov Stern, PhD, chief of cognitive neuroscience in the department of neurology at Columbia University, New York, and his research colleagues.
Research indicates that aerobic exercise provides cognitive benefits across the lifespan, but controlled exercise studies have been limited to elderly individuals, the researchers wrote. To examine the effects of aerobic exercise on cognitive function in younger, healthy adults, they conducted a randomized, parallel-group, observer-masked, community-based clinical trial. The investigators enrolled 132 cognitively normal people aged 20-67 years with aerobic capacity below the median. About 70% were women, and participants’ mean age was about 40 years.
“We hypothesized that aerobic exercise would have cognitive benefits, even in this younger age range, but that age might moderate the nature or degree of the benefit,” Dr. Stern and his colleagues wrote.
Participants were nonsmoking, habitual nonexercisers with below-average fitness by American Heart Association standards. The investigators used baseline aerobic capacity testing to establish safe exercise measures and heart rate targets.
The investigators randomly assigned participants to a group that performed aerobic exercise or to a control group that performed stretching and toning four times per week for 6 months. Outcome measures included domains of cognitive function (such as executive function, episodic memory, processing speed, language, and attention), everyday function, aerobic capacity, body mass index, and cortical thickness.
During a 2-week run-in period, participants went to their choice of five YMCA of New York City fitness centers three times per week. They had to attend at least five of these sessions to stay in the study. In both study arms, training sessions consisted of 10-15 minutes of warm-up and cooldown and 30-40 minutes of workout. Coaches contacted participants weekly to monitor their progress, and participants wore heart rate monitors during each session. Exercises in the control group were designed to promote flexibility and improve core strength. In the aerobic exercise group, participants had a choice of exercises such as walking on a treadmill, cycling on a stationary bike, or using an elliptical machine, and they gradually increased their exercise intensity to 75% of maximum heart rate by week 5. A total of 94 participants – 50 in the control group and 44 in the aerobic exercise group – completed the 6-month trial.
Executive function, but not other cognitive measures, improved significantly in the aerobic exercise group. The effect on executive function was greater in older participants. For example, at age 40 years, the executive function measure increased by 0.228 standard deviation units from baseline; at age 60, it increased by 0.596 standard deviation units.
In addition, cortical thickness increased significantly in the aerobic exercise group in the left caudal middle frontal cortex Brodmann area; this effect did not differ by age. Improvement on executive function in the aerobic exercise group was greater among participants without an APOE E4 allele, contrasting with the findings of prior studies.
“Since a difference of 0.5 standard deviations is equivalent to 20 years of age-related difference in performance on these tests, the people who exercised were testing as if they were about 10 years younger at age 40 and about 20 years younger at age 60,” Dr. Stern said in a press release. “Since thinking skills at the start of the study were poorer for participants who were older, our findings suggest that aerobic exercise is more likely to improve age-related declines in thinking skills rather than improve performance in those without a decline.”
Furthermore, aerobic exercise significantly increased aerobic capacity and significantly decreased body mass index, whereas stretching and toning did not.
“Participants in this trial scheduled their exercise sessions on their own and exercised by themselves,” the authors noted. “In addition, they were allowed to choose whatever aerobic exercise modality they preferred, so long as they reached target heart rates, enhancing the flexibility of the intervention.” Limitations of the study include its relatively small sample size and the large number of participants who dropped out of the study between consenting to participate and randomization.
The trial was funded by the National Institutes of Health. Dr. Stern reported receiving a grant from the California Walnut Commission and consulting with Eli Lilly, Axovant Sciences, Takeda, and AbbVie. A coauthor reported grant support from AposTherapy, LIH Medical, and the Everest Foundation.
SOURCE: Stern Y et al. Neurology. 2019 Jan 30. doi: 10.1212/WNL.0000000000007003.
published in Neurology.
“The effect of aerobic exercise on executive function was more pronounced as age increased, suggesting that it may mitigate age-related declines,” wrote Yaakov Stern, PhD, chief of cognitive neuroscience in the department of neurology at Columbia University, New York, and his research colleagues.
Research indicates that aerobic exercise provides cognitive benefits across the lifespan, but controlled exercise studies have been limited to elderly individuals, the researchers wrote. To examine the effects of aerobic exercise on cognitive function in younger, healthy adults, they conducted a randomized, parallel-group, observer-masked, community-based clinical trial. The investigators enrolled 132 cognitively normal people aged 20-67 years with aerobic capacity below the median. About 70% were women, and participants’ mean age was about 40 years.
“We hypothesized that aerobic exercise would have cognitive benefits, even in this younger age range, but that age might moderate the nature or degree of the benefit,” Dr. Stern and his colleagues wrote.
Participants were nonsmoking, habitual nonexercisers with below-average fitness by American Heart Association standards. The investigators used baseline aerobic capacity testing to establish safe exercise measures and heart rate targets.
The investigators randomly assigned participants to a group that performed aerobic exercise or to a control group that performed stretching and toning four times per week for 6 months. Outcome measures included domains of cognitive function (such as executive function, episodic memory, processing speed, language, and attention), everyday function, aerobic capacity, body mass index, and cortical thickness.
During a 2-week run-in period, participants went to their choice of five YMCA of New York City fitness centers three times per week. They had to attend at least five of these sessions to stay in the study. In both study arms, training sessions consisted of 10-15 minutes of warm-up and cooldown and 30-40 minutes of workout. Coaches contacted participants weekly to monitor their progress, and participants wore heart rate monitors during each session. Exercises in the control group were designed to promote flexibility and improve core strength. In the aerobic exercise group, participants had a choice of exercises such as walking on a treadmill, cycling on a stationary bike, or using an elliptical machine, and they gradually increased their exercise intensity to 75% of maximum heart rate by week 5. A total of 94 participants – 50 in the control group and 44 in the aerobic exercise group – completed the 6-month trial.
Executive function, but not other cognitive measures, improved significantly in the aerobic exercise group. The effect on executive function was greater in older participants. For example, at age 40 years, the executive function measure increased by 0.228 standard deviation units from baseline; at age 60, it increased by 0.596 standard deviation units.
In addition, cortical thickness increased significantly in the aerobic exercise group in the left caudal middle frontal cortex Brodmann area; this effect did not differ by age. Improvement on executive function in the aerobic exercise group was greater among participants without an APOE E4 allele, contrasting with the findings of prior studies.
“Since a difference of 0.5 standard deviations is equivalent to 20 years of age-related difference in performance on these tests, the people who exercised were testing as if they were about 10 years younger at age 40 and about 20 years younger at age 60,” Dr. Stern said in a press release. “Since thinking skills at the start of the study were poorer for participants who were older, our findings suggest that aerobic exercise is more likely to improve age-related declines in thinking skills rather than improve performance in those without a decline.”
Furthermore, aerobic exercise significantly increased aerobic capacity and significantly decreased body mass index, whereas stretching and toning did not.
“Participants in this trial scheduled their exercise sessions on their own and exercised by themselves,” the authors noted. “In addition, they were allowed to choose whatever aerobic exercise modality they preferred, so long as they reached target heart rates, enhancing the flexibility of the intervention.” Limitations of the study include its relatively small sample size and the large number of participants who dropped out of the study between consenting to participate and randomization.
The trial was funded by the National Institutes of Health. Dr. Stern reported receiving a grant from the California Walnut Commission and consulting with Eli Lilly, Axovant Sciences, Takeda, and AbbVie. A coauthor reported grant support from AposTherapy, LIH Medical, and the Everest Foundation.
SOURCE: Stern Y et al. Neurology. 2019 Jan 30. doi: 10.1212/WNL.0000000000007003.
published in Neurology.
“The effect of aerobic exercise on executive function was more pronounced as age increased, suggesting that it may mitigate age-related declines,” wrote Yaakov Stern, PhD, chief of cognitive neuroscience in the department of neurology at Columbia University, New York, and his research colleagues.
Research indicates that aerobic exercise provides cognitive benefits across the lifespan, but controlled exercise studies have been limited to elderly individuals, the researchers wrote. To examine the effects of aerobic exercise on cognitive function in younger, healthy adults, they conducted a randomized, parallel-group, observer-masked, community-based clinical trial. The investigators enrolled 132 cognitively normal people aged 20-67 years with aerobic capacity below the median. About 70% were women, and participants’ mean age was about 40 years.
“We hypothesized that aerobic exercise would have cognitive benefits, even in this younger age range, but that age might moderate the nature or degree of the benefit,” Dr. Stern and his colleagues wrote.
Participants were nonsmoking, habitual nonexercisers with below-average fitness by American Heart Association standards. The investigators used baseline aerobic capacity testing to establish safe exercise measures and heart rate targets.
The investigators randomly assigned participants to a group that performed aerobic exercise or to a control group that performed stretching and toning four times per week for 6 months. Outcome measures included domains of cognitive function (such as executive function, episodic memory, processing speed, language, and attention), everyday function, aerobic capacity, body mass index, and cortical thickness.
During a 2-week run-in period, participants went to their choice of five YMCA of New York City fitness centers three times per week. They had to attend at least five of these sessions to stay in the study. In both study arms, training sessions consisted of 10-15 minutes of warm-up and cooldown and 30-40 minutes of workout. Coaches contacted participants weekly to monitor their progress, and participants wore heart rate monitors during each session. Exercises in the control group were designed to promote flexibility and improve core strength. In the aerobic exercise group, participants had a choice of exercises such as walking on a treadmill, cycling on a stationary bike, or using an elliptical machine, and they gradually increased their exercise intensity to 75% of maximum heart rate by week 5. A total of 94 participants – 50 in the control group and 44 in the aerobic exercise group – completed the 6-month trial.
Executive function, but not other cognitive measures, improved significantly in the aerobic exercise group. The effect on executive function was greater in older participants. For example, at age 40 years, the executive function measure increased by 0.228 standard deviation units from baseline; at age 60, it increased by 0.596 standard deviation units.
In addition, cortical thickness increased significantly in the aerobic exercise group in the left caudal middle frontal cortex Brodmann area; this effect did not differ by age. Improvement on executive function in the aerobic exercise group was greater among participants without an APOE E4 allele, contrasting with the findings of prior studies.
“Since a difference of 0.5 standard deviations is equivalent to 20 years of age-related difference in performance on these tests, the people who exercised were testing as if they were about 10 years younger at age 40 and about 20 years younger at age 60,” Dr. Stern said in a press release. “Since thinking skills at the start of the study were poorer for participants who were older, our findings suggest that aerobic exercise is more likely to improve age-related declines in thinking skills rather than improve performance in those without a decline.”
Furthermore, aerobic exercise significantly increased aerobic capacity and significantly decreased body mass index, whereas stretching and toning did not.
“Participants in this trial scheduled their exercise sessions on their own and exercised by themselves,” the authors noted. “In addition, they were allowed to choose whatever aerobic exercise modality they preferred, so long as they reached target heart rates, enhancing the flexibility of the intervention.” Limitations of the study include its relatively small sample size and the large number of participants who dropped out of the study between consenting to participate and randomization.
The trial was funded by the National Institutes of Health. Dr. Stern reported receiving a grant from the California Walnut Commission and consulting with Eli Lilly, Axovant Sciences, Takeda, and AbbVie. A coauthor reported grant support from AposTherapy, LIH Medical, and the Everest Foundation.
SOURCE: Stern Y et al. Neurology. 2019 Jan 30. doi: 10.1212/WNL.0000000000007003.
FROM NEUROLOGY
Key clinical point: Among adults with below-average fitness, a 6-month aerobic exercise program significantly improves executive function.
Major finding: The effect is more pronounced as age increases.
Study details: A randomized, parallel-group, observer-masked, community-based clinical trial of 132 cognitively normal adults aged 20-67 years.
Disclosures: The study was funded by the National Institutes of Health. Dr. Stern reported receiving a grant from the California Walnut Commission and consulted with Eli Lilly, Axovant Sciences, Takeda, and AbbVie. Another reported grant support from AposTherapy, LIH Medical, and the Everest Foundation.
Source: Stern Y et al. Neurology. 2019 Jan 30. doi: 10.1212/WNL.0000000000007003.
Antidepressants for chronic pain
Approximately 55 years ago, tricyclic antidepressants (TCAs) began to be used to treat neuropathic pain.1 Eventually, clinical trials emerged suggesting the utility of TCAs for other chronic pain conditions, such as fibromyalgia (FM) and migraine prophylaxis. However, despite TCAs’ effectiveness in mitigating painful conditions, their adverse effects limited their use.
Pharmacologic advancements have led to the development of other antidepressant classes, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), and the use of these agents has come to eclipse that of TCAs. In the realm of pain management, such developments have raised the hope of possible alternative co-analgesic agents that could avoid the adverse effects associated with TCAs. Some of these agents have demonstrated efficacy for managing chronic pain states, while others have demonstrated only limited utility.
This article provides a synopsis of systematic reviews and meta-analyses examining the role of antidepressant therapy for managing several chronic pain conditions, including pain associated with neuropathy, FM, headache, and irritable bowel syndrome (IBS). Because the literature base is rapidly evolving, it is necessary to revisit the information gleaned from clinical data with respect to treatment effectiveness, and to clarify how antidepressants might be positioned in the management of chronic pain.
The effectiveness of antidepressants for pain
The pathophysiologic processes that precipitate and maintain chronic pain conditions are complex (Box 12-10). The pain-mitigating effects of antidepressants can be thought of in terms of direct analgesic effects and indirect effects (Box 22,3,8,10,11-33).
Box 1
The pathophysiologic processes precipitating and maintaining chronic pain conditions are complex. Persistent and chronic pain results from changes in sensitivity within both ascending pathways (relaying pain information from the periphery to the spinal cord and brain) and descending pain pathways (functioning to modulate ascending pain information).2,3 Tissue damage or peripheral nerve injury can lead to a cascade of neuroplastic changes within the CNS, resulting in hyperexcitability within the ascending pain pathways.
The descending pain pathways consist of the midbrain periaqueductal gray area (PGA), the rostroventral medulla (RVM), and the dorsolateral pontomesencephalic tegmentum (DLPT). The axons of the RVM (the outflow of which is serotonergic) and DLPT (the outflow of which is noradrenergic) terminate in the dorsal horn of the spinal cord,4 and thereby dampen pain signals arising from the periphery. Diminished output from descending pain pathways can heighten the pain experience. Input from the cortex, hypothalamus, and amygdala (among other structures) converges upon the PGA, RVM and DLPT, and can influence the degree of pain modulation emerging from descending pathways. In this way, thoughts, appraisals, and mood are believed to comprise cognitive and affective modifiers of pain experiences.
Devising effective chronic pain treatment becomes challenging; multimodal treatment approaches often are advocated, including pharmacologic treatment with analgesics in combination with co-analgesic medications such as antidepressants. Although a description of multimodal treatment is beyond the scope of this article, such treatment also would encompass physical therapy, occupational therapy, and psychotherapeutic interventions to augment rehabilitative efforts and the functional capabilities of patients who struggle with persisting pain.
Although the direct pain-mitigating effects of antidepressants are not fully understood, it is believed that augmentation of monoamine neurotransmission from supraspinal nuclei (ie, the RVM and DLPT) modulate pain transmission from the periphery.5,6 In addition, there is evidence that some effects of tricyclic antidepressants can modulate several other functions that impact peripheral and central sensitization.7-10
During the last several decades, antidepressants have been used to address—and have demonstrated clinical utility for—a variety of chronic pain states. However, antidepressants are not a panacea; some chronic pain conditions are more responsive to antidepressants than are others. The chronic painful states most amenable to antidepressants are those that result primarily from a process of neural sensitization, as opposed to acute somatic or visceral nociception. Hence, several meta-analyses and evidence-based reviews have long suggested the usefulness of antidepressants for mitigating pain associated with neuropathy,34,35 FM,36,37 headache,38 and IBS.39,40
Box 2
The pain-mitigating effects of antidepressants can be thought of in terms of direct analgesic effects (impacting neurotransmission of descending pathways independent of influences on mood) and indirect effects (presumably impacting cortical and limbic output to the periaqueductal gray area, the rostroventral medulla, and the dorsolateral pontomesencephalic tegmentum brought about by improvement in mood and/or cognitive appraisals) (Figure2,3,8,10,11,15,20,22,28,29). Support for the direct analgesic effects has been garnered from initial empirical work that demonstrated pain relief among patients with pain who are not depressed. Additionally, among patients who have depression and experience pain, analgesia reportedly often occurs within 2 weeks, which is before antidepressant effects are appreciated,11-15 and, at least for some antidepressants, occurs at doses far lower than those required to produce mood-elevating effects.11,12,16
On the other hand, it is well established that significant comorbidities exist between chronic pain states and psychiatric disorders (eg, depression and somatic symptom and related disorders).17-21 There may be common physiological substrates underlying chronic pain and depression.20,22 There are bidirectional influences of limbic (affective) systems and those CNS structures involved in pain processing and integration. The effects of pain and depression are reciprocal; the presence of one makes the management of the other more challenging.23-27 Mood disturbances can, therefore, impact pain processing by acting as affective and cognitive amplifiers of pain by leading to catastrophizing, pain severity augmentation, poor coping with pain-related stress, etc.28,29 It is plausible that the mood-elevating effects of antidepressants can improve pain by indirect effects, by modulating limbic activity, which in turn, impacts coping, cognitive appraisals of pain, etc.
Patients with somatoform disorders (using pre-DSM-5 terminology) frequently present with chronic pain, often in multiple sites.19 Such patients are characterized by hypervigilance for, and a predisposition to focus on, physical sensations and to appraise these sensations as reflecting a pathological state.30 Neuroimaging studies have begun to identify those neural circuits involved in somatoform disorders, many of which act as cognitive and affective amplifiers of visceral-somatic sensory processing. Many of these neural circuits overlap, and interact with, those involved in pain processing.31 Antidepressants can mitigate the severity of unexplained physical complaints, including pain, among patients who somatize32,33; however, due to the heterogeneity of studies upon which this claim is based, the quality of the evidence is reportedly low.33 There is uncertainty whether, or to what extent, antidepressant benefits among patients who somatize are due to a direct impact on pain modulation, or indirect effects on mood or cognitive appraisals/perceptions.
Despite the uncertainties about the exact mechanisms through which antidepressants exert analgesic effects, antidepressants can be appropriately used to treat patients with selected chronic pain syndromes, regardless of whether or not the patient has a psychiatric comorbidity. For those patients with pain and psychiatric comorbidities, the benefits may be brought about via direct mechanisms, indirect mechanisms, or a combination of both.
Continue to: Neuropathic pain
Neuropathic pain
Several treatment guidelines advocate for the use of antidepressants for neuropathic pain.41-44 For decades, TCAs have been employed off-label to successfully treat many patients with neuropathic pain states. Early investigations suggested that TCAs were robustly efficacious in managing patients with neuropathy.45-48 Calculated number-needed-to-treat (NNT) values for TCAs were quite low (ie, reflecting that few patients would need to be treated to yield a positive response in one patient compared with placebo), and were comparable to, if not slightly better than, the NNTs generated for anticonvulsants and α2-δ ligands, such as gabapentin or pregabalin.45-48
Unfortunately, early studies involving TCAs conducted many years ago do not meet contemporary standards of methodological rigor; they featured relatively small samples of patients assessed for brief post-treatment intervals with variable outcome measures. Thus, the NNT values obtained in meta-analyses based on these studies may overestimate treatment benefits.49 Further, NNT values derived from meta-analyses tended to combine all drugs within a particular antidepressant class (eg, amitriptyline, nortriptyline, desipramine, and imipramine among the TCAs) employed at diverse doses. Taken together, these limitations raise questions about the results of those meta-analyses.
Subsequent meta-analyses, which employed strict criteria to eliminate data from studies with potential sources of bias and used a primary outcome of frequencies of patients reporting at least 30% pain reduction compared with a placebo-controlled sample, suggest that the effectiveness of TCAs as a class for treating neuropathic pain is not as compelling as once was thought. Meta-analyses of studies employing specific TCAs revealed that there was little evidence to support the use of desipramine,50 imipramine,51 or nortriptyline52 in managing diabetic neuropathy or postherpetic neuralgia. Studies evaluating amitriptyline (dose range 12.5 to 150 mg/d), found low-level evidence of effectiveness; the benefit was expected to be present for a small subset (approximately 25%) of patients with neuropathic pain.53
There is moderate-quality evidence that duloxetine (60 to 120 mg/d) can produce a ≥50% improvement in pain severity ratings among patients with diabetic peripheral neuropathy.54 Although head-to-head studies with other antidepressants are limited, it appears that duloxetine and amitriptyline have comparable efficacy, even though the NNTs for amitriptyline were derived from lower-quality studies than those for duloxetine. Duloxetine is the only antidepressant to receive FDA approval for managing diabetic neuropathy. By contrast, studies assessing the utility of venlafaxine in neuropathic pain comprised small samples for brief durations, which limits the ability to draw clear (unbiased) support for its usefulness.55
Given the diversity of pathophysiologic processes underlying the disturbances that cause neuropathic pain disorders, it is unsurprising that the effectiveness of amitriptyline and duloxetine were not generalizable to all neuropathic pain states. Although amitriptyline produced pain-mitigating effects in patients with diabetic neuropathy and post-herpetic neuralgia, and duloxetine mitigated pain among patients with diabetic neuropathy, there was no evidence to suggest their effectiveness in phantom limb pain or human immunodeficiency virus-related and spinal cord-related neuropathies.35,53,54,56-58
Continue to: Fibromyalgia
Fibromyalgia
As with the issues encountered in interpreting the effectiveness of antidepressants in neuropathic pain, interpreting results gleaned from clinical trials of antidepressants for treating FM are fraught with similar difficulties. Although amitriptyline has been a first-line treatment for FM for many years, the evidence upon which such recommendations were based consisted of low-level studies that had a significant potential for bias.59 Large randomized trials would offer more compelling data regarding the efficacy of amitriptyline, but the prohibitive costs of such studies makes it unlikely they will be conducted. Amitriptyline (25 to 50 mg/d) was effective in mitigating FM-related pain in a small percentage of patients studied, with an estimated NNT of 4.59 Adverse effects, often contributing to treatment discontinuation, were encountered more frequently among patients who received amitriptyline compared with placebo.
Selective serotonin reuptake inhibitors failed to demonstrate significant pain relief (estimated NNT of 10), or improvement in fatigue or sleep problems, even though the studies upon which such conclusions were based were low-level studies with a high potential for bias.60 Although SSRIs have limited utility for mitigating pain, they are still quite useful for reducing depression among patients with FM.60
By contrast, the SNRIs duloxetine and milnacipran provided clinically relevant benefit over placebo in the frequency of patients reporting pain relief of ≥30%, as well as patients’ global impression of change.61 These agents, however, failed to provide clinically relevant benefit over placebo in improving health-related quality of life, reducing sleep problems, or improving fatigue. Nonetheless, duloxetine and milnacipran are FDA-approved for managing pain in FM. Studies assessing the efficacy of venlafaxine in the treatment of FM to date have been limited by small sample sizes, inconsistent dosing, lack of a placebo control, and lack of blinding, which limits the ability to clearly delineate the role of venlafaxine in managing FM.62
Mirtazapine (15 to 45 mg/d) showed a clinically relevant benefit compared with placebo for participant-reported pain relief of ≥30% and sleep disturbances. There was no benefit in terms of participant-reported improvement of quality of life, fatigue, or negative mood.63 The evidence was considered to be of low quality overall.
Headache
Amitriptyline has been employed off-label to address headache prophylaxis since 1964.64 Compared with placebo, it is efficacious in ameliorating migraine frequency and intensity as well as the frequency of tension headache.65,66 However, SSRIs and SNRIs (venlafaxine) failed to produce significant reductions in migraine frequency or severity or the frequencies of tension headache when compared with placebo.67,68
Continue to: Irritable bowel syndrome
Irritable bowel syndrome
Early studies addressing antidepressant efficacy in IBS reveal inconsistencies. For example, whereas some suggest that TCAs are effective in mitigating chronic, severe abdominal pain,39,40 others concluded that TCAs failed to demonstrate a significant analgesic benefit.69 A recent meta-analysis that restricted analysis of efficacy to randomized controlled trials (RCTs) with more rigorous methodological adherence found that pain relief in IBS is possible with both TCAs as well as SSRIs. However, adverse effects were more commonly encountered with TCAs than with SSRIs. Some of the inconsistencies in treatment efficacy reported in early studies may be due to variations in responsiveness of subsets of IBS patients. Specifically, the utility of TCAs appears to be best among patients with diarrheal-type (as opposed to constipation-type) IBS, presumably due to TCAs’ anticholinergic effects, whereas SSRIs may provide more of a benefit for patients with predominantly constipation-type IBS.40,70
Other chronic pain conditions
Antidepressants have been used to assist in the management of several other pain conditions, including oral-facial pain, interstitial cystitis, non-cardiac chest pain, and others. The role of antidepressants for such conditions remains unclear due to limitations in the prevailing empirical work, such as few trials, small sample sizes, variations in outcome measures, and insufficient randomization and blinding.71-76 The interpretation of results from systematic reviews and meta-analyses is limited because of these shortcomings.77 Hence, it has not always been possible to determine whether, and to what extent, patients with such conditions may benefit from antidepressants.
Neuromodulatory effects and efficacy for pain
The interplay of norepinephrine (NE) and serotonin (5-HT) neurotransmitter systems and cellular mechanisms involved in the descending modulation of pain pathways is complex. Experimental animal models of pain modulation suggest that 5-HT can both inhibit as well as promote pain perception by different physiological mechanisms, in contrast to NE, which is predominately inhibitory. While 5-HT in the descending modulating system can inhibit pain transmission ascending to the brain from the periphery, it appears that an intact noradrenergic system is necessary for the inhibitory influences of the serotonergic system to be appreciated.16,78,79 Deficiencies in one or both of these neurotransmitter systems may contribute to hyperactive pain processing, and thereby precipitate or maintain chronic pain.
Pain mitigation may be achieved best by enhancing both neurotransmitters simultaneously, less so by enhancing NE alone, and least by enhancing 5-HT alone.6 The ability to impact pain modulation would, therefore, depend on the degree to which an antidepressant capitalizes on both noradrenergic and serotonergic neurotransmission. Antidepressants commonly employed to manage pain are presented in Table 147,60,68,80-88 according to their primary neurotransmitter effects. Thus, the literature summarized above suggests that antidepressants that influence both NE and 5-HT transmission have greater analgesic effects than antidepressants with more specific effects, such as influencing 5-HT reuptake alone.80-85 It is unsurprising, therefore, that the SSRIs have not been demonstrated to be as consistently analgesic.47,60,68,80,86-88
Similarly, pharmacodynamic and pharmacokinetic differences within antidepressant classes may influence analgesic effectiveness. Simultaneous effects on NE and 5-HT are achieved at low doses with duloxetine and milnacipran. By contrast, 5-HT effects predominate at low doses for venlafaxine. To achieve pain-mitigating effects, higher doses of venlafaxine generally are required.89 Therefore, inconsistencies across studies regarding the analgesic benefits of venlafaxine may be attributable to variability in dosing; patients treated with lower doses may not have experienced sufficient NE effects to garner positive results.
Continue to: The differences in analgesic efficacy...
The differences in analgesic efficacy among specific TCAs may be understood in a similar fashion. Specifically, tertiary TCAs (imipramine and amitriptyline) inhibit both 5-HT and NE reuptake.6,90 Secondary amines (desipramine and nortriptyline) predominantly impact NE reuptake, possibly accounting for the lesser pain-mitigating benefit achieved with these agents, such as for treating neuropathic pain. Further, in vivo imipramine and amitriptyline are rapidly metabolized to secondary amines that are potent and selective NE reuptake inhibitors. In this way, the secondary amines may substantially lose the ability to modulate pain transmission because of the loss of concurrent 5-HT influences.90
Clinical pearls
The following practical points can help guide clinicians regarding the usefulness of antidepressants for pain management:
- Antidepressants can alleviate symptoms of depression and pain. The pain-mitigating effects of antidepressants are possible even among chronic pain patients who are not depressed. Antidepressants may confer benefits for chronic pain patients with depression and other comorbid conditions, such as somatic symptom and related disorders.
- Antidepressants are useful for select chronic pain states. Although the noradrenergic and serotonergic antidepressants (SNRIs and, to some extent, amitriptyline) appear to have efficacy for neuropathic pain and FM, the benefits of SSRIs appear to be less robust. On the other hand, SSRIs and TCAs may have potential benefit for patients with IBS. However, the results of meta-analyses are limited in the ability to provide information about which patients will best respond to which specific antidepressant or how well. Future research directed at identifying characteristics that can predict which patients are likely to benefit from one antidepressant vs another would help inform how best to tailor treatment to individual needs.
- The pain-mitigating effects of antidepressants often emerge early in the course of treatment (often before mood-elevating effects are observed). For example, in the case of amitriptyline, pain relief may be possible for some patients at doses generally lower than those required for mood-elevating effects. To date, there is limited information in the literature to determine what constitutes a sufficient duration of treatment, or when treatment should be modified.
- Failure to reduce pain should raise questions about whether the dose should be increased, an alternative agent should be tried, or combinations with other analgesic agents should be considered. Failure to achieve pain-mitigating effects with one antidepressant does not mean failure with others. Hence, failure to achieve desired effects with one agent might warrant an empirical trial with another agent. Presently, too few double-blind RCTs have been conducted to assess the pain-mitigating effects of other antidepressants (eg, bupropion and newer SNRIs such as desvenlafaxine and levomilnacipran). Meta-analysis of the analgesic effectiveness of these agents or comparisons to the efficacy of other antidepressant classes is, therefore, impossible at this time.
Because many chronic pain states are complex, patients will seldom experience clinically relevant benefit from any one intervention.53 The bigger implication for clinical research is to determine whether there is a sequence or combination of medication use that will provide overall better clinical effectiveness.53 Only limited data are available exploring the utility of combining pharmacologic approaches to address pain.91 For example, preliminary evidence suggests that combinations of complementary strategies, such as duloxetine combined with pregabalin, may result in significantly greater numbers of FM patients achieving ≥30% pain reduction compared with monotherapy with either agent alone or placebo.92
- Antidepressant selection may need to be based on medication-related adverse effect profiles and the potential for drug interactions. These factors are useful to consider in delineating multimodal treatment regimens for chronic pain in light of patients’ comorbidities and co-medication regimen. For example, the adverse effects of TCAs (anticholinergic and alpha-adrenergic influences) limit their utility for treating pain. Some of these effects can be more problematic in select populations, such as older adults or those with orthostatic difficulties, among others. TCAs are contraindicated in patients with closed-angle glaucoma, recent myocardial infarction, cardiac arrhythmias, poorly controlled seizures, or severe benign prostatic hypertrophy. Although the pain-mitigating effects of SNRIs have not been demonstrated to significantly exceed those of TCAs,68,93,94 SNRIs would offer an advantage of greater tolerability of adverse effects and relative safety in patients with comorbid medical conditions that would otherwise preclude TCA use. The adverse effects and common drug interactions associated with antidepressants are summarized in Table 295.
Conclusion
Chronic, nonmalignant pain conditions afflict many patients and significantly impair their ability to function. Because of heightened concerns related to the appropriateness of, and restricting inordinate access to, long-term opioid analgesics, clinicians need to explore the usefulness of co-analgesic agents, such as antidepressants. Significant comorbidities exist between psychiatric disorders and chronic pain, and psychiatrists are uniquely positioned to diagnose and treat psychiatric comorbidities, as well as pain, among their patients, especially since they understand the kinetics and dynamics of antidepressants.
Bottom Line
Antidepressants can alleviate symptoms of depression and pain. Noradrenergic and serotonergic antidepressants appear to have efficacy for pain associated with neuropathy and fibromyalgia, while selective serotonin reuptake inhibitors and tricyclic antidepressants may have benefit for patients with irritable bowel syndrome. However, evidence regarding which patients will best respond to which specific antidepressant is limited.
Continue to: Related Resources
Related Resources
- Williams AM, Knox ED. When to prescribe antidepressants to treat comorbid depression and pain disorders. Current Psychiatry. 2017;16(1):55-58.
- Maletic V, Demuri B. Chronic pain and depression: treatment of 2 culprits in common. Current Psychiatry. 2016;15(3):41,47-50,52.
Drug Brand Names
Amitriptyline • Elavil, Endep
Bupropion • Wellbutrin, Zyban
Carisoprodol • Rela, Soma
Cyclobenzaprine • Amrix, Flexeril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Duloxetine • Cymbalta
Fluoxetine • Prozac
Gabapentin • Horizant, Neurontin
Imipramine • Tofranil
Levomilnacipran • Fetzima
Methadone • Dolophine, Methadose
Milnacipran • Savella
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Pregabalin • Lyrica, Lyrica CR
Tapentadol • Nucynta
Tramadol • Ultram
Trazodone • Desyrel, Oleptro
Venlafaxine • Effexor
Warfarin • Coumadin, Jantoven
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34. Collins SL, Moore RA, McQuay HJ, et al. Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. J Pain Symptom Manage. 2000;20(6):449-458.
35. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain: a Cochrane review. J Neurol Neurosurg Psychiatry. 2010;81(12):1372-1373.
36. Arnold LM, Keck PE, Welge JA. Antidepressant treatment of fibromyalgia. A meta-analysis and review. Psychosomatics. 2000;41(2):104-113.
37. O’Malley PG, Balden E, Tomkins G, et al. Treatment of fibromyalgia with antidepressants: a meta-analysis. J Gen Intern Med. 2000;15(9):659-666.
38. Tomkins GE, Jackson JL, O’Malley PG, et al. Treatment of chronic headache with antidepressants: a meta-analysis. Am J Med. 2001;111(1):54-63.
39. Jackson JL, O’Malley PG, Tomkins G, et al. Treatment of functional gastrointestinal disorders with antidepressant medications: a meta-analysis. Am J Med. 2000;108(1):65-72.
40. Lesbros-Pantoflickova D, Michetti P, Fried M et al. Meta-analysis: the treatment of irritable bowel syndrome. Aliment Pharmacol Ther. 2004;20(11-12):1253-1269.
41. Centre for Clinical Practice at NICE (UK). Neuropathic pain: the pharmacological management of neuropathic pain in adults in non-specialist settings. London, UK: National Institute for Health and Care Excellence, (UK); 2013.
42. O’Connor AB, Dworkin RH. Treatment of neuropathic pain: an overview of recent guidelines. Am J Med. 2009;122(suppl 10):S22-S32.
43. Moulin D, Boulanger A, Clark AJ, et al; Canadian Pain Society. Pharmacological management of chronic neuropathic pain: revised consensus statement from the Canadian Pain Society. Pain Res Manag. 2014;19(6):328-35.
44. Mu A, Weinberg E, Moulin DE, et al. Pharmacologic management of chronic neuropathic pain: Review of the Canadian Pain Society consensus statement. Can Fam Physician. 2017;63(11):844-852.
45. Finnerup NB, Otto M, McQuay HJ, et al. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain. 2005;118(3):289-305.
46. Hempenstall K, Nurmikko TJ, Johnson RW, et al. Analgesic therapy in postherpetic neuralgia: a quantitative systematic review. PLoS Med. 2005;2(7):e164.
47. Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain. 1999;83(3):389-400.
48. Wu CL, Raja SN. An update on the treatment of postherpetic neuralgia. J Pain. 2008;9(suppl 1):S19-S30.
49. Kroenke K, Krebs EE, Bair MJ. Pharmacotherapy of chronic pain: a synthesis of recommendations from systematic reviews. Gen Hosp Psychiatry. 2009;31(3):206-219.
50. Hearn L, Moore RA, Derry S, et al. Desipramine for neuropathic pain in adults. Cochrane Database Syst Rev. 2014;(9):CD011003.
51. Hearn L, Derry S, Phillips T, et al. Imipramine for neuropathic pain in adults. Cochrane Database Syst Rev. 2014;(5):CD010769.
52. Derry S, Wiffen PJ, Aldington D, et al. Nortriptyline for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;1:CD011209.
53. Moore R, Derry S, Aldington D, et al. Amitriptyline for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;(7):CD008242.
54. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev. 2014;(1):CD007115.
55. Gallagher HC, Gallagher RM, Butler M, et al. Venlafaxine for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;(8):CD011091.
56. Alviar MJ, Hale T, Dungca M. Pharmacologic interventions for treating phantom limb pain. Cochrane Database Syst Rev. 2016;10:CD006380.
57. Dinat N, Marinda E, Moch S, et al. Randomized, Double-Blind, Crossover Trial of Amitriptyline for Analgesia in Painful HIV-Associated Sensory Neuropathy. PLoS One. 2015;10(5):e0126297. doi: 10.1371/journal.pone.0126297.eCollection 2015.
58. Mehta S, McIntyre A, Janzen S, et al; Spinal Cord Injury Rehabilitation Evidence Team. Systematic review of pharmacologic treatments of pain after spinal cord injury: an update. Arch Phys Med Rehabil. 2016;97(8):1381-1391.e1.
59. Moore RA, Derry S, Aldington D, et al. Amitriptyline for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2012;(12):CD008242..
60. Walitt B, Urrútia G, Nishishinya MB, et al. Selective serotonin reuptake inhibitors for fibromyalgia syndrome. Cochrane Database Syst Rev. 2015;(6):CD011735.
61. Welsch P, Üçeyler N, Klose P, et al. Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia. Cochrane Database Syst Rev. 2018;(2):CD010292.
62. VanderWeide LA, Smith SM, Trinkley KE. A systematic review of the efficacy of venlafaxine for the treatment of fibromyalgia. J Clin Pharm Ther. 2015;40(1):1-6.
63. Welsch P, Bernardy K, Derry S, et al. Mirtazapine for fibromyalgia in adults. Cochrane Database Syst Rev. 2018;(8):CD012708.
64. Lance JW, Curran DA. Treatment of chronic tension headache. Lancet. 1964;283(7345):1236-1239.
65. Jackson JL, William S, Laura S, et al. Tricyclic antidepressants and headaches: systematic review and meta-analysis. BMJ. 2010;341:c5222. doi: https://doi.org/10.1136/bmj.c5222
66. Xu XM, Liu Y, Dong MX, et al. Tricyclic antidepressants for preventing migraine in adults. Medicine. 2017;96(22):e6989. doi: 10.1097/MD.0000000000006989.
67. Banzi R, Cusi C, Randazzo C, et al. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the prevention of migraine in adults. Cochrane Database Syst Rev. 2015;(4):CD002919.
68. Banzi R, Cusi C, Randazzo C, et al. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the prevention of tension-type headache in adults. Cochrane Database Syst Rev. 2015;(5):CD011681.
69. Quartero AO, Meineche-Schmidt V, Muris J, et al. Bulking agents, antispasmodic and antidepressant medication for the treatment of irritable bowel syndrome. Cochrane Database Syst Rev. 2005;(2):CD003460.
70. Ford AC, Talley NJ, Schoenfeld PS, et al. Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut. 2009;58(3):367-378.
71. Coss-Adame E, Erdogan A, Rao SS. Treatment of esophageal (noncardiac) chest pain: an expert review. Clin Gastroenterol Hepatol. 2014;12(8):1224-1245.
72. Kelada E, Jones A. Interstitial cystitis. Arch Gynecol Obstet. 2007;275(4):223-229.
73. Leo RJ, Dewani S. A systematic review of the utility of antidepressant pharmacotherapy in the treatment of vulvodynia pain. J Sex Med. 2013;10(10):2497-2505.
74. McMillan R, Forssell H, Buchanan JA, et al. Interventions for treating burning mouth syndrome. Cochrane Database Syst Rev. 2016;11:CD002779.
75. Patel DN. Inconclusive results of a systematic review of efficacy of antidepressants on orofacial pain disorders. Evid Based Dent. 2013;14(2):55-56.
76. Wang W, Sun YH, Wang YY, et al. Treatment of functional chest pain with antidepressants: a meta-analysis. Pain Physician. 2012;15(2):E131-E142.
77. Lavis JN. How can we support the use of systematic reviews in policymaking? PLoS Med. 2009;6(11):e1000141. doi: 10.1371/journal.pmed.1000141.
78. Sorkin L. Nociceptive transmission within the spinal cord. Mt Sinai J Med. 1991;58(3):208-216.
79. Yokogawa F, Kiuchi Y, Ishikawa Y, et al. An investigation of monoamine receptors involved in antinociceptive effects of antidepressants. Anesth Analg. 2002;95(1):163-168, table of contents.
80. Lynch ME. Antidepressants as analgesics: a review of randomized controlled trials. J Psychiatry Neurosci. 2001;26(1):30-36.
81. Max MB. Treatment of post-herpetic neuralgia: antidepressants. Ann Neurol. 1994;35(suppl):S50-S53.
82. Max MB, Lynch SA, Muir J, et al. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med. 1992;326(19):1250-1256.
83. McQuay HJ, Tramèr M, Nye BA, et al. A systematic review of antidepressants in neuropathic pain. Pain. 1996;68(2-3):217-227.
84. Mochizucki D. Serotonin and noradrenaline reuptake inhibitors in animal models of pain. Hum Psychopharmacol Clin Exp. 2004;19(suppl 1):15-19.
85. Sussman N. SNRIs versus SSRIs: mechanisms of action in treating depression and painful physical symptoms. Primary Care Companion J Clin Psychiatry. 2003;5(suppl 7):19-26.
86. Bundeff AW, Woodis CB. Selective serotonin reuptake inhibitors for the treatment of irritable bowel syndrome. Ann Pharmacother. 2014;48(6):777-784.
87. Jung AC, Staiger T, Sullivan M. The efficacy of selective serotonin reuptake inhibitors for the management of chronic pain. J Gen Intern Med. 1997;12(6):384-389.
88. Xie C, Tang Y, Wang Y, et al. Efficacy and safety of antidepressants for the treatment of irritable bowel syndrome: a meta-analysis. PLoS One. 2015;10(8):e0127815. doi: 10.1371/journal.pone.0127815. eCollection 2015.
89. Zijlstra TR , Barendregt PJ , van de Laar MA. Venlafaxine in fibromyalgia: results of a randomized, placebo-controlled, double-blind trial. Arthritis Rheum. 2002;46(suppl 9):S105.
90. Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology. 2001;25(6):871-880.
91. Thorpe J, Shum B, Moore RA, et al. Combination pharmacotherapy for the treatment of fibromyalgia in adults. Cochrane Database Syst Rev. 2018;(2):CD010585.
92. Gilron I, Chaparro LE, Tu D, et al. Combination of pregabalin with duloxetine for fibromyalgia: a randomized controlled trial. Pain. 2016;157(7):1532-1540.
93. Häuser W, Petzke F, Üçeyler N, et al. Comparative efficacy and acceptability of amitriptyline, duloxetine and milnacipran in fibromyalgia syndrome: a systematic review with meta-analysis. Rheumatology (Oxford). 2011;50(3):532-543.
94. Hossain SM, Hussain SM, Ekram AR. Duloxetine in painful diabetic neuropathy: a systematic review. Clin J Pain. 2016;32(11):1005-1010.
95. Riediger C, Schuster T, Barlinn K, et al. Adverse effects of antidepressants for chronic pain: a systematic review and meta-analysis. Front Neurol. 2017;8:307.
Approximately 55 years ago, tricyclic antidepressants (TCAs) began to be used to treat neuropathic pain.1 Eventually, clinical trials emerged suggesting the utility of TCAs for other chronic pain conditions, such as fibromyalgia (FM) and migraine prophylaxis. However, despite TCAs’ effectiveness in mitigating painful conditions, their adverse effects limited their use.
Pharmacologic advancements have led to the development of other antidepressant classes, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), and the use of these agents has come to eclipse that of TCAs. In the realm of pain management, such developments have raised the hope of possible alternative co-analgesic agents that could avoid the adverse effects associated with TCAs. Some of these agents have demonstrated efficacy for managing chronic pain states, while others have demonstrated only limited utility.
This article provides a synopsis of systematic reviews and meta-analyses examining the role of antidepressant therapy for managing several chronic pain conditions, including pain associated with neuropathy, FM, headache, and irritable bowel syndrome (IBS). Because the literature base is rapidly evolving, it is necessary to revisit the information gleaned from clinical data with respect to treatment effectiveness, and to clarify how antidepressants might be positioned in the management of chronic pain.
The effectiveness of antidepressants for pain
The pathophysiologic processes that precipitate and maintain chronic pain conditions are complex (Box 12-10). The pain-mitigating effects of antidepressants can be thought of in terms of direct analgesic effects and indirect effects (Box 22,3,8,10,11-33).
Box 1
The pathophysiologic processes precipitating and maintaining chronic pain conditions are complex. Persistent and chronic pain results from changes in sensitivity within both ascending pathways (relaying pain information from the periphery to the spinal cord and brain) and descending pain pathways (functioning to modulate ascending pain information).2,3 Tissue damage or peripheral nerve injury can lead to a cascade of neuroplastic changes within the CNS, resulting in hyperexcitability within the ascending pain pathways.
The descending pain pathways consist of the midbrain periaqueductal gray area (PGA), the rostroventral medulla (RVM), and the dorsolateral pontomesencephalic tegmentum (DLPT). The axons of the RVM (the outflow of which is serotonergic) and DLPT (the outflow of which is noradrenergic) terminate in the dorsal horn of the spinal cord,4 and thereby dampen pain signals arising from the periphery. Diminished output from descending pain pathways can heighten the pain experience. Input from the cortex, hypothalamus, and amygdala (among other structures) converges upon the PGA, RVM and DLPT, and can influence the degree of pain modulation emerging from descending pathways. In this way, thoughts, appraisals, and mood are believed to comprise cognitive and affective modifiers of pain experiences.
Devising effective chronic pain treatment becomes challenging; multimodal treatment approaches often are advocated, including pharmacologic treatment with analgesics in combination with co-analgesic medications such as antidepressants. Although a description of multimodal treatment is beyond the scope of this article, such treatment also would encompass physical therapy, occupational therapy, and psychotherapeutic interventions to augment rehabilitative efforts and the functional capabilities of patients who struggle with persisting pain.
Although the direct pain-mitigating effects of antidepressants are not fully understood, it is believed that augmentation of monoamine neurotransmission from supraspinal nuclei (ie, the RVM and DLPT) modulate pain transmission from the periphery.5,6 In addition, there is evidence that some effects of tricyclic antidepressants can modulate several other functions that impact peripheral and central sensitization.7-10
During the last several decades, antidepressants have been used to address—and have demonstrated clinical utility for—a variety of chronic pain states. However, antidepressants are not a panacea; some chronic pain conditions are more responsive to antidepressants than are others. The chronic painful states most amenable to antidepressants are those that result primarily from a process of neural sensitization, as opposed to acute somatic or visceral nociception. Hence, several meta-analyses and evidence-based reviews have long suggested the usefulness of antidepressants for mitigating pain associated with neuropathy,34,35 FM,36,37 headache,38 and IBS.39,40
Box 2
The pain-mitigating effects of antidepressants can be thought of in terms of direct analgesic effects (impacting neurotransmission of descending pathways independent of influences on mood) and indirect effects (presumably impacting cortical and limbic output to the periaqueductal gray area, the rostroventral medulla, and the dorsolateral pontomesencephalic tegmentum brought about by improvement in mood and/or cognitive appraisals) (Figure2,3,8,10,11,15,20,22,28,29). Support for the direct analgesic effects has been garnered from initial empirical work that demonstrated pain relief among patients with pain who are not depressed. Additionally, among patients who have depression and experience pain, analgesia reportedly often occurs within 2 weeks, which is before antidepressant effects are appreciated,11-15 and, at least for some antidepressants, occurs at doses far lower than those required to produce mood-elevating effects.11,12,16
On the other hand, it is well established that significant comorbidities exist between chronic pain states and psychiatric disorders (eg, depression and somatic symptom and related disorders).17-21 There may be common physiological substrates underlying chronic pain and depression.20,22 There are bidirectional influences of limbic (affective) systems and those CNS structures involved in pain processing and integration. The effects of pain and depression are reciprocal; the presence of one makes the management of the other more challenging.23-27 Mood disturbances can, therefore, impact pain processing by acting as affective and cognitive amplifiers of pain by leading to catastrophizing, pain severity augmentation, poor coping with pain-related stress, etc.28,29 It is plausible that the mood-elevating effects of antidepressants can improve pain by indirect effects, by modulating limbic activity, which in turn, impacts coping, cognitive appraisals of pain, etc.
Patients with somatoform disorders (using pre-DSM-5 terminology) frequently present with chronic pain, often in multiple sites.19 Such patients are characterized by hypervigilance for, and a predisposition to focus on, physical sensations and to appraise these sensations as reflecting a pathological state.30 Neuroimaging studies have begun to identify those neural circuits involved in somatoform disorders, many of which act as cognitive and affective amplifiers of visceral-somatic sensory processing. Many of these neural circuits overlap, and interact with, those involved in pain processing.31 Antidepressants can mitigate the severity of unexplained physical complaints, including pain, among patients who somatize32,33; however, due to the heterogeneity of studies upon which this claim is based, the quality of the evidence is reportedly low.33 There is uncertainty whether, or to what extent, antidepressant benefits among patients who somatize are due to a direct impact on pain modulation, or indirect effects on mood or cognitive appraisals/perceptions.
Despite the uncertainties about the exact mechanisms through which antidepressants exert analgesic effects, antidepressants can be appropriately used to treat patients with selected chronic pain syndromes, regardless of whether or not the patient has a psychiatric comorbidity. For those patients with pain and psychiatric comorbidities, the benefits may be brought about via direct mechanisms, indirect mechanisms, or a combination of both.
Continue to: Neuropathic pain
Neuropathic pain
Several treatment guidelines advocate for the use of antidepressants for neuropathic pain.41-44 For decades, TCAs have been employed off-label to successfully treat many patients with neuropathic pain states. Early investigations suggested that TCAs were robustly efficacious in managing patients with neuropathy.45-48 Calculated number-needed-to-treat (NNT) values for TCAs were quite low (ie, reflecting that few patients would need to be treated to yield a positive response in one patient compared with placebo), and were comparable to, if not slightly better than, the NNTs generated for anticonvulsants and α2-δ ligands, such as gabapentin or pregabalin.45-48
Unfortunately, early studies involving TCAs conducted many years ago do not meet contemporary standards of methodological rigor; they featured relatively small samples of patients assessed for brief post-treatment intervals with variable outcome measures. Thus, the NNT values obtained in meta-analyses based on these studies may overestimate treatment benefits.49 Further, NNT values derived from meta-analyses tended to combine all drugs within a particular antidepressant class (eg, amitriptyline, nortriptyline, desipramine, and imipramine among the TCAs) employed at diverse doses. Taken together, these limitations raise questions about the results of those meta-analyses.
Subsequent meta-analyses, which employed strict criteria to eliminate data from studies with potential sources of bias and used a primary outcome of frequencies of patients reporting at least 30% pain reduction compared with a placebo-controlled sample, suggest that the effectiveness of TCAs as a class for treating neuropathic pain is not as compelling as once was thought. Meta-analyses of studies employing specific TCAs revealed that there was little evidence to support the use of desipramine,50 imipramine,51 or nortriptyline52 in managing diabetic neuropathy or postherpetic neuralgia. Studies evaluating amitriptyline (dose range 12.5 to 150 mg/d), found low-level evidence of effectiveness; the benefit was expected to be present for a small subset (approximately 25%) of patients with neuropathic pain.53
There is moderate-quality evidence that duloxetine (60 to 120 mg/d) can produce a ≥50% improvement in pain severity ratings among patients with diabetic peripheral neuropathy.54 Although head-to-head studies with other antidepressants are limited, it appears that duloxetine and amitriptyline have comparable efficacy, even though the NNTs for amitriptyline were derived from lower-quality studies than those for duloxetine. Duloxetine is the only antidepressant to receive FDA approval for managing diabetic neuropathy. By contrast, studies assessing the utility of venlafaxine in neuropathic pain comprised small samples for brief durations, which limits the ability to draw clear (unbiased) support for its usefulness.55
Given the diversity of pathophysiologic processes underlying the disturbances that cause neuropathic pain disorders, it is unsurprising that the effectiveness of amitriptyline and duloxetine were not generalizable to all neuropathic pain states. Although amitriptyline produced pain-mitigating effects in patients with diabetic neuropathy and post-herpetic neuralgia, and duloxetine mitigated pain among patients with diabetic neuropathy, there was no evidence to suggest their effectiveness in phantom limb pain or human immunodeficiency virus-related and spinal cord-related neuropathies.35,53,54,56-58
Continue to: Fibromyalgia
Fibromyalgia
As with the issues encountered in interpreting the effectiveness of antidepressants in neuropathic pain, interpreting results gleaned from clinical trials of antidepressants for treating FM are fraught with similar difficulties. Although amitriptyline has been a first-line treatment for FM for many years, the evidence upon which such recommendations were based consisted of low-level studies that had a significant potential for bias.59 Large randomized trials would offer more compelling data regarding the efficacy of amitriptyline, but the prohibitive costs of such studies makes it unlikely they will be conducted. Amitriptyline (25 to 50 mg/d) was effective in mitigating FM-related pain in a small percentage of patients studied, with an estimated NNT of 4.59 Adverse effects, often contributing to treatment discontinuation, were encountered more frequently among patients who received amitriptyline compared with placebo.
Selective serotonin reuptake inhibitors failed to demonstrate significant pain relief (estimated NNT of 10), or improvement in fatigue or sleep problems, even though the studies upon which such conclusions were based were low-level studies with a high potential for bias.60 Although SSRIs have limited utility for mitigating pain, they are still quite useful for reducing depression among patients with FM.60
By contrast, the SNRIs duloxetine and milnacipran provided clinically relevant benefit over placebo in the frequency of patients reporting pain relief of ≥30%, as well as patients’ global impression of change.61 These agents, however, failed to provide clinically relevant benefit over placebo in improving health-related quality of life, reducing sleep problems, or improving fatigue. Nonetheless, duloxetine and milnacipran are FDA-approved for managing pain in FM. Studies assessing the efficacy of venlafaxine in the treatment of FM to date have been limited by small sample sizes, inconsistent dosing, lack of a placebo control, and lack of blinding, which limits the ability to clearly delineate the role of venlafaxine in managing FM.62
Mirtazapine (15 to 45 mg/d) showed a clinically relevant benefit compared with placebo for participant-reported pain relief of ≥30% and sleep disturbances. There was no benefit in terms of participant-reported improvement of quality of life, fatigue, or negative mood.63 The evidence was considered to be of low quality overall.
Headache
Amitriptyline has been employed off-label to address headache prophylaxis since 1964.64 Compared with placebo, it is efficacious in ameliorating migraine frequency and intensity as well as the frequency of tension headache.65,66 However, SSRIs and SNRIs (venlafaxine) failed to produce significant reductions in migraine frequency or severity or the frequencies of tension headache when compared with placebo.67,68
Continue to: Irritable bowel syndrome
Irritable bowel syndrome
Early studies addressing antidepressant efficacy in IBS reveal inconsistencies. For example, whereas some suggest that TCAs are effective in mitigating chronic, severe abdominal pain,39,40 others concluded that TCAs failed to demonstrate a significant analgesic benefit.69 A recent meta-analysis that restricted analysis of efficacy to randomized controlled trials (RCTs) with more rigorous methodological adherence found that pain relief in IBS is possible with both TCAs as well as SSRIs. However, adverse effects were more commonly encountered with TCAs than with SSRIs. Some of the inconsistencies in treatment efficacy reported in early studies may be due to variations in responsiveness of subsets of IBS patients. Specifically, the utility of TCAs appears to be best among patients with diarrheal-type (as opposed to constipation-type) IBS, presumably due to TCAs’ anticholinergic effects, whereas SSRIs may provide more of a benefit for patients with predominantly constipation-type IBS.40,70
Other chronic pain conditions
Antidepressants have been used to assist in the management of several other pain conditions, including oral-facial pain, interstitial cystitis, non-cardiac chest pain, and others. The role of antidepressants for such conditions remains unclear due to limitations in the prevailing empirical work, such as few trials, small sample sizes, variations in outcome measures, and insufficient randomization and blinding.71-76 The interpretation of results from systematic reviews and meta-analyses is limited because of these shortcomings.77 Hence, it has not always been possible to determine whether, and to what extent, patients with such conditions may benefit from antidepressants.
Neuromodulatory effects and efficacy for pain
The interplay of norepinephrine (NE) and serotonin (5-HT) neurotransmitter systems and cellular mechanisms involved in the descending modulation of pain pathways is complex. Experimental animal models of pain modulation suggest that 5-HT can both inhibit as well as promote pain perception by different physiological mechanisms, in contrast to NE, which is predominately inhibitory. While 5-HT in the descending modulating system can inhibit pain transmission ascending to the brain from the periphery, it appears that an intact noradrenergic system is necessary for the inhibitory influences of the serotonergic system to be appreciated.16,78,79 Deficiencies in one or both of these neurotransmitter systems may contribute to hyperactive pain processing, and thereby precipitate or maintain chronic pain.
Pain mitigation may be achieved best by enhancing both neurotransmitters simultaneously, less so by enhancing NE alone, and least by enhancing 5-HT alone.6 The ability to impact pain modulation would, therefore, depend on the degree to which an antidepressant capitalizes on both noradrenergic and serotonergic neurotransmission. Antidepressants commonly employed to manage pain are presented in Table 147,60,68,80-88 according to their primary neurotransmitter effects. Thus, the literature summarized above suggests that antidepressants that influence both NE and 5-HT transmission have greater analgesic effects than antidepressants with more specific effects, such as influencing 5-HT reuptake alone.80-85 It is unsurprising, therefore, that the SSRIs have not been demonstrated to be as consistently analgesic.47,60,68,80,86-88
Similarly, pharmacodynamic and pharmacokinetic differences within antidepressant classes may influence analgesic effectiveness. Simultaneous effects on NE and 5-HT are achieved at low doses with duloxetine and milnacipran. By contrast, 5-HT effects predominate at low doses for venlafaxine. To achieve pain-mitigating effects, higher doses of venlafaxine generally are required.89 Therefore, inconsistencies across studies regarding the analgesic benefits of venlafaxine may be attributable to variability in dosing; patients treated with lower doses may not have experienced sufficient NE effects to garner positive results.
Continue to: The differences in analgesic efficacy...
The differences in analgesic efficacy among specific TCAs may be understood in a similar fashion. Specifically, tertiary TCAs (imipramine and amitriptyline) inhibit both 5-HT and NE reuptake.6,90 Secondary amines (desipramine and nortriptyline) predominantly impact NE reuptake, possibly accounting for the lesser pain-mitigating benefit achieved with these agents, such as for treating neuropathic pain. Further, in vivo imipramine and amitriptyline are rapidly metabolized to secondary amines that are potent and selective NE reuptake inhibitors. In this way, the secondary amines may substantially lose the ability to modulate pain transmission because of the loss of concurrent 5-HT influences.90
Clinical pearls
The following practical points can help guide clinicians regarding the usefulness of antidepressants for pain management:
- Antidepressants can alleviate symptoms of depression and pain. The pain-mitigating effects of antidepressants are possible even among chronic pain patients who are not depressed. Antidepressants may confer benefits for chronic pain patients with depression and other comorbid conditions, such as somatic symptom and related disorders.
- Antidepressants are useful for select chronic pain states. Although the noradrenergic and serotonergic antidepressants (SNRIs and, to some extent, amitriptyline) appear to have efficacy for neuropathic pain and FM, the benefits of SSRIs appear to be less robust. On the other hand, SSRIs and TCAs may have potential benefit for patients with IBS. However, the results of meta-analyses are limited in the ability to provide information about which patients will best respond to which specific antidepressant or how well. Future research directed at identifying characteristics that can predict which patients are likely to benefit from one antidepressant vs another would help inform how best to tailor treatment to individual needs.
- The pain-mitigating effects of antidepressants often emerge early in the course of treatment (often before mood-elevating effects are observed). For example, in the case of amitriptyline, pain relief may be possible for some patients at doses generally lower than those required for mood-elevating effects. To date, there is limited information in the literature to determine what constitutes a sufficient duration of treatment, or when treatment should be modified.
- Failure to reduce pain should raise questions about whether the dose should be increased, an alternative agent should be tried, or combinations with other analgesic agents should be considered. Failure to achieve pain-mitigating effects with one antidepressant does not mean failure with others. Hence, failure to achieve desired effects with one agent might warrant an empirical trial with another agent. Presently, too few double-blind RCTs have been conducted to assess the pain-mitigating effects of other antidepressants (eg, bupropion and newer SNRIs such as desvenlafaxine and levomilnacipran). Meta-analysis of the analgesic effectiveness of these agents or comparisons to the efficacy of other antidepressant classes is, therefore, impossible at this time.
Because many chronic pain states are complex, patients will seldom experience clinically relevant benefit from any one intervention.53 The bigger implication for clinical research is to determine whether there is a sequence or combination of medication use that will provide overall better clinical effectiveness.53 Only limited data are available exploring the utility of combining pharmacologic approaches to address pain.91 For example, preliminary evidence suggests that combinations of complementary strategies, such as duloxetine combined with pregabalin, may result in significantly greater numbers of FM patients achieving ≥30% pain reduction compared with monotherapy with either agent alone or placebo.92
- Antidepressant selection may need to be based on medication-related adverse effect profiles and the potential for drug interactions. These factors are useful to consider in delineating multimodal treatment regimens for chronic pain in light of patients’ comorbidities and co-medication regimen. For example, the adverse effects of TCAs (anticholinergic and alpha-adrenergic influences) limit their utility for treating pain. Some of these effects can be more problematic in select populations, such as older adults or those with orthostatic difficulties, among others. TCAs are contraindicated in patients with closed-angle glaucoma, recent myocardial infarction, cardiac arrhythmias, poorly controlled seizures, or severe benign prostatic hypertrophy. Although the pain-mitigating effects of SNRIs have not been demonstrated to significantly exceed those of TCAs,68,93,94 SNRIs would offer an advantage of greater tolerability of adverse effects and relative safety in patients with comorbid medical conditions that would otherwise preclude TCA use. The adverse effects and common drug interactions associated with antidepressants are summarized in Table 295.
Conclusion
Chronic, nonmalignant pain conditions afflict many patients and significantly impair their ability to function. Because of heightened concerns related to the appropriateness of, and restricting inordinate access to, long-term opioid analgesics, clinicians need to explore the usefulness of co-analgesic agents, such as antidepressants. Significant comorbidities exist between psychiatric disorders and chronic pain, and psychiatrists are uniquely positioned to diagnose and treat psychiatric comorbidities, as well as pain, among their patients, especially since they understand the kinetics and dynamics of antidepressants.
Bottom Line
Antidepressants can alleviate symptoms of depression and pain. Noradrenergic and serotonergic antidepressants appear to have efficacy for pain associated with neuropathy and fibromyalgia, while selective serotonin reuptake inhibitors and tricyclic antidepressants may have benefit for patients with irritable bowel syndrome. However, evidence regarding which patients will best respond to which specific antidepressant is limited.
Continue to: Related Resources
Related Resources
- Williams AM, Knox ED. When to prescribe antidepressants to treat comorbid depression and pain disorders. Current Psychiatry. 2017;16(1):55-58.
- Maletic V, Demuri B. Chronic pain and depression: treatment of 2 culprits in common. Current Psychiatry. 2016;15(3):41,47-50,52.
Drug Brand Names
Amitriptyline • Elavil, Endep
Bupropion • Wellbutrin, Zyban
Carisoprodol • Rela, Soma
Cyclobenzaprine • Amrix, Flexeril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Duloxetine • Cymbalta
Fluoxetine • Prozac
Gabapentin • Horizant, Neurontin
Imipramine • Tofranil
Levomilnacipran • Fetzima
Methadone • Dolophine, Methadose
Milnacipran • Savella
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Pregabalin • Lyrica, Lyrica CR
Tapentadol • Nucynta
Tramadol • Ultram
Trazodone • Desyrel, Oleptro
Venlafaxine • Effexor
Warfarin • Coumadin, Jantoven
Approximately 55 years ago, tricyclic antidepressants (TCAs) began to be used to treat neuropathic pain.1 Eventually, clinical trials emerged suggesting the utility of TCAs for other chronic pain conditions, such as fibromyalgia (FM) and migraine prophylaxis. However, despite TCAs’ effectiveness in mitigating painful conditions, their adverse effects limited their use.
Pharmacologic advancements have led to the development of other antidepressant classes, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), and the use of these agents has come to eclipse that of TCAs. In the realm of pain management, such developments have raised the hope of possible alternative co-analgesic agents that could avoid the adverse effects associated with TCAs. Some of these agents have demonstrated efficacy for managing chronic pain states, while others have demonstrated only limited utility.
This article provides a synopsis of systematic reviews and meta-analyses examining the role of antidepressant therapy for managing several chronic pain conditions, including pain associated with neuropathy, FM, headache, and irritable bowel syndrome (IBS). Because the literature base is rapidly evolving, it is necessary to revisit the information gleaned from clinical data with respect to treatment effectiveness, and to clarify how antidepressants might be positioned in the management of chronic pain.
The effectiveness of antidepressants for pain
The pathophysiologic processes that precipitate and maintain chronic pain conditions are complex (Box 12-10). The pain-mitigating effects of antidepressants can be thought of in terms of direct analgesic effects and indirect effects (Box 22,3,8,10,11-33).
Box 1
The pathophysiologic processes precipitating and maintaining chronic pain conditions are complex. Persistent and chronic pain results from changes in sensitivity within both ascending pathways (relaying pain information from the periphery to the spinal cord and brain) and descending pain pathways (functioning to modulate ascending pain information).2,3 Tissue damage or peripheral nerve injury can lead to a cascade of neuroplastic changes within the CNS, resulting in hyperexcitability within the ascending pain pathways.
The descending pain pathways consist of the midbrain periaqueductal gray area (PGA), the rostroventral medulla (RVM), and the dorsolateral pontomesencephalic tegmentum (DLPT). The axons of the RVM (the outflow of which is serotonergic) and DLPT (the outflow of which is noradrenergic) terminate in the dorsal horn of the spinal cord,4 and thereby dampen pain signals arising from the periphery. Diminished output from descending pain pathways can heighten the pain experience. Input from the cortex, hypothalamus, and amygdala (among other structures) converges upon the PGA, RVM and DLPT, and can influence the degree of pain modulation emerging from descending pathways. In this way, thoughts, appraisals, and mood are believed to comprise cognitive and affective modifiers of pain experiences.
Devising effective chronic pain treatment becomes challenging; multimodal treatment approaches often are advocated, including pharmacologic treatment with analgesics in combination with co-analgesic medications such as antidepressants. Although a description of multimodal treatment is beyond the scope of this article, such treatment also would encompass physical therapy, occupational therapy, and psychotherapeutic interventions to augment rehabilitative efforts and the functional capabilities of patients who struggle with persisting pain.
Although the direct pain-mitigating effects of antidepressants are not fully understood, it is believed that augmentation of monoamine neurotransmission from supraspinal nuclei (ie, the RVM and DLPT) modulate pain transmission from the periphery.5,6 In addition, there is evidence that some effects of tricyclic antidepressants can modulate several other functions that impact peripheral and central sensitization.7-10
During the last several decades, antidepressants have been used to address—and have demonstrated clinical utility for—a variety of chronic pain states. However, antidepressants are not a panacea; some chronic pain conditions are more responsive to antidepressants than are others. The chronic painful states most amenable to antidepressants are those that result primarily from a process of neural sensitization, as opposed to acute somatic or visceral nociception. Hence, several meta-analyses and evidence-based reviews have long suggested the usefulness of antidepressants for mitigating pain associated with neuropathy,34,35 FM,36,37 headache,38 and IBS.39,40
Box 2
The pain-mitigating effects of antidepressants can be thought of in terms of direct analgesic effects (impacting neurotransmission of descending pathways independent of influences on mood) and indirect effects (presumably impacting cortical and limbic output to the periaqueductal gray area, the rostroventral medulla, and the dorsolateral pontomesencephalic tegmentum brought about by improvement in mood and/or cognitive appraisals) (Figure2,3,8,10,11,15,20,22,28,29). Support for the direct analgesic effects has been garnered from initial empirical work that demonstrated pain relief among patients with pain who are not depressed. Additionally, among patients who have depression and experience pain, analgesia reportedly often occurs within 2 weeks, which is before antidepressant effects are appreciated,11-15 and, at least for some antidepressants, occurs at doses far lower than those required to produce mood-elevating effects.11,12,16
On the other hand, it is well established that significant comorbidities exist between chronic pain states and psychiatric disorders (eg, depression and somatic symptom and related disorders).17-21 There may be common physiological substrates underlying chronic pain and depression.20,22 There are bidirectional influences of limbic (affective) systems and those CNS structures involved in pain processing and integration. The effects of pain and depression are reciprocal; the presence of one makes the management of the other more challenging.23-27 Mood disturbances can, therefore, impact pain processing by acting as affective and cognitive amplifiers of pain by leading to catastrophizing, pain severity augmentation, poor coping with pain-related stress, etc.28,29 It is plausible that the mood-elevating effects of antidepressants can improve pain by indirect effects, by modulating limbic activity, which in turn, impacts coping, cognitive appraisals of pain, etc.
Patients with somatoform disorders (using pre-DSM-5 terminology) frequently present with chronic pain, often in multiple sites.19 Such patients are characterized by hypervigilance for, and a predisposition to focus on, physical sensations and to appraise these sensations as reflecting a pathological state.30 Neuroimaging studies have begun to identify those neural circuits involved in somatoform disorders, many of which act as cognitive and affective amplifiers of visceral-somatic sensory processing. Many of these neural circuits overlap, and interact with, those involved in pain processing.31 Antidepressants can mitigate the severity of unexplained physical complaints, including pain, among patients who somatize32,33; however, due to the heterogeneity of studies upon which this claim is based, the quality of the evidence is reportedly low.33 There is uncertainty whether, or to what extent, antidepressant benefits among patients who somatize are due to a direct impact on pain modulation, or indirect effects on mood or cognitive appraisals/perceptions.
Despite the uncertainties about the exact mechanisms through which antidepressants exert analgesic effects, antidepressants can be appropriately used to treat patients with selected chronic pain syndromes, regardless of whether or not the patient has a psychiatric comorbidity. For those patients with pain and psychiatric comorbidities, the benefits may be brought about via direct mechanisms, indirect mechanisms, or a combination of both.
Continue to: Neuropathic pain
Neuropathic pain
Several treatment guidelines advocate for the use of antidepressants for neuropathic pain.41-44 For decades, TCAs have been employed off-label to successfully treat many patients with neuropathic pain states. Early investigations suggested that TCAs were robustly efficacious in managing patients with neuropathy.45-48 Calculated number-needed-to-treat (NNT) values for TCAs were quite low (ie, reflecting that few patients would need to be treated to yield a positive response in one patient compared with placebo), and were comparable to, if not slightly better than, the NNTs generated for anticonvulsants and α2-δ ligands, such as gabapentin or pregabalin.45-48
Unfortunately, early studies involving TCAs conducted many years ago do not meet contemporary standards of methodological rigor; they featured relatively small samples of patients assessed for brief post-treatment intervals with variable outcome measures. Thus, the NNT values obtained in meta-analyses based on these studies may overestimate treatment benefits.49 Further, NNT values derived from meta-analyses tended to combine all drugs within a particular antidepressant class (eg, amitriptyline, nortriptyline, desipramine, and imipramine among the TCAs) employed at diverse doses. Taken together, these limitations raise questions about the results of those meta-analyses.
Subsequent meta-analyses, which employed strict criteria to eliminate data from studies with potential sources of bias and used a primary outcome of frequencies of patients reporting at least 30% pain reduction compared with a placebo-controlled sample, suggest that the effectiveness of TCAs as a class for treating neuropathic pain is not as compelling as once was thought. Meta-analyses of studies employing specific TCAs revealed that there was little evidence to support the use of desipramine,50 imipramine,51 or nortriptyline52 in managing diabetic neuropathy or postherpetic neuralgia. Studies evaluating amitriptyline (dose range 12.5 to 150 mg/d), found low-level evidence of effectiveness; the benefit was expected to be present for a small subset (approximately 25%) of patients with neuropathic pain.53
There is moderate-quality evidence that duloxetine (60 to 120 mg/d) can produce a ≥50% improvement in pain severity ratings among patients with diabetic peripheral neuropathy.54 Although head-to-head studies with other antidepressants are limited, it appears that duloxetine and amitriptyline have comparable efficacy, even though the NNTs for amitriptyline were derived from lower-quality studies than those for duloxetine. Duloxetine is the only antidepressant to receive FDA approval for managing diabetic neuropathy. By contrast, studies assessing the utility of venlafaxine in neuropathic pain comprised small samples for brief durations, which limits the ability to draw clear (unbiased) support for its usefulness.55
Given the diversity of pathophysiologic processes underlying the disturbances that cause neuropathic pain disorders, it is unsurprising that the effectiveness of amitriptyline and duloxetine were not generalizable to all neuropathic pain states. Although amitriptyline produced pain-mitigating effects in patients with diabetic neuropathy and post-herpetic neuralgia, and duloxetine mitigated pain among patients with diabetic neuropathy, there was no evidence to suggest their effectiveness in phantom limb pain or human immunodeficiency virus-related and spinal cord-related neuropathies.35,53,54,56-58
Continue to: Fibromyalgia
Fibromyalgia
As with the issues encountered in interpreting the effectiveness of antidepressants in neuropathic pain, interpreting results gleaned from clinical trials of antidepressants for treating FM are fraught with similar difficulties. Although amitriptyline has been a first-line treatment for FM for many years, the evidence upon which such recommendations were based consisted of low-level studies that had a significant potential for bias.59 Large randomized trials would offer more compelling data regarding the efficacy of amitriptyline, but the prohibitive costs of such studies makes it unlikely they will be conducted. Amitriptyline (25 to 50 mg/d) was effective in mitigating FM-related pain in a small percentage of patients studied, with an estimated NNT of 4.59 Adverse effects, often contributing to treatment discontinuation, were encountered more frequently among patients who received amitriptyline compared with placebo.
Selective serotonin reuptake inhibitors failed to demonstrate significant pain relief (estimated NNT of 10), or improvement in fatigue or sleep problems, even though the studies upon which such conclusions were based were low-level studies with a high potential for bias.60 Although SSRIs have limited utility for mitigating pain, they are still quite useful for reducing depression among patients with FM.60
By contrast, the SNRIs duloxetine and milnacipran provided clinically relevant benefit over placebo in the frequency of patients reporting pain relief of ≥30%, as well as patients’ global impression of change.61 These agents, however, failed to provide clinically relevant benefit over placebo in improving health-related quality of life, reducing sleep problems, or improving fatigue. Nonetheless, duloxetine and milnacipran are FDA-approved for managing pain in FM. Studies assessing the efficacy of venlafaxine in the treatment of FM to date have been limited by small sample sizes, inconsistent dosing, lack of a placebo control, and lack of blinding, which limits the ability to clearly delineate the role of venlafaxine in managing FM.62
Mirtazapine (15 to 45 mg/d) showed a clinically relevant benefit compared with placebo for participant-reported pain relief of ≥30% and sleep disturbances. There was no benefit in terms of participant-reported improvement of quality of life, fatigue, or negative mood.63 The evidence was considered to be of low quality overall.
Headache
Amitriptyline has been employed off-label to address headache prophylaxis since 1964.64 Compared with placebo, it is efficacious in ameliorating migraine frequency and intensity as well as the frequency of tension headache.65,66 However, SSRIs and SNRIs (venlafaxine) failed to produce significant reductions in migraine frequency or severity or the frequencies of tension headache when compared with placebo.67,68
Continue to: Irritable bowel syndrome
Irritable bowel syndrome
Early studies addressing antidepressant efficacy in IBS reveal inconsistencies. For example, whereas some suggest that TCAs are effective in mitigating chronic, severe abdominal pain,39,40 others concluded that TCAs failed to demonstrate a significant analgesic benefit.69 A recent meta-analysis that restricted analysis of efficacy to randomized controlled trials (RCTs) with more rigorous methodological adherence found that pain relief in IBS is possible with both TCAs as well as SSRIs. However, adverse effects were more commonly encountered with TCAs than with SSRIs. Some of the inconsistencies in treatment efficacy reported in early studies may be due to variations in responsiveness of subsets of IBS patients. Specifically, the utility of TCAs appears to be best among patients with diarrheal-type (as opposed to constipation-type) IBS, presumably due to TCAs’ anticholinergic effects, whereas SSRIs may provide more of a benefit for patients with predominantly constipation-type IBS.40,70
Other chronic pain conditions
Antidepressants have been used to assist in the management of several other pain conditions, including oral-facial pain, interstitial cystitis, non-cardiac chest pain, and others. The role of antidepressants for such conditions remains unclear due to limitations in the prevailing empirical work, such as few trials, small sample sizes, variations in outcome measures, and insufficient randomization and blinding.71-76 The interpretation of results from systematic reviews and meta-analyses is limited because of these shortcomings.77 Hence, it has not always been possible to determine whether, and to what extent, patients with such conditions may benefit from antidepressants.
Neuromodulatory effects and efficacy for pain
The interplay of norepinephrine (NE) and serotonin (5-HT) neurotransmitter systems and cellular mechanisms involved in the descending modulation of pain pathways is complex. Experimental animal models of pain modulation suggest that 5-HT can both inhibit as well as promote pain perception by different physiological mechanisms, in contrast to NE, which is predominately inhibitory. While 5-HT in the descending modulating system can inhibit pain transmission ascending to the brain from the periphery, it appears that an intact noradrenergic system is necessary for the inhibitory influences of the serotonergic system to be appreciated.16,78,79 Deficiencies in one or both of these neurotransmitter systems may contribute to hyperactive pain processing, and thereby precipitate or maintain chronic pain.
Pain mitigation may be achieved best by enhancing both neurotransmitters simultaneously, less so by enhancing NE alone, and least by enhancing 5-HT alone.6 The ability to impact pain modulation would, therefore, depend on the degree to which an antidepressant capitalizes on both noradrenergic and serotonergic neurotransmission. Antidepressants commonly employed to manage pain are presented in Table 147,60,68,80-88 according to their primary neurotransmitter effects. Thus, the literature summarized above suggests that antidepressants that influence both NE and 5-HT transmission have greater analgesic effects than antidepressants with more specific effects, such as influencing 5-HT reuptake alone.80-85 It is unsurprising, therefore, that the SSRIs have not been demonstrated to be as consistently analgesic.47,60,68,80,86-88
Similarly, pharmacodynamic and pharmacokinetic differences within antidepressant classes may influence analgesic effectiveness. Simultaneous effects on NE and 5-HT are achieved at low doses with duloxetine and milnacipran. By contrast, 5-HT effects predominate at low doses for venlafaxine. To achieve pain-mitigating effects, higher doses of venlafaxine generally are required.89 Therefore, inconsistencies across studies regarding the analgesic benefits of venlafaxine may be attributable to variability in dosing; patients treated with lower doses may not have experienced sufficient NE effects to garner positive results.
Continue to: The differences in analgesic efficacy...
The differences in analgesic efficacy among specific TCAs may be understood in a similar fashion. Specifically, tertiary TCAs (imipramine and amitriptyline) inhibit both 5-HT and NE reuptake.6,90 Secondary amines (desipramine and nortriptyline) predominantly impact NE reuptake, possibly accounting for the lesser pain-mitigating benefit achieved with these agents, such as for treating neuropathic pain. Further, in vivo imipramine and amitriptyline are rapidly metabolized to secondary amines that are potent and selective NE reuptake inhibitors. In this way, the secondary amines may substantially lose the ability to modulate pain transmission because of the loss of concurrent 5-HT influences.90
Clinical pearls
The following practical points can help guide clinicians regarding the usefulness of antidepressants for pain management:
- Antidepressants can alleviate symptoms of depression and pain. The pain-mitigating effects of antidepressants are possible even among chronic pain patients who are not depressed. Antidepressants may confer benefits for chronic pain patients with depression and other comorbid conditions, such as somatic symptom and related disorders.
- Antidepressants are useful for select chronic pain states. Although the noradrenergic and serotonergic antidepressants (SNRIs and, to some extent, amitriptyline) appear to have efficacy for neuropathic pain and FM, the benefits of SSRIs appear to be less robust. On the other hand, SSRIs and TCAs may have potential benefit for patients with IBS. However, the results of meta-analyses are limited in the ability to provide information about which patients will best respond to which specific antidepressant or how well. Future research directed at identifying characteristics that can predict which patients are likely to benefit from one antidepressant vs another would help inform how best to tailor treatment to individual needs.
- The pain-mitigating effects of antidepressants often emerge early in the course of treatment (often before mood-elevating effects are observed). For example, in the case of amitriptyline, pain relief may be possible for some patients at doses generally lower than those required for mood-elevating effects. To date, there is limited information in the literature to determine what constitutes a sufficient duration of treatment, or when treatment should be modified.
- Failure to reduce pain should raise questions about whether the dose should be increased, an alternative agent should be tried, or combinations with other analgesic agents should be considered. Failure to achieve pain-mitigating effects with one antidepressant does not mean failure with others. Hence, failure to achieve desired effects with one agent might warrant an empirical trial with another agent. Presently, too few double-blind RCTs have been conducted to assess the pain-mitigating effects of other antidepressants (eg, bupropion and newer SNRIs such as desvenlafaxine and levomilnacipran). Meta-analysis of the analgesic effectiveness of these agents or comparisons to the efficacy of other antidepressant classes is, therefore, impossible at this time.
Because many chronic pain states are complex, patients will seldom experience clinically relevant benefit from any one intervention.53 The bigger implication for clinical research is to determine whether there is a sequence or combination of medication use that will provide overall better clinical effectiveness.53 Only limited data are available exploring the utility of combining pharmacologic approaches to address pain.91 For example, preliminary evidence suggests that combinations of complementary strategies, such as duloxetine combined with pregabalin, may result in significantly greater numbers of FM patients achieving ≥30% pain reduction compared with monotherapy with either agent alone or placebo.92
- Antidepressant selection may need to be based on medication-related adverse effect profiles and the potential for drug interactions. These factors are useful to consider in delineating multimodal treatment regimens for chronic pain in light of patients’ comorbidities and co-medication regimen. For example, the adverse effects of TCAs (anticholinergic and alpha-adrenergic influences) limit their utility for treating pain. Some of these effects can be more problematic in select populations, such as older adults or those with orthostatic difficulties, among others. TCAs are contraindicated in patients with closed-angle glaucoma, recent myocardial infarction, cardiac arrhythmias, poorly controlled seizures, or severe benign prostatic hypertrophy. Although the pain-mitigating effects of SNRIs have not been demonstrated to significantly exceed those of TCAs,68,93,94 SNRIs would offer an advantage of greater tolerability of adverse effects and relative safety in patients with comorbid medical conditions that would otherwise preclude TCA use. The adverse effects and common drug interactions associated with antidepressants are summarized in Table 295.
Conclusion
Chronic, nonmalignant pain conditions afflict many patients and significantly impair their ability to function. Because of heightened concerns related to the appropriateness of, and restricting inordinate access to, long-term opioid analgesics, clinicians need to explore the usefulness of co-analgesic agents, such as antidepressants. Significant comorbidities exist between psychiatric disorders and chronic pain, and psychiatrists are uniquely positioned to diagnose and treat psychiatric comorbidities, as well as pain, among their patients, especially since they understand the kinetics and dynamics of antidepressants.
Bottom Line
Antidepressants can alleviate symptoms of depression and pain. Noradrenergic and serotonergic antidepressants appear to have efficacy for pain associated with neuropathy and fibromyalgia, while selective serotonin reuptake inhibitors and tricyclic antidepressants may have benefit for patients with irritable bowel syndrome. However, evidence regarding which patients will best respond to which specific antidepressant is limited.
Continue to: Related Resources
Related Resources
- Williams AM, Knox ED. When to prescribe antidepressants to treat comorbid depression and pain disorders. Current Psychiatry. 2017;16(1):55-58.
- Maletic V, Demuri B. Chronic pain and depression: treatment of 2 culprits in common. Current Psychiatry. 2016;15(3):41,47-50,52.
Drug Brand Names
Amitriptyline • Elavil, Endep
Bupropion • Wellbutrin, Zyban
Carisoprodol • Rela, Soma
Cyclobenzaprine • Amrix, Flexeril
Desipramine • Norpramin
Desvenlafaxine • Pristiq
Duloxetine • Cymbalta
Fluoxetine • Prozac
Gabapentin • Horizant, Neurontin
Imipramine • Tofranil
Levomilnacipran • Fetzima
Methadone • Dolophine, Methadose
Milnacipran • Savella
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Pregabalin • Lyrica, Lyrica CR
Tapentadol • Nucynta
Tramadol • Ultram
Trazodone • Desyrel, Oleptro
Venlafaxine • Effexor
Warfarin • Coumadin, Jantoven
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50. Hearn L, Moore RA, Derry S, et al. Desipramine for neuropathic pain in adults. Cochrane Database Syst Rev. 2014;(9):CD011003.
51. Hearn L, Derry S, Phillips T, et al. Imipramine for neuropathic pain in adults. Cochrane Database Syst Rev. 2014;(5):CD010769.
52. Derry S, Wiffen PJ, Aldington D, et al. Nortriptyline for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;1:CD011209.
53. Moore R, Derry S, Aldington D, et al. Amitriptyline for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;(7):CD008242.
54. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev. 2014;(1):CD007115.
55. Gallagher HC, Gallagher RM, Butler M, et al. Venlafaxine for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;(8):CD011091.
56. Alviar MJ, Hale T, Dungca M. Pharmacologic interventions for treating phantom limb pain. Cochrane Database Syst Rev. 2016;10:CD006380.
57. Dinat N, Marinda E, Moch S, et al. Randomized, Double-Blind, Crossover Trial of Amitriptyline for Analgesia in Painful HIV-Associated Sensory Neuropathy. PLoS One. 2015;10(5):e0126297. doi: 10.1371/journal.pone.0126297.eCollection 2015.
58. Mehta S, McIntyre A, Janzen S, et al; Spinal Cord Injury Rehabilitation Evidence Team. Systematic review of pharmacologic treatments of pain after spinal cord injury: an update. Arch Phys Med Rehabil. 2016;97(8):1381-1391.e1.
59. Moore RA, Derry S, Aldington D, et al. Amitriptyline for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2012;(12):CD008242..
60. Walitt B, Urrútia G, Nishishinya MB, et al. Selective serotonin reuptake inhibitors for fibromyalgia syndrome. Cochrane Database Syst Rev. 2015;(6):CD011735.
61. Welsch P, Üçeyler N, Klose P, et al. Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia. Cochrane Database Syst Rev. 2018;(2):CD010292.
62. VanderWeide LA, Smith SM, Trinkley KE. A systematic review of the efficacy of venlafaxine for the treatment of fibromyalgia. J Clin Pharm Ther. 2015;40(1):1-6.
63. Welsch P, Bernardy K, Derry S, et al. Mirtazapine for fibromyalgia in adults. Cochrane Database Syst Rev. 2018;(8):CD012708.
64. Lance JW, Curran DA. Treatment of chronic tension headache. Lancet. 1964;283(7345):1236-1239.
65. Jackson JL, William S, Laura S, et al. Tricyclic antidepressants and headaches: systematic review and meta-analysis. BMJ. 2010;341:c5222. doi: https://doi.org/10.1136/bmj.c5222
66. Xu XM, Liu Y, Dong MX, et al. Tricyclic antidepressants for preventing migraine in adults. Medicine. 2017;96(22):e6989. doi: 10.1097/MD.0000000000006989.
67. Banzi R, Cusi C, Randazzo C, et al. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the prevention of migraine in adults. Cochrane Database Syst Rev. 2015;(4):CD002919.
68. Banzi R, Cusi C, Randazzo C, et al. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the prevention of tension-type headache in adults. Cochrane Database Syst Rev. 2015;(5):CD011681.
69. Quartero AO, Meineche-Schmidt V, Muris J, et al. Bulking agents, antispasmodic and antidepressant medication for the treatment of irritable bowel syndrome. Cochrane Database Syst Rev. 2005;(2):CD003460.
70. Ford AC, Talley NJ, Schoenfeld PS, et al. Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut. 2009;58(3):367-378.
71. Coss-Adame E, Erdogan A, Rao SS. Treatment of esophageal (noncardiac) chest pain: an expert review. Clin Gastroenterol Hepatol. 2014;12(8):1224-1245.
72. Kelada E, Jones A. Interstitial cystitis. Arch Gynecol Obstet. 2007;275(4):223-229.
73. Leo RJ, Dewani S. A systematic review of the utility of antidepressant pharmacotherapy in the treatment of vulvodynia pain. J Sex Med. 2013;10(10):2497-2505.
74. McMillan R, Forssell H, Buchanan JA, et al. Interventions for treating burning mouth syndrome. Cochrane Database Syst Rev. 2016;11:CD002779.
75. Patel DN. Inconclusive results of a systematic review of efficacy of antidepressants on orofacial pain disorders. Evid Based Dent. 2013;14(2):55-56.
76. Wang W, Sun YH, Wang YY, et al. Treatment of functional chest pain with antidepressants: a meta-analysis. Pain Physician. 2012;15(2):E131-E142.
77. Lavis JN. How can we support the use of systematic reviews in policymaking? PLoS Med. 2009;6(11):e1000141. doi: 10.1371/journal.pmed.1000141.
78. Sorkin L. Nociceptive transmission within the spinal cord. Mt Sinai J Med. 1991;58(3):208-216.
79. Yokogawa F, Kiuchi Y, Ishikawa Y, et al. An investigation of monoamine receptors involved in antinociceptive effects of antidepressants. Anesth Analg. 2002;95(1):163-168, table of contents.
80. Lynch ME. Antidepressants as analgesics: a review of randomized controlled trials. J Psychiatry Neurosci. 2001;26(1):30-36.
81. Max MB. Treatment of post-herpetic neuralgia: antidepressants. Ann Neurol. 1994;35(suppl):S50-S53.
82. Max MB, Lynch SA, Muir J, et al. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med. 1992;326(19):1250-1256.
83. McQuay HJ, Tramèr M, Nye BA, et al. A systematic review of antidepressants in neuropathic pain. Pain. 1996;68(2-3):217-227.
84. Mochizucki D. Serotonin and noradrenaline reuptake inhibitors in animal models of pain. Hum Psychopharmacol Clin Exp. 2004;19(suppl 1):15-19.
85. Sussman N. SNRIs versus SSRIs: mechanisms of action in treating depression and painful physical symptoms. Primary Care Companion J Clin Psychiatry. 2003;5(suppl 7):19-26.
86. Bundeff AW, Woodis CB. Selective serotonin reuptake inhibitors for the treatment of irritable bowel syndrome. Ann Pharmacother. 2014;48(6):777-784.
87. Jung AC, Staiger T, Sullivan M. The efficacy of selective serotonin reuptake inhibitors for the management of chronic pain. J Gen Intern Med. 1997;12(6):384-389.
88. Xie C, Tang Y, Wang Y, et al. Efficacy and safety of antidepressants for the treatment of irritable bowel syndrome: a meta-analysis. PLoS One. 2015;10(8):e0127815. doi: 10.1371/journal.pone.0127815. eCollection 2015.
89. Zijlstra TR , Barendregt PJ , van de Laar MA. Venlafaxine in fibromyalgia: results of a randomized, placebo-controlled, double-blind trial. Arthritis Rheum. 2002;46(suppl 9):S105.
90. Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology. 2001;25(6):871-880.
91. Thorpe J, Shum B, Moore RA, et al. Combination pharmacotherapy for the treatment of fibromyalgia in adults. Cochrane Database Syst Rev. 2018;(2):CD010585.
92. Gilron I, Chaparro LE, Tu D, et al. Combination of pregabalin with duloxetine for fibromyalgia: a randomized controlled trial. Pain. 2016;157(7):1532-1540.
93. Häuser W, Petzke F, Üçeyler N, et al. Comparative efficacy and acceptability of amitriptyline, duloxetine and milnacipran in fibromyalgia syndrome: a systematic review with meta-analysis. Rheumatology (Oxford). 2011;50(3):532-543.
94. Hossain SM, Hussain SM, Ekram AR. Duloxetine in painful diabetic neuropathy: a systematic review. Clin J Pain. 2016;32(11):1005-1010.
95. Riediger C, Schuster T, Barlinn K, et al. Adverse effects of antidepressants for chronic pain: a systematic review and meta-analysis. Front Neurol. 2017;8:307.
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51. Hearn L, Derry S, Phillips T, et al. Imipramine for neuropathic pain in adults. Cochrane Database Syst Rev. 2014;(5):CD010769.
52. Derry S, Wiffen PJ, Aldington D, et al. Nortriptyline for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;1:CD011209.
53. Moore R, Derry S, Aldington D, et al. Amitriptyline for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;(7):CD008242.
54. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev. 2014;(1):CD007115.
55. Gallagher HC, Gallagher RM, Butler M, et al. Venlafaxine for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;(8):CD011091.
56. Alviar MJ, Hale T, Dungca M. Pharmacologic interventions for treating phantom limb pain. Cochrane Database Syst Rev. 2016;10:CD006380.
57. Dinat N, Marinda E, Moch S, et al. Randomized, Double-Blind, Crossover Trial of Amitriptyline for Analgesia in Painful HIV-Associated Sensory Neuropathy. PLoS One. 2015;10(5):e0126297. doi: 10.1371/journal.pone.0126297.eCollection 2015.
58. Mehta S, McIntyre A, Janzen S, et al; Spinal Cord Injury Rehabilitation Evidence Team. Systematic review of pharmacologic treatments of pain after spinal cord injury: an update. Arch Phys Med Rehabil. 2016;97(8):1381-1391.e1.
59. Moore RA, Derry S, Aldington D, et al. Amitriptyline for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2012;(12):CD008242..
60. Walitt B, Urrútia G, Nishishinya MB, et al. Selective serotonin reuptake inhibitors for fibromyalgia syndrome. Cochrane Database Syst Rev. 2015;(6):CD011735.
61. Welsch P, Üçeyler N, Klose P, et al. Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia. Cochrane Database Syst Rev. 2018;(2):CD010292.
62. VanderWeide LA, Smith SM, Trinkley KE. A systematic review of the efficacy of venlafaxine for the treatment of fibromyalgia. J Clin Pharm Ther. 2015;40(1):1-6.
63. Welsch P, Bernardy K, Derry S, et al. Mirtazapine for fibromyalgia in adults. Cochrane Database Syst Rev. 2018;(8):CD012708.
64. Lance JW, Curran DA. Treatment of chronic tension headache. Lancet. 1964;283(7345):1236-1239.
65. Jackson JL, William S, Laura S, et al. Tricyclic antidepressants and headaches: systematic review and meta-analysis. BMJ. 2010;341:c5222. doi: https://doi.org/10.1136/bmj.c5222
66. Xu XM, Liu Y, Dong MX, et al. Tricyclic antidepressants for preventing migraine in adults. Medicine. 2017;96(22):e6989. doi: 10.1097/MD.0000000000006989.
67. Banzi R, Cusi C, Randazzo C, et al. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the prevention of migraine in adults. Cochrane Database Syst Rev. 2015;(4):CD002919.
68. Banzi R, Cusi C, Randazzo C, et al. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the prevention of tension-type headache in adults. Cochrane Database Syst Rev. 2015;(5):CD011681.
69. Quartero AO, Meineche-Schmidt V, Muris J, et al. Bulking agents, antispasmodic and antidepressant medication for the treatment of irritable bowel syndrome. Cochrane Database Syst Rev. 2005;(2):CD003460.
70. Ford AC, Talley NJ, Schoenfeld PS, et al. Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut. 2009;58(3):367-378.
71. Coss-Adame E, Erdogan A, Rao SS. Treatment of esophageal (noncardiac) chest pain: an expert review. Clin Gastroenterol Hepatol. 2014;12(8):1224-1245.
72. Kelada E, Jones A. Interstitial cystitis. Arch Gynecol Obstet. 2007;275(4):223-229.
73. Leo RJ, Dewani S. A systematic review of the utility of antidepressant pharmacotherapy in the treatment of vulvodynia pain. J Sex Med. 2013;10(10):2497-2505.
74. McMillan R, Forssell H, Buchanan JA, et al. Interventions for treating burning mouth syndrome. Cochrane Database Syst Rev. 2016;11:CD002779.
75. Patel DN. Inconclusive results of a systematic review of efficacy of antidepressants on orofacial pain disorders. Evid Based Dent. 2013;14(2):55-56.
76. Wang W, Sun YH, Wang YY, et al. Treatment of functional chest pain with antidepressants: a meta-analysis. Pain Physician. 2012;15(2):E131-E142.
77. Lavis JN. How can we support the use of systematic reviews in policymaking? PLoS Med. 2009;6(11):e1000141. doi: 10.1371/journal.pmed.1000141.
78. Sorkin L. Nociceptive transmission within the spinal cord. Mt Sinai J Med. 1991;58(3):208-216.
79. Yokogawa F, Kiuchi Y, Ishikawa Y, et al. An investigation of monoamine receptors involved in antinociceptive effects of antidepressants. Anesth Analg. 2002;95(1):163-168, table of contents.
80. Lynch ME. Antidepressants as analgesics: a review of randomized controlled trials. J Psychiatry Neurosci. 2001;26(1):30-36.
81. Max MB. Treatment of post-herpetic neuralgia: antidepressants. Ann Neurol. 1994;35(suppl):S50-S53.
82. Max MB, Lynch SA, Muir J, et al. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med. 1992;326(19):1250-1256.
83. McQuay HJ, Tramèr M, Nye BA, et al. A systematic review of antidepressants in neuropathic pain. Pain. 1996;68(2-3):217-227.
84. Mochizucki D. Serotonin and noradrenaline reuptake inhibitors in animal models of pain. Hum Psychopharmacol Clin Exp. 2004;19(suppl 1):15-19.
85. Sussman N. SNRIs versus SSRIs: mechanisms of action in treating depression and painful physical symptoms. Primary Care Companion J Clin Psychiatry. 2003;5(suppl 7):19-26.
86. Bundeff AW, Woodis CB. Selective serotonin reuptake inhibitors for the treatment of irritable bowel syndrome. Ann Pharmacother. 2014;48(6):777-784.
87. Jung AC, Staiger T, Sullivan M. The efficacy of selective serotonin reuptake inhibitors for the management of chronic pain. J Gen Intern Med. 1997;12(6):384-389.
88. Xie C, Tang Y, Wang Y, et al. Efficacy and safety of antidepressants for the treatment of irritable bowel syndrome: a meta-analysis. PLoS One. 2015;10(8):e0127815. doi: 10.1371/journal.pone.0127815. eCollection 2015.
89. Zijlstra TR , Barendregt PJ , van de Laar MA. Venlafaxine in fibromyalgia: results of a randomized, placebo-controlled, double-blind trial. Arthritis Rheum. 2002;46(suppl 9):S105.
90. Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG. Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors. Neuropsychopharmacology. 2001;25(6):871-880.
91. Thorpe J, Shum B, Moore RA, et al. Combination pharmacotherapy for the treatment of fibromyalgia in adults. Cochrane Database Syst Rev. 2018;(2):CD010585.
92. Gilron I, Chaparro LE, Tu D, et al. Combination of pregabalin with duloxetine for fibromyalgia: a randomized controlled trial. Pain. 2016;157(7):1532-1540.
93. Häuser W, Petzke F, Üçeyler N, et al. Comparative efficacy and acceptability of amitriptyline, duloxetine and milnacipran in fibromyalgia syndrome: a systematic review with meta-analysis. Rheumatology (Oxford). 2011;50(3):532-543.
94. Hossain SM, Hussain SM, Ekram AR. Duloxetine in painful diabetic neuropathy: a systematic review. Clin J Pain. 2016;32(11):1005-1010.
95. Riediger C, Schuster T, Barlinn K, et al. Adverse effects of antidepressants for chronic pain: a systematic review and meta-analysis. Front Neurol. 2017;8:307.
