Neurology

Many Americans who are treated with prescription opioid analgesics would be better off with less opioid or none at all. To that end, published opioid prescribing guidelines do provide guidance on the mechanics of tapering patients off opioids^1-4—but they have a major flaw: They do not adequately account for the fact that people who have a diagnosis of chronic pain are a heterogeneous group and require diagnosis-specific treatment planning. A patient-centered approach to opioid tapers must account for the reality that many people who are given a prescription for an opioid to treat pain have significant mental health conditions—for which opioids act as a psychotropic agent. An opioid taper must therefore address psychological trauma, in particular.⁵ (See “Tapering and harm-reduction strategies have failed.”^6-14)

In this article, we present an evidence-based consensus approach to opioid tapering for your practice that is informed by a broader understanding of why patients take prescription opioids and why they, occasionally, switch to illicit drugs when their prescription is tapered. This consensus approach is based on the experience of the authors, members of the pain faculty of Project ECHO (Extension for Community Healthcare Outcomes) of the ECHO Institute, a worldwide initiative that uses adult learning techniques and interactive video technology to connect community providers with specialists at centers of excellence in regular real-time collaborative sessions. We are variously experts in pain medicine, primary care, psychology, addiction medicine, pharmacy, behavioral health therapy, occupational medicine, and Chinese medicine.

Why Americans obtain prescription opioids

There are 4 principal reasons why patients obtain prescription opioids, beyond indicated analgesic uses:

1. Patients seek the antianxiety and antidepressant effects of opioids. Multiple converging lines of evidence suggest that antianxiety and antidepressant effects of opioids are a significant reason that patients in the United States persist in requesting prescriptions for opioids:

• In our experience with more than 500 primary care telemedicine case presentations, at least 50% of patients say that the main effect of opioids prescribed for them is “it makes me feel calm” or “more relaxed.”
• In a 2007 survey of 91,823 US residents older than 18 years, nonmedical use of opioids was statistically associated with panic, social anxiety, and depressive symptoms.¹⁵
• Ten years later, Von Korff and colleagues found that more than half of opioid prescriptions written in the United States were for the small percentage of patients who have a diagnosis of serious anxiety or depression.¹³
• In 2016, Yovell and colleagues reported that ultra-low-dosage buprenorphine markedly reduced suicidal ideation over 4 weeks in 62 patients with varied levels of depression.¹⁶

There is also mechanistic evidence that the antianxiety and antidepressant effects of opioids are significant reasons Americans persist in requesting prescription opioids. The literature suggests that opioid receptors play a role in mood regulation, including alleviation of depression and anxiety; recent research suggests that oxycodone might be a unique mood-altering drug compared to other common prescription opioids because of its ability to affect mood through the δ opioid receptor.^17-20

It should not be a surprise that Americans often turn to opioids to address posttraumatic stress disorder (PTSD), anxiety, and depression. A recent study of the state of the US mental health system concluded that mental health services in the United States are inadequate—despite evidence that > 50% of Americans seek, or consider seeking, treatment for mental health problems for themselves or others.²¹

2. Patients experience pain unrelated to tissue damage. Rather, they are in pain “for psychological reasons.”²² In 2016, Davis and Vanderah wrote: “We theorize that a functional change in the [central nervous system] can occur in response to certain emotional states or traumatic experiences (eg, child abuse, assault, accidents).” They connect this change to central sensitization and a reduced pain-perception threshold,²³ and strongly suspect that many patients with chronic pain have undiagnosed and untreated psychological trauma that has changed the way their central nervous system processes sensory stimuli. The authors call this “trauma-induced hyperalgesia.”

Continue to: Psychological trauma...

Psychological trauma is uniquely capable of producing hyperalgesia, compared to anxiety or depression. In a study of veterans, Defrin and colleagues demonstrated hyperalgesia in patients who had a diagnosis of PTSD but not in controls group who had an anxiety disorder only.²⁴

High-dosage prescribing of opioids has fallen by 48% since 2011, yet the decline has not reduced overdose events of any kind.

To support successful opioid tapering, trauma-induced hyperalgesia, when present, must be addressed. Treatment of what the International Association for the Study of Pain calls “pain due to psychological factors”²² requires specific trauma therapy. However, our experience validates what researchers have to say about access to treatment of psychological trauma in the United States: “…[C]linical research has identified certain psychological interventions that effectively ameliorate the symptoms of PTSD. But most people struggling with PTSD don’t receive those treatments.”²⁵

We have no doubt that this is due, in part, to underdiagnosis of psychological trauma, even in mental health clinics. According to Miele and colleagues, “PTSD remains largely undiagnosed and undertreated in mental health outpatients, even in teaching hospitals, with diagnosis rates as low as 4% while published prevalence is between 7% and 50% in this population.”²⁶

3. Patients suffer from opioid use disorder (OUD) and complain of pain to obtain opioids by prescription. For patients with OUD, their use is out of control; they devote increasing mental and physical resources to obtaining, using, and recovering from substances; and they continue to use despite adverse consequences.²⁷ The prevalence of OUD in primary care clinics varies strikingly by the location of clinics. In Washington state, the prevalence of moderate and severe OUD in a large population of patients who had been prescribed opioids through primary care clinics was recently determined to be between 21.5% and 23.9%.¹³

4. Patients are obtaining opioid prescriptions for people other than themselves. While this is a reason that patients obtain opioid prescriptions, it is not necessarily common. Statistics show that the likelihood of a prescription being diverted intentionally is low: Dart and colleagues found that diversion has become uncommon in the general population.²⁸

Continue to: Why we taper opioid analgesics

 

 

Why we taper opioid analgesics

Reasons for an opioid taper include concern that the patient has, or will develop, an OUD; will experience accidental or intentional overdose; might be diverting opioids; is not benefiting from opioid therapy for pain; or is experiencing severe adverse effects. A patient who has nociceptive pain and might have ­opioid-induced hyperalgesia will require a much different opioid taper plan than a patient with untreated PTSD or a patient with severe OUD.

Misunderstanding can lead to inappropriate tapering

We often encounter primary care providers who believe that a large percentage of patients on chronic opioid therapy inevitably develop OUD. This is a common reason for initiating opioid taper. Most patients on a chronic opioid do become physically dependent, but only a small percentage of patients develop psychological dependence (ie, ­addiction or OUD).²⁹

Physical dependence is “a state of adaptation that is manifested by a drug class–­specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.”³⁰ Symptoms of opioid withdrawal include muscle aches; abdominal cramping; increased lacrimation, rhinorrhea, and perspiration; diarrhea; agitation and anxiety; insomnia; and piloerection. Opioid withdrawal symptoms are caused by physical dependence, not by addiction. They can be mitigated by tapering slowly and instituting adjuvant medications, such as clonidine, to attenuate symptoms.

Psychological dependence, or addiction (that is, OUD, as described in the Diagnostic and Statistical Manual of Mental Disorders 5th edition²⁷), comprises primarily 3 behavioral criteria:

• Loss of control of the medication, with compulsive use
• Continued use despite adverse consequences of using opioids, such as arrest for driving under the influence and deterioration of social, family, or work performance
• Obsession or preoccupation with obtaining and using the substance. In properly selected chronic opioid therapy patients, there is evidence that new-onset OUD is not as common as has been thought. A recent study of the risk for opioid addiction after use of an opioid for ≥ 90 days for chronic noncancer pain found that the absolute rate of de novo OUD among patients treated for 90 days was 0.72%.²⁹ A systematic review by Fishbain and colleagues of 24 studies of opioid-exposed patients found a risk of 3.27% overall—0.19% for patients who did not have a history of abuse or addiction.³¹ As Director of the National Institute on Drug Abuse Norma Volkow, MD, wrote in 2016: “Addiction occurs in only a small percentage of people who are exposed to opioids—even among those with preexisting vulnerabilities.”³²

Assessment should focus on why the patient is taking an opioid

A strong case can be made that less opioid is better for many of the people for whom these medications are prescribed for chronic noncancer pain. However, a one-size-fits-all dosage reduction and addiction-focused ­approach to opioid tapering has not worked: The assessment and treatment paradigm must change, in our view.

Continue to: During assessment...

During assessment, we must adopt the means to identify the reason that a patient is using a prescription opioid. It is of particular importance that we identify patients using opioids for their psychotropic properties, particularly when the goal is to cope with the effects of psychological trauma. The subsequent treatment protocol will then need to include time for effective, evidence-based behavioral health treatment of anxiety, PTSD, or depression. If opioids are serving primarily as psychotropic medication, an attempt to taper before establishing effective behavioral health treatment might lead the patient to pursue illegal means of procuring opioid medication.

Antianxiety and antidepressant effects of opioids are a significant reason that patients persist in requesting prescriptions.

We acknowledge that primary care physicians are not reimbursed for trauma screening and that evidence-based intensive trauma treatment is generally unavailable in the United States. Both of these shortcomings must be corrected if we want to stem the opioid crisis.

If diversion is suspected and there is evidence that the patient is not currently taking prescribed opioids (eg, a negative urine drug screen), discontinuing the opioid prescription is the immediate next step for the sake of public safety.

Considering a taper? Take this 5-step approach

Once it appears that tapering an opioid is indicated, we propose that you take the following steps:

• Establish whether it is safe to continue prescribing (follow the route provided in “2 decisions to make before continuing to prescribe an opioid for chronic noncancer pain”); if continuing it is not safe, take steps to protect the patient and the community
• Determine whether assessment by a trauma-informed behavioral health expert is needed, assuming that, in your judgment, it is safe to continue the opioid (TABLE³³). When behavioral health assessment is needed, you need 3 questions answered by that assessment: (1) Are psychological factors present that might put the patient at risk during an opioid taper? (2) What are those factors? (3) What needs to done about them before the taper is started? Recalling that psychological trauma often is not assessed by behavioral health colleagues, it is necessary to provide the behavioral health provider with a specific request to assess trauma burden, and state the physical diagnoses that are causing pain or provide a clear statement that no such diagnoses can be made. (See the FIGURE, which we developed in conjunction with behavioral health colleagues to help the consultant understand what the primary care physician needs from a behavioral health assessment.)
• Obtain consultation from a physical therapist, pain medicine specialist, and, if possible, an alternative or complementary medicine provider to determine what nonpharmacotherapeutic modalities can be instituted to treat pain before tapering the opioid.
• Initiate the Screening, Brief Intervention and Referral to Treatment (SBIRT) approach if OUD is suspected (www.samhsa.gov/sbirt).³⁴ This motivational interviewing tool identifies patients with a substance use disorder, severity of use, and appropriate level of treatment. (If OUD is suspected during assessment, next steps are to stop prescribing and implement harm-reduction strategies, such as primary care level medically assisted treatment [MAT] with buprenorphine, followed by expert behavioral health-centered addiction treatment.)
• Experiment with dosage reduction according to published guidance, if (1) psychological factors are absent or have been adequately addressed, according to the behavioral health consultant, and (2) nonpharmacotherapeutic strategies are in place.^8-11

Shifting to a patient-centered approach

The timing and choice of opioid tapers, in relation to harm reduction and intervention targeting the root cause of a patient’s complaint of pain, have not been adequately explored. In our practice, we’ve shifted from an addiction-centered, dosage-centered approach to opioid taper to a patient-centered approach³⁵ that emphasizes behavioral-medical integration—an approach that we broadly endorse. Such an approach (1) is based on a clear understanding of why the patient is taking opioid pain medication, (2) engages medical and complementary or alternative medicine specialists, (3) addresses underdiagnosis of psychological trauma, and (4) requires a quantum leap in access to trauma-specific behavioral health treatment resources. ³⁶

Continue to: To underscore the case...

To underscore the case for shifting to a patient-centered approach³⁵ we present sample cases in “How a patient-centered approach to tapering opioids looks in practice.”

An eye toward the future. To inform future approaches to opioid tapering, more resources need to be deployed to

• support screening and risk stratification for PTSD, anxiety, and related disorders at the primary care level,
• continue the effort to identify and treat OUD,
• develop best-practice responses to screening, and
• make harm-reduction strategies that are now reserved for patients with OUD available to those who don't have OUD.

We urge that research be pursued into best practices for chronic pain interventions that target psychological trauma, anxiety, and depression.

CORRESPONDENCE
Bennet Davis MD, 2092 East Calle de Dulcinea, Tucson, AZ 85718; [email protected].

Many Americans who are treated with prescription opioid analgesics would be better off with less opioid or none at all. To that end, published opioid prescribing guidelines do provide guidance on the mechanics of tapering patients off opioids^1-4—but they have a major flaw: They do not adequately account for the fact that people who have a diagnosis of chronic pain are a heterogeneous group and require diagnosis-specific treatment planning. A patient-centered approach to opioid tapers must account for the reality that many people who are given a prescription for an opioid to treat pain have significant mental health conditions—for which opioids act as a psychotropic agent. An opioid taper must therefore address psychological trauma, in particular.⁵ (See “Tapering and harm-reduction strategies have failed.”^6-14)

In this article, we present an evidence-based consensus approach to opioid tapering for your practice that is informed by a broader understanding of why patients take prescription opioids and why they, occasionally, switch to illicit drugs when their prescription is tapered. This consensus approach is based on the experience of the authors, members of the pain faculty of Project ECHO (Extension for Community Healthcare Outcomes) of the ECHO Institute, a worldwide initiative that uses adult learning techniques and interactive video technology to connect community providers with specialists at centers of excellence in regular real-time collaborative sessions. We are variously experts in pain medicine, primary care, psychology, addiction medicine, pharmacy, behavioral health therapy, occupational medicine, and Chinese medicine.

Why Americans obtain prescription opioids

There are 4 principal reasons why patients obtain prescription opioids, beyond indicated analgesic uses:

1. Patients seek the antianxiety and antidepressant effects of opioids. Multiple converging lines of evidence suggest that antianxiety and antidepressant effects of opioids are a significant reason that patients in the United States persist in requesting prescriptions for opioids:

• In our experience with more than 500 primary care telemedicine case presentations, at least 50% of patients say that the main effect of opioids prescribed for them is “it makes me feel calm” or “more relaxed.”
• In a 2007 survey of 91,823 US residents older than 18 years, nonmedical use of opioids was statistically associated with panic, social anxiety, and depressive symptoms.¹⁵
• Ten years later, Von Korff and colleagues found that more than half of opioid prescriptions written in the United States were for the small percentage of patients who have a diagnosis of serious anxiety or depression.¹³
• In 2016, Yovell and colleagues reported that ultra-low-dosage buprenorphine markedly reduced suicidal ideation over 4 weeks in 62 patients with varied levels of depression.¹⁶

There is also mechanistic evidence that the antianxiety and antidepressant effects of opioids are significant reasons Americans persist in requesting prescription opioids. The literature suggests that opioid receptors play a role in mood regulation, including alleviation of depression and anxiety; recent research suggests that oxycodone might be a unique mood-altering drug compared to other common prescription opioids because of its ability to affect mood through the δ opioid receptor.^17-20

It should not be a surprise that Americans often turn to opioids to address posttraumatic stress disorder (PTSD), anxiety, and depression. A recent study of the state of the US mental health system concluded that mental health services in the United States are inadequate—despite evidence that > 50% of Americans seek, or consider seeking, treatment for mental health problems for themselves or others.²¹

2. Patients experience pain unrelated to tissue damage. Rather, they are in pain “for psychological reasons.”²² In 2016, Davis and Vanderah wrote: “We theorize that a functional change in the [central nervous system] can occur in response to certain emotional states or traumatic experiences (eg, child abuse, assault, accidents).” They connect this change to central sensitization and a reduced pain-perception threshold,²³ and strongly suspect that many patients with chronic pain have undiagnosed and untreated psychological trauma that has changed the way their central nervous system processes sensory stimuli. The authors call this “trauma-induced hyperalgesia.”

Continue to: Psychological trauma...

Psychological trauma is uniquely capable of producing hyperalgesia, compared to anxiety or depression. In a study of veterans, Defrin and colleagues demonstrated hyperalgesia in patients who had a diagnosis of PTSD but not in controls group who had an anxiety disorder only.²⁴

High-dosage prescribing of opioids has fallen by 48% since 2011, yet the decline has not reduced overdose events of any kind.

To support successful opioid tapering, trauma-induced hyperalgesia, when present, must be addressed. Treatment of what the International Association for the Study of Pain calls “pain due to psychological factors”²² requires specific trauma therapy. However, our experience validates what researchers have to say about access to treatment of psychological trauma in the United States: “…[C]linical research has identified certain psychological interventions that effectively ameliorate the symptoms of PTSD. But most people struggling with PTSD don’t receive those treatments.”²⁵

We have no doubt that this is due, in part, to underdiagnosis of psychological trauma, even in mental health clinics. According to Miele and colleagues, “PTSD remains largely undiagnosed and undertreated in mental health outpatients, even in teaching hospitals, with diagnosis rates as low as 4% while published prevalence is between 7% and 50% in this population.”²⁶

3. Patients suffer from opioid use disorder (OUD) and complain of pain to obtain opioids by prescription. For patients with OUD, their use is out of control; they devote increasing mental and physical resources to obtaining, using, and recovering from substances; and they continue to use despite adverse consequences.²⁷ The prevalence of OUD in primary care clinics varies strikingly by the location of clinics. In Washington state, the prevalence of moderate and severe OUD in a large population of patients who had been prescribed opioids through primary care clinics was recently determined to be between 21.5% and 23.9%.¹³

4. Patients are obtaining opioid prescriptions for people other than themselves. While this is a reason that patients obtain opioid prescriptions, it is not necessarily common. Statistics show that the likelihood of a prescription being diverted intentionally is low: Dart and colleagues found that diversion has become uncommon in the general population.²⁸

Continue to: Why we taper opioid analgesics

 

 

Why we taper opioid analgesics

Reasons for an opioid taper include concern that the patient has, or will develop, an OUD; will experience accidental or intentional overdose; might be diverting opioids; is not benefiting from opioid therapy for pain; or is experiencing severe adverse effects. A patient who has nociceptive pain and might have ­opioid-induced hyperalgesia will require a much different opioid taper plan than a patient with untreated PTSD or a patient with severe OUD.

Misunderstanding can lead to inappropriate tapering

We often encounter primary care providers who believe that a large percentage of patients on chronic opioid therapy inevitably develop OUD. This is a common reason for initiating opioid taper. Most patients on a chronic opioid do become physically dependent, but only a small percentage of patients develop psychological dependence (ie, ­addiction or OUD).²⁹

Physical dependence is “a state of adaptation that is manifested by a drug class–­specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.”³⁰ Symptoms of opioid withdrawal include muscle aches; abdominal cramping; increased lacrimation, rhinorrhea, and perspiration; diarrhea; agitation and anxiety; insomnia; and piloerection. Opioid withdrawal symptoms are caused by physical dependence, not by addiction. They can be mitigated by tapering slowly and instituting adjuvant medications, such as clonidine, to attenuate symptoms.

Psychological dependence, or addiction (that is, OUD, as described in the Diagnostic and Statistical Manual of Mental Disorders 5th edition²⁷), comprises primarily 3 behavioral criteria:

• Loss of control of the medication, with compulsive use
• Continued use despite adverse consequences of using opioids, such as arrest for driving under the influence and deterioration of social, family, or work performance
• Obsession or preoccupation with obtaining and using the substance. In properly selected chronic opioid therapy patients, there is evidence that new-onset OUD is not as common as has been thought. A recent study of the risk for opioid addiction after use of an opioid for ≥ 90 days for chronic noncancer pain found that the absolute rate of de novo OUD among patients treated for 90 days was 0.72%.²⁹ A systematic review by Fishbain and colleagues of 24 studies of opioid-exposed patients found a risk of 3.27% overall—0.19% for patients who did not have a history of abuse or addiction.³¹ As Director of the National Institute on Drug Abuse Norma Volkow, MD, wrote in 2016: “Addiction occurs in only a small percentage of people who are exposed to opioids—even among those with preexisting vulnerabilities.”³²

Assessment should focus on why the patient is taking an opioid

A strong case can be made that less opioid is better for many of the people for whom these medications are prescribed for chronic noncancer pain. However, a one-size-fits-all dosage reduction and addiction-focused ­approach to opioid tapering has not worked: The assessment and treatment paradigm must change, in our view.

Continue to: During assessment...

During assessment, we must adopt the means to identify the reason that a patient is using a prescription opioid. It is of particular importance that we identify patients using opioids for their psychotropic properties, particularly when the goal is to cope with the effects of psychological trauma. The subsequent treatment protocol will then need to include time for effective, evidence-based behavioral health treatment of anxiety, PTSD, or depression. If opioids are serving primarily as psychotropic medication, an attempt to taper before establishing effective behavioral health treatment might lead the patient to pursue illegal means of procuring opioid medication.

Antianxiety and antidepressant effects of opioids are a significant reason that patients persist in requesting prescriptions.

We acknowledge that primary care physicians are not reimbursed for trauma screening and that evidence-based intensive trauma treatment is generally unavailable in the United States. Both of these shortcomings must be corrected if we want to stem the opioid crisis.

If diversion is suspected and there is evidence that the patient is not currently taking prescribed opioids (eg, a negative urine drug screen), discontinuing the opioid prescription is the immediate next step for the sake of public safety.

Considering a taper? Take this 5-step approach

Once it appears that tapering an opioid is indicated, we propose that you take the following steps:

• Establish whether it is safe to continue prescribing (follow the route provided in “2 decisions to make before continuing to prescribe an opioid for chronic noncancer pain”); if continuing it is not safe, take steps to protect the patient and the community
• Determine whether assessment by a trauma-informed behavioral health expert is needed, assuming that, in your judgment, it is safe to continue the opioid (TABLE³³). When behavioral health assessment is needed, you need 3 questions answered by that assessment: (1) Are psychological factors present that might put the patient at risk during an opioid taper? (2) What are those factors? (3) What needs to done about them before the taper is started? Recalling that psychological trauma often is not assessed by behavioral health colleagues, it is necessary to provide the behavioral health provider with a specific request to assess trauma burden, and state the physical diagnoses that are causing pain or provide a clear statement that no such diagnoses can be made. (See the FIGURE, which we developed in conjunction with behavioral health colleagues to help the consultant understand what the primary care physician needs from a behavioral health assessment.)
• Obtain consultation from a physical therapist, pain medicine specialist, and, if possible, an alternative or complementary medicine provider to determine what nonpharmacotherapeutic modalities can be instituted to treat pain before tapering the opioid.
• Initiate the Screening, Brief Intervention and Referral to Treatment (SBIRT) approach if OUD is suspected (www.samhsa.gov/sbirt).³⁴ This motivational interviewing tool identifies patients with a substance use disorder, severity of use, and appropriate level of treatment. (If OUD is suspected during assessment, next steps are to stop prescribing and implement harm-reduction strategies, such as primary care level medically assisted treatment [MAT] with buprenorphine, followed by expert behavioral health-centered addiction treatment.)
• Experiment with dosage reduction according to published guidance, if (1) psychological factors are absent or have been adequately addressed, according to the behavioral health consultant, and (2) nonpharmacotherapeutic strategies are in place.^8-11

Shifting to a patient-centered approach

The timing and choice of opioid tapers, in relation to harm reduction and intervention targeting the root cause of a patient’s complaint of pain, have not been adequately explored. In our practice, we’ve shifted from an addiction-centered, dosage-centered approach to opioid taper to a patient-centered approach³⁵ that emphasizes behavioral-medical integration—an approach that we broadly endorse. Such an approach (1) is based on a clear understanding of why the patient is taking opioid pain medication, (2) engages medical and complementary or alternative medicine specialists, (3) addresses underdiagnosis of psychological trauma, and (4) requires a quantum leap in access to trauma-specific behavioral health treatment resources. ³⁶

Continue to: To underscore the case...

To underscore the case for shifting to a patient-centered approach³⁵ we present sample cases in “How a patient-centered approach to tapering opioids looks in practice.”

An eye toward the future. To inform future approaches to opioid tapering, more resources need to be deployed to

• support screening and risk stratification for PTSD, anxiety, and related disorders at the primary care level,
• continue the effort to identify and treat OUD,
• develop best-practice responses to screening, and
• make harm-reduction strategies that are now reserved for patients with OUD available to those who don't have OUD.

We urge that research be pursued into best practices for chronic pain interventions that target psychological trauma, anxiety, and depression.

CORRESPONDENCE
Bennet Davis MD, 2092 East Calle de Dulcinea, Tucson, AZ 85718; [email protected].

Many Americans who are treated with prescription opioid analgesics would be better off with less opioid or none at all. To that end, published opioid prescribing guidelines do provide guidance on the mechanics of tapering patients off opioids^1-4—but they have a major flaw: They do not adequately account for the fact that people who have a diagnosis of chronic pain are a heterogeneous group and require diagnosis-specific treatment planning. A patient-centered approach to opioid tapers must account for the reality that many people who are given a prescription for an opioid to treat pain have significant mental health conditions—for which opioids act as a psychotropic agent. An opioid taper must therefore address psychological trauma, in particular.⁵ (See “Tapering and harm-reduction strategies have failed.”^6-14)

In this article, we present an evidence-based consensus approach to opioid tapering for your practice that is informed by a broader understanding of why patients take prescription opioids and why they, occasionally, switch to illicit drugs when their prescription is tapered. This consensus approach is based on the experience of the authors, members of the pain faculty of Project ECHO (Extension for Community Healthcare Outcomes) of the ECHO Institute, a worldwide initiative that uses adult learning techniques and interactive video technology to connect community providers with specialists at centers of excellence in regular real-time collaborative sessions. We are variously experts in pain medicine, primary care, psychology, addiction medicine, pharmacy, behavioral health therapy, occupational medicine, and Chinese medicine.

Why Americans obtain prescription opioids

There are 4 principal reasons why patients obtain prescription opioids, beyond indicated analgesic uses:

1. Patients seek the antianxiety and antidepressant effects of opioids. Multiple converging lines of evidence suggest that antianxiety and antidepressant effects of opioids are a significant reason that patients in the United States persist in requesting prescriptions for opioids:

• In our experience with more than 500 primary care telemedicine case presentations, at least 50% of patients say that the main effect of opioids prescribed for them is “it makes me feel calm” or “more relaxed.”
• In a 2007 survey of 91,823 US residents older than 18 years, nonmedical use of opioids was statistically associated with panic, social anxiety, and depressive symptoms.¹⁵
• Ten years later, Von Korff and colleagues found that more than half of opioid prescriptions written in the United States were for the small percentage of patients who have a diagnosis of serious anxiety or depression.¹³
• In 2016, Yovell and colleagues reported that ultra-low-dosage buprenorphine markedly reduced suicidal ideation over 4 weeks in 62 patients with varied levels of depression.¹⁶

There is also mechanistic evidence that the antianxiety and antidepressant effects of opioids are significant reasons Americans persist in requesting prescription opioids. The literature suggests that opioid receptors play a role in mood regulation, including alleviation of depression and anxiety; recent research suggests that oxycodone might be a unique mood-altering drug compared to other common prescription opioids because of its ability to affect mood through the δ opioid receptor.^17-20

It should not be a surprise that Americans often turn to opioids to address posttraumatic stress disorder (PTSD), anxiety, and depression. A recent study of the state of the US mental health system concluded that mental health services in the United States are inadequate—despite evidence that > 50% of Americans seek, or consider seeking, treatment for mental health problems for themselves or others.²¹

2. Patients experience pain unrelated to tissue damage. Rather, they are in pain “for psychological reasons.”²² In 2016, Davis and Vanderah wrote: “We theorize that a functional change in the [central nervous system] can occur in response to certain emotional states or traumatic experiences (eg, child abuse, assault, accidents).” They connect this change to central sensitization and a reduced pain-perception threshold,²³ and strongly suspect that many patients with chronic pain have undiagnosed and untreated psychological trauma that has changed the way their central nervous system processes sensory stimuli. The authors call this “trauma-induced hyperalgesia.”

Continue to: Psychological trauma...

Psychological trauma is uniquely capable of producing hyperalgesia, compared to anxiety or depression. In a study of veterans, Defrin and colleagues demonstrated hyperalgesia in patients who had a diagnosis of PTSD but not in controls group who had an anxiety disorder only.²⁴

High-dosage prescribing of opioids has fallen by 48% since 2011, yet the decline has not reduced overdose events of any kind.

To support successful opioid tapering, trauma-induced hyperalgesia, when present, must be addressed. Treatment of what the International Association for the Study of Pain calls “pain due to psychological factors”²² requires specific trauma therapy. However, our experience validates what researchers have to say about access to treatment of psychological trauma in the United States: “…[C]linical research has identified certain psychological interventions that effectively ameliorate the symptoms of PTSD. But most people struggling with PTSD don’t receive those treatments.”²⁵

We have no doubt that this is due, in part, to underdiagnosis of psychological trauma, even in mental health clinics. According to Miele and colleagues, “PTSD remains largely undiagnosed and undertreated in mental health outpatients, even in teaching hospitals, with diagnosis rates as low as 4% while published prevalence is between 7% and 50% in this population.”²⁶

3. Patients suffer from opioid use disorder (OUD) and complain of pain to obtain opioids by prescription. For patients with OUD, their use is out of control; they devote increasing mental and physical resources to obtaining, using, and recovering from substances; and they continue to use despite adverse consequences.²⁷ The prevalence of OUD in primary care clinics varies strikingly by the location of clinics. In Washington state, the prevalence of moderate and severe OUD in a large population of patients who had been prescribed opioids through primary care clinics was recently determined to be between 21.5% and 23.9%.¹³

4. Patients are obtaining opioid prescriptions for people other than themselves. While this is a reason that patients obtain opioid prescriptions, it is not necessarily common. Statistics show that the likelihood of a prescription being diverted intentionally is low: Dart and colleagues found that diversion has become uncommon in the general population.²⁸

Continue to: Why we taper opioid analgesics

 

 

Why we taper opioid analgesics

Reasons for an opioid taper include concern that the patient has, or will develop, an OUD; will experience accidental or intentional overdose; might be diverting opioids; is not benefiting from opioid therapy for pain; or is experiencing severe adverse effects. A patient who has nociceptive pain and might have ­opioid-induced hyperalgesia will require a much different opioid taper plan than a patient with untreated PTSD or a patient with severe OUD.

Misunderstanding can lead to inappropriate tapering

We often encounter primary care providers who believe that a large percentage of patients on chronic opioid therapy inevitably develop OUD. This is a common reason for initiating opioid taper. Most patients on a chronic opioid do become physically dependent, but only a small percentage of patients develop psychological dependence (ie, ­addiction or OUD).²⁹

Physical dependence is “a state of adaptation that is manifested by a drug class–­specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.”³⁰ Symptoms of opioid withdrawal include muscle aches; abdominal cramping; increased lacrimation, rhinorrhea, and perspiration; diarrhea; agitation and anxiety; insomnia; and piloerection. Opioid withdrawal symptoms are caused by physical dependence, not by addiction. They can be mitigated by tapering slowly and instituting adjuvant medications, such as clonidine, to attenuate symptoms.

Psychological dependence, or addiction (that is, OUD, as described in the Diagnostic and Statistical Manual of Mental Disorders 5th edition²⁷), comprises primarily 3 behavioral criteria:

• Loss of control of the medication, with compulsive use
• Continued use despite adverse consequences of using opioids, such as arrest for driving under the influence and deterioration of social, family, or work performance
• Obsession or preoccupation with obtaining and using the substance. In properly selected chronic opioid therapy patients, there is evidence that new-onset OUD is not as common as has been thought. A recent study of the risk for opioid addiction after use of an opioid for ≥ 90 days for chronic noncancer pain found that the absolute rate of de novo OUD among patients treated for 90 days was 0.72%.²⁹ A systematic review by Fishbain and colleagues of 24 studies of opioid-exposed patients found a risk of 3.27% overall—0.19% for patients who did not have a history of abuse or addiction.³¹ As Director of the National Institute on Drug Abuse Norma Volkow, MD, wrote in 2016: “Addiction occurs in only a small percentage of people who are exposed to opioids—even among those with preexisting vulnerabilities.”³²

Assessment should focus on why the patient is taking an opioid

A strong case can be made that less opioid is better for many of the people for whom these medications are prescribed for chronic noncancer pain. However, a one-size-fits-all dosage reduction and addiction-focused ­approach to opioid tapering has not worked: The assessment and treatment paradigm must change, in our view.

Continue to: During assessment...

During assessment, we must adopt the means to identify the reason that a patient is using a prescription opioid. It is of particular importance that we identify patients using opioids for their psychotropic properties, particularly when the goal is to cope with the effects of psychological trauma. The subsequent treatment protocol will then need to include time for effective, evidence-based behavioral health treatment of anxiety, PTSD, or depression. If opioids are serving primarily as psychotropic medication, an attempt to taper before establishing effective behavioral health treatment might lead the patient to pursue illegal means of procuring opioid medication.

Antianxiety and antidepressant effects of opioids are a significant reason that patients persist in requesting prescriptions.

We acknowledge that primary care physicians are not reimbursed for trauma screening and that evidence-based intensive trauma treatment is generally unavailable in the United States. Both of these shortcomings must be corrected if we want to stem the opioid crisis.

If diversion is suspected and there is evidence that the patient is not currently taking prescribed opioids (eg, a negative urine drug screen), discontinuing the opioid prescription is the immediate next step for the sake of public safety.

Considering a taper? Take this 5-step approach

Once it appears that tapering an opioid is indicated, we propose that you take the following steps:

• Establish whether it is safe to continue prescribing (follow the route provided in “2 decisions to make before continuing to prescribe an opioid for chronic noncancer pain”); if continuing it is not safe, take steps to protect the patient and the community
• Determine whether assessment by a trauma-informed behavioral health expert is needed, assuming that, in your judgment, it is safe to continue the opioid (TABLE³³). When behavioral health assessment is needed, you need 3 questions answered by that assessment: (1) Are psychological factors present that might put the patient at risk during an opioid taper? (2) What are those factors? (3) What needs to done about them before the taper is started? Recalling that psychological trauma often is not assessed by behavioral health colleagues, it is necessary to provide the behavioral health provider with a specific request to assess trauma burden, and state the physical diagnoses that are causing pain or provide a clear statement that no such diagnoses can be made. (See the FIGURE, which we developed in conjunction with behavioral health colleagues to help the consultant understand what the primary care physician needs from a behavioral health assessment.)
• Obtain consultation from a physical therapist, pain medicine specialist, and, if possible, an alternative or complementary medicine provider to determine what nonpharmacotherapeutic modalities can be instituted to treat pain before tapering the opioid.
• Initiate the Screening, Brief Intervention and Referral to Treatment (SBIRT) approach if OUD is suspected (www.samhsa.gov/sbirt).³⁴ This motivational interviewing tool identifies patients with a substance use disorder, severity of use, and appropriate level of treatment. (If OUD is suspected during assessment, next steps are to stop prescribing and implement harm-reduction strategies, such as primary care level medically assisted treatment [MAT] with buprenorphine, followed by expert behavioral health-centered addiction treatment.)
• Experiment with dosage reduction according to published guidance, if (1) psychological factors are absent or have been adequately addressed, according to the behavioral health consultant, and (2) nonpharmacotherapeutic strategies are in place.^8-11

Shifting to a patient-centered approach

The timing and choice of opioid tapers, in relation to harm reduction and intervention targeting the root cause of a patient’s complaint of pain, have not been adequately explored. In our practice, we’ve shifted from an addiction-centered, dosage-centered approach to opioid taper to a patient-centered approach³⁵ that emphasizes behavioral-medical integration—an approach that we broadly endorse. Such an approach (1) is based on a clear understanding of why the patient is taking opioid pain medication, (2) engages medical and complementary or alternative medicine specialists, (3) addresses underdiagnosis of psychological trauma, and (4) requires a quantum leap in access to trauma-specific behavioral health treatment resources. ³⁶

Continue to: To underscore the case...

To underscore the case for shifting to a patient-centered approach³⁵ we present sample cases in “How a patient-centered approach to tapering opioids looks in practice.”

An eye toward the future. To inform future approaches to opioid tapering, more resources need to be deployed to

• support screening and risk stratification for PTSD, anxiety, and related disorders at the primary care level,
• continue the effort to identify and treat OUD,
• develop best-practice responses to screening, and
• make harm-reduction strategies that are now reserved for patients with OUD available to those who don't have OUD.

We urge that research be pursued into best practices for chronic pain interventions that target psychological trauma, anxiety, and depression.

CORRESPONDENCE
Bennet Davis MD, 2092 East Calle de Dulcinea, Tucson, AZ 85718; [email protected].

BALTIMORE – Older patients may have better outcomes at 1 year after resective surgery for epilepsy than the general population does, according to research presented at the annual meeting of the American Epilepsy Society. A tendency toward greater prevalence of lesional epilepsy and temporal lobe epilepsy (TLE) in the older patients in the study population could explain this difference in outcomes. Although surgery might entail greater risks in older patients, the decision to operate should be based on the patient’s inherent risk, and not on his or her age, said Juan S. Bottan, MD, neurosurgery resident at Hospital Pedro De Elizalde in Buenos Aires, and colleagues.

Zerbor/Thinkstock

Epilepsy surgery as a treatment for elderly patients is controversial. These patients generally are not considered to be surgical candidates because of concerns about long disease duration and increased surgical risk. Recent literature, however, suggests that elderly patients can benefit from surgery. Lang et al. found that epilepsy surgery success rates can be higher in selected older patients than in younger patients, although older patients may be at greater risk for postoperative hygroma and memory deficits.

Dr. Bottan and colleagues sought to analyze the role of resective surgery in patients older than age 60 years by evaluating surgical outcomes and safety. The investigators retrospectively analyzed 595 patients who underwent resective epilepsy surgery at Western University in London, Ontario, during 1999-2019. Eligible participants had drug-resistant epilepsy that had failed the best medical management. The researchers identified 31 patients aged 60 years or older and randomly selected 60 patients aged 59 years or younger as a control group. Dr. Bottan and colleagues analyzed the population’s characteristics, presurgical evaluations, postoperative outcome, and complications.

The investigators found no significant differences between groups in terms of hemisphere dominance, side of surgery, the ratio of patients with lesional epilepsy to patients with nonlesional epilepsy, and incidence of TLE over extratemporal epilepsy.

Nevertheless, extratemporal epilepsy was more frequent in older patients. Age and duration of epilepsy were significantly greater in older patients, and invasive recording was significantly more common in younger patients.

The most common pathology results in older patients were mesial temporal sclerosis (39%), gliosis (19%), and other (19%). Among younger patients, the most common pathology results were mesial temporal sclerosis (25%), gliosis (25%), and focal cortical dysplasia (15%).

The rates of Engel Class I outcome at 6 months, 1 year, and 2 years were 92.9%, 88.5%, and 94.7% among older patients and 75%, 63.5%, and 75.8% among younger patients, respectively. The difference between groups in Engel Class I outcome at 1 year was statistically significant. Patients with TLE had a better seizure outcome, regardless of age group, but the rate of good outcome was higher among older patients. The rate of complications was higher among older patients, but the difference was not statistically significant.

The study was not supported by external funding, and the investigators had no disclosures.

[email protected]

SOURCE: Bottan JS et al. AES 2019, Abstract 1.343.

BALTIMORE – Older patients may have better outcomes at 1 year after resective surgery for epilepsy than the general population does, according to research presented at the annual meeting of the American Epilepsy Society. A tendency toward greater prevalence of lesional epilepsy and temporal lobe epilepsy (TLE) in the older patients in the study population could explain this difference in outcomes. Although surgery might entail greater risks in older patients, the decision to operate should be based on the patient’s inherent risk, and not on his or her age, said Juan S. Bottan, MD, neurosurgery resident at Hospital Pedro De Elizalde in Buenos Aires, and colleagues.

Zerbor/Thinkstock

Epilepsy surgery as a treatment for elderly patients is controversial. These patients generally are not considered to be surgical candidates because of concerns about long disease duration and increased surgical risk. Recent literature, however, suggests that elderly patients can benefit from surgery. Lang et al. found that epilepsy surgery success rates can be higher in selected older patients than in younger patients, although older patients may be at greater risk for postoperative hygroma and memory deficits.

Dr. Bottan and colleagues sought to analyze the role of resective surgery in patients older than age 60 years by evaluating surgical outcomes and safety. The investigators retrospectively analyzed 595 patients who underwent resective epilepsy surgery at Western University in London, Ontario, during 1999-2019. Eligible participants had drug-resistant epilepsy that had failed the best medical management. The researchers identified 31 patients aged 60 years or older and randomly selected 60 patients aged 59 years or younger as a control group. Dr. Bottan and colleagues analyzed the population’s characteristics, presurgical evaluations, postoperative outcome, and complications.

The investigators found no significant differences between groups in terms of hemisphere dominance, side of surgery, the ratio of patients with lesional epilepsy to patients with nonlesional epilepsy, and incidence of TLE over extratemporal epilepsy.

Nevertheless, extratemporal epilepsy was more frequent in older patients. Age and duration of epilepsy were significantly greater in older patients, and invasive recording was significantly more common in younger patients.

The most common pathology results in older patients were mesial temporal sclerosis (39%), gliosis (19%), and other (19%). Among younger patients, the most common pathology results were mesial temporal sclerosis (25%), gliosis (25%), and focal cortical dysplasia (15%).

The rates of Engel Class I outcome at 6 months, 1 year, and 2 years were 92.9%, 88.5%, and 94.7% among older patients and 75%, 63.5%, and 75.8% among younger patients, respectively. The difference between groups in Engel Class I outcome at 1 year was statistically significant. Patients with TLE had a better seizure outcome, regardless of age group, but the rate of good outcome was higher among older patients. The rate of complications was higher among older patients, but the difference was not statistically significant.

The study was not supported by external funding, and the investigators had no disclosures.

[email protected]

SOURCE: Bottan JS et al. AES 2019, Abstract 1.343.

BALTIMORE – Older patients may have better outcomes at 1 year after resective surgery for epilepsy than the general population does, according to research presented at the annual meeting of the American Epilepsy Society. A tendency toward greater prevalence of lesional epilepsy and temporal lobe epilepsy (TLE) in the older patients in the study population could explain this difference in outcomes. Although surgery might entail greater risks in older patients, the decision to operate should be based on the patient’s inherent risk, and not on his or her age, said Juan S. Bottan, MD, neurosurgery resident at Hospital Pedro De Elizalde in Buenos Aires, and colleagues.

Zerbor/Thinkstock

Epilepsy surgery as a treatment for elderly patients is controversial. These patients generally are not considered to be surgical candidates because of concerns about long disease duration and increased surgical risk. Recent literature, however, suggests that elderly patients can benefit from surgery. Lang et al. found that epilepsy surgery success rates can be higher in selected older patients than in younger patients, although older patients may be at greater risk for postoperative hygroma and memory deficits.

Dr. Bottan and colleagues sought to analyze the role of resective surgery in patients older than age 60 years by evaluating surgical outcomes and safety. The investigators retrospectively analyzed 595 patients who underwent resective epilepsy surgery at Western University in London, Ontario, during 1999-2019. Eligible participants had drug-resistant epilepsy that had failed the best medical management. The researchers identified 31 patients aged 60 years or older and randomly selected 60 patients aged 59 years or younger as a control group. Dr. Bottan and colleagues analyzed the population’s characteristics, presurgical evaluations, postoperative outcome, and complications.

The investigators found no significant differences between groups in terms of hemisphere dominance, side of surgery, the ratio of patients with lesional epilepsy to patients with nonlesional epilepsy, and incidence of TLE over extratemporal epilepsy.

Nevertheless, extratemporal epilepsy was more frequent in older patients. Age and duration of epilepsy were significantly greater in older patients, and invasive recording was significantly more common in younger patients.

The most common pathology results in older patients were mesial temporal sclerosis (39%), gliosis (19%), and other (19%). Among younger patients, the most common pathology results were mesial temporal sclerosis (25%), gliosis (25%), and focal cortical dysplasia (15%).

The rates of Engel Class I outcome at 6 months, 1 year, and 2 years were 92.9%, 88.5%, and 94.7% among older patients and 75%, 63.5%, and 75.8% among younger patients, respectively. The difference between groups in Engel Class I outcome at 1 year was statistically significant. Patients with TLE had a better seizure outcome, regardless of age group, but the rate of good outcome was higher among older patients. The rate of complications was higher among older patients, but the difference was not statistically significant.

The study was not supported by external funding, and the investigators had no disclosures.

[email protected]

SOURCE: Bottan JS et al. AES 2019, Abstract 1.343.

BALTIMORE – Free-text diary entries by patients with epilepsy are a “largely untapped” source of information about the frequency and treatment of seizure clusters, researchers said at the annual meeting of the American Epilepsy Society. In addition, patients may describe other clinically relevant concerns such as tiredness, depression, head injury, or seizures while driving, researchers said.

Jake Remaly/MDedge News

To examine how seizure clusters are reflected in the electronic diaries of patients with epilepsy, Joyce A. Cramer, a clinical research consultant and colleagues examined data from EpiDiary, a set of mobile and Web-based apps designed to help patients with epilepsy manage their medications and record their symptoms. EpiDiary prompts patients to indicate whether they were seizure free, had a seizure, or had a seizure cluster on a given day. Patients also have the ability to enter free-text notes.

“This was the first-ever review of the unstructured, free-text notes,” Ms. Cramer said.

Investigators used lexical analysis to identify free-text comments that potentially were about seizure clusters, based on the use of words such as “lots,” “many,” or “repeat.” Researchers reviewed every flagged comment to confirm whether it pertained to a seizure cluster. They defined a cluster as two or more seizures on a calendar day.

An algorithm flagged 5,955 entries by 1,839 users. Clinician review confirmed that 2,645 of the flagged comments (44.4%) pertained to seizure clusters. Of the confirmed clusters, 512 (19.4%) were found only through the free-text notes and had not been documented through structured data elements such as seizure cluster check-boxes or seizure counts.

“Extra medicine was taken for clusters by 553 users on 3,818 days,” the researchers reported. “This was 30.1% of all users and 56.5% of those commenting on clusters.” In some instances, patients named specific medications, including lorazepam, clonazepam, midazolam, clobazam, rectal diazepam, other diazepam, and clorazepate.

Free-text diary entries could help researchers study various topics. The authors highlighted examples of entries that “contained other clinically relevant information,” including the following:

• Massive ongoing cluster with about 20% apneic events.
• My constant question seems to be: HOW can I function in life when just small outings bring about this incessant tiredness?
• Started feeling like I was having an aura and pulled over.
• Thought about suicide for the first time in a while.

Interpretations of the seizure cluster data are limited, the researchers noted. The algorithm might have missed some free-text comments that were about seizure clusters. And in some instances, researchers used words such as “puffs” to identify seizures when a connection to seizures was not entirely clear. In addition, patients may have used a definition of cluster that was different from the definition used by the investigators.

UCB Pharma and Irody, the company that owns EpiDiary, funded the study. Irody’s founder and president was a coauthor, and another author holds stock or options in Irody. Ms. Cramer consults for Irody, UCB, and other pharmaceutical companies.

[email protected]

SOURCE: Fisher RS et al. AES 2019. Abstract 1.424.

BALTIMORE – Free-text diary entries by patients with epilepsy are a “largely untapped” source of information about the frequency and treatment of seizure clusters, researchers said at the annual meeting of the American Epilepsy Society. In addition, patients may describe other clinically relevant concerns such as tiredness, depression, head injury, or seizures while driving, researchers said.

Jake Remaly/MDedge News

To examine how seizure clusters are reflected in the electronic diaries of patients with epilepsy, Joyce A. Cramer, a clinical research consultant and colleagues examined data from EpiDiary, a set of mobile and Web-based apps designed to help patients with epilepsy manage their medications and record their symptoms. EpiDiary prompts patients to indicate whether they were seizure free, had a seizure, or had a seizure cluster on a given day. Patients also have the ability to enter free-text notes.

“This was the first-ever review of the unstructured, free-text notes,” Ms. Cramer said.

Investigators used lexical analysis to identify free-text comments that potentially were about seizure clusters, based on the use of words such as “lots,” “many,” or “repeat.” Researchers reviewed every flagged comment to confirm whether it pertained to a seizure cluster. They defined a cluster as two or more seizures on a calendar day.

An algorithm flagged 5,955 entries by 1,839 users. Clinician review confirmed that 2,645 of the flagged comments (44.4%) pertained to seizure clusters. Of the confirmed clusters, 512 (19.4%) were found only through the free-text notes and had not been documented through structured data elements such as seizure cluster check-boxes or seizure counts.

“Extra medicine was taken for clusters by 553 users on 3,818 days,” the researchers reported. “This was 30.1% of all users and 56.5% of those commenting on clusters.” In some instances, patients named specific medications, including lorazepam, clonazepam, midazolam, clobazam, rectal diazepam, other diazepam, and clorazepate.

Free-text diary entries could help researchers study various topics. The authors highlighted examples of entries that “contained other clinically relevant information,” including the following:

• Massive ongoing cluster with about 20% apneic events.
• My constant question seems to be: HOW can I function in life when just small outings bring about this incessant tiredness?
• Started feeling like I was having an aura and pulled over.
• Thought about suicide for the first time in a while.

Interpretations of the seizure cluster data are limited, the researchers noted. The algorithm might have missed some free-text comments that were about seizure clusters. And in some instances, researchers used words such as “puffs” to identify seizures when a connection to seizures was not entirely clear. In addition, patients may have used a definition of cluster that was different from the definition used by the investigators.

UCB Pharma and Irody, the company that owns EpiDiary, funded the study. Irody’s founder and president was a coauthor, and another author holds stock or options in Irody. Ms. Cramer consults for Irody, UCB, and other pharmaceutical companies.

[email protected]

SOURCE: Fisher RS et al. AES 2019. Abstract 1.424.

BALTIMORE – Free-text diary entries by patients with epilepsy are a “largely untapped” source of information about the frequency and treatment of seizure clusters, researchers said at the annual meeting of the American Epilepsy Society. In addition, patients may describe other clinically relevant concerns such as tiredness, depression, head injury, or seizures while driving, researchers said.

Jake Remaly/MDedge News

To examine how seizure clusters are reflected in the electronic diaries of patients with epilepsy, Joyce A. Cramer, a clinical research consultant and colleagues examined data from EpiDiary, a set of mobile and Web-based apps designed to help patients with epilepsy manage their medications and record their symptoms. EpiDiary prompts patients to indicate whether they were seizure free, had a seizure, or had a seizure cluster on a given day. Patients also have the ability to enter free-text notes.

“This was the first-ever review of the unstructured, free-text notes,” Ms. Cramer said.

Investigators used lexical analysis to identify free-text comments that potentially were about seizure clusters, based on the use of words such as “lots,” “many,” or “repeat.” Researchers reviewed every flagged comment to confirm whether it pertained to a seizure cluster. They defined a cluster as two or more seizures on a calendar day.

An algorithm flagged 5,955 entries by 1,839 users. Clinician review confirmed that 2,645 of the flagged comments (44.4%) pertained to seizure clusters. Of the confirmed clusters, 512 (19.4%) were found only through the free-text notes and had not been documented through structured data elements such as seizure cluster check-boxes or seizure counts.

“Extra medicine was taken for clusters by 553 users on 3,818 days,” the researchers reported. “This was 30.1% of all users and 56.5% of those commenting on clusters.” In some instances, patients named specific medications, including lorazepam, clonazepam, midazolam, clobazam, rectal diazepam, other diazepam, and clorazepate.

Free-text diary entries could help researchers study various topics. The authors highlighted examples of entries that “contained other clinically relevant information,” including the following:

• Massive ongoing cluster with about 20% apneic events.
• My constant question seems to be: HOW can I function in life when just small outings bring about this incessant tiredness?
• Started feeling like I was having an aura and pulled over.
• Thought about suicide for the first time in a while.

Interpretations of the seizure cluster data are limited, the researchers noted. The algorithm might have missed some free-text comments that were about seizure clusters. And in some instances, researchers used words such as “puffs” to identify seizures when a connection to seizures was not entirely clear. In addition, patients may have used a definition of cluster that was different from the definition used by the investigators.

UCB Pharma and Irody, the company that owns EpiDiary, funded the study. Irody’s founder and president was a coauthor, and another author holds stock or options in Irody. Ms. Cramer consults for Irody, UCB, and other pharmaceutical companies.

[email protected]

SOURCE: Fisher RS et al. AES 2019. Abstract 1.424.

BALTIMORE – Head CTs for breakthrough seizures in chronic epilepsy are useful for known structural triggers such as brain tumors, but they don’t change management for most patients, according to a review from the SUNY Upstate Medical University, Syracuse, N.Y., emergency department.

gorodenkoff/Getty Images

“Nonselective use of ED neuroimaging in patients with no new neurological findings” and no known structural problem, is “very low yield, and increases the use of hospital resources and radiation exposure without impacting the immediate care,” concluded investigators led by Shahram Izadyar, MD, an epileptologist and associate professor of neurology at the university.

In short, CTs for breakthrough seizures – routine in many EDs – usually are a waste of time and money. Absent a known structural cause, “there really isn’t a reason to do imaging,” he said at the American Epilepsy Society annual meeting.

Dr. Izadyar wanted to look into the issue after noticing how common CTs were among his breakthrough patients. He and his team reviewed 90 adults with an established diagnosis of epilepsy and on at least one antiepileptic who presented to the university ED for breakthrough seizures during 2017-2018; 39 (43.3%) had head CTs, 51 (56.7%) did not.

CT changed management in three of the four patients (4.4%) who had a known brain tumor, leading, for instance, to steroids for increased tumor edema. The rest of the patients had nonfocal exams, and imaging had no impact on management.

There was no rhyme or reason why some people got CTs and others didn’t; it seemed to be dependent on the provider. Defensive medicine probably had something to do with it, as well as saving time by ordering a CT instead of doing a neurologic exam, Dr. Izadyar said.

People aren’t going to stop doing defensive medicine, but even a small reduction in unnecessary CTs would “be a positive change.” There’s the cost issue, but also the radiation exposure, which is considerable when people end up in the ED every few months for breakthrough seizures, he said.

There were no differences between the CT and no-CT groups in the suspected causes of breakthroughs (P = .93). About half the cases were probably because of noncompliance, about a quarter from sleep deprivation, and the rest from a change in seizure medication or some other issue.

Dr. Izadyar said the next step is taking the findings to his ED colleagues, and perhaps calculating how much money the university would save by skipping CTs in chronic epilepsy patients with no known structural problem.

There were slightly more men than women in the study, and the mean age was 38 years.

There was no industry funding, and the investigators didn’t have any relevant disclosures.

[email protected]

SOURCE: Ali S et al. AES 2019. Abstract 1.213.

BALTIMORE – Head CTs for breakthrough seizures in chronic epilepsy are useful for known structural triggers such as brain tumors, but they don’t change management for most patients, according to a review from the SUNY Upstate Medical University, Syracuse, N.Y., emergency department.

gorodenkoff/Getty Images

“Nonselective use of ED neuroimaging in patients with no new neurological findings” and no known structural problem, is “very low yield, and increases the use of hospital resources and radiation exposure without impacting the immediate care,” concluded investigators led by Shahram Izadyar, MD, an epileptologist and associate professor of neurology at the university.

In short, CTs for breakthrough seizures – routine in many EDs – usually are a waste of time and money. Absent a known structural cause, “there really isn’t a reason to do imaging,” he said at the American Epilepsy Society annual meeting.

Dr. Izadyar wanted to look into the issue after noticing how common CTs were among his breakthrough patients. He and his team reviewed 90 adults with an established diagnosis of epilepsy and on at least one antiepileptic who presented to the university ED for breakthrough seizures during 2017-2018; 39 (43.3%) had head CTs, 51 (56.7%) did not.

CT changed management in three of the four patients (4.4%) who had a known brain tumor, leading, for instance, to steroids for increased tumor edema. The rest of the patients had nonfocal exams, and imaging had no impact on management.

There was no rhyme or reason why some people got CTs and others didn’t; it seemed to be dependent on the provider. Defensive medicine probably had something to do with it, as well as saving time by ordering a CT instead of doing a neurologic exam, Dr. Izadyar said.

People aren’t going to stop doing defensive medicine, but even a small reduction in unnecessary CTs would “be a positive change.” There’s the cost issue, but also the radiation exposure, which is considerable when people end up in the ED every few months for breakthrough seizures, he said.

There were no differences between the CT and no-CT groups in the suspected causes of breakthroughs (P = .93). About half the cases were probably because of noncompliance, about a quarter from sleep deprivation, and the rest from a change in seizure medication or some other issue.

Dr. Izadyar said the next step is taking the findings to his ED colleagues, and perhaps calculating how much money the university would save by skipping CTs in chronic epilepsy patients with no known structural problem.

There were slightly more men than women in the study, and the mean age was 38 years.

There was no industry funding, and the investigators didn’t have any relevant disclosures.

[email protected]

SOURCE: Ali S et al. AES 2019. Abstract 1.213.

BALTIMORE – Head CTs for breakthrough seizures in chronic epilepsy are useful for known structural triggers such as brain tumors, but they don’t change management for most patients, according to a review from the SUNY Upstate Medical University, Syracuse, N.Y., emergency department.

gorodenkoff/Getty Images

“Nonselective use of ED neuroimaging in patients with no new neurological findings” and no known structural problem, is “very low yield, and increases the use of hospital resources and radiation exposure without impacting the immediate care,” concluded investigators led by Shahram Izadyar, MD, an epileptologist and associate professor of neurology at the university.

In short, CTs for breakthrough seizures – routine in many EDs – usually are a waste of time and money. Absent a known structural cause, “there really isn’t a reason to do imaging,” he said at the American Epilepsy Society annual meeting.

Dr. Izadyar wanted to look into the issue after noticing how common CTs were among his breakthrough patients. He and his team reviewed 90 adults with an established diagnosis of epilepsy and on at least one antiepileptic who presented to the university ED for breakthrough seizures during 2017-2018; 39 (43.3%) had head CTs, 51 (56.7%) did not.

CT changed management in three of the four patients (4.4%) who had a known brain tumor, leading, for instance, to steroids for increased tumor edema. The rest of the patients had nonfocal exams, and imaging had no impact on management.

There was no rhyme or reason why some people got CTs and others didn’t; it seemed to be dependent on the provider. Defensive medicine probably had something to do with it, as well as saving time by ordering a CT instead of doing a neurologic exam, Dr. Izadyar said.

People aren’t going to stop doing defensive medicine, but even a small reduction in unnecessary CTs would “be a positive change.” There’s the cost issue, but also the radiation exposure, which is considerable when people end up in the ED every few months for breakthrough seizures, he said.

There were no differences between the CT and no-CT groups in the suspected causes of breakthroughs (P = .93). About half the cases were probably because of noncompliance, about a quarter from sleep deprivation, and the rest from a change in seizure medication or some other issue.

Dr. Izadyar said the next step is taking the findings to his ED colleagues, and perhaps calculating how much money the university would save by skipping CTs in chronic epilepsy patients with no known structural problem.

There were slightly more men than women in the study, and the mean age was 38 years.

There was no industry funding, and the investigators didn’t have any relevant disclosures.

[email protected]

SOURCE: Ali S et al. AES 2019. Abstract 1.213.

BALTIMORE – The rates of breastfeeding initiation and adherence are lower in women with epilepsy, compared with the general population, according to data presented at the annual meeting of the American Epilepsy Society. Seizure control, education by the treating neurologist, and postpartum lactation consultative support are associated with adherence to breastfeeding, said the researchers.

©Lev Olkha/iStockphoto.com

“We need to understand and address the challenges that women with epilepsy face beyond seizure control and medication management when they are being seen by various health care providers to ensure the best quality of life for them and their babies,” Abrar Al-Faraj, MD, instructor of neurology at Boston University, said in a press release. “The strong efforts to advocate for breastfeeding in the general population should include women with chronic diseases such as epilepsy.”
 

A retrospective study of women who underwent pregnancy

Data have established the benefits of breastfeeding in the general population. Recent studies have confirmed that for women with epilepsy and their children, breastfeeding is safe and may provide neurodevelopmental benefits. Data also indicate, however, that rates of breastfeeding are significantly lower in women with epilepsy than in the general population. Dr. Al-Faraj and colleagues sought to compare the rates of initiation of and adherence to breastfeeding in women with epilepsy with those in healthy controls. They also intended to identify the factors that affect breastfeeding in women with epilepsy and assess the influence of support systems (e.g., lactation consult services) on breastfeeding.

The investigators retrospectively studied 102 women with epilepsy who were treated at the Beth Israel Deaconess Medical Center (BIDMC) Epilepsy Clinic and underwent pregnancies between 2009 and 2018. They compared these women to 113 healthy controls without epilepsy who were treated at the obstetrical service at BIDMC during the same period. Dr. Al-Faraj and colleagues reviewed patients’ medical records for demographic information, epilepsy type, degree of seizure control during pregnancy and post partum, number of antiepileptic medications (AEDs), breastfeeding education by providers (i.e., neurologists and epilepsy nurses), lactation consult, and rate of initiation of and adherence to breastfeeding at 6 weeks and 3 and 6 months. The investigators excluded from their analysis patients with other chronic medical conditions, those taking medications other than AEDs that may affect breastfeeding, and those with limited follow-up during pregnancy and post partum.
 

Education and support were correlated with breastfeeding

Participants’ ages ranged from 20 years to 40 years. The rate of breastfeeding initiation was significantly lower in women with epilepsy (51%) than in controls (87%). The rate declined significantly to 38.2% at 6 weeks in women with epilepsy, compared to 76% in controls. The rate of adherence at 3 months was 36.2% in women with epilepsy, and adherence at 6 months was 18.6%.

The reasons for not breastfeeding were known for 17.6% of women with epilepsy. These reasons included fear of AED exposure through breast milk, recommendations by providers (e.g., pediatricians and obstetricians) not to breastfeed, failed breastfeeding attempts because of technical difficulties (e.g., the baby’s inability to latch), and lack of milk supply. Treating neurologists discussed breastfeeding with 52.9% of women with epilepsy, and epilepsy nurses discussed it with 91% of women with epilepsy. Among the 66% of patients who received obstetrical care at BIDMC, 13% of women with epilepsy had lactation consultation post partum, compared with 58% of controls. Breastfeeding education by the treating neurologist was significantly and positively correlated with decision to breastfeed and initiation of breastfeeding. Postpartum lactation consult support was also associated with a significantly higher rate of breastfeeding initiation, adherence at 6 weeks, adherence at 3 months, and adherence at 6 months. Women with well-controlled seizures were more likely to continue breastfeeding at 6 weeks, compared with women with uncontrolled seizures. The researchers found no statistically significant difference in the breastfeeding initiation rate, however, between women with controlled seizures and those with uncontrolled seizures.

“Women with poor seizure control are a particularly vulnerable group and have the greatest need for intervention to improve breastfeeding rates,” said Dr. Al-Faraj and colleagues. Focused physician education and support measures such as lactation consultation may be potential interventions to improve the treatment of women with epilepsy, they added. “Further prospective investigations are needed to identify other factors that prevent the decision to initiate or adhere to breastfeeding in women with epilepsy and evaluate interventions that may be implemented as a public health measure to support this vulnerable population.”

The study did not have external funding, and the investigators reported no disclosures.

[email protected]

SOURCE: Al-Faraj AO et al. AES 2019, Abstract 1.246.

BALTIMORE – The rates of breastfeeding initiation and adherence are lower in women with epilepsy, compared with the general population, according to data presented at the annual meeting of the American Epilepsy Society. Seizure control, education by the treating neurologist, and postpartum lactation consultative support are associated with adherence to breastfeeding, said the researchers.

©Lev Olkha/iStockphoto.com

“We need to understand and address the challenges that women with epilepsy face beyond seizure control and medication management when they are being seen by various health care providers to ensure the best quality of life for them and their babies,” Abrar Al-Faraj, MD, instructor of neurology at Boston University, said in a press release. “The strong efforts to advocate for breastfeeding in the general population should include women with chronic diseases such as epilepsy.”
 

A retrospective study of women who underwent pregnancy

Data have established the benefits of breastfeeding in the general population. Recent studies have confirmed that for women with epilepsy and their children, breastfeeding is safe and may provide neurodevelopmental benefits. Data also indicate, however, that rates of breastfeeding are significantly lower in women with epilepsy than in the general population. Dr. Al-Faraj and colleagues sought to compare the rates of initiation of and adherence to breastfeeding in women with epilepsy with those in healthy controls. They also intended to identify the factors that affect breastfeeding in women with epilepsy and assess the influence of support systems (e.g., lactation consult services) on breastfeeding.

The investigators retrospectively studied 102 women with epilepsy who were treated at the Beth Israel Deaconess Medical Center (BIDMC) Epilepsy Clinic and underwent pregnancies between 2009 and 2018. They compared these women to 113 healthy controls without epilepsy who were treated at the obstetrical service at BIDMC during the same period. Dr. Al-Faraj and colleagues reviewed patients’ medical records for demographic information, epilepsy type, degree of seizure control during pregnancy and post partum, number of antiepileptic medications (AEDs), breastfeeding education by providers (i.e., neurologists and epilepsy nurses), lactation consult, and rate of initiation of and adherence to breastfeeding at 6 weeks and 3 and 6 months. The investigators excluded from their analysis patients with other chronic medical conditions, those taking medications other than AEDs that may affect breastfeeding, and those with limited follow-up during pregnancy and post partum.
 

Education and support were correlated with breastfeeding

Participants’ ages ranged from 20 years to 40 years. The rate of breastfeeding initiation was significantly lower in women with epilepsy (51%) than in controls (87%). The rate declined significantly to 38.2% at 6 weeks in women with epilepsy, compared to 76% in controls. The rate of adherence at 3 months was 36.2% in women with epilepsy, and adherence at 6 months was 18.6%.

The reasons for not breastfeeding were known for 17.6% of women with epilepsy. These reasons included fear of AED exposure through breast milk, recommendations by providers (e.g., pediatricians and obstetricians) not to breastfeed, failed breastfeeding attempts because of technical difficulties (e.g., the baby’s inability to latch), and lack of milk supply. Treating neurologists discussed breastfeeding with 52.9% of women with epilepsy, and epilepsy nurses discussed it with 91% of women with epilepsy. Among the 66% of patients who received obstetrical care at BIDMC, 13% of women with epilepsy had lactation consultation post partum, compared with 58% of controls. Breastfeeding education by the treating neurologist was significantly and positively correlated with decision to breastfeed and initiation of breastfeeding. Postpartum lactation consult support was also associated with a significantly higher rate of breastfeeding initiation, adherence at 6 weeks, adherence at 3 months, and adherence at 6 months. Women with well-controlled seizures were more likely to continue breastfeeding at 6 weeks, compared with women with uncontrolled seizures. The researchers found no statistically significant difference in the breastfeeding initiation rate, however, between women with controlled seizures and those with uncontrolled seizures.

“Women with poor seizure control are a particularly vulnerable group and have the greatest need for intervention to improve breastfeeding rates,” said Dr. Al-Faraj and colleagues. Focused physician education and support measures such as lactation consultation may be potential interventions to improve the treatment of women with epilepsy, they added. “Further prospective investigations are needed to identify other factors that prevent the decision to initiate or adhere to breastfeeding in women with epilepsy and evaluate interventions that may be implemented as a public health measure to support this vulnerable population.”

The study did not have external funding, and the investigators reported no disclosures.

[email protected]

SOURCE: Al-Faraj AO et al. AES 2019, Abstract 1.246.

BALTIMORE – The rates of breastfeeding initiation and adherence are lower in women with epilepsy, compared with the general population, according to data presented at the annual meeting of the American Epilepsy Society. Seizure control, education by the treating neurologist, and postpartum lactation consultative support are associated with adherence to breastfeeding, said the researchers.

©Lev Olkha/iStockphoto.com

“We need to understand and address the challenges that women with epilepsy face beyond seizure control and medication management when they are being seen by various health care providers to ensure the best quality of life for them and their babies,” Abrar Al-Faraj, MD, instructor of neurology at Boston University, said in a press release. “The strong efforts to advocate for breastfeeding in the general population should include women with chronic diseases such as epilepsy.”
 

A retrospective study of women who underwent pregnancy

Data have established the benefits of breastfeeding in the general population. Recent studies have confirmed that for women with epilepsy and their children, breastfeeding is safe and may provide neurodevelopmental benefits. Data also indicate, however, that rates of breastfeeding are significantly lower in women with epilepsy than in the general population. Dr. Al-Faraj and colleagues sought to compare the rates of initiation of and adherence to breastfeeding in women with epilepsy with those in healthy controls. They also intended to identify the factors that affect breastfeeding in women with epilepsy and assess the influence of support systems (e.g., lactation consult services) on breastfeeding.

The investigators retrospectively studied 102 women with epilepsy who were treated at the Beth Israel Deaconess Medical Center (BIDMC) Epilepsy Clinic and underwent pregnancies between 2009 and 2018. They compared these women to 113 healthy controls without epilepsy who were treated at the obstetrical service at BIDMC during the same period. Dr. Al-Faraj and colleagues reviewed patients’ medical records for demographic information, epilepsy type, degree of seizure control during pregnancy and post partum, number of antiepileptic medications (AEDs), breastfeeding education by providers (i.e., neurologists and epilepsy nurses), lactation consult, and rate of initiation of and adherence to breastfeeding at 6 weeks and 3 and 6 months. The investigators excluded from their analysis patients with other chronic medical conditions, those taking medications other than AEDs that may affect breastfeeding, and those with limited follow-up during pregnancy and post partum.
 

Education and support were correlated with breastfeeding

Participants’ ages ranged from 20 years to 40 years. The rate of breastfeeding initiation was significantly lower in women with epilepsy (51%) than in controls (87%). The rate declined significantly to 38.2% at 6 weeks in women with epilepsy, compared to 76% in controls. The rate of adherence at 3 months was 36.2% in women with epilepsy, and adherence at 6 months was 18.6%.

The reasons for not breastfeeding were known for 17.6% of women with epilepsy. These reasons included fear of AED exposure through breast milk, recommendations by providers (e.g., pediatricians and obstetricians) not to breastfeed, failed breastfeeding attempts because of technical difficulties (e.g., the baby’s inability to latch), and lack of milk supply. Treating neurologists discussed breastfeeding with 52.9% of women with epilepsy, and epilepsy nurses discussed it with 91% of women with epilepsy. Among the 66% of patients who received obstetrical care at BIDMC, 13% of women with epilepsy had lactation consultation post partum, compared with 58% of controls. Breastfeeding education by the treating neurologist was significantly and positively correlated with decision to breastfeed and initiation of breastfeeding. Postpartum lactation consult support was also associated with a significantly higher rate of breastfeeding initiation, adherence at 6 weeks, adherence at 3 months, and adherence at 6 months. Women with well-controlled seizures were more likely to continue breastfeeding at 6 weeks, compared with women with uncontrolled seizures. The researchers found no statistically significant difference in the breastfeeding initiation rate, however, between women with controlled seizures and those with uncontrolled seizures.

“Women with poor seizure control are a particularly vulnerable group and have the greatest need for intervention to improve breastfeeding rates,” said Dr. Al-Faraj and colleagues. Focused physician education and support measures such as lactation consultation may be potential interventions to improve the treatment of women with epilepsy, they added. “Further prospective investigations are needed to identify other factors that prevent the decision to initiate or adhere to breastfeeding in women with epilepsy and evaluate interventions that may be implemented as a public health measure to support this vulnerable population.”

The study did not have external funding, and the investigators reported no disclosures.

[email protected]

SOURCE: Al-Faraj AO et al. AES 2019, Abstract 1.246.

SAN DIEGO – Positive findings from a post hoc subanalysis of two unsuccessful studies represent “a major step forward in Alzheimer’s disease research” and could set the antiamyloid antibody up as a “foothold” in slowing disease progression, study investigators said at the Clinical Trials on Alzheimer’s Disease conference.

Michele G. Sullivan/MDedge News

After full follow-up of 78 weeks, patients with mild Alzheimer’s disease (AD) who took the highest 10-mg/kg dose for a full 14 doses experienced up to a 53% slowing of functional decline on the Clinical Dementia Rating–Sum of Boxes (CDR-SB) in one study and a 48% slowing in the other study – relative to placebo – a result that might give them “an extra year or 2” of independence; they might perhaps retain the ability to drive and even stay employed, said Sharon Cohen, MD, a panelist at the meeting’s aducanumab presentation session and a clinical investigator in EMERGE, one of two phase 3 studies from which the data were derived.

Samantha Budd Haeberlein, PhD, Biogen’s vice president and head of late-stage clinical development in Alzheimer’s disease, presented the new data. They “are complex” and require much more study before investigators, clinicians, and federal regulators can fully embrace them, said the panelists who discussed the results. Nevertheless, Biogen, which is codeveloping the antibody with partner Eisai, said in October it will put aducanumab forward to the Food and Drug Administration in a new drug application for the first-ever AD disease-modifying agent. FDA regulators have said they will review the data.

The new subanalysis comprised 570 of 3,285 patients in two identical studies with negative primary endpoint results. One, ENGAGE, failed to reach both its primary and secondary endpoints; the other, EMERGE, was halted last spring after a futility analysis determined that aducanumab was unlikely to confer significant benefit. The post hoc subanalysis looked at a combined subset of those who received the highest 10-mg/kg dose for the full 78 weeks of each trial. The statistically significant functional endpoints occurred in this group, comprised largely of apolipoprotein E epsilon-4 (APOE4) allele carriers.

“The futility analysis of EMERGE was highly unfortunate,” said panelist Paul Aisen, MD, founding director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles. “Clearly in the final analysis, EMERGE was positive in the primary endpoints, and now the secondary analysis of both studies is positive and consistent.” The diverging trajectory of placebo and treatment groups continued to the end of follow-up in both studies, a finding that at least suggests continuing improvement, he added.

Biogen undertook the pooled analysis after ENGAGE’s futility analysis. Early in the development program, concern about amyloid-related imaging abnormalities (ARIA) in APOE4 carriers led Biogen to stratify doses in that group.

“When we started [creating aducanumab trials], we stratified the dose so that e4 carriers had the lowest dose, but in PRIME [the phase 1b study], we saw the best result from the 10-mg/kg dose, so we believed that was important for efficacy. However, we didn’t have sufficient evidence to believe that it was safe to put carriers on that dose. In EMERGE, we saw that carriers could safely take it until the end of the study.”

Since the trials were running almost synchronously, a new version of randomization ensued. This allowed more e4 carriers to go forward on the 10-mg/kg dose.

“I would not normally recommend changing dose in the middle of a phase 3 trial, but it did have a real impact in the high-dose group,” Dr. Haeberlein said. Additionally, by the time of data lock after the futility analysis, more patients had completed the entire 78 weeks at the 10-mg/kg dose. Cumulative dosing ended up being quite different in the APOE4 carriers after this new version ensued. Before, the median cumulative dose for both carriers and noncarriers was 116 mg/kg. After the change, the median cumulative dose was 153 mg/kg. And before the alteration, 21% in EMERGE and 15% in ENGAGE received the full 14 possible 10-mg/kg doses. After the change, 51% in EMERGE and 47% in ENGAGE received the full 14 doses of 10 mg/kg.

The pooled analysis comprised this combined group, which was then largely composed of APOE4 carriers.

Imaging confirmed such dose-driven reductions in both brain amyloid plaques and phosphorylated tau. Although amyloid reduction has never been tied to cognitive or functional benefits, tau reduction has been associated with nonsignificant cognitive benefits in prior studies.

In the primary analysis of ENGAGE, aducanumab conferred no cognitive or functional benefit. In EMERGE, there were significant cognitive improvements on both the Mini Mental State Exam score (an 18% slowing of decline relative to placebo) and the Alzheimer’s Disease Assessment Scale cognitive portion (a 27% slowing).

However, the functional improvements seen in the pooled post hoc data “are a big deal,” and probably more meaningful to patients and families than the memory improvements, Dr. Cohen said.

“Those of us who know this disease well know what it means to lose yourself slice by slice, and anything you can hang onto is a triumph,” said Dr. Cohen, medical director and principal investigator of the Toronto Memory Program, an independent medical facility for dementia care and research. “I am pleased with a 27% slowing of cognitive decline, but a 40% slowing of functional decline is what will be really meaningful to patients. This is a long, slow disease, and if we can slow it at all, we’re winning out.”

Safety endpoints, especially ARIA, were not unexpected considering past studies. ARIA occurred in 41% of patients treated with the high aducanumab dose in EMERGE and in 40% in ENGAGE. It was largely asymptomatic (80% in EMERGE and 71% in ENGAGE). Headache was the next most common adverse event, followed by dizziness, visual disturbance, and nausea and vomiting. ARIA generally resolved within 4-6 weeks, and most patients continued their 10-mg/kg dose.

Biogen intends to begin a new study, an open-label nonrandomized trial that will offer the 10-mg/kg dose to all patients in both trials, including those who took placebo. This may provide interesting data regarding redosing patients who were off their successful 10-mg/kg dose for an extended period of time, said Laurie Ryan, PhD, chief of the Dementias of Aging Branch in the Division of Neuroscience at the National Institute on Aging.

“If those in the high-dose group had a regression of their improvements and then improved again when restarted, that would certainly tell us something,” she said in an interview. Likewise, researchers will be carefully looking at any placebo group response. “But we have to remember that this will not be a randomized study,” and will bring with it all the issues that such a study typically carries.

“I agree it’s unfortunate that they had to stop the EMERGE trial,” she said. “It really did complicate the results, even though they are certainly trending in the right way. But we have had a number of post hoc analyses that show APOE4-positive benefiting, or e4-negative benefiting, and these haven’t panned out.”

[email protected]

SAN DIEGO – Positive findings from a post hoc subanalysis of two unsuccessful studies represent “a major step forward in Alzheimer’s disease research” and could set the antiamyloid antibody up as a “foothold” in slowing disease progression, study investigators said at the Clinical Trials on Alzheimer’s Disease conference.

Michele G. Sullivan/MDedge News

After full follow-up of 78 weeks, patients with mild Alzheimer’s disease (AD) who took the highest 10-mg/kg dose for a full 14 doses experienced up to a 53% slowing of functional decline on the Clinical Dementia Rating–Sum of Boxes (CDR-SB) in one study and a 48% slowing in the other study – relative to placebo – a result that might give them “an extra year or 2” of independence; they might perhaps retain the ability to drive and even stay employed, said Sharon Cohen, MD, a panelist at the meeting’s aducanumab presentation session and a clinical investigator in EMERGE, one of two phase 3 studies from which the data were derived.

Samantha Budd Haeberlein, PhD, Biogen’s vice president and head of late-stage clinical development in Alzheimer’s disease, presented the new data. They “are complex” and require much more study before investigators, clinicians, and federal regulators can fully embrace them, said the panelists who discussed the results. Nevertheless, Biogen, which is codeveloping the antibody with partner Eisai, said in October it will put aducanumab forward to the Food and Drug Administration in a new drug application for the first-ever AD disease-modifying agent. FDA regulators have said they will review the data.

The new subanalysis comprised 570 of 3,285 patients in two identical studies with negative primary endpoint results. One, ENGAGE, failed to reach both its primary and secondary endpoints; the other, EMERGE, was halted last spring after a futility analysis determined that aducanumab was unlikely to confer significant benefit. The post hoc subanalysis looked at a combined subset of those who received the highest 10-mg/kg dose for the full 78 weeks of each trial. The statistically significant functional endpoints occurred in this group, comprised largely of apolipoprotein E epsilon-4 (APOE4) allele carriers.

“The futility analysis of EMERGE was highly unfortunate,” said panelist Paul Aisen, MD, founding director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles. “Clearly in the final analysis, EMERGE was positive in the primary endpoints, and now the secondary analysis of both studies is positive and consistent.” The diverging trajectory of placebo and treatment groups continued to the end of follow-up in both studies, a finding that at least suggests continuing improvement, he added.

Biogen undertook the pooled analysis after ENGAGE’s futility analysis. Early in the development program, concern about amyloid-related imaging abnormalities (ARIA) in APOE4 carriers led Biogen to stratify doses in that group.

“When we started [creating aducanumab trials], we stratified the dose so that e4 carriers had the lowest dose, but in PRIME [the phase 1b study], we saw the best result from the 10-mg/kg dose, so we believed that was important for efficacy. However, we didn’t have sufficient evidence to believe that it was safe to put carriers on that dose. In EMERGE, we saw that carriers could safely take it until the end of the study.”

Since the trials were running almost synchronously, a new version of randomization ensued. This allowed more e4 carriers to go forward on the 10-mg/kg dose.

“I would not normally recommend changing dose in the middle of a phase 3 trial, but it did have a real impact in the high-dose group,” Dr. Haeberlein said. Additionally, by the time of data lock after the futility analysis, more patients had completed the entire 78 weeks at the 10-mg/kg dose. Cumulative dosing ended up being quite different in the APOE4 carriers after this new version ensued. Before, the median cumulative dose for both carriers and noncarriers was 116 mg/kg. After the change, the median cumulative dose was 153 mg/kg. And before the alteration, 21% in EMERGE and 15% in ENGAGE received the full 14 possible 10-mg/kg doses. After the change, 51% in EMERGE and 47% in ENGAGE received the full 14 doses of 10 mg/kg.

The pooled analysis comprised this combined group, which was then largely composed of APOE4 carriers.

Imaging confirmed such dose-driven reductions in both brain amyloid plaques and phosphorylated tau. Although amyloid reduction has never been tied to cognitive or functional benefits, tau reduction has been associated with nonsignificant cognitive benefits in prior studies.

In the primary analysis of ENGAGE, aducanumab conferred no cognitive or functional benefit. In EMERGE, there were significant cognitive improvements on both the Mini Mental State Exam score (an 18% slowing of decline relative to placebo) and the Alzheimer’s Disease Assessment Scale cognitive portion (a 27% slowing).

However, the functional improvements seen in the pooled post hoc data “are a big deal,” and probably more meaningful to patients and families than the memory improvements, Dr. Cohen said.

“Those of us who know this disease well know what it means to lose yourself slice by slice, and anything you can hang onto is a triumph,” said Dr. Cohen, medical director and principal investigator of the Toronto Memory Program, an independent medical facility for dementia care and research. “I am pleased with a 27% slowing of cognitive decline, but a 40% slowing of functional decline is what will be really meaningful to patients. This is a long, slow disease, and if we can slow it at all, we’re winning out.”

Safety endpoints, especially ARIA, were not unexpected considering past studies. ARIA occurred in 41% of patients treated with the high aducanumab dose in EMERGE and in 40% in ENGAGE. It was largely asymptomatic (80% in EMERGE and 71% in ENGAGE). Headache was the next most common adverse event, followed by dizziness, visual disturbance, and nausea and vomiting. ARIA generally resolved within 4-6 weeks, and most patients continued their 10-mg/kg dose.

Biogen intends to begin a new study, an open-label nonrandomized trial that will offer the 10-mg/kg dose to all patients in both trials, including those who took placebo. This may provide interesting data regarding redosing patients who were off their successful 10-mg/kg dose for an extended period of time, said Laurie Ryan, PhD, chief of the Dementias of Aging Branch in the Division of Neuroscience at the National Institute on Aging.

“If those in the high-dose group had a regression of their improvements and then improved again when restarted, that would certainly tell us something,” she said in an interview. Likewise, researchers will be carefully looking at any placebo group response. “But we have to remember that this will not be a randomized study,” and will bring with it all the issues that such a study typically carries.

“I agree it’s unfortunate that they had to stop the EMERGE trial,” she said. “It really did complicate the results, even though they are certainly trending in the right way. But we have had a number of post hoc analyses that show APOE4-positive benefiting, or e4-negative benefiting, and these haven’t panned out.”

[email protected]

SAN DIEGO – Positive findings from a post hoc subanalysis of two unsuccessful studies represent “a major step forward in Alzheimer’s disease research” and could set the antiamyloid antibody up as a “foothold” in slowing disease progression, study investigators said at the Clinical Trials on Alzheimer’s Disease conference.

Michele G. Sullivan/MDedge News

After full follow-up of 78 weeks, patients with mild Alzheimer’s disease (AD) who took the highest 10-mg/kg dose for a full 14 doses experienced up to a 53% slowing of functional decline on the Clinical Dementia Rating–Sum of Boxes (CDR-SB) in one study and a 48% slowing in the other study – relative to placebo – a result that might give them “an extra year or 2” of independence; they might perhaps retain the ability to drive and even stay employed, said Sharon Cohen, MD, a panelist at the meeting’s aducanumab presentation session and a clinical investigator in EMERGE, one of two phase 3 studies from which the data were derived.

Samantha Budd Haeberlein, PhD, Biogen’s vice president and head of late-stage clinical development in Alzheimer’s disease, presented the new data. They “are complex” and require much more study before investigators, clinicians, and federal regulators can fully embrace them, said the panelists who discussed the results. Nevertheless, Biogen, which is codeveloping the antibody with partner Eisai, said in October it will put aducanumab forward to the Food and Drug Administration in a new drug application for the first-ever AD disease-modifying agent. FDA regulators have said they will review the data.

The new subanalysis comprised 570 of 3,285 patients in two identical studies with negative primary endpoint results. One, ENGAGE, failed to reach both its primary and secondary endpoints; the other, EMERGE, was halted last spring after a futility analysis determined that aducanumab was unlikely to confer significant benefit. The post hoc subanalysis looked at a combined subset of those who received the highest 10-mg/kg dose for the full 78 weeks of each trial. The statistically significant functional endpoints occurred in this group, comprised largely of apolipoprotein E epsilon-4 (APOE4) allele carriers.

“The futility analysis of EMERGE was highly unfortunate,” said panelist Paul Aisen, MD, founding director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles. “Clearly in the final analysis, EMERGE was positive in the primary endpoints, and now the secondary analysis of both studies is positive and consistent.” The diverging trajectory of placebo and treatment groups continued to the end of follow-up in both studies, a finding that at least suggests continuing improvement, he added.

Biogen undertook the pooled analysis after ENGAGE’s futility analysis. Early in the development program, concern about amyloid-related imaging abnormalities (ARIA) in APOE4 carriers led Biogen to stratify doses in that group.

“When we started [creating aducanumab trials], we stratified the dose so that e4 carriers had the lowest dose, but in PRIME [the phase 1b study], we saw the best result from the 10-mg/kg dose, so we believed that was important for efficacy. However, we didn’t have sufficient evidence to believe that it was safe to put carriers on that dose. In EMERGE, we saw that carriers could safely take it until the end of the study.”

Since the trials were running almost synchronously, a new version of randomization ensued. This allowed more e4 carriers to go forward on the 10-mg/kg dose.

“I would not normally recommend changing dose in the middle of a phase 3 trial, but it did have a real impact in the high-dose group,” Dr. Haeberlein said. Additionally, by the time of data lock after the futility analysis, more patients had completed the entire 78 weeks at the 10-mg/kg dose. Cumulative dosing ended up being quite different in the APOE4 carriers after this new version ensued. Before, the median cumulative dose for both carriers and noncarriers was 116 mg/kg. After the change, the median cumulative dose was 153 mg/kg. And before the alteration, 21% in EMERGE and 15% in ENGAGE received the full 14 possible 10-mg/kg doses. After the change, 51% in EMERGE and 47% in ENGAGE received the full 14 doses of 10 mg/kg.

The pooled analysis comprised this combined group, which was then largely composed of APOE4 carriers.

Imaging confirmed such dose-driven reductions in both brain amyloid plaques and phosphorylated tau. Although amyloid reduction has never been tied to cognitive or functional benefits, tau reduction has been associated with nonsignificant cognitive benefits in prior studies.

In the primary analysis of ENGAGE, aducanumab conferred no cognitive or functional benefit. In EMERGE, there were significant cognitive improvements on both the Mini Mental State Exam score (an 18% slowing of decline relative to placebo) and the Alzheimer’s Disease Assessment Scale cognitive portion (a 27% slowing).

However, the functional improvements seen in the pooled post hoc data “are a big deal,” and probably more meaningful to patients and families than the memory improvements, Dr. Cohen said.

“Those of us who know this disease well know what it means to lose yourself slice by slice, and anything you can hang onto is a triumph,” said Dr. Cohen, medical director and principal investigator of the Toronto Memory Program, an independent medical facility for dementia care and research. “I am pleased with a 27% slowing of cognitive decline, but a 40% slowing of functional decline is what will be really meaningful to patients. This is a long, slow disease, and if we can slow it at all, we’re winning out.”

Safety endpoints, especially ARIA, were not unexpected considering past studies. ARIA occurred in 41% of patients treated with the high aducanumab dose in EMERGE and in 40% in ENGAGE. It was largely asymptomatic (80% in EMERGE and 71% in ENGAGE). Headache was the next most common adverse event, followed by dizziness, visual disturbance, and nausea and vomiting. ARIA generally resolved within 4-6 weeks, and most patients continued their 10-mg/kg dose.

Biogen intends to begin a new study, an open-label nonrandomized trial that will offer the 10-mg/kg dose to all patients in both trials, including those who took placebo. This may provide interesting data regarding redosing patients who were off their successful 10-mg/kg dose for an extended period of time, said Laurie Ryan, PhD, chief of the Dementias of Aging Branch in the Division of Neuroscience at the National Institute on Aging.

“If those in the high-dose group had a regression of their improvements and then improved again when restarted, that would certainly tell us something,” she said in an interview. Likewise, researchers will be carefully looking at any placebo group response. “But we have to remember that this will not be a randomized study,” and will bring with it all the issues that such a study typically carries.

“I agree it’s unfortunate that they had to stop the EMERGE trial,” she said. “It really did complicate the results, even though they are certainly trending in the right way. But we have had a number of post hoc analyses that show APOE4-positive benefiting, or e4-negative benefiting, and these haven’t panned out.”

[email protected]

SAN DIEGO – Intensive blood pressure control over 4 years reduced the overall risk of all-cause dementia by 17%, compared with standard care, but in subanalyses of the Systolic Blood Pressure Intervention Trial (SPRINT) it was also associated with significant decreases in cognitive function and total brain volume, researchers said at the Clinical Trials on Alzheimer’s Disease conference.

Michele G. Sullivan/MDedge News

Whether these between-group differences were clinically meaningful was the topic of some debate, but they were enough to prompt Mary Sano, PhD, to strongly state her reservations.

“The cardiovascular effects of SPRINT were impressive, but I am concerned about minimizing the potentially negative effect on cognition,” said Dr. Sano, professor of psychiatry and director of the Alzheimer’s Disease Research Center at the Icahn School of Medicine at Mount Sinai, New York. “Do I really want to treat a healthy, nonimpaired patient like this if I have to warn them that their cognition might actually get worse? We just cannot minimize this risk. There is very strong evidence that [intensive treatment of blood pressure] might be a step backward in cognition. Would you lower your own blood pressure at a risk of losing some points on your cognition?”

The subanalyses were conducted as part of the SPRINT Memory and Cognition In Decreased Hypertension (SPRINT MIND) substudy, which looked at cardiovascular and mortality outcomes in 9,361 subjects whose hypertension was managed intensively or by standard care (target systolic blood pressure less than 120 mm Hg vs. less than 140 mm Hg). The trial was stopped early because of a 25% reduction in the primary composite cardiovascular disease endpoint and a 27% reduction in all-cause mortality in the intensive-treatment group.

SPRINT MIND examined the risks of incident probable dementia, mild cognitive impairment (MCI), and a composite outcome of both. Intensive control reduced the risk of MCI by 19% and the combined outcome by 15%.

At the conference, SPRINT MIND investigators presented three long-term subanalyses with a median intervention and follow-up time of about 4 years.

Sarah Gaussoin of Wake Forest University, Winston-Salem, N.C., presented unpublished data detailing the effects of intensive control on several dementia subtypes: nonamnestic single domain, nonamnestic multidomain, amnestic single domain, and amnestic multidomain. There were 640 subjects in this analysis.

After a median of 3.3 years of intervention and 5 years of follow-up, there were no differences in the rate of incident probable dementia between the single- and multidomain nonamnestic groups. “We did see a strong 22% decreased risk in single-domain versus multidomain amnestic MCI, however,” she said.

Nicholas Pajewski, PhD, also of Wake Forest University, discussed more detailed cognitive outcomes in SPRINT MIND among 2,900 subjects who had a full battery of cognitive testing at every assessment over 5 years. The outcomes included memory deficit and processing speed.

Dr. Pajewski reported finding no significant difference between the groups in the rates of memory decline in either outcome. But there was a greater rate of decline in processing speed in the intensively treated group, he added. The difference was small but statistically significant.

The difference was largely driven by results of a single cognitive test – the Trail Making Test Part A. “It corresponded to about a 1.25-second increase over 4 years,” in processing speed on this test, Dr. Pajewski said.

There were no between-group differences in any of the other domains explored, including language, executive function, global cognitive function, or the Montreal Cognitive Assessment.

“Obviously, these results are perplexing,” given the overall positive results of SPRINT MIND, he said. “Intensive blood pressure control is a beneficial thing, and we expected to see an effect on memory, or a blunting of decline, and instead we saw some small decrements going the other way. This led us to speculate about what’s going on.”

The trial relied on a narrow definition of MCI that might have affected the outcomes. There was also a very broad range of ages in the study, ranging from 53 to 86 years. More importantly, he said, the original SPRINT study didn’t collect cognitive data at baseline, so there was no way to know how many subjects already might have had MCI when they entered the trial.

Ilya Nasrallah, MD, PhD, of the University of Pennsylvania, Philadelphia, presented MRI data on white-matter lesions, hippocampal volume fractional anisotropy in the cingulum, and cerebral blood flow. The median time between scans was 4 years, with a median treatment time of 3.4 years.

The standard-care group showed a significantly greater increase in white-matter lesion volume at the follow-up scan than did the intensive-treatment group (1.45 cm³ vs. 0.92 cm³). But the intensively treated group had significantly more brain atrophy, losing a median of 30.6 cm^3, compared with a loss of 26.9 cm³ in the standard-treatment group.

“It was a very small difference amounting to less than 1% of the total brain volume, but it was still statistically significant,” Dr. Nasrallah said.

Loss of gray-matter volume drove about two-thirds of the difference in the intensively treated group. There was a corresponding increase in cerebrospinal fluid volume that was driven by differences in the ventricles and the subarachnoid space.

However, there were no significant differences in right, left, or total hippocampal volume. There also were no differences in cingulate bundle anisotropy or cerebral blood flow.

SPRINT was funded by the National Institutes of Health. None of the investigators reported having financial conflicts of interest.

[email protected]

SAN DIEGO – Intensive blood pressure control over 4 years reduced the overall risk of all-cause dementia by 17%, compared with standard care, but in subanalyses of the Systolic Blood Pressure Intervention Trial (SPRINT) it was also associated with significant decreases in cognitive function and total brain volume, researchers said at the Clinical Trials on Alzheimer’s Disease conference.

Michele G. Sullivan/MDedge News

Whether these between-group differences were clinically meaningful was the topic of some debate, but they were enough to prompt Mary Sano, PhD, to strongly state her reservations.

“The cardiovascular effects of SPRINT were impressive, but I am concerned about minimizing the potentially negative effect on cognition,” said Dr. Sano, professor of psychiatry and director of the Alzheimer’s Disease Research Center at the Icahn School of Medicine at Mount Sinai, New York. “Do I really want to treat a healthy, nonimpaired patient like this if I have to warn them that their cognition might actually get worse? We just cannot minimize this risk. There is very strong evidence that [intensive treatment of blood pressure] might be a step backward in cognition. Would you lower your own blood pressure at a risk of losing some points on your cognition?”

The subanalyses were conducted as part of the SPRINT Memory and Cognition In Decreased Hypertension (SPRINT MIND) substudy, which looked at cardiovascular and mortality outcomes in 9,361 subjects whose hypertension was managed intensively or by standard care (target systolic blood pressure less than 120 mm Hg vs. less than 140 mm Hg). The trial was stopped early because of a 25% reduction in the primary composite cardiovascular disease endpoint and a 27% reduction in all-cause mortality in the intensive-treatment group.

SPRINT MIND examined the risks of incident probable dementia, mild cognitive impairment (MCI), and a composite outcome of both. Intensive control reduced the risk of MCI by 19% and the combined outcome by 15%.

At the conference, SPRINT MIND investigators presented three long-term subanalyses with a median intervention and follow-up time of about 4 years.

Sarah Gaussoin of Wake Forest University, Winston-Salem, N.C., presented unpublished data detailing the effects of intensive control on several dementia subtypes: nonamnestic single domain, nonamnestic multidomain, amnestic single domain, and amnestic multidomain. There were 640 subjects in this analysis.

After a median of 3.3 years of intervention and 5 years of follow-up, there were no differences in the rate of incident probable dementia between the single- and multidomain nonamnestic groups. “We did see a strong 22% decreased risk in single-domain versus multidomain amnestic MCI, however,” she said.

Nicholas Pajewski, PhD, also of Wake Forest University, discussed more detailed cognitive outcomes in SPRINT MIND among 2,900 subjects who had a full battery of cognitive testing at every assessment over 5 years. The outcomes included memory deficit and processing speed.

Dr. Pajewski reported finding no significant difference between the groups in the rates of memory decline in either outcome. But there was a greater rate of decline in processing speed in the intensively treated group, he added. The difference was small but statistically significant.

The difference was largely driven by results of a single cognitive test – the Trail Making Test Part A. “It corresponded to about a 1.25-second increase over 4 years,” in processing speed on this test, Dr. Pajewski said.

There were no between-group differences in any of the other domains explored, including language, executive function, global cognitive function, or the Montreal Cognitive Assessment.

“Obviously, these results are perplexing,” given the overall positive results of SPRINT MIND, he said. “Intensive blood pressure control is a beneficial thing, and we expected to see an effect on memory, or a blunting of decline, and instead we saw some small decrements going the other way. This led us to speculate about what’s going on.”

The trial relied on a narrow definition of MCI that might have affected the outcomes. There was also a very broad range of ages in the study, ranging from 53 to 86 years. More importantly, he said, the original SPRINT study didn’t collect cognitive data at baseline, so there was no way to know how many subjects already might have had MCI when they entered the trial.

Ilya Nasrallah, MD, PhD, of the University of Pennsylvania, Philadelphia, presented MRI data on white-matter lesions, hippocampal volume fractional anisotropy in the cingulum, and cerebral blood flow. The median time between scans was 4 years, with a median treatment time of 3.4 years.

The standard-care group showed a significantly greater increase in white-matter lesion volume at the follow-up scan than did the intensive-treatment group (1.45 cm³ vs. 0.92 cm³). But the intensively treated group had significantly more brain atrophy, losing a median of 30.6 cm^3, compared with a loss of 26.9 cm³ in the standard-treatment group.

“It was a very small difference amounting to less than 1% of the total brain volume, but it was still statistically significant,” Dr. Nasrallah said.

Loss of gray-matter volume drove about two-thirds of the difference in the intensively treated group. There was a corresponding increase in cerebrospinal fluid volume that was driven by differences in the ventricles and the subarachnoid space.

However, there were no significant differences in right, left, or total hippocampal volume. There also were no differences in cingulate bundle anisotropy or cerebral blood flow.

SPRINT was funded by the National Institutes of Health. None of the investigators reported having financial conflicts of interest.

[email protected]

SAN DIEGO – Intensive blood pressure control over 4 years reduced the overall risk of all-cause dementia by 17%, compared with standard care, but in subanalyses of the Systolic Blood Pressure Intervention Trial (SPRINT) it was also associated with significant decreases in cognitive function and total brain volume, researchers said at the Clinical Trials on Alzheimer’s Disease conference.

Michele G. Sullivan/MDedge News

Whether these between-group differences were clinically meaningful was the topic of some debate, but they were enough to prompt Mary Sano, PhD, to strongly state her reservations.

“The cardiovascular effects of SPRINT were impressive, but I am concerned about minimizing the potentially negative effect on cognition,” said Dr. Sano, professor of psychiatry and director of the Alzheimer’s Disease Research Center at the Icahn School of Medicine at Mount Sinai, New York. “Do I really want to treat a healthy, nonimpaired patient like this if I have to warn them that their cognition might actually get worse? We just cannot minimize this risk. There is very strong evidence that [intensive treatment of blood pressure] might be a step backward in cognition. Would you lower your own blood pressure at a risk of losing some points on your cognition?”

The subanalyses were conducted as part of the SPRINT Memory and Cognition In Decreased Hypertension (SPRINT MIND) substudy, which looked at cardiovascular and mortality outcomes in 9,361 subjects whose hypertension was managed intensively or by standard care (target systolic blood pressure less than 120 mm Hg vs. less than 140 mm Hg). The trial was stopped early because of a 25% reduction in the primary composite cardiovascular disease endpoint and a 27% reduction in all-cause mortality in the intensive-treatment group.

SPRINT MIND examined the risks of incident probable dementia, mild cognitive impairment (MCI), and a composite outcome of both. Intensive control reduced the risk of MCI by 19% and the combined outcome by 15%.

At the conference, SPRINT MIND investigators presented three long-term subanalyses with a median intervention and follow-up time of about 4 years.

Sarah Gaussoin of Wake Forest University, Winston-Salem, N.C., presented unpublished data detailing the effects of intensive control on several dementia subtypes: nonamnestic single domain, nonamnestic multidomain, amnestic single domain, and amnestic multidomain. There were 640 subjects in this analysis.

After a median of 3.3 years of intervention and 5 years of follow-up, there were no differences in the rate of incident probable dementia between the single- and multidomain nonamnestic groups. “We did see a strong 22% decreased risk in single-domain versus multidomain amnestic MCI, however,” she said.

Nicholas Pajewski, PhD, also of Wake Forest University, discussed more detailed cognitive outcomes in SPRINT MIND among 2,900 subjects who had a full battery of cognitive testing at every assessment over 5 years. The outcomes included memory deficit and processing speed.

Dr. Pajewski reported finding no significant difference between the groups in the rates of memory decline in either outcome. But there was a greater rate of decline in processing speed in the intensively treated group, he added. The difference was small but statistically significant.

The difference was largely driven by results of a single cognitive test – the Trail Making Test Part A. “It corresponded to about a 1.25-second increase over 4 years,” in processing speed on this test, Dr. Pajewski said.

There were no between-group differences in any of the other domains explored, including language, executive function, global cognitive function, or the Montreal Cognitive Assessment.

“Obviously, these results are perplexing,” given the overall positive results of SPRINT MIND, he said. “Intensive blood pressure control is a beneficial thing, and we expected to see an effect on memory, or a blunting of decline, and instead we saw some small decrements going the other way. This led us to speculate about what’s going on.”

The trial relied on a narrow definition of MCI that might have affected the outcomes. There was also a very broad range of ages in the study, ranging from 53 to 86 years. More importantly, he said, the original SPRINT study didn’t collect cognitive data at baseline, so there was no way to know how many subjects already might have had MCI when they entered the trial.

Ilya Nasrallah, MD, PhD, of the University of Pennsylvania, Philadelphia, presented MRI data on white-matter lesions, hippocampal volume fractional anisotropy in the cingulum, and cerebral blood flow. The median time between scans was 4 years, with a median treatment time of 3.4 years.

The standard-care group showed a significantly greater increase in white-matter lesion volume at the follow-up scan than did the intensive-treatment group (1.45 cm³ vs. 0.92 cm³). But the intensively treated group had significantly more brain atrophy, losing a median of 30.6 cm^3, compared with a loss of 26.9 cm³ in the standard-treatment group.

“It was a very small difference amounting to less than 1% of the total brain volume, but it was still statistically significant,” Dr. Nasrallah said.

Loss of gray-matter volume drove about two-thirds of the difference in the intensively treated group. There was a corresponding increase in cerebrospinal fluid volume that was driven by differences in the ventricles and the subarachnoid space.

However, there were no significant differences in right, left, or total hippocampal volume. There also were no differences in cingulate bundle anisotropy or cerebral blood flow.

SPRINT was funded by the National Institutes of Health. None of the investigators reported having financial conflicts of interest.

[email protected]

About 20% of patients who receive tablets containing 50 mg or 100 mg of ubrogepant for the acute treatment of migraine are pain free 2 hours later, compared with 12% of patients who receive placebo, according to phase 3 trial results published Dec. 4 in the New England Journal of Medicine. In addition, about 38% of patients who receive ubrogepant no longer have their most bothersome migraine-associated symptom, such as photophobia, phonophobia, or nausea, at 2 hours, compared with 28% of patients who receive placebo, said David W. Dodick, MD, and colleagues.

Dr. Dodick, professor of neurology at the Mayo Clinic in Phoenix, and his coauthors described efficacy and safety results from the ACHIEVE I trial. Another phase 3 study of ubrogepant, ACHIEVE II, was published in JAMA in November. That trial evaluated 25- and 50-mg doses of ubrogepant versus placebo and found rates of pain freedom and absence of the most bothersome symptom in the placebo and active treatment arms that were similar to those in ACHIEVE I.

Assessing a gepant for acute migraine treatment

Ubrogepant is an oral calcitonin gene–related peptide (CGRP) receptor antagonist. Allergan, the company developing the drug, has said it expects the Food and Drug Administration to decide in December whether to approve the drug.

To compare ubrogepant 50 mg, ubrogepant 100 mg, and placebo for the acute treatment of migraine, investigators conducted the randomized ACHIEVE I trial. Researchers enrolled 1,672 adults with migraine with or without aura. They excluded patients with clinically significant cardiovascular or cerebrovascular disease. During the trial, patients treated a single migraine attack, and they had the option to take a second dose. In all, 1,436 participants took an initial dose. Patients had an average age of 40.5 years, about 88% were women, and 82% were white.

In ACHIEVE I, the most common adverse events within 48 hours of treatment were nausea, somnolence, and dry mouth, and these events occurred more frequently in the 100-mg–dose group, Dr. Dodick and colleagues reported. Among patients who received ubrogepant, serious adverse events more than 48 hours after treatment but within 30 days of treatment included appendicitis, spontaneous abortion, pericardial effusion, and seizure. No serious adverse events occurred in the placebo group.

The authors noted that, “there was no active comparator and no evaluation of consistency of effect across multiple migraine attacks; therefore it is not possible to determine whether the drug is more or less effective than standard therapies or consistently effective with repeated use.” In addition, “safety and side-effect data from this trial were based on evaluation of a single attack, and therefore safety after repeated use cannot be inferred; an extension trial has assessed the long-term safety of ubrogepant,” they said.

The present trial was performed well, commented Alan M. Rapoport, MD. “The coprimary endpoints of pain freedom and most bothersome symptom freedom, both at 2 hours after dosing, were statistically superior for both doses of ubrogepant versus placebo,” he said. “Some of the secondary endpoints, such as pain relief at 2 hours post dose and sustained pain relief from 2 to 24 hours, were statistically better than placebo.”

“Based on this data, I suspect that the FDA would approve this gepant after appropriate safety data,” said Dr. Rapoport, clinical professor of neurology at the University of California, Los Angeles and editor-in-chief of Neurology Reviews. “Many more patients need to take this drug before we can be sure it is safe and effective.”

The CGRP therapeutic landscape

“Other gepants have been shown to be effective, although some have caused a degree of liver toxicity,” said Dr. Rapoport. “Blocking the effect of CGRP on the migraine peripheral nervous system, in this case by preventing the ligand from docking at its receptor by administering an oral CGRP receptor blocker, appears to be effective.” Researchers are studying another oral gepant for similar approval, he added.

Ubrogepant stands to join other treatments targeting CGRP.

“There are currently three, and soon to be four, injectable monoclonal antibodies against CGRP functionality, which are preventive, not acute-care drugs,” Dr. Rapoport said. “The first released was a subcutaneous injection of a CGRP receptor blocker, and the other two are subcutaneous injections of CGRP ligand blockers. The last drug will be an intravenous infusion of a ligand blocker. These recently approved migraine treatments have greatly improved the lives of many of our patients, even when other preventives have failed. I expect ubrogepant and other gepants will do the same for the acute care of migraine.”

Allergan funded the trials of ubrogepant, and some of the authors are Allergan employees and stockholders. Dr. Dodick reported consulting fees and advisory board fees from Allergan and various pharmaceutical companies.

[email protected]

SOURCE: Dodick DW et al. N Engl J Med. 2019;381(23):2230-41. doi: 10.1056/NEJMoa1813049.

About 20% of patients who receive tablets containing 50 mg or 100 mg of ubrogepant for the acute treatment of migraine are pain free 2 hours later, compared with 12% of patients who receive placebo, according to phase 3 trial results published Dec. 4 in the New England Journal of Medicine. In addition, about 38% of patients who receive ubrogepant no longer have their most bothersome migraine-associated symptom, such as photophobia, phonophobia, or nausea, at 2 hours, compared with 28% of patients who receive placebo, said David W. Dodick, MD, and colleagues.

Dr. Dodick, professor of neurology at the Mayo Clinic in Phoenix, and his coauthors described efficacy and safety results from the ACHIEVE I trial. Another phase 3 study of ubrogepant, ACHIEVE II, was published in JAMA in November. That trial evaluated 25- and 50-mg doses of ubrogepant versus placebo and found rates of pain freedom and absence of the most bothersome symptom in the placebo and active treatment arms that were similar to those in ACHIEVE I.

Assessing a gepant for acute migraine treatment

Ubrogepant is an oral calcitonin gene–related peptide (CGRP) receptor antagonist. Allergan, the company developing the drug, has said it expects the Food and Drug Administration to decide in December whether to approve the drug.

To compare ubrogepant 50 mg, ubrogepant 100 mg, and placebo for the acute treatment of migraine, investigators conducted the randomized ACHIEVE I trial. Researchers enrolled 1,672 adults with migraine with or without aura. They excluded patients with clinically significant cardiovascular or cerebrovascular disease. During the trial, patients treated a single migraine attack, and they had the option to take a second dose. In all, 1,436 participants took an initial dose. Patients had an average age of 40.5 years, about 88% were women, and 82% were white.

In ACHIEVE I, the most common adverse events within 48 hours of treatment were nausea, somnolence, and dry mouth, and these events occurred more frequently in the 100-mg–dose group, Dr. Dodick and colleagues reported. Among patients who received ubrogepant, serious adverse events more than 48 hours after treatment but within 30 days of treatment included appendicitis, spontaneous abortion, pericardial effusion, and seizure. No serious adverse events occurred in the placebo group.

The authors noted that, “there was no active comparator and no evaluation of consistency of effect across multiple migraine attacks; therefore it is not possible to determine whether the drug is more or less effective than standard therapies or consistently effective with repeated use.” In addition, “safety and side-effect data from this trial were based on evaluation of a single attack, and therefore safety after repeated use cannot be inferred; an extension trial has assessed the long-term safety of ubrogepant,” they said.

The present trial was performed well, commented Alan M. Rapoport, MD. “The coprimary endpoints of pain freedom and most bothersome symptom freedom, both at 2 hours after dosing, were statistically superior for both doses of ubrogepant versus placebo,” he said. “Some of the secondary endpoints, such as pain relief at 2 hours post dose and sustained pain relief from 2 to 24 hours, were statistically better than placebo.”

“Based on this data, I suspect that the FDA would approve this gepant after appropriate safety data,” said Dr. Rapoport, clinical professor of neurology at the University of California, Los Angeles and editor-in-chief of Neurology Reviews. “Many more patients need to take this drug before we can be sure it is safe and effective.”

The CGRP therapeutic landscape

“Other gepants have been shown to be effective, although some have caused a degree of liver toxicity,” said Dr. Rapoport. “Blocking the effect of CGRP on the migraine peripheral nervous system, in this case by preventing the ligand from docking at its receptor by administering an oral CGRP receptor blocker, appears to be effective.” Researchers are studying another oral gepant for similar approval, he added.

Ubrogepant stands to join other treatments targeting CGRP.

“There are currently three, and soon to be four, injectable monoclonal antibodies against CGRP functionality, which are preventive, not acute-care drugs,” Dr. Rapoport said. “The first released was a subcutaneous injection of a CGRP receptor blocker, and the other two are subcutaneous injections of CGRP ligand blockers. The last drug will be an intravenous infusion of a ligand blocker. These recently approved migraine treatments have greatly improved the lives of many of our patients, even when other preventives have failed. I expect ubrogepant and other gepants will do the same for the acute care of migraine.”

Allergan funded the trials of ubrogepant, and some of the authors are Allergan employees and stockholders. Dr. Dodick reported consulting fees and advisory board fees from Allergan and various pharmaceutical companies.

[email protected]

SOURCE: Dodick DW et al. N Engl J Med. 2019;381(23):2230-41. doi: 10.1056/NEJMoa1813049.

About 20% of patients who receive tablets containing 50 mg or 100 mg of ubrogepant for the acute treatment of migraine are pain free 2 hours later, compared with 12% of patients who receive placebo, according to phase 3 trial results published Dec. 4 in the New England Journal of Medicine. In addition, about 38% of patients who receive ubrogepant no longer have their most bothersome migraine-associated symptom, such as photophobia, phonophobia, or nausea, at 2 hours, compared with 28% of patients who receive placebo, said David W. Dodick, MD, and colleagues.

Dr. Dodick, professor of neurology at the Mayo Clinic in Phoenix, and his coauthors described efficacy and safety results from the ACHIEVE I trial. Another phase 3 study of ubrogepant, ACHIEVE II, was published in JAMA in November. That trial evaluated 25- and 50-mg doses of ubrogepant versus placebo and found rates of pain freedom and absence of the most bothersome symptom in the placebo and active treatment arms that were similar to those in ACHIEVE I.

Assessing a gepant for acute migraine treatment

Ubrogepant is an oral calcitonin gene–related peptide (CGRP) receptor antagonist. Allergan, the company developing the drug, has said it expects the Food and Drug Administration to decide in December whether to approve the drug.

To compare ubrogepant 50 mg, ubrogepant 100 mg, and placebo for the acute treatment of migraine, investigators conducted the randomized ACHIEVE I trial. Researchers enrolled 1,672 adults with migraine with or without aura. They excluded patients with clinically significant cardiovascular or cerebrovascular disease. During the trial, patients treated a single migraine attack, and they had the option to take a second dose. In all, 1,436 participants took an initial dose. Patients had an average age of 40.5 years, about 88% were women, and 82% were white.

In ACHIEVE I, the most common adverse events within 48 hours of treatment were nausea, somnolence, and dry mouth, and these events occurred more frequently in the 100-mg–dose group, Dr. Dodick and colleagues reported. Among patients who received ubrogepant, serious adverse events more than 48 hours after treatment but within 30 days of treatment included appendicitis, spontaneous abortion, pericardial effusion, and seizure. No serious adverse events occurred in the placebo group.

The authors noted that, “there was no active comparator and no evaluation of consistency of effect across multiple migraine attacks; therefore it is not possible to determine whether the drug is more or less effective than standard therapies or consistently effective with repeated use.” In addition, “safety and side-effect data from this trial were based on evaluation of a single attack, and therefore safety after repeated use cannot be inferred; an extension trial has assessed the long-term safety of ubrogepant,” they said.

The present trial was performed well, commented Alan M. Rapoport, MD. “The coprimary endpoints of pain freedom and most bothersome symptom freedom, both at 2 hours after dosing, were statistically superior for both doses of ubrogepant versus placebo,” he said. “Some of the secondary endpoints, such as pain relief at 2 hours post dose and sustained pain relief from 2 to 24 hours, were statistically better than placebo.”

“Based on this data, I suspect that the FDA would approve this gepant after appropriate safety data,” said Dr. Rapoport, clinical professor of neurology at the University of California, Los Angeles and editor-in-chief of Neurology Reviews. “Many more patients need to take this drug before we can be sure it is safe and effective.”

The CGRP therapeutic landscape

“Other gepants have been shown to be effective, although some have caused a degree of liver toxicity,” said Dr. Rapoport. “Blocking the effect of CGRP on the migraine peripheral nervous system, in this case by preventing the ligand from docking at its receptor by administering an oral CGRP receptor blocker, appears to be effective.” Researchers are studying another oral gepant for similar approval, he added.

Ubrogepant stands to join other treatments targeting CGRP.

“There are currently three, and soon to be four, injectable monoclonal antibodies against CGRP functionality, which are preventive, not acute-care drugs,” Dr. Rapoport said. “The first released was a subcutaneous injection of a CGRP receptor blocker, and the other two are subcutaneous injections of CGRP ligand blockers. The last drug will be an intravenous infusion of a ligand blocker. These recently approved migraine treatments have greatly improved the lives of many of our patients, even when other preventives have failed. I expect ubrogepant and other gepants will do the same for the acute care of migraine.”

Allergan funded the trials of ubrogepant, and some of the authors are Allergan employees and stockholders. Dr. Dodick reported consulting fees and advisory board fees from Allergan and various pharmaceutical companies.

[email protected]

SOURCE: Dodick DW et al. N Engl J Med. 2019;381(23):2230-41. doi: 10.1056/NEJMoa1813049.

CHICAGO – Individuals who sustain gunshot wounds have an increased risk for rehospitalization years, and even decades, after their initial injury.

Kateywhat/ThinkStock

A study of individuals at a single institution who were hospitalized and had a prior history of gunshot wound found some patterns of injury that set patients up for a greater likelihood of readmission.

In particular, patients who sustained visceral gunshot wounds were over six times more likely to be readmitted to the hospital, Corbin Pomeranz, MD, a radiology resident at Thomas Jefferson University, Philadelphia, said in an interview at the annual meeting of the Radiological Society of North America. Dr. Pomeranz led the retrospective study that begins to fill a knowledge gap about what happens over the long term to those who sustain gunshot wounds.

“There continues to be profound lack of substantial information related to gun violence, particularly in predicting long-term outcomes,” Dr. Pomeranz and coauthors wrote in the abstract accompanying the presentation.

The researchers performed a single-site retrospective analysis over 3 months in 2018, tapping into an imaging database and looking for inpatient imaging exams that were nonacute, but related to gunshot wounds. From this information, the researchers went back to the original gunshot wound injury imaging, and recorded the pattern of injury, classifying wounds as neurologic, vascular, visceral, musculoskeletal, or involving multiple systems.

The investigators were able to glean additional information including the initial admitting hospital unit, information about interval admissions or surgeries, and demographic data. Regarding the nature of the gunshot injury itself, Dr. Pomeranz and coauthors went back to the earlier imaging studies to note bullet morphology, recording whether the bullet was intact, deformed, or had splintered into shrapnel within injured tissues.

In all, 174 imaging studies involving 110 patients were examined. Men made up 92% of the study population; the average age was 49.7 years. Neurologic and visceral gunshot wounds were moderately correlated with subsequent readmission (r = .436; P less than .001). However, some of this effect was blunted when patient age was controlled for in the statistical analysis.

Patients who were initially admitted to the intensive care unit, and who presumably had more severe injuries, were also more likely to be readmitted (r = .494, P less than .001). Here, “controlling for age had very little effect on the strength of the relationship between these two variables,” noted Dr. Pomeranz and coauthors.

A more elaborate statistical model incorporated several independent variables including age, type of injury, and body region involved, as well as bullet morphology. In this model, visceral injury was the strongest predictor for readmission, with an odds ratio of 6.44.

Dr. Pomeranz said that both the initial gunshot wound and subsequent gaps in care can contribute to readmissions. A patient who has a spinal cord injury may not be reimbursed adequately for supportive cushioning, or an appropriate wheelchair, and so may require admission for decubitus ulcers.

The number of admissions for osteomyelitis, which made up more than half of the subsequent admissions, initially surprised Dr. Pomeranz, until he realized that lack of mobility and sensory losses from gunshot-induced spinal cord injuries could easily lead to nonhealing lower extremity wounds, with osteomyelitis as a sequela.

Several patients were admitted for small bowel obstructions with no interval surgery since treatment for the gunshot wound. These readmissions, said Dr. Pomeranz, were assessed as related to the gunshot wound since it’s extremely rare for a patient with no history of abdominal surgery and no malignancy to have a small bowel obstruction. Exploratory laparotomies are common in the context of abdominal trauma caused by gunshot wounds, and either the gunshot itself or the laparotomy was the likely cause of adhesions.

Dr. Pomeranz acknowledged the many limitations of the study, but pointed out that some will be addressed when he and his coauthors conduct a larger study they have planned to look at readmissions from gunshot wounds at multiple hospitals in the Philadelphia area. The small sample size in the current study meant that the impact of socioeconomic status and other lifestyle and social variables and comorbidities couldn’t be adequately addressed in the statistical analysis. By casting a wider net within the greater Philadelphia area, the investigators should be able to track patients who receive care in more than one hospital system, increasing participant numbers, he said.

“Morbidity and outcomes from gun violence can only be assessed after a firm understanding of injury patterns on imaging,” noted Dr. Pomeranz. He said that interdisciplinary research investigating individual and societal short- and long-term costs of gun violence is sorely needed to inform public policy.

Dr. Pomeranz reported no outside sources of funding and reported that he had no conflicts of interest.

[email protected]

SOURCE: Pomeranz C et al. RSNA 2019, Presentation HP226-SD-THA3.

CHICAGO – Individuals who sustain gunshot wounds have an increased risk for rehospitalization years, and even decades, after their initial injury.

Kateywhat/ThinkStock

A study of individuals at a single institution who were hospitalized and had a prior history of gunshot wound found some patterns of injury that set patients up for a greater likelihood of readmission.

In particular, patients who sustained visceral gunshot wounds were over six times more likely to be readmitted to the hospital, Corbin Pomeranz, MD, a radiology resident at Thomas Jefferson University, Philadelphia, said in an interview at the annual meeting of the Radiological Society of North America. Dr. Pomeranz led the retrospective study that begins to fill a knowledge gap about what happens over the long term to those who sustain gunshot wounds.

“There continues to be profound lack of substantial information related to gun violence, particularly in predicting long-term outcomes,” Dr. Pomeranz and coauthors wrote in the abstract accompanying the presentation.

The researchers performed a single-site retrospective analysis over 3 months in 2018, tapping into an imaging database and looking for inpatient imaging exams that were nonacute, but related to gunshot wounds. From this information, the researchers went back to the original gunshot wound injury imaging, and recorded the pattern of injury, classifying wounds as neurologic, vascular, visceral, musculoskeletal, or involving multiple systems.

The investigators were able to glean additional information including the initial admitting hospital unit, information about interval admissions or surgeries, and demographic data. Regarding the nature of the gunshot injury itself, Dr. Pomeranz and coauthors went back to the earlier imaging studies to note bullet morphology, recording whether the bullet was intact, deformed, or had splintered into shrapnel within injured tissues.

In all, 174 imaging studies involving 110 patients were examined. Men made up 92% of the study population; the average age was 49.7 years. Neurologic and visceral gunshot wounds were moderately correlated with subsequent readmission (r = .436; P less than .001). However, some of this effect was blunted when patient age was controlled for in the statistical analysis.

Patients who were initially admitted to the intensive care unit, and who presumably had more severe injuries, were also more likely to be readmitted (r = .494, P less than .001). Here, “controlling for age had very little effect on the strength of the relationship between these two variables,” noted Dr. Pomeranz and coauthors.

A more elaborate statistical model incorporated several independent variables including age, type of injury, and body region involved, as well as bullet morphology. In this model, visceral injury was the strongest predictor for readmission, with an odds ratio of 6.44.

Dr. Pomeranz said that both the initial gunshot wound and subsequent gaps in care can contribute to readmissions. A patient who has a spinal cord injury may not be reimbursed adequately for supportive cushioning, or an appropriate wheelchair, and so may require admission for decubitus ulcers.

The number of admissions for osteomyelitis, which made up more than half of the subsequent admissions, initially surprised Dr. Pomeranz, until he realized that lack of mobility and sensory losses from gunshot-induced spinal cord injuries could easily lead to nonhealing lower extremity wounds, with osteomyelitis as a sequela.

Several patients were admitted for small bowel obstructions with no interval surgery since treatment for the gunshot wound. These readmissions, said Dr. Pomeranz, were assessed as related to the gunshot wound since it’s extremely rare for a patient with no history of abdominal surgery and no malignancy to have a small bowel obstruction. Exploratory laparotomies are common in the context of abdominal trauma caused by gunshot wounds, and either the gunshot itself or the laparotomy was the likely cause of adhesions.

Dr. Pomeranz acknowledged the many limitations of the study, but pointed out that some will be addressed when he and his coauthors conduct a larger study they have planned to look at readmissions from gunshot wounds at multiple hospitals in the Philadelphia area. The small sample size in the current study meant that the impact of socioeconomic status and other lifestyle and social variables and comorbidities couldn’t be adequately addressed in the statistical analysis. By casting a wider net within the greater Philadelphia area, the investigators should be able to track patients who receive care in more than one hospital system, increasing participant numbers, he said.

“Morbidity and outcomes from gun violence can only be assessed after a firm understanding of injury patterns on imaging,” noted Dr. Pomeranz. He said that interdisciplinary research investigating individual and societal short- and long-term costs of gun violence is sorely needed to inform public policy.

Dr. Pomeranz reported no outside sources of funding and reported that he had no conflicts of interest.

[email protected]

SOURCE: Pomeranz C et al. RSNA 2019, Presentation HP226-SD-THA3.

CHICAGO – Individuals who sustain gunshot wounds have an increased risk for rehospitalization years, and even decades, after their initial injury.

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A study of individuals at a single institution who were hospitalized and had a prior history of gunshot wound found some patterns of injury that set patients up for a greater likelihood of readmission.

In particular, patients who sustained visceral gunshot wounds were over six times more likely to be readmitted to the hospital, Corbin Pomeranz, MD, a radiology resident at Thomas Jefferson University, Philadelphia, said in an interview at the annual meeting of the Radiological Society of North America. Dr. Pomeranz led the retrospective study that begins to fill a knowledge gap about what happens over the long term to those who sustain gunshot wounds.

“There continues to be profound lack of substantial information related to gun violence, particularly in predicting long-term outcomes,” Dr. Pomeranz and coauthors wrote in the abstract accompanying the presentation.

The researchers performed a single-site retrospective analysis over 3 months in 2018, tapping into an imaging database and looking for inpatient imaging exams that were nonacute, but related to gunshot wounds. From this information, the researchers went back to the original gunshot wound injury imaging, and recorded the pattern of injury, classifying wounds as neurologic, vascular, visceral, musculoskeletal, or involving multiple systems.

The investigators were able to glean additional information including the initial admitting hospital unit, information about interval admissions or surgeries, and demographic data. Regarding the nature of the gunshot injury itself, Dr. Pomeranz and coauthors went back to the earlier imaging studies to note bullet morphology, recording whether the bullet was intact, deformed, or had splintered into shrapnel within injured tissues.

In all, 174 imaging studies involving 110 patients were examined. Men made up 92% of the study population; the average age was 49.7 years. Neurologic and visceral gunshot wounds were moderately correlated with subsequent readmission (r = .436; P less than .001). However, some of this effect was blunted when patient age was controlled for in the statistical analysis.

Patients who were initially admitted to the intensive care unit, and who presumably had more severe injuries, were also more likely to be readmitted (r = .494, P less than .001). Here, “controlling for age had very little effect on the strength of the relationship between these two variables,” noted Dr. Pomeranz and coauthors.

A more elaborate statistical model incorporated several independent variables including age, type of injury, and body region involved, as well as bullet morphology. In this model, visceral injury was the strongest predictor for readmission, with an odds ratio of 6.44.

Dr. Pomeranz said that both the initial gunshot wound and subsequent gaps in care can contribute to readmissions. A patient who has a spinal cord injury may not be reimbursed adequately for supportive cushioning, or an appropriate wheelchair, and so may require admission for decubitus ulcers.

The number of admissions for osteomyelitis, which made up more than half of the subsequent admissions, initially surprised Dr. Pomeranz, until he realized that lack of mobility and sensory losses from gunshot-induced spinal cord injuries could easily lead to nonhealing lower extremity wounds, with osteomyelitis as a sequela.

Several patients were admitted for small bowel obstructions with no interval surgery since treatment for the gunshot wound. These readmissions, said Dr. Pomeranz, were assessed as related to the gunshot wound since it’s extremely rare for a patient with no history of abdominal surgery and no malignancy to have a small bowel obstruction. Exploratory laparotomies are common in the context of abdominal trauma caused by gunshot wounds, and either the gunshot itself or the laparotomy was the likely cause of adhesions.

Dr. Pomeranz acknowledged the many limitations of the study, but pointed out that some will be addressed when he and his coauthors conduct a larger study they have planned to look at readmissions from gunshot wounds at multiple hospitals in the Philadelphia area. The small sample size in the current study meant that the impact of socioeconomic status and other lifestyle and social variables and comorbidities couldn’t be adequately addressed in the statistical analysis. By casting a wider net within the greater Philadelphia area, the investigators should be able to track patients who receive care in more than one hospital system, increasing participant numbers, he said.

“Morbidity and outcomes from gun violence can only be assessed after a firm understanding of injury patterns on imaging,” noted Dr. Pomeranz. He said that interdisciplinary research investigating individual and societal short- and long-term costs of gun violence is sorely needed to inform public policy.

Dr. Pomeranz reported no outside sources of funding and reported that he had no conflicts of interest.

[email protected]

SOURCE: Pomeranz C et al. RSNA 2019, Presentation HP226-SD-THA3.