Clinical Review

Eating disorders affect nearly 1% of US adults,¹ and disordered eating, or unspecified eating disorder, affects at least 1% of all pregnancies.² Among 739 pregnant women assessed with the Eating Disorder Diagnostic scale, 7.5% of patients met criteria for an eating disorder, with 8.8% of women reporting binge eating and 2.3% of pregnant women engaging in regular compensatory behaviors. In fact, 23.4% of the study population expressed concerns about pregnancy-related weight gain and body shape.³ Eating disorders during pregnancy are more common than previously thought, and they create unique clinical challenges for obstetric providers.

Types of eating disorders

There are 3 major types of eating disorders: anorexia nervosa, bulimia nervosa, and binge eating disorder, with significant fluidity existing between all 3 conditions.

Anorexia nervosa is a condition in which an individual believes he or she is significantly overweight despite being underweight. Patients with anorexia nervosa often restrict food intake and have compulsive rituals around eating and exercise, leading to weight loss and starvation.⁴

Bulimia nervosa is marked by intensive dieting, uncontrolled episodes of overeating, and compensatory behaviors.⁴ Compensatory behaviors include self-induced vomiting; excessive exercise; and misuse of laxatives, diuretics, or other medications.

Binge eating disorder is classified as recurrent episodes of uncontrolled overeating without compensatory purging behaviors, leading to excessive weight gain.⁴

Eating disorders and pregnancy

Pregnancy can impact the course of pre­existing eating disorders, and women also can develop symptoms of eating disorders for the first time during pregnancy. This is clinically significant as there are both maternal and fetal consequences to a mother’s disordered eating.

The risks of anorexia nervosa include vitamin deficiencies (vitamin B12/folate), dehydration leading to renal injury and electrolyte imbalances, hypoglycemia, abnormal lipid profiles, cardiac arrhythmia, and even death. The mortality rate of patients with anorexia nervosa may approach 10%; however, death during pregnancy is quite rare.² Bulimia nervosa also carries the risks of protein and vitamin deficiencies, hypoglycemia and hyperglycemia, and death, with mortality estimated at 7% for those with a 5-year history of the illness. However, death in pregnancy due to the condition is again quite rare.⁵

Eating disorders can cause significant maternal and fetal complications during pregnancy and postpartum.

Maternal complications. When women with eating disorders become pregnant, they have increased risks of some pregnancy complications. Approximately 10% to 25% of pregnant women with eating disorders develop hyperemesis gravidarum.⁶ The nausea can serve as a trigger for a woman with an eating disorder, particularly among women with a history of purging behaviors.

Cesarean delivery is more common among women with eating disorders, which may be due to preexisting fetal compromise, leading to poor tolerance of labor, or to clinicians perceiving these pregnancies as higher risk.⁷

It is well known that eating disorders are highly comorbid with depression and other psychiatric conditions. In fact, 30% to 40% of women with an eating disorder develop symptoms of postpartum depression.⁸

Continue to: Fetal risks and complications...

Fetal risks and complications. Excessive caloric restriction and dieting can lead to folate deficiency, which in turn increases the risk of neural tube defects. Such defects are more common among women with eating disorders.⁹ Intrauterine growth restriction also can be a concern, most likely because of maternal malnutrition and poor maternal weight gain.¹⁰ In addition, women with eating disorders are more likely to have a preterm delivery or experience perinatal mortality or stillbirth.¹⁰

Bulimia nervosa is associated with low birthweight, while anorexia nervosa is associated with the very premature birth, low birthweight, and perinatal death.¹¹ Eating disorders during pregnancy can have long-term psychological impacts on children, including increased likelihood of childhood hyperactivity, conduct, and adjustment disorder.¹²

Assessing patients for an eating disorder

Diagnosis of eating disorders is an interview-guided process using clinical criteria of the Diagnostic and Statistical Manual of Mental Disorders, 5th edition.⁴ The Eating Disorder Examination is a semi-structured interview composed of 4 subsections (restraint, eating concern, shape concern, and weight concern). The interview’s aim is to assess the psychopathology associated with eating disorders, and it is used in research settings rather than clinically.

1. Do you make yourself sick because you feel uncomfortably full?
2. Do you worry that you have lost control over how much you eat?
3. Have you recently lost more than one stone (14 lb) in a 3-month period?
4. Do you believe yourself to be fat when others say you are too thin?
5. Would you say that food dominates your life?

Referral. Patients for whom you have a concern for any eating disorder should be referred to a psychiatrist for formal diagnosis. Integrated multidisciplinary care of pregnant patients with eating disorders is necessary to improve maternal and fetal outcomes. Care teams should include obstetricians or maternal-fetal medicine clinicians experienced in caring for patients with eating disorders, psychiatrists, psychologists, nutritionists, and social workers. General treatment principles require an assessment for appropriate setting of intervention, which depends on presentation severity, assessment of nutritional status, treatment of psychiatric comorbidity, and psychotherapeutic intervention.

Overall management strategy

The initial treatment strategy for pregnant women with eating disorders should involve evaluating for severe illness and life-threatening complications of the specific disorder. All patients should be screened for suicidal ideation, severe malnutrition, electrolyte abnormalities, dehydration, hemodynamic instability, and cardiac arrhythmia. Patients with any of these severe features should be admitted for medical hospitalization and psychiatric evaluation.¹⁴ Patients that are hospitalized should be watched closely for refeeding syndrome—potentially life threatening metabolic disturbances that occur when nutrition is reinstituted to patients who are severely malnourished.

Patients without severe features or acute life-threatening complications can be managed safely on an outpatient basis with close medical monitoring. Psychiatric providers should be involved to assess for treatment needs including psychotherapy and psychotropic medications. There are numerous pharmacologic options available for patients, with the use of selective serotonin reuptake inhibitors (SSRIs) most common. While SSRI use has been controversial in pregnancy in the past, the risks of untreated illness carry risk to the mother and unborn child that outweigh the small risks associated with SSRI exposure in pregnancy.¹⁵

Women should have established care with a nutritionist or dietician who can ensure adequate counseling regarding meal planning and multivitamin supplementation. The numerous food restrictions in pregnancy, such as avoidance of unpasteurized cheese or deli meats, may be triggering for many patients with a history of restrictive eating.

One of the greatest difficulties for women with disordered eating in pregnancy revolves around weight gain. Many patients find the various measurements of pregnancy (maternal weight gain, fetal weight, fetal heart rate, and fundal height) triggering, which can make appropriate maternal and fetal weight gain in pregnancy very challenging. One strategy for managing this includes using fetal weight and growth as a surrogate for appropriate maternal gestational weight gain. One other strategy involves blind weights, where the woman is turned away from the scale so her weight is not disclosed to her. Patients often will not be able to achieve the expected 28 to 40 lb of pregnancy weight gain. It is best to have an open, honest conversation in early pregnancy to discuss how she would like to address weight in her pregnancy.

Continue to: Postpregnancy concerns...

Postpregnancy concerns

Patients with eating disorders are at high risk of relapse in the postpartum period, even if they are able to achieve full remission in pregnancy. Rapid postpartum weight loss may be a sign of disordered eating. Postpartum depression also is a concern, and women should be followed closely for surveillance of symptoms. Finally, postpartum contraception is extremely important. The menstrual irregularities that are common among women with eating disorders along with common misconceptions regarding fertility in the postpartum period increase the risk of unplanned pregnancy.

Remain cognizant of eating disorders

A clear surveillance plan early in the pregnancy that is developed in conjunction with the patient and her care team is crucial in improving maternal and fetal outcomes among women with an eating disorder. Clinician knowledge of complications and risks specific to disordered eating and pregnancy can affect outcomes for both mother and baby.

Eating disorders affect nearly 1% of US adults,¹ and disordered eating, or unspecified eating disorder, affects at least 1% of all pregnancies.² Among 739 pregnant women assessed with the Eating Disorder Diagnostic scale, 7.5% of patients met criteria for an eating disorder, with 8.8% of women reporting binge eating and 2.3% of pregnant women engaging in regular compensatory behaviors. In fact, 23.4% of the study population expressed concerns about pregnancy-related weight gain and body shape.³ Eating disorders during pregnancy are more common than previously thought, and they create unique clinical challenges for obstetric providers.

Types of eating disorders

There are 3 major types of eating disorders: anorexia nervosa, bulimia nervosa, and binge eating disorder, with significant fluidity existing between all 3 conditions.

Anorexia nervosa is a condition in which an individual believes he or she is significantly overweight despite being underweight. Patients with anorexia nervosa often restrict food intake and have compulsive rituals around eating and exercise, leading to weight loss and starvation.⁴

Bulimia nervosa is marked by intensive dieting, uncontrolled episodes of overeating, and compensatory behaviors.⁴ Compensatory behaviors include self-induced vomiting; excessive exercise; and misuse of laxatives, diuretics, or other medications.

Binge eating disorder is classified as recurrent episodes of uncontrolled overeating without compensatory purging behaviors, leading to excessive weight gain.⁴

Eating disorders and pregnancy

Pregnancy can impact the course of pre­existing eating disorders, and women also can develop symptoms of eating disorders for the first time during pregnancy. This is clinically significant as there are both maternal and fetal consequences to a mother’s disordered eating.

The risks of anorexia nervosa include vitamin deficiencies (vitamin B12/folate), dehydration leading to renal injury and electrolyte imbalances, hypoglycemia, abnormal lipid profiles, cardiac arrhythmia, and even death. The mortality rate of patients with anorexia nervosa may approach 10%; however, death during pregnancy is quite rare.² Bulimia nervosa also carries the risks of protein and vitamin deficiencies, hypoglycemia and hyperglycemia, and death, with mortality estimated at 7% for those with a 5-year history of the illness. However, death in pregnancy due to the condition is again quite rare.⁵

Eating disorders can cause significant maternal and fetal complications during pregnancy and postpartum.

Maternal complications. When women with eating disorders become pregnant, they have increased risks of some pregnancy complications. Approximately 10% to 25% of pregnant women with eating disorders develop hyperemesis gravidarum.⁶ The nausea can serve as a trigger for a woman with an eating disorder, particularly among women with a history of purging behaviors.

Cesarean delivery is more common among women with eating disorders, which may be due to preexisting fetal compromise, leading to poor tolerance of labor, or to clinicians perceiving these pregnancies as higher risk.⁷

It is well known that eating disorders are highly comorbid with depression and other psychiatric conditions. In fact, 30% to 40% of women with an eating disorder develop symptoms of postpartum depression.⁸

Continue to: Fetal risks and complications...

Fetal risks and complications. Excessive caloric restriction and dieting can lead to folate deficiency, which in turn increases the risk of neural tube defects. Such defects are more common among women with eating disorders.⁹ Intrauterine growth restriction also can be a concern, most likely because of maternal malnutrition and poor maternal weight gain.¹⁰ In addition, women with eating disorders are more likely to have a preterm delivery or experience perinatal mortality or stillbirth.¹⁰

Bulimia nervosa is associated with low birthweight, while anorexia nervosa is associated with the very premature birth, low birthweight, and perinatal death.¹¹ Eating disorders during pregnancy can have long-term psychological impacts on children, including increased likelihood of childhood hyperactivity, conduct, and adjustment disorder.¹²

Assessing patients for an eating disorder

Diagnosis of eating disorders is an interview-guided process using clinical criteria of the Diagnostic and Statistical Manual of Mental Disorders, 5th edition.⁴ The Eating Disorder Examination is a semi-structured interview composed of 4 subsections (restraint, eating concern, shape concern, and weight concern). The interview’s aim is to assess the psychopathology associated with eating disorders, and it is used in research settings rather than clinically.

1. Do you make yourself sick because you feel uncomfortably full?
2. Do you worry that you have lost control over how much you eat?
3. Have you recently lost more than one stone (14 lb) in a 3-month period?
4. Do you believe yourself to be fat when others say you are too thin?
5. Would you say that food dominates your life?

Referral. Patients for whom you have a concern for any eating disorder should be referred to a psychiatrist for formal diagnosis. Integrated multidisciplinary care of pregnant patients with eating disorders is necessary to improve maternal and fetal outcomes. Care teams should include obstetricians or maternal-fetal medicine clinicians experienced in caring for patients with eating disorders, psychiatrists, psychologists, nutritionists, and social workers. General treatment principles require an assessment for appropriate setting of intervention, which depends on presentation severity, assessment of nutritional status, treatment of psychiatric comorbidity, and psychotherapeutic intervention.

Overall management strategy

The initial treatment strategy for pregnant women with eating disorders should involve evaluating for severe illness and life-threatening complications of the specific disorder. All patients should be screened for suicidal ideation, severe malnutrition, electrolyte abnormalities, dehydration, hemodynamic instability, and cardiac arrhythmia. Patients with any of these severe features should be admitted for medical hospitalization and psychiatric evaluation.¹⁴ Patients that are hospitalized should be watched closely for refeeding syndrome—potentially life threatening metabolic disturbances that occur when nutrition is reinstituted to patients who are severely malnourished.

Patients without severe features or acute life-threatening complications can be managed safely on an outpatient basis with close medical monitoring. Psychiatric providers should be involved to assess for treatment needs including psychotherapy and psychotropic medications. There are numerous pharmacologic options available for patients, with the use of selective serotonin reuptake inhibitors (SSRIs) most common. While SSRI use has been controversial in pregnancy in the past, the risks of untreated illness carry risk to the mother and unborn child that outweigh the small risks associated with SSRI exposure in pregnancy.¹⁵

Women should have established care with a nutritionist or dietician who can ensure adequate counseling regarding meal planning and multivitamin supplementation. The numerous food restrictions in pregnancy, such as avoidance of unpasteurized cheese or deli meats, may be triggering for many patients with a history of restrictive eating.

One of the greatest difficulties for women with disordered eating in pregnancy revolves around weight gain. Many patients find the various measurements of pregnancy (maternal weight gain, fetal weight, fetal heart rate, and fundal height) triggering, which can make appropriate maternal and fetal weight gain in pregnancy very challenging. One strategy for managing this includes using fetal weight and growth as a surrogate for appropriate maternal gestational weight gain. One other strategy involves blind weights, where the woman is turned away from the scale so her weight is not disclosed to her. Patients often will not be able to achieve the expected 28 to 40 lb of pregnancy weight gain. It is best to have an open, honest conversation in early pregnancy to discuss how she would like to address weight in her pregnancy.

Continue to: Postpregnancy concerns...

Postpregnancy concerns

Patients with eating disorders are at high risk of relapse in the postpartum period, even if they are able to achieve full remission in pregnancy. Rapid postpartum weight loss may be a sign of disordered eating. Postpartum depression also is a concern, and women should be followed closely for surveillance of symptoms. Finally, postpartum contraception is extremely important. The menstrual irregularities that are common among women with eating disorders along with common misconceptions regarding fertility in the postpartum period increase the risk of unplanned pregnancy.

Remain cognizant of eating disorders

A clear surveillance plan early in the pregnancy that is developed in conjunction with the patient and her care team is crucial in improving maternal and fetal outcomes among women with an eating disorder. Clinician knowledge of complications and risks specific to disordered eating and pregnancy can affect outcomes for both mother and baby.

Eating disorders affect nearly 1% of US adults,¹ and disordered eating, or unspecified eating disorder, affects at least 1% of all pregnancies.² Among 739 pregnant women assessed with the Eating Disorder Diagnostic scale, 7.5% of patients met criteria for an eating disorder, with 8.8% of women reporting binge eating and 2.3% of pregnant women engaging in regular compensatory behaviors. In fact, 23.4% of the study population expressed concerns about pregnancy-related weight gain and body shape.³ Eating disorders during pregnancy are more common than previously thought, and they create unique clinical challenges for obstetric providers.

Types of eating disorders

There are 3 major types of eating disorders: anorexia nervosa, bulimia nervosa, and binge eating disorder, with significant fluidity existing between all 3 conditions.

Anorexia nervosa is a condition in which an individual believes he or she is significantly overweight despite being underweight. Patients with anorexia nervosa often restrict food intake and have compulsive rituals around eating and exercise, leading to weight loss and starvation.⁴

Bulimia nervosa is marked by intensive dieting, uncontrolled episodes of overeating, and compensatory behaviors.⁴ Compensatory behaviors include self-induced vomiting; excessive exercise; and misuse of laxatives, diuretics, or other medications.

Binge eating disorder is classified as recurrent episodes of uncontrolled overeating without compensatory purging behaviors, leading to excessive weight gain.⁴

Eating disorders and pregnancy

Pregnancy can impact the course of pre­existing eating disorders, and women also can develop symptoms of eating disorders for the first time during pregnancy. This is clinically significant as there are both maternal and fetal consequences to a mother’s disordered eating.

The risks of anorexia nervosa include vitamin deficiencies (vitamin B12/folate), dehydration leading to renal injury and electrolyte imbalances, hypoglycemia, abnormal lipid profiles, cardiac arrhythmia, and even death. The mortality rate of patients with anorexia nervosa may approach 10%; however, death during pregnancy is quite rare.² Bulimia nervosa also carries the risks of protein and vitamin deficiencies, hypoglycemia and hyperglycemia, and death, with mortality estimated at 7% for those with a 5-year history of the illness. However, death in pregnancy due to the condition is again quite rare.⁵

Eating disorders can cause significant maternal and fetal complications during pregnancy and postpartum.

Maternal complications. When women with eating disorders become pregnant, they have increased risks of some pregnancy complications. Approximately 10% to 25% of pregnant women with eating disorders develop hyperemesis gravidarum.⁶ The nausea can serve as a trigger for a woman with an eating disorder, particularly among women with a history of purging behaviors.

Cesarean delivery is more common among women with eating disorders, which may be due to preexisting fetal compromise, leading to poor tolerance of labor, or to clinicians perceiving these pregnancies as higher risk.⁷

It is well known that eating disorders are highly comorbid with depression and other psychiatric conditions. In fact, 30% to 40% of women with an eating disorder develop symptoms of postpartum depression.⁸

Continue to: Fetal risks and complications...

Fetal risks and complications. Excessive caloric restriction and dieting can lead to folate deficiency, which in turn increases the risk of neural tube defects. Such defects are more common among women with eating disorders.⁹ Intrauterine growth restriction also can be a concern, most likely because of maternal malnutrition and poor maternal weight gain.¹⁰ In addition, women with eating disorders are more likely to have a preterm delivery or experience perinatal mortality or stillbirth.¹⁰

Bulimia nervosa is associated with low birthweight, while anorexia nervosa is associated with the very premature birth, low birthweight, and perinatal death.¹¹ Eating disorders during pregnancy can have long-term psychological impacts on children, including increased likelihood of childhood hyperactivity, conduct, and adjustment disorder.¹²

Assessing patients for an eating disorder

Diagnosis of eating disorders is an interview-guided process using clinical criteria of the Diagnostic and Statistical Manual of Mental Disorders, 5th edition.⁴ The Eating Disorder Examination is a semi-structured interview composed of 4 subsections (restraint, eating concern, shape concern, and weight concern). The interview’s aim is to assess the psychopathology associated with eating disorders, and it is used in research settings rather than clinically.

1. Do you make yourself sick because you feel uncomfortably full?
2. Do you worry that you have lost control over how much you eat?
3. Have you recently lost more than one stone (14 lb) in a 3-month period?
4. Do you believe yourself to be fat when others say you are too thin?
5. Would you say that food dominates your life?

Referral. Patients for whom you have a concern for any eating disorder should be referred to a psychiatrist for formal diagnosis. Integrated multidisciplinary care of pregnant patients with eating disorders is necessary to improve maternal and fetal outcomes. Care teams should include obstetricians or maternal-fetal medicine clinicians experienced in caring for patients with eating disorders, psychiatrists, psychologists, nutritionists, and social workers. General treatment principles require an assessment for appropriate setting of intervention, which depends on presentation severity, assessment of nutritional status, treatment of psychiatric comorbidity, and psychotherapeutic intervention.

Overall management strategy

The initial treatment strategy for pregnant women with eating disorders should involve evaluating for severe illness and life-threatening complications of the specific disorder. All patients should be screened for suicidal ideation, severe malnutrition, electrolyte abnormalities, dehydration, hemodynamic instability, and cardiac arrhythmia. Patients with any of these severe features should be admitted for medical hospitalization and psychiatric evaluation.¹⁴ Patients that are hospitalized should be watched closely for refeeding syndrome—potentially life threatening metabolic disturbances that occur when nutrition is reinstituted to patients who are severely malnourished.

Patients without severe features or acute life-threatening complications can be managed safely on an outpatient basis with close medical monitoring. Psychiatric providers should be involved to assess for treatment needs including psychotherapy and psychotropic medications. There are numerous pharmacologic options available for patients, with the use of selective serotonin reuptake inhibitors (SSRIs) most common. While SSRI use has been controversial in pregnancy in the past, the risks of untreated illness carry risk to the mother and unborn child that outweigh the small risks associated with SSRI exposure in pregnancy.¹⁵

Women should have established care with a nutritionist or dietician who can ensure adequate counseling regarding meal planning and multivitamin supplementation. The numerous food restrictions in pregnancy, such as avoidance of unpasteurized cheese or deli meats, may be triggering for many patients with a history of restrictive eating.

One of the greatest difficulties for women with disordered eating in pregnancy revolves around weight gain. Many patients find the various measurements of pregnancy (maternal weight gain, fetal weight, fetal heart rate, and fundal height) triggering, which can make appropriate maternal and fetal weight gain in pregnancy very challenging. One strategy for managing this includes using fetal weight and growth as a surrogate for appropriate maternal gestational weight gain. One other strategy involves blind weights, where the woman is turned away from the scale so her weight is not disclosed to her. Patients often will not be able to achieve the expected 28 to 40 lb of pregnancy weight gain. It is best to have an open, honest conversation in early pregnancy to discuss how she would like to address weight in her pregnancy.

Continue to: Postpregnancy concerns...

Postpregnancy concerns

Patients with eating disorders are at high risk of relapse in the postpartum period, even if they are able to achieve full remission in pregnancy. Rapid postpartum weight loss may be a sign of disordered eating. Postpartum depression also is a concern, and women should be followed closely for surveillance of symptoms. Finally, postpartum contraception is extremely important. The menstrual irregularities that are common among women with eating disorders along with common misconceptions regarding fertility in the postpartum period increase the risk of unplanned pregnancy.

Remain cognizant of eating disorders

A clear surveillance plan early in the pregnancy that is developed in conjunction with the patient and her care team is crucial in improving maternal and fetal outcomes among women with an eating disorder. Clinician knowledge of complications and risks specific to disordered eating and pregnancy can affect outcomes for both mother and baby.

CASE New mother receives unneeded opioids after CD

A house officer wrote orders for a healthy patient who had just had an uncomplicated cesarean delivery (CD). The hospital’s tradition dictates orders for oxycodone plus acetaminophen tablets in addition to ibuprofen for all new mothers. At the time of the patient’s discharge, the same house officer prescribed 30 tablets of oxycodone plus acetaminophen “just in case,” although the patient had required only a few tablets while in the hospital on postoperative day 2 and none on the day of discharge.

Stuck in the habit

Prescribing postpartum opioids in the United States is almost habitual. Both optimizing patient satisfaction and minimizing patient phone calls may be driving this well-established pattern. Interestingly, a survey study of obstetric providers in 14 countries found that clinicians in 13 countries prescribe opioids “almost never” after vaginal delivery.¹ The United States was the 1 outlier, with providers reporting prescribing opioids “on a regular basis” after vaginal birth. Similarly, providers in 10 countries reported prescribing opioids “almost never” after CD, while those in the United States reported prescribing opioids “almost always” in this context.

Moreover, mounting data suggest that many patients do not require the quantity of opioids prescribed and that our overprescribing may be causing more harm than good.

The problem of overprescribing opioids after childbirth

Opioid analgesia has long been the mainstay of treatment for postpartum pain, which when poorly controlled is associated with the development of postpartum depression and chronic pain.² However, common adverse effects of opioids, including nausea, drowsiness, and dizziness, similarly can interfere with self-care and infant care. Of additional concern, a 2016 claims data study found that 1 of 300 opioid-naïve women who were prescribed opioids at discharge after CD used these medications persistently in the first year postpartum.³

Many women do not use the opioids that are prescribed to them at discharge, thus making tablets available for potential diversion into the community—a commonly recognized source of opioid misuse and abuse.^4,5 In a 2018 Committee Opinion on postpartum pain management, the American College of Obstetricians and Gynecologists (ACOG) stated that “a stepwise, multimodal approach emphasizing nonopioid analgesia as first-line therapy is safe and effective for vaginal deliveries and cesarean deliveries.”⁶ The Committee Opinion also asserted that “opioid medication is an adjunct for patients with uncontrolled pain despite adequate first-line therapy.”⁶

Despite efforts by the Centers for Disease Control and Prevention (CDC) and ACOG to improve opioid prescribing patterns after childbirth, the vast majority of women receive opioids in the hospital and at discharge not only after CD, but after vaginal delivery as well.^4,7 Why has tradition prevailed over data, and why have we not changed?

Continue to: Common misconceptions about reducing opioid use...

Common misconceptions about reducing opioid use

Two misconceptions persist regarding reducing opioid prescriptions for postpartum pain.

Misconception #1: Patients will be in pain

Randomized controlled trials that compared nonopioid with opioid regimens in the emergency room setting and opioid use after outpatient general surgery procedures have demonstrated that pain control for patients receiving opioids was equivalent to that for patients with pain managed with nonopioid regimens.^8-10 In the obstetric setting, a survey study of 720 women who underwent CD found that higher quantities of opioid tablets prescribed at discharge were not associated with improved pain, higher satisfaction, or lower refill rates at 2 weeks postpartum.⁴ However, greater quantities of opioids prescribed at the time of discharge were associated with greater opioid consumption.

Recently, several quality improvement studies implemented various interventions and successfully decreased postpartum opioid consumption without compromising pain management. One quality improvement project eliminated the routine use of opioids after CD and decreased the proportion of patients using any opioids in the hospital from 68% to 45%, with no changes in pain scores.¹¹ A similar study implemented an enhanced recovery after surgery (ERAS) program for women after CD; mean in-patient opioid use decreased from 10.7 to 5.4 average daily morphine equivalents, with improvement in the proportion of time that patients reported their pain as acceptable.¹²

Misconception #2: Clinicians will be overwhelmed with pages and phone calls

Providers commonly fear that decreasing opioid use will lead to an increased volume of pages and phone calls from patients requesting additional medication. However, data suggest otherwise. For example, a quality improvement study that eliminated the routine use of opioids after CD tracked the number of phone calls that were received requesting rescue opioid prescriptions after discharge.¹¹ Although the percentage of women discharged with opioids decreased from 90.6% to 40.3%, the requests for rescue opioid prescriptions did not change. Of 191 women, 4 requested a rescue prescription prior to the intervention compared with no women after the intervention. At the same time, according to unpublished data (Dr. Holland), satisfaction among nurses, house staff, and faculty did not change.

Similarly, a quality improvement project that implemented shared decision-making to inform the quantity of opioids prescribed at discharge demonstrated that the number of tablets prescribed decreased from 33.2 to 26.5, and there was no change in the rate of patients requesting opioid refills.¹³

Success stories: Strategies for reducing opioid use after childbirth

While overall rates of opioid prescribing after vaginal delivery and CD remain high throughout the United States, various institutions have developed successful and reproducible strategies to reduce opioid use after childbirth both in the hospital and at discharge. We highlight 3 strategies below.

Strategy 1: ERAS initiatives

An integrated health care system in northern California studied the effects of an ERAS protocol for CD across 15 medical centers.¹² The intervention centered on 4 pillars: multimodal pain management, early mobility, optimal nutrition, and patient engagement through education. Specifically, multimodal pain management consisted of the following:

• intrathecal opioids during CD
• scheduled intravenous acetaminophen for 24 hours followed by oral acetaminophen every 6 hours
• nonsteroidal anti-inflammatory drugs (NSAIDs) every 6 hours
• oral oxycodone for breakthrough pain
• decoupling of opioid medication from nonopioids in the post-CD order set
• decoupling of opioid and nonopioid medications in the discharge order set along with a reduction from 30 to 20 tablets as the default discharge quantity.

Continue to: Among 4,689 and 4,624 patients who underwent CD...

Among 4,689 and 4,624 patients who underwent CD before and after the intervention, the daily morphine milligram equivalents (MME) consumed in the hospital decreased from 10.7 to 5.4. The percentage of women who required no opioids while in the hospital increased from 8.3% to 21.4% after ERAS implementation, while the percentage of time that patients reported acceptable pain scores increased from 82.1% to 86.4%. The average number of opioid tablets prescribed at discharge also decreased, from 37 to 26 MME.¹² (The TABLE shows oxycodone doses converted to MMEs.)

Strategy 2: Order set change to eliminate routine use of opioids

A tertiary care center in Boston, Massachusetts, implemented a quality improvement project aimed at eliminating the routine use of opioid medication after CD through an order set change.¹¹ The intervention consisted of the following:

• intrathecal morphine
• multimodal postoperative pain management including scheduled oral acetaminophen for 72 hours followed by as-needed oral acetaminophen, scheduled NSAIDs for 72 hours followed by as-needed NSAIDs
• no postoperative order for opioids unless the patient had a contraindication to acetaminophen or NSAIDs, had a history of opioid dependence, or underwent complex surgery
• counseling patients that opioids were available for breakthrough pain if needed. In this case, nursing staff would page the responding clinician, who would order oxycodone 5 mg every 6 hours for 6 doses.
• specific criteria for discharge quantities of opioids: if the patient required no opioids in the hospital, she received no opioids at discharge; if the patient required opioids in the hospital but none at the time of discharge, she received no more than 10 tablets of oxycodone 5 mg; if the patient required opioids at the time of discharge, she received a maximum of 20 tablets of oxycodone 5 mg.

Among 191 and 181 women undergoing CD before and after the intervention, the percentage of patients who received any opioids in the hospital decreased from 68.1% to 45.3%.¹¹ Similarly, the percentage of patients receiving a discharge prescription for opioids decreased from 90.6% to 40.3%, while patient pain scores and satisfaction with pain control remained unchanged.

Strategy 3: Shared decision-making tool

Another tertiary care center in Boston evaluated the effects of a shared decision-making tool on opioid discharge prescribing after CD.¹⁵ The intervention consisted of a 10-minute clinician-facilitated session incorporating:

• education around anticipated patterns of postoperative pain
• expected outpatient opioid use after CD
• risks and benefits of opioids and nonopioids
• education around opioid disposal and access to refills.

Among the 50 women enrolled in the study, the number of oxycodone 5-mg tablets prescribed at discharge decreased from the institutional standard of 40 to 20. Ninety percent of women reported being satisfied or very satisfied with their pain control, while only 4 of 50 women required an opioid refill. A follow-up quality improvement project, which implemented the shared decision-making model along with a standardized multimodal pain management protocol, demonstrated a similar decrease in the quantity of opioids prescribed at discharge.¹³

Continue to: Change is here to stay: A new culture of postpartum analgesia...

Change is here to stay: A new culture of postpartum analgesia

The CDC continues to champion responsible opioid prescribing, while ACOG advocates for a reassessment of the way that opioids are utilized postpartum. The majority of women in the United States, however, continue to receive opioids after both vaginal delivery and CD. Consciously or not, we clinicians may be contributing to an outdated tradition that is potentially harmful both to patients and society. Reproducible strategies exist to reduce opioid use without compromising pain control or overwhelming clinicians with phone calls. It is time to embrace the change.

CASE New mother receives unneeded opioids after CD

A house officer wrote orders for a healthy patient who had just had an uncomplicated cesarean delivery (CD). The hospital’s tradition dictates orders for oxycodone plus acetaminophen tablets in addition to ibuprofen for all new mothers. At the time of the patient’s discharge, the same house officer prescribed 30 tablets of oxycodone plus acetaminophen “just in case,” although the patient had required only a few tablets while in the hospital on postoperative day 2 and none on the day of discharge.

Stuck in the habit

Prescribing postpartum opioids in the United States is almost habitual. Both optimizing patient satisfaction and minimizing patient phone calls may be driving this well-established pattern. Interestingly, a survey study of obstetric providers in 14 countries found that clinicians in 13 countries prescribe opioids “almost never” after vaginal delivery.¹ The United States was the 1 outlier, with providers reporting prescribing opioids “on a regular basis” after vaginal birth. Similarly, providers in 10 countries reported prescribing opioids “almost never” after CD, while those in the United States reported prescribing opioids “almost always” in this context.

Moreover, mounting data suggest that many patients do not require the quantity of opioids prescribed and that our overprescribing may be causing more harm than good.

The problem of overprescribing opioids after childbirth

Opioid analgesia has long been the mainstay of treatment for postpartum pain, which when poorly controlled is associated with the development of postpartum depression and chronic pain.² However, common adverse effects of opioids, including nausea, drowsiness, and dizziness, similarly can interfere with self-care and infant care. Of additional concern, a 2016 claims data study found that 1 of 300 opioid-naïve women who were prescribed opioids at discharge after CD used these medications persistently in the first year postpartum.³

Many women do not use the opioids that are prescribed to them at discharge, thus making tablets available for potential diversion into the community—a commonly recognized source of opioid misuse and abuse.^4,5 In a 2018 Committee Opinion on postpartum pain management, the American College of Obstetricians and Gynecologists (ACOG) stated that “a stepwise, multimodal approach emphasizing nonopioid analgesia as first-line therapy is safe and effective for vaginal deliveries and cesarean deliveries.”⁶ The Committee Opinion also asserted that “opioid medication is an adjunct for patients with uncontrolled pain despite adequate first-line therapy.”⁶

Despite efforts by the Centers for Disease Control and Prevention (CDC) and ACOG to improve opioid prescribing patterns after childbirth, the vast majority of women receive opioids in the hospital and at discharge not only after CD, but after vaginal delivery as well.^4,7 Why has tradition prevailed over data, and why have we not changed?

Continue to: Common misconceptions about reducing opioid use...

Common misconceptions about reducing opioid use

Two misconceptions persist regarding reducing opioid prescriptions for postpartum pain.

Misconception #1: Patients will be in pain

Randomized controlled trials that compared nonopioid with opioid regimens in the emergency room setting and opioid use after outpatient general surgery procedures have demonstrated that pain control for patients receiving opioids was equivalent to that for patients with pain managed with nonopioid regimens.^8-10 In the obstetric setting, a survey study of 720 women who underwent CD found that higher quantities of opioid tablets prescribed at discharge were not associated with improved pain, higher satisfaction, or lower refill rates at 2 weeks postpartum.⁴ However, greater quantities of opioids prescribed at the time of discharge were associated with greater opioid consumption.

Recently, several quality improvement studies implemented various interventions and successfully decreased postpartum opioid consumption without compromising pain management. One quality improvement project eliminated the routine use of opioids after CD and decreased the proportion of patients using any opioids in the hospital from 68% to 45%, with no changes in pain scores.¹¹ A similar study implemented an enhanced recovery after surgery (ERAS) program for women after CD; mean in-patient opioid use decreased from 10.7 to 5.4 average daily morphine equivalents, with improvement in the proportion of time that patients reported their pain as acceptable.¹²

Misconception #2: Clinicians will be overwhelmed with pages and phone calls

Providers commonly fear that decreasing opioid use will lead to an increased volume of pages and phone calls from patients requesting additional medication. However, data suggest otherwise. For example, a quality improvement study that eliminated the routine use of opioids after CD tracked the number of phone calls that were received requesting rescue opioid prescriptions after discharge.¹¹ Although the percentage of women discharged with opioids decreased from 90.6% to 40.3%, the requests for rescue opioid prescriptions did not change. Of 191 women, 4 requested a rescue prescription prior to the intervention compared with no women after the intervention. At the same time, according to unpublished data (Dr. Holland), satisfaction among nurses, house staff, and faculty did not change.

Similarly, a quality improvement project that implemented shared decision-making to inform the quantity of opioids prescribed at discharge demonstrated that the number of tablets prescribed decreased from 33.2 to 26.5, and there was no change in the rate of patients requesting opioid refills.¹³

Success stories: Strategies for reducing opioid use after childbirth

While overall rates of opioid prescribing after vaginal delivery and CD remain high throughout the United States, various institutions have developed successful and reproducible strategies to reduce opioid use after childbirth both in the hospital and at discharge. We highlight 3 strategies below.

Strategy 1: ERAS initiatives

An integrated health care system in northern California studied the effects of an ERAS protocol for CD across 15 medical centers.¹² The intervention centered on 4 pillars: multimodal pain management, early mobility, optimal nutrition, and patient engagement through education. Specifically, multimodal pain management consisted of the following:

• intrathecal opioids during CD
• scheduled intravenous acetaminophen for 24 hours followed by oral acetaminophen every 6 hours
• nonsteroidal anti-inflammatory drugs (NSAIDs) every 6 hours
• oral oxycodone for breakthrough pain
• decoupling of opioid medication from nonopioids in the post-CD order set
• decoupling of opioid and nonopioid medications in the discharge order set along with a reduction from 30 to 20 tablets as the default discharge quantity.

Continue to: Among 4,689 and 4,624 patients who underwent CD...

Among 4,689 and 4,624 patients who underwent CD before and after the intervention, the daily morphine milligram equivalents (MME) consumed in the hospital decreased from 10.7 to 5.4. The percentage of women who required no opioids while in the hospital increased from 8.3% to 21.4% after ERAS implementation, while the percentage of time that patients reported acceptable pain scores increased from 82.1% to 86.4%. The average number of opioid tablets prescribed at discharge also decreased, from 37 to 26 MME.¹² (The TABLE shows oxycodone doses converted to MMEs.)

Strategy 2: Order set change to eliminate routine use of opioids

A tertiary care center in Boston, Massachusetts, implemented a quality improvement project aimed at eliminating the routine use of opioid medication after CD through an order set change.¹¹ The intervention consisted of the following:

• intrathecal morphine
• multimodal postoperative pain management including scheduled oral acetaminophen for 72 hours followed by as-needed oral acetaminophen, scheduled NSAIDs for 72 hours followed by as-needed NSAIDs
• no postoperative order for opioids unless the patient had a contraindication to acetaminophen or NSAIDs, had a history of opioid dependence, or underwent complex surgery
• counseling patients that opioids were available for breakthrough pain if needed. In this case, nursing staff would page the responding clinician, who would order oxycodone 5 mg every 6 hours for 6 doses.
• specific criteria for discharge quantities of opioids: if the patient required no opioids in the hospital, she received no opioids at discharge; if the patient required opioids in the hospital but none at the time of discharge, she received no more than 10 tablets of oxycodone 5 mg; if the patient required opioids at the time of discharge, she received a maximum of 20 tablets of oxycodone 5 mg.

Among 191 and 181 women undergoing CD before and after the intervention, the percentage of patients who received any opioids in the hospital decreased from 68.1% to 45.3%.¹¹ Similarly, the percentage of patients receiving a discharge prescription for opioids decreased from 90.6% to 40.3%, while patient pain scores and satisfaction with pain control remained unchanged.

Strategy 3: Shared decision-making tool

Another tertiary care center in Boston evaluated the effects of a shared decision-making tool on opioid discharge prescribing after CD.¹⁵ The intervention consisted of a 10-minute clinician-facilitated session incorporating:

• education around anticipated patterns of postoperative pain
• expected outpatient opioid use after CD
• risks and benefits of opioids and nonopioids
• education around opioid disposal and access to refills.

Among the 50 women enrolled in the study, the number of oxycodone 5-mg tablets prescribed at discharge decreased from the institutional standard of 40 to 20. Ninety percent of women reported being satisfied or very satisfied with their pain control, while only 4 of 50 women required an opioid refill. A follow-up quality improvement project, which implemented the shared decision-making model along with a standardized multimodal pain management protocol, demonstrated a similar decrease in the quantity of opioids prescribed at discharge.¹³

Continue to: Change is here to stay: A new culture of postpartum analgesia...

Change is here to stay: A new culture of postpartum analgesia

The CDC continues to champion responsible opioid prescribing, while ACOG advocates for a reassessment of the way that opioids are utilized postpartum. The majority of women in the United States, however, continue to receive opioids after both vaginal delivery and CD. Consciously or not, we clinicians may be contributing to an outdated tradition that is potentially harmful both to patients and society. Reproducible strategies exist to reduce opioid use without compromising pain control or overwhelming clinicians with phone calls. It is time to embrace the change.

CASE New mother receives unneeded opioids after CD

A house officer wrote orders for a healthy patient who had just had an uncomplicated cesarean delivery (CD). The hospital’s tradition dictates orders for oxycodone plus acetaminophen tablets in addition to ibuprofen for all new mothers. At the time of the patient’s discharge, the same house officer prescribed 30 tablets of oxycodone plus acetaminophen “just in case,” although the patient had required only a few tablets while in the hospital on postoperative day 2 and none on the day of discharge.

Stuck in the habit

Prescribing postpartum opioids in the United States is almost habitual. Both optimizing patient satisfaction and minimizing patient phone calls may be driving this well-established pattern. Interestingly, a survey study of obstetric providers in 14 countries found that clinicians in 13 countries prescribe opioids “almost never” after vaginal delivery.¹ The United States was the 1 outlier, with providers reporting prescribing opioids “on a regular basis” after vaginal birth. Similarly, providers in 10 countries reported prescribing opioids “almost never” after CD, while those in the United States reported prescribing opioids “almost always” in this context.

Moreover, mounting data suggest that many patients do not require the quantity of opioids prescribed and that our overprescribing may be causing more harm than good.

The problem of overprescribing opioids after childbirth

Opioid analgesia has long been the mainstay of treatment for postpartum pain, which when poorly controlled is associated with the development of postpartum depression and chronic pain.² However, common adverse effects of opioids, including nausea, drowsiness, and dizziness, similarly can interfere with self-care and infant care. Of additional concern, a 2016 claims data study found that 1 of 300 opioid-naïve women who were prescribed opioids at discharge after CD used these medications persistently in the first year postpartum.³

Many women do not use the opioids that are prescribed to them at discharge, thus making tablets available for potential diversion into the community—a commonly recognized source of opioid misuse and abuse.^4,5 In a 2018 Committee Opinion on postpartum pain management, the American College of Obstetricians and Gynecologists (ACOG) stated that “a stepwise, multimodal approach emphasizing nonopioid analgesia as first-line therapy is safe and effective for vaginal deliveries and cesarean deliveries.”⁶ The Committee Opinion also asserted that “opioid medication is an adjunct for patients with uncontrolled pain despite adequate first-line therapy.”⁶

Despite efforts by the Centers for Disease Control and Prevention (CDC) and ACOG to improve opioid prescribing patterns after childbirth, the vast majority of women receive opioids in the hospital and at discharge not only after CD, but after vaginal delivery as well.^4,7 Why has tradition prevailed over data, and why have we not changed?

Continue to: Common misconceptions about reducing opioid use...

Common misconceptions about reducing opioid use

Two misconceptions persist regarding reducing opioid prescriptions for postpartum pain.

Misconception #1: Patients will be in pain

Randomized controlled trials that compared nonopioid with opioid regimens in the emergency room setting and opioid use after outpatient general surgery procedures have demonstrated that pain control for patients receiving opioids was equivalent to that for patients with pain managed with nonopioid regimens.^8-10 In the obstetric setting, a survey study of 720 women who underwent CD found that higher quantities of opioid tablets prescribed at discharge were not associated with improved pain, higher satisfaction, or lower refill rates at 2 weeks postpartum.⁴ However, greater quantities of opioids prescribed at the time of discharge were associated with greater opioid consumption.

Recently, several quality improvement studies implemented various interventions and successfully decreased postpartum opioid consumption without compromising pain management. One quality improvement project eliminated the routine use of opioids after CD and decreased the proportion of patients using any opioids in the hospital from 68% to 45%, with no changes in pain scores.¹¹ A similar study implemented an enhanced recovery after surgery (ERAS) program for women after CD; mean in-patient opioid use decreased from 10.7 to 5.4 average daily morphine equivalents, with improvement in the proportion of time that patients reported their pain as acceptable.¹²

Misconception #2: Clinicians will be overwhelmed with pages and phone calls

Providers commonly fear that decreasing opioid use will lead to an increased volume of pages and phone calls from patients requesting additional medication. However, data suggest otherwise. For example, a quality improvement study that eliminated the routine use of opioids after CD tracked the number of phone calls that were received requesting rescue opioid prescriptions after discharge.¹¹ Although the percentage of women discharged with opioids decreased from 90.6% to 40.3%, the requests for rescue opioid prescriptions did not change. Of 191 women, 4 requested a rescue prescription prior to the intervention compared with no women after the intervention. At the same time, according to unpublished data (Dr. Holland), satisfaction among nurses, house staff, and faculty did not change.

Similarly, a quality improvement project that implemented shared decision-making to inform the quantity of opioids prescribed at discharge demonstrated that the number of tablets prescribed decreased from 33.2 to 26.5, and there was no change in the rate of patients requesting opioid refills.¹³

Success stories: Strategies for reducing opioid use after childbirth

While overall rates of opioid prescribing after vaginal delivery and CD remain high throughout the United States, various institutions have developed successful and reproducible strategies to reduce opioid use after childbirth both in the hospital and at discharge. We highlight 3 strategies below.

Strategy 1: ERAS initiatives

An integrated health care system in northern California studied the effects of an ERAS protocol for CD across 15 medical centers.¹² The intervention centered on 4 pillars: multimodal pain management, early mobility, optimal nutrition, and patient engagement through education. Specifically, multimodal pain management consisted of the following:

• intrathecal opioids during CD
• scheduled intravenous acetaminophen for 24 hours followed by oral acetaminophen every 6 hours
• nonsteroidal anti-inflammatory drugs (NSAIDs) every 6 hours
• oral oxycodone for breakthrough pain
• decoupling of opioid medication from nonopioids in the post-CD order set
• decoupling of opioid and nonopioid medications in the discharge order set along with a reduction from 30 to 20 tablets as the default discharge quantity.

Continue to: Among 4,689 and 4,624 patients who underwent CD...

Among 4,689 and 4,624 patients who underwent CD before and after the intervention, the daily morphine milligram equivalents (MME) consumed in the hospital decreased from 10.7 to 5.4. The percentage of women who required no opioids while in the hospital increased from 8.3% to 21.4% after ERAS implementation, while the percentage of time that patients reported acceptable pain scores increased from 82.1% to 86.4%. The average number of opioid tablets prescribed at discharge also decreased, from 37 to 26 MME.¹² (The TABLE shows oxycodone doses converted to MMEs.)

Strategy 2: Order set change to eliminate routine use of opioids

A tertiary care center in Boston, Massachusetts, implemented a quality improvement project aimed at eliminating the routine use of opioid medication after CD through an order set change.¹¹ The intervention consisted of the following:

• intrathecal morphine
• multimodal postoperative pain management including scheduled oral acetaminophen for 72 hours followed by as-needed oral acetaminophen, scheduled NSAIDs for 72 hours followed by as-needed NSAIDs
• no postoperative order for opioids unless the patient had a contraindication to acetaminophen or NSAIDs, had a history of opioid dependence, or underwent complex surgery
• counseling patients that opioids were available for breakthrough pain if needed. In this case, nursing staff would page the responding clinician, who would order oxycodone 5 mg every 6 hours for 6 doses.
• specific criteria for discharge quantities of opioids: if the patient required no opioids in the hospital, she received no opioids at discharge; if the patient required opioids in the hospital but none at the time of discharge, she received no more than 10 tablets of oxycodone 5 mg; if the patient required opioids at the time of discharge, she received a maximum of 20 tablets of oxycodone 5 mg.

Among 191 and 181 women undergoing CD before and after the intervention, the percentage of patients who received any opioids in the hospital decreased from 68.1% to 45.3%.¹¹ Similarly, the percentage of patients receiving a discharge prescription for opioids decreased from 90.6% to 40.3%, while patient pain scores and satisfaction with pain control remained unchanged.

Strategy 3: Shared decision-making tool

Another tertiary care center in Boston evaluated the effects of a shared decision-making tool on opioid discharge prescribing after CD.¹⁵ The intervention consisted of a 10-minute clinician-facilitated session incorporating:

• education around anticipated patterns of postoperative pain
• expected outpatient opioid use after CD
• risks and benefits of opioids and nonopioids
• education around opioid disposal and access to refills.

Among the 50 women enrolled in the study, the number of oxycodone 5-mg tablets prescribed at discharge decreased from the institutional standard of 40 to 20. Ninety percent of women reported being satisfied or very satisfied with their pain control, while only 4 of 50 women required an opioid refill. A follow-up quality improvement project, which implemented the shared decision-making model along with a standardized multimodal pain management protocol, demonstrated a similar decrease in the quantity of opioids prescribed at discharge.¹³

Continue to: Change is here to stay: A new culture of postpartum analgesia...

Change is here to stay: A new culture of postpartum analgesia

The CDC continues to champion responsible opioid prescribing, while ACOG advocates for a reassessment of the way that opioids are utilized postpartum. The majority of women in the United States, however, continue to receive opioids after both vaginal delivery and CD. Consciously or not, we clinicians may be contributing to an outdated tradition that is potentially harmful both to patients and society. Reproducible strategies exist to reduce opioid use without compromising pain control or overwhelming clinicians with phone calls. It is time to embrace the change.

Medical malpractice (more formally, professional liability, but we will use the term malpractice) has been of concern to ObGyns for many years, and for good reasons. This specialty has some of the highest incidents of malpractice claims, some of the largest verdicts, and some of the highest malpractice insurance rates. We look more closely at ObGyn malpractice issues in a 3-part “What’s the Verdict” series over the next few months.

In part 1, we discuss the background on malpractice and reasons why malpractice rates have been so high—including large verdicts and lawsuit-prone physicians. In the second part we will look at recent experience and developments in malpractice exposure—who is sued and why. Finally, in the third part we will consider suggestions for reducing the likelihood of a malpractice lawsuit, with a special focus on recent research regarding apologies.

Two reports of recent trials involving ObGyn care illustrate the risk of “the big verdict.”^1,2 (Note that the following vignettes are drawn from actual cases but are outlines of those cases and not complete descriptions of the claims. Because the information does not come from formal court records, the facts may be inaccurate and are incomplete; they should be viewed as illustrations only.)

CASE 1 Delayed delivery, $19M verdict

At 39 weeks’ gestation, a woman was admitted to the hospital in spontaneous labor. Artificial rupture of membranes with clear amniotic fluid was noted. Active contractions occurred for 11 hours. Oxytocin was then initiated, and 17 minutes later, profound fetal bradycardia was detected. There was recurrent evidence of fetal distress with meconium. After a nursing staff change a second nurse restarted oxytocin for a prolonged period. The physician allowed labor to continue despite fetal distress, and performed a cesarean delivery (CD) 4.5 hours later. Five hours postdelivery the neonate was noted to have a pneumothorax, lung damage, and respiratory failure. The infant died at 18 days of age.

The jury felt that there was negligence—failure to timely diagnose fetal distress and failure to timely perform CD, all of which resulted in a verdict for the plaintiff. The jury awarded in excess of $19 million.¹

CASE 2 An undiagnosed tumor, $20M verdict

A patient underwent bilateral mastectomy. Following surgery, she reported pain and swelling at the surgical site for 2 years, and the defendant physician “dismissed” her complaint, refusing to evaluate it as the provider felt it was related to scar tissue. Three years after the mastectomies, the patient underwent surgical exploration and removal of 3 ribs and sternum secondary to a desmoid tumor. Surgical mesh and chest reconstruction was required, necessitating long-term opioids and sleeping medications that “will slow her wits, dull her senses and limit activities of daily living.” Of note, discrepancies were found in the medical records maintained by the defendant. (There was, for example, no report in the record of the plaintiff’s pain until late in the process.) The plaintiff based her claim on the fact that her pain and lump were neither evaluated nor discovered until it was too late.

The jury awarded $20 million. The verdict was reduced to $2 million by the court based on state statutory limits on malpractice damages.^2,3

Continue to: Medical malpractice: Evolution of a standard of care...

Medical malpractice: Evolution of a standard of care

Medical malpractice is not a modern invention. Some historians trace malpractice to the Code of Hammurabi (2030 BC), through Roman law,⁴ into English common law.⁵ It was sufficiently established by 1765 that the classic legal treatise of the century referred to medical malpractice.^6,7 Although medical malpractice existed for a long time, actual malpractice cases were relatively rare before the last half of the 20th century.⁸

Defensive medicine born out of necessity. The number of malpractice cases increased substantially—described as a “geometric increase”—after 1960, with a 300% rise between 1965 and 1970.^7,9 This “malpractice maelstrom of the 70s”⁷ resulted in dramatic increases in malpractice insurance costs and invited the practice of defensive medicine—medically unnecessary or unjustified tests and services.¹⁰Although there is controversy about what is defensive medicine and what is reasonably cautious medicine, the practice may account for 3% of total health care spending.¹¹ Mello and others have estimated that there may be a $55 billion annual cost related to the medical malpractice system.¹²

Several malpractice crises and waves of malpractice or tort reform ensued,¹³ beginning in the 1970s and extending into the 2000s.¹¹ Malpractice law is primarily a matter of state law, so reform essentially has been at the state level—as we will see in the second part in this series.

Defining a standard of care

Medical malpractice is the application of standard legal principles to medical practice. Those principles generally are torts (intentional torts and negligence), and sometimes contracts.¹⁴ Eventually, medical malpractice came to focus primarily on negligence. The legal purposes of imposing negligence liability are compensation (to repay the plaintiff the costs of the harm caused by the defendant) and deterrence (to discourage careless conduct that can harm others.)

Negligence is essentially carelessness that falls below the acceptable standard of care. Negligence may arise, for example, from¹⁵:

• doing something (giving a drug to a patient with a known allergy to it)
• not doing something (failing to test for a possible tumor, as in the second case above)
• not giving appropriate informed consent
• failing to conduct an adequate examination
• abandoning a patient
• failing to refer a patient to a specialist (or conduct a consultation).

(In recent years, law reforms directed specifically at medical malpractice have somewhat separated medical malpractice from other tort law.)

In malpractice cases, the core question is whether the provider did (or did not) do something that a reasonably careful physician would have done. It is axiomatic that not all bad outcomes are negligent. Indeed, not all mistakes are negligent—only the mistakes that were unreasonable given all of the circumstances. In the first case above, for example, given all of the facts that preceded it, the delay of the physician for 4.5 hours after the fetal distress started was, as seen by the jury, not just a mistake but an unreasonable mistake. Hence, it was negligent. In the second case, the failure to investigate the pain and swelling in the surgical site for 2 years (or failure to refer the patient to another physician) was seen by the jury as an unreasonable mistake—one that would not have been made by a reasonably careful practitioner.

Continue to: The big verdict...

The big verdict

Everyone—every professional providing service, every manufacturer, every driver—eventually will make an unreasonable mistake (ie, commit negligence). If that negligence results in harming someone else, our standard legal response is that the negligent person should be financially responsible for the harm to the other. So, a driver who fails to stop at a red light and hits another car is responsible for those damages. But the damages may vary—perhaps a banged-up fender, or, in another instance, with the same negligence, perhaps terrible personal injuries that will disable the other driver for life. Thus, the damages can vary for the same level of carelessness. The “big verdict” may therefore fall on someone who was not especially careless.

Big verdicts often involve long-term care. The opening case vignettes illustrate a concern of medical malpractice generally—especially for ObGyn practice—the very high verdict. Very high verdicts generally reflect catastrophic damages that will continue for a long time. Bixenstine and colleagues found, for example, that catastrophic payouts often involved “patient age less than 1 year, quadriplegia, brain damage, or lifelong care.”¹⁶ In the case of serious injuries during delivery, for example, the harm to the child may last a lifetime and require years and years of intensive medical services.

Million-dollar-plus payouts are on the rise. The percentage of paid claims (through settlement or trial) that are above $1 million is increasing. These million-dollar cases represent 36% of the total dollars paid in ObGyn malpractice claims, even though they represent only 8% of the number of claims paid.¹⁶ The increase in the big verdict cases (above $1 million) suggests that ObGyn practition­ers should consider their malpractice policy limits—a million dollars may not be enough.

In big verdict cases, the great harm to the plaintiff is often combined with facts that produce extraordinary sympathy for the plaintiff. Sometimes there is decidedly unsympathetic conduct by the defendant as well. In the second case, for example, the problems with the medical record may have suggested to the jury that the doctor was either trying to hide something or did not care enough about the patient even to note a serious complaint. In a case we reviewed in an earlier “What’s the Verdict” column, a physician left the room for several minutes during a critical time—to take a call from a stockbroker.^16-18

The big verdict does not necessarily suggest that the defendant was especially or grossly negligent.¹⁶ It was a bad injury that occurred, for instance. On the other hand, the physician with several malpractice judgments may suggest that this is a problem physician.

Physicians facing multiple lawsuits are the exceptions

A number of studies have demonstrated that only a small proportion of physicians are responsible for a disproportionate number of paid medical malpractice claims. (“Paid claims” are those in which the plaintiff receives money from the doctor’s insurance. “Filed claims” are all malpractice lawsuits filed. Many claims are filed, but few are paid.)

ObGyn has high number of paid claims and high risk of claim payment recurrence. Studdert and colleagues found that the probability of future paid malpractice climbed with each past paid claim.¹⁹ They also found that 1% of physicians accounted for 32% of all paid claims. The number of paid claims varied by specialty—obstetrics and gynecology accounted for the second largest number of paid claims (13%). The risk of recurrence (more than one paid claim) was highest among 4 surgical specialties and ObGyns (about double the recurrence rate in these specialties compared with internal medicine).¹⁹

A minority of physicians responsible for lion share of paid claims. Black and colleagues followed up the Studdert study. Although there were some differences in what they found, the results were very similar.²⁰ For example, they found that having even a single prior paid claim strongly predicted future claims over the next 5 years. They also found that some “outlier” physicians with multiple paid claims “are responsible for a significant share of paid claims.” They specifically found that, even for physicians in high-risk specialties in high-risk states, “bad luck is highly unlikely to explain” multiple claims within 5 years.

Continue to: Both of the studies just mentioned relied on...

Both of the studies just mentioned relied on the National Practitioner Data Bank for information about paid claims. This source has some limitations in capturing claims or payments made by hospitals or other institutions for the actions of its agent-physicians. Some of these limitations were resolved in another recent study that looked at Indiana state insurance and licensing discipline records (over a 41-year period).²¹ Not surprisingly, this study found that claims paid increase with more severe licensure discipline. On the other hand, although, the “frequent fliers” in terms of malpractice claims made and paid could be identified as a “small number of repeat defendants,” these physicians were not routinely disciplined by the state medical board. This was only a single state study, of course, but it also found that a few physicians accounted for a significant number of the claims. The state board was not taking licensing action against this small group, however.

Should the few bad apples be picked from the orchard?

Collectively, these studies are fairly overwhelming in demonstrating that there are some physicians who are “prone” to malpractice claims (for whom all physicians in the specialty are probably paying higher malpractice rates), but who do not attract the attention of licensing agencies for careful examination. In addition to its self-interest in eliminating physicians prone to malpractice claims and payments, the obligation of professions to protect the public interest suggests that state boards should be more aggressive in pursuing those physicians practicing risky medicine.

This medical malpractice series will continue next month with a look at how to reduce malpractice exposure.

Medical malpractice (more formally, professional liability, but we will use the term malpractice) has been of concern to ObGyns for many years, and for good reasons. This specialty has some of the highest incidents of malpractice claims, some of the largest verdicts, and some of the highest malpractice insurance rates. We look more closely at ObGyn malpractice issues in a 3-part “What’s the Verdict” series over the next few months.

In part 1, we discuss the background on malpractice and reasons why malpractice rates have been so high—including large verdicts and lawsuit-prone physicians. In the second part we will look at recent experience and developments in malpractice exposure—who is sued and why. Finally, in the third part we will consider suggestions for reducing the likelihood of a malpractice lawsuit, with a special focus on recent research regarding apologies.

Two reports of recent trials involving ObGyn care illustrate the risk of “the big verdict.”^1,2 (Note that the following vignettes are drawn from actual cases but are outlines of those cases and not complete descriptions of the claims. Because the information does not come from formal court records, the facts may be inaccurate and are incomplete; they should be viewed as illustrations only.)

CASE 1 Delayed delivery, $19M verdict

At 39 weeks’ gestation, a woman was admitted to the hospital in spontaneous labor. Artificial rupture of membranes with clear amniotic fluid was noted. Active contractions occurred for 11 hours. Oxytocin was then initiated, and 17 minutes later, profound fetal bradycardia was detected. There was recurrent evidence of fetal distress with meconium. After a nursing staff change a second nurse restarted oxytocin for a prolonged period. The physician allowed labor to continue despite fetal distress, and performed a cesarean delivery (CD) 4.5 hours later. Five hours postdelivery the neonate was noted to have a pneumothorax, lung damage, and respiratory failure. The infant died at 18 days of age.

The jury felt that there was negligence—failure to timely diagnose fetal distress and failure to timely perform CD, all of which resulted in a verdict for the plaintiff. The jury awarded in excess of $19 million.¹

CASE 2 An undiagnosed tumor, $20M verdict

A patient underwent bilateral mastectomy. Following surgery, she reported pain and swelling at the surgical site for 2 years, and the defendant physician “dismissed” her complaint, refusing to evaluate it as the provider felt it was related to scar tissue. Three years after the mastectomies, the patient underwent surgical exploration and removal of 3 ribs and sternum secondary to a desmoid tumor. Surgical mesh and chest reconstruction was required, necessitating long-term opioids and sleeping medications that “will slow her wits, dull her senses and limit activities of daily living.” Of note, discrepancies were found in the medical records maintained by the defendant. (There was, for example, no report in the record of the plaintiff’s pain until late in the process.) The plaintiff based her claim on the fact that her pain and lump were neither evaluated nor discovered until it was too late.

The jury awarded $20 million. The verdict was reduced to $2 million by the court based on state statutory limits on malpractice damages.^2,3

Continue to: Medical malpractice: Evolution of a standard of care...

Medical malpractice: Evolution of a standard of care

Medical malpractice is not a modern invention. Some historians trace malpractice to the Code of Hammurabi (2030 BC), through Roman law,⁴ into English common law.⁵ It was sufficiently established by 1765 that the classic legal treatise of the century referred to medical malpractice.^6,7 Although medical malpractice existed for a long time, actual malpractice cases were relatively rare before the last half of the 20th century.⁸

Defensive medicine born out of necessity. The number of malpractice cases increased substantially—described as a “geometric increase”—after 1960, with a 300% rise between 1965 and 1970.^7,9 This “malpractice maelstrom of the 70s”⁷ resulted in dramatic increases in malpractice insurance costs and invited the practice of defensive medicine—medically unnecessary or unjustified tests and services.¹⁰Although there is controversy about what is defensive medicine and what is reasonably cautious medicine, the practice may account for 3% of total health care spending.¹¹ Mello and others have estimated that there may be a $55 billion annual cost related to the medical malpractice system.¹²

Several malpractice crises and waves of malpractice or tort reform ensued,¹³ beginning in the 1970s and extending into the 2000s.¹¹ Malpractice law is primarily a matter of state law, so reform essentially has been at the state level—as we will see in the second part in this series.

Defining a standard of care

Medical malpractice is the application of standard legal principles to medical practice. Those principles generally are torts (intentional torts and negligence), and sometimes contracts.¹⁴ Eventually, medical malpractice came to focus primarily on negligence. The legal purposes of imposing negligence liability are compensation (to repay the plaintiff the costs of the harm caused by the defendant) and deterrence (to discourage careless conduct that can harm others.)

Negligence is essentially carelessness that falls below the acceptable standard of care. Negligence may arise, for example, from¹⁵:

• doing something (giving a drug to a patient with a known allergy to it)
• not doing something (failing to test for a possible tumor, as in the second case above)
• not giving appropriate informed consent
• failing to conduct an adequate examination
• abandoning a patient
• failing to refer a patient to a specialist (or conduct a consultation).

(In recent years, law reforms directed specifically at medical malpractice have somewhat separated medical malpractice from other tort law.)

In malpractice cases, the core question is whether the provider did (or did not) do something that a reasonably careful physician would have done. It is axiomatic that not all bad outcomes are negligent. Indeed, not all mistakes are negligent—only the mistakes that were unreasonable given all of the circumstances. In the first case above, for example, given all of the facts that preceded it, the delay of the physician for 4.5 hours after the fetal distress started was, as seen by the jury, not just a mistake but an unreasonable mistake. Hence, it was negligent. In the second case, the failure to investigate the pain and swelling in the surgical site for 2 years (or failure to refer the patient to another physician) was seen by the jury as an unreasonable mistake—one that would not have been made by a reasonably careful practitioner.

Continue to: The big verdict...

The big verdict

Everyone—every professional providing service, every manufacturer, every driver—eventually will make an unreasonable mistake (ie, commit negligence). If that negligence results in harming someone else, our standard legal response is that the negligent person should be financially responsible for the harm to the other. So, a driver who fails to stop at a red light and hits another car is responsible for those damages. But the damages may vary—perhaps a banged-up fender, or, in another instance, with the same negligence, perhaps terrible personal injuries that will disable the other driver for life. Thus, the damages can vary for the same level of carelessness. The “big verdict” may therefore fall on someone who was not especially careless.

Big verdicts often involve long-term care. The opening case vignettes illustrate a concern of medical malpractice generally—especially for ObGyn practice—the very high verdict. Very high verdicts generally reflect catastrophic damages that will continue for a long time. Bixenstine and colleagues found, for example, that catastrophic payouts often involved “patient age less than 1 year, quadriplegia, brain damage, or lifelong care.”¹⁶ In the case of serious injuries during delivery, for example, the harm to the child may last a lifetime and require years and years of intensive medical services.

Million-dollar-plus payouts are on the rise. The percentage of paid claims (through settlement or trial) that are above $1 million is increasing. These million-dollar cases represent 36% of the total dollars paid in ObGyn malpractice claims, even though they represent only 8% of the number of claims paid.¹⁶ The increase in the big verdict cases (above $1 million) suggests that ObGyn practition­ers should consider their malpractice policy limits—a million dollars may not be enough.

In big verdict cases, the great harm to the plaintiff is often combined with facts that produce extraordinary sympathy for the plaintiff. Sometimes there is decidedly unsympathetic conduct by the defendant as well. In the second case, for example, the problems with the medical record may have suggested to the jury that the doctor was either trying to hide something or did not care enough about the patient even to note a serious complaint. In a case we reviewed in an earlier “What’s the Verdict” column, a physician left the room for several minutes during a critical time—to take a call from a stockbroker.^16-18

The big verdict does not necessarily suggest that the defendant was especially or grossly negligent.¹⁶ It was a bad injury that occurred, for instance. On the other hand, the physician with several malpractice judgments may suggest that this is a problem physician.

Physicians facing multiple lawsuits are the exceptions

A number of studies have demonstrated that only a small proportion of physicians are responsible for a disproportionate number of paid medical malpractice claims. (“Paid claims” are those in which the plaintiff receives money from the doctor’s insurance. “Filed claims” are all malpractice lawsuits filed. Many claims are filed, but few are paid.)

ObGyn has high number of paid claims and high risk of claim payment recurrence. Studdert and colleagues found that the probability of future paid malpractice climbed with each past paid claim.¹⁹ They also found that 1% of physicians accounted for 32% of all paid claims. The number of paid claims varied by specialty—obstetrics and gynecology accounted for the second largest number of paid claims (13%). The risk of recurrence (more than one paid claim) was highest among 4 surgical specialties and ObGyns (about double the recurrence rate in these specialties compared with internal medicine).¹⁹

A minority of physicians responsible for lion share of paid claims. Black and colleagues followed up the Studdert study. Although there were some differences in what they found, the results were very similar.²⁰ For example, they found that having even a single prior paid claim strongly predicted future claims over the next 5 years. They also found that some “outlier” physicians with multiple paid claims “are responsible for a significant share of paid claims.” They specifically found that, even for physicians in high-risk specialties in high-risk states, “bad luck is highly unlikely to explain” multiple claims within 5 years.

Continue to: Both of the studies just mentioned relied on...

Both of the studies just mentioned relied on the National Practitioner Data Bank for information about paid claims. This source has some limitations in capturing claims or payments made by hospitals or other institutions for the actions of its agent-physicians. Some of these limitations were resolved in another recent study that looked at Indiana state insurance and licensing discipline records (over a 41-year period).²¹ Not surprisingly, this study found that claims paid increase with more severe licensure discipline. On the other hand, although, the “frequent fliers” in terms of malpractice claims made and paid could be identified as a “small number of repeat defendants,” these physicians were not routinely disciplined by the state medical board. This was only a single state study, of course, but it also found that a few physicians accounted for a significant number of the claims. The state board was not taking licensing action against this small group, however.

Should the few bad apples be picked from the orchard?

Collectively, these studies are fairly overwhelming in demonstrating that there are some physicians who are “prone” to malpractice claims (for whom all physicians in the specialty are probably paying higher malpractice rates), but who do not attract the attention of licensing agencies for careful examination. In addition to its self-interest in eliminating physicians prone to malpractice claims and payments, the obligation of professions to protect the public interest suggests that state boards should be more aggressive in pursuing those physicians practicing risky medicine.

This medical malpractice series will continue next month with a look at how to reduce malpractice exposure.

Medical malpractice (more formally, professional liability, but we will use the term malpractice) has been of concern to ObGyns for many years, and for good reasons. This specialty has some of the highest incidents of malpractice claims, some of the largest verdicts, and some of the highest malpractice insurance rates. We look more closely at ObGyn malpractice issues in a 3-part “What’s the Verdict” series over the next few months.

In part 1, we discuss the background on malpractice and reasons why malpractice rates have been so high—including large verdicts and lawsuit-prone physicians. In the second part we will look at recent experience and developments in malpractice exposure—who is sued and why. Finally, in the third part we will consider suggestions for reducing the likelihood of a malpractice lawsuit, with a special focus on recent research regarding apologies.

Two reports of recent trials involving ObGyn care illustrate the risk of “the big verdict.”^1,2 (Note that the following vignettes are drawn from actual cases but are outlines of those cases and not complete descriptions of the claims. Because the information does not come from formal court records, the facts may be inaccurate and are incomplete; they should be viewed as illustrations only.)

CASE 1 Delayed delivery, $19M verdict

At 39 weeks’ gestation, a woman was admitted to the hospital in spontaneous labor. Artificial rupture of membranes with clear amniotic fluid was noted. Active contractions occurred for 11 hours. Oxytocin was then initiated, and 17 minutes later, profound fetal bradycardia was detected. There was recurrent evidence of fetal distress with meconium. After a nursing staff change a second nurse restarted oxytocin for a prolonged period. The physician allowed labor to continue despite fetal distress, and performed a cesarean delivery (CD) 4.5 hours later. Five hours postdelivery the neonate was noted to have a pneumothorax, lung damage, and respiratory failure. The infant died at 18 days of age.

The jury felt that there was negligence—failure to timely diagnose fetal distress and failure to timely perform CD, all of which resulted in a verdict for the plaintiff. The jury awarded in excess of $19 million.¹

CASE 2 An undiagnosed tumor, $20M verdict

A patient underwent bilateral mastectomy. Following surgery, she reported pain and swelling at the surgical site for 2 years, and the defendant physician “dismissed” her complaint, refusing to evaluate it as the provider felt it was related to scar tissue. Three years after the mastectomies, the patient underwent surgical exploration and removal of 3 ribs and sternum secondary to a desmoid tumor. Surgical mesh and chest reconstruction was required, necessitating long-term opioids and sleeping medications that “will slow her wits, dull her senses and limit activities of daily living.” Of note, discrepancies were found in the medical records maintained by the defendant. (There was, for example, no report in the record of the plaintiff’s pain until late in the process.) The plaintiff based her claim on the fact that her pain and lump were neither evaluated nor discovered until it was too late.

The jury awarded $20 million. The verdict was reduced to $2 million by the court based on state statutory limits on malpractice damages.^2,3

Continue to: Medical malpractice: Evolution of a standard of care...

Medical malpractice: Evolution of a standard of care

Medical malpractice is not a modern invention. Some historians trace malpractice to the Code of Hammurabi (2030 BC), through Roman law,⁴ into English common law.⁵ It was sufficiently established by 1765 that the classic legal treatise of the century referred to medical malpractice.^6,7 Although medical malpractice existed for a long time, actual malpractice cases were relatively rare before the last half of the 20th century.⁸

Defensive medicine born out of necessity. The number of malpractice cases increased substantially—described as a “geometric increase”—after 1960, with a 300% rise between 1965 and 1970.^7,9 This “malpractice maelstrom of the 70s”⁷ resulted in dramatic increases in malpractice insurance costs and invited the practice of defensive medicine—medically unnecessary or unjustified tests and services.¹⁰Although there is controversy about what is defensive medicine and what is reasonably cautious medicine, the practice may account for 3% of total health care spending.¹¹ Mello and others have estimated that there may be a $55 billion annual cost related to the medical malpractice system.¹²

Several malpractice crises and waves of malpractice or tort reform ensued,¹³ beginning in the 1970s and extending into the 2000s.¹¹ Malpractice law is primarily a matter of state law, so reform essentially has been at the state level—as we will see in the second part in this series.

Defining a standard of care

Medical malpractice is the application of standard legal principles to medical practice. Those principles generally are torts (intentional torts and negligence), and sometimes contracts.¹⁴ Eventually, medical malpractice came to focus primarily on negligence. The legal purposes of imposing negligence liability are compensation (to repay the plaintiff the costs of the harm caused by the defendant) and deterrence (to discourage careless conduct that can harm others.)

Negligence is essentially carelessness that falls below the acceptable standard of care. Negligence may arise, for example, from¹⁵:

• doing something (giving a drug to a patient with a known allergy to it)
• not doing something (failing to test for a possible tumor, as in the second case above)
• not giving appropriate informed consent
• failing to conduct an adequate examination
• abandoning a patient
• failing to refer a patient to a specialist (or conduct a consultation).

(In recent years, law reforms directed specifically at medical malpractice have somewhat separated medical malpractice from other tort law.)

In malpractice cases, the core question is whether the provider did (or did not) do something that a reasonably careful physician would have done. It is axiomatic that not all bad outcomes are negligent. Indeed, not all mistakes are negligent—only the mistakes that were unreasonable given all of the circumstances. In the first case above, for example, given all of the facts that preceded it, the delay of the physician for 4.5 hours after the fetal distress started was, as seen by the jury, not just a mistake but an unreasonable mistake. Hence, it was negligent. In the second case, the failure to investigate the pain and swelling in the surgical site for 2 years (or failure to refer the patient to another physician) was seen by the jury as an unreasonable mistake—one that would not have been made by a reasonably careful practitioner.

Continue to: The big verdict...

The big verdict

Everyone—every professional providing service, every manufacturer, every driver—eventually will make an unreasonable mistake (ie, commit negligence). If that negligence results in harming someone else, our standard legal response is that the negligent person should be financially responsible for the harm to the other. So, a driver who fails to stop at a red light and hits another car is responsible for those damages. But the damages may vary—perhaps a banged-up fender, or, in another instance, with the same negligence, perhaps terrible personal injuries that will disable the other driver for life. Thus, the damages can vary for the same level of carelessness. The “big verdict” may therefore fall on someone who was not especially careless.

Big verdicts often involve long-term care. The opening case vignettes illustrate a concern of medical malpractice generally—especially for ObGyn practice—the very high verdict. Very high verdicts generally reflect catastrophic damages that will continue for a long time. Bixenstine and colleagues found, for example, that catastrophic payouts often involved “patient age less than 1 year, quadriplegia, brain damage, or lifelong care.”¹⁶ In the case of serious injuries during delivery, for example, the harm to the child may last a lifetime and require years and years of intensive medical services.

Million-dollar-plus payouts are on the rise. The percentage of paid claims (through settlement or trial) that are above $1 million is increasing. These million-dollar cases represent 36% of the total dollars paid in ObGyn malpractice claims, even though they represent only 8% of the number of claims paid.¹⁶ The increase in the big verdict cases (above $1 million) suggests that ObGyn practition­ers should consider their malpractice policy limits—a million dollars may not be enough.

In big verdict cases, the great harm to the plaintiff is often combined with facts that produce extraordinary sympathy for the plaintiff. Sometimes there is decidedly unsympathetic conduct by the defendant as well. In the second case, for example, the problems with the medical record may have suggested to the jury that the doctor was either trying to hide something or did not care enough about the patient even to note a serious complaint. In a case we reviewed in an earlier “What’s the Verdict” column, a physician left the room for several minutes during a critical time—to take a call from a stockbroker.^16-18

The big verdict does not necessarily suggest that the defendant was especially or grossly negligent.¹⁶ It was a bad injury that occurred, for instance. On the other hand, the physician with several malpractice judgments may suggest that this is a problem physician.

Physicians facing multiple lawsuits are the exceptions

A number of studies have demonstrated that only a small proportion of physicians are responsible for a disproportionate number of paid medical malpractice claims. (“Paid claims” are those in which the plaintiff receives money from the doctor’s insurance. “Filed claims” are all malpractice lawsuits filed. Many claims are filed, but few are paid.)

ObGyn has high number of paid claims and high risk of claim payment recurrence. Studdert and colleagues found that the probability of future paid malpractice climbed with each past paid claim.¹⁹ They also found that 1% of physicians accounted for 32% of all paid claims. The number of paid claims varied by specialty—obstetrics and gynecology accounted for the second largest number of paid claims (13%). The risk of recurrence (more than one paid claim) was highest among 4 surgical specialties and ObGyns (about double the recurrence rate in these specialties compared with internal medicine).¹⁹

A minority of physicians responsible for lion share of paid claims. Black and colleagues followed up the Studdert study. Although there were some differences in what they found, the results were very similar.²⁰ For example, they found that having even a single prior paid claim strongly predicted future claims over the next 5 years. They also found that some “outlier” physicians with multiple paid claims “are responsible for a significant share of paid claims.” They specifically found that, even for physicians in high-risk specialties in high-risk states, “bad luck is highly unlikely to explain” multiple claims within 5 years.

Continue to: Both of the studies just mentioned relied on...

Both of the studies just mentioned relied on the National Practitioner Data Bank for information about paid claims. This source has some limitations in capturing claims or payments made by hospitals or other institutions for the actions of its agent-physicians. Some of these limitations were resolved in another recent study that looked at Indiana state insurance and licensing discipline records (over a 41-year period).²¹ Not surprisingly, this study found that claims paid increase with more severe licensure discipline. On the other hand, although, the “frequent fliers” in terms of malpractice claims made and paid could be identified as a “small number of repeat defendants,” these physicians were not routinely disciplined by the state medical board. This was only a single state study, of course, but it also found that a few physicians accounted for a significant number of the claims. The state board was not taking licensing action against this small group, however.

Should the few bad apples be picked from the orchard?

Collectively, these studies are fairly overwhelming in demonstrating that there are some physicians who are “prone” to malpractice claims (for whom all physicians in the specialty are probably paying higher malpractice rates), but who do not attract the attention of licensing agencies for careful examination. In addition to its self-interest in eliminating physicians prone to malpractice claims and payments, the obligation of professions to protect the public interest suggests that state boards should be more aggressive in pursuing those physicians practicing risky medicine.

This medical malpractice series will continue next month with a look at how to reduce malpractice exposure.

The ketogenic diet has been therapeutically employed by physicians since the times of Hippocrates, primarily for its effect on the nervous system.¹ The neurologic literature is inundated with the uses of this medicinal diet for applications in the treatment of epilepsy, neurodegenerative disease, malignancy, and enzyme deficiencies, among others.² In recent years, physicians and scientists have moved to study the application of a ketogenic diet in the realms of cardiovascular disease,³ autoimmune disease,⁴ management of diabetes mellitus (DM) and obesity,^3,5 and enhancement of sports and combat performance,⁶ all with promising results. Increased interest in alternative therapies among the lay population and the efficacy purported by many adherents has spurred intrigue by health care professionals. Over the last decade, there has seen a boom in so-called holistic approaches to health; included are the Paleo Diet, Primal Blueprint Diet, Bulletproof Diet, and the ketogenic/low-carbohydrate, high-fat diet. The benefits of ketones in these diets—through intermittent fasting or cyclical ketosis—–for cognitive enhancement, overall well-being, amelioration of chronic disease states, and increased health span have been promulgated to the lay population. But to date, there is a large gap in the literature on the applications of ketones as well as the ketogenic diet in dermatology and skin health and disease.

The aim of this article is not to summarize the uses of ketones and the ketogenic diet in dermatologic applications (because, unfortunately, those studies have not been undertaken) but to provide evidence from all available literature to support the need for targeted research and to encourage dermatologists to investigate ketones and their role in treating skin disease, primarily in an adjunctive manner. In doing so, a clearly medicinal diet may gain a foothold in the disease-treatment repertoire and among health-promoting agents of the dermatologist. Given the amount of capital being spent on health care, there is an ever-increasing need for low-cost, safe, and tolerable treatments that can be used for multiple disease processes and to promote health. We believe the ketogenic diet is such an adjunctive therapeutic option, as it has clearly been proven to be tolerable, safe, and efficacious for many people over the last millennia.

We conducted a PubMed search of articles indexed for MEDLINE using varying combinations of the terms ketones, ketogenic, skin, inflammation, metabolic, oxidation, dermatology, and dermatologic and found 12 articles. Herein, we summarize the relevant articles and the works cited by those articles.

Adverse Effects of the Ketogenic Diet

As with all medical therapies, the ketogenic diet is not without risk of adverse effects, which should be communicated at the outset of this article and with patients in the clinic. The only known absolute contraindications to a ketogenic diet are porphyria and pyruvate carboxylase deficiency secondary to underlying metabolic derangements.⁷ Certain metabolic cytopathies and carnitine deficiency are relative contraindications, and patients with these conditions should be cautiously placed on this diet and closely monitored. Dehydration, acidosis, lethargy, hypoglycemia, dyslipidemia, electrolyte imbalances, prurigo pigmentosa, and gastrointestinal distress may be an acute issue, but these effects are transient and can be managed. Chronic adverse effects are nephrolithiasis (there are recommended screening procedures for those at risk and prophylactic therapies, which is beyond the scope of this article) and weight loss.⁷

NLRP3 Inflammasome Suppression

Youm et al⁸ reported their findings in Nature Medicine that β-hydroxybutyrate, a ketone body that naturally circulates in the human body, specifically suppresses activity of the NLRP3 inflammasome. The NLRP3 inflammasome serves as the activating platform for IL-1β.⁸ Aberrant and elevated IL-1β levels cause or are associated with a number of dermatologic diseases—namely, the autoinflammatory syndromes (familial cold autoinflammatory syndrome, Muckle-Wells syndrome, neonatal-onset multisystemic disease/chronic infantile neurological cutaneous articular syndrome), hyperimmunoglobulinemia D with periodic fever syndrome, tumor necrosis factor–receptor associated periodic syndrome, juvenile idiopathic arthritis, relapsing polychondritis, Schnitzler syndrome, Sweet syndrome, Behçet disease, gout, sunburn and contact hypersensitivity, hidradenitis suppurativa, and metastatic melanoma.⁷ Clearly, the ketogenic diet may be employed in a therapeutic manner (though to what degree, we need further study) for these dermatologic conditions based on the interaction with the NRLP3 inflammasome and IL-1β.

Acne

A link between acne and diet has long been suspected, but a lack of well-controlled studies has caused only speculation to remain. Recent literature suggests that the effects of insulin may be a notable driver of acne through effects on sex hormones and subsequent effects on sebum production and inflammation. Cordain et al⁹ discuss the mechanism by which insulin can worsen acne in a valuable article, which Paoli et al¹⁰ later corroborated. Essentially, insulin propagates acne by 2 known mechanisms. First, an increase in serum insulin causes a rise in insulinlike growth factor 1 levels and a decrease in insulinlike growth factor binding protein 3 levels, which directly influences keratinocyte proliferation and reduces retinoic acid receptor/retinoid X receptor activity in the skin, causing hyperkeratinization and concomitant abnormal desquamation of the follicular epithelium.^9,10 Second, this increase in insulinlike growth factor 1 and insulin causes a decrease in sex hormone–binding globulin and leads to increased androgen production and circulation in the skin, which causes an increase in sebum production. These factors combined with skin that is colonized with Cutibacterium acnes lead to an inflammatory response and the disease known as acne vulgaris.^9,10 A ketogenic diet could help ameliorate acne because it results in very little insulin secretion, unlike the typical Western diet, which causes frequent large spikes in insulin levels. Furthermore, the anti-inflammatory effects of ketones would benefit the inflammatory nature of this disease.

DM and Diabetic Skin Disease

Diabetes mellitus carries with it the risk for skin diseases specific to the diabetic disease process, such as increased risk for bacterial and fungal infections, venous stasis, pruritus (secondary to poor circulation), acanthosis nigricans, diabetic dermopathy, necrobiosis lipoidica diabeticorum, digital sclerosis, and bullosis diabeticorum.¹¹ It is well established that better control of DM results in better disease state outcomes.¹² The ketogenic diet has shown itself to be a formidable and successful treatment in the diseases of carbohydrate intolerance (eg, metabolic syndrome, insulin resistance, type 2 DM) because of several known mechanisms, including less glucose entering the body and thus less fat deposition, end-product glycation, and free-radical production (discussed below); enhanced fat loss and metabolic efficiency; increased insulin sensitivity; and decreased inflammation.¹³ Lowering a patient’s insulin resistance through a ketogenic diet may help prevent or treat diabetic skin disease.

Dermatologic Malignancy

A ketogenic diet has been of interest in oncology research as an adjunctive therapy for several reasons: anti-inflammatory effects, antioxidation effects, possible effects on mammalian target of rapamycin (mTOR) regulation,⁷ and exploitation of the Warburg effect.¹⁴ One article discusses how mTOR, a cell-cycle regulator of particular importance in cancer biology, can be influenced by ketones both directly and indirectly through modulating the inflammatory response.⁷ It has been shown that suppressing mTOR activity limits and slows tumor growth and spread. Ketones also may prove to be a unique method of metabolically exploiting cancer physiology. The Warburg effect, which earned Otto Warburg the Nobel Prize in Physiology or Medicine in 1931, is the observation that cancerous cells produce adenosine triphosphate solely through aerobic glycolysis followed by lactic acid fermentation.¹⁴ This phenomenon is the basis of the positron emission tomography scan. There are several small studies of the effects of ketogenic diets on malignancy, and although none of these studies are of substantial size or control, they show that a ketogenic diet can halt or even reverse tumor growth.¹⁵ The hypothesis is that because cancer cells cannot metabolize ketones (but normal cells can), the Warburg effect can be taken advantage of through a ketogenic diet to aid in the treatment of malignant disease.¹⁴ If further studies find it a formidable treatment, it most certainly would be helpful for the dermatologist involved in the treatment of cutaneous cancers.

Oxidative Stress

Oxidative stress, a state brought about when reactive oxygen species (ROS) production exceeds the antioxidant capacity of the cell and causes damage, is known to be a central part of certain skin diseases (eg, acne, psoriasis, cutaneous malignancy, varicose ulcers, cutaneous allergic reactions, and drug-induced skin photosensitivity).⁷ There are 2 proven mechanisms by which a ketogenic diet can augment the body’s innate antioxidation capacity. First, ketones activate a potent antioxidant upregulating protein known as NRF2, which is bound in cytosol and remains inactive until activated by certain stimuli (ie, ketones).¹⁶ Migration to the nucleus causes transcriptional changes in DNA to upregulate, via a myriad of pathways, antioxidant production in the cell; most notably, it results in increased glutathione levels.¹⁷ NRF2 also targets several genes involved in chronic inflammatory skin diseases that cause an increase in the antioxidant capacity.¹⁸ As an aside, several foods encouraged on a ketogenic diet also activate NRF2 independently of ketones (eg, coffee, broccoli).¹⁹ Second, a ketogenic diet results in fewer produced ROS and an increase in the nicotinamide adenine dinucleotide ratio produced by the mitochondria; in short, it is a more efficient way of producing cellular energy while enhancing mitochondrial function. When fewer ROS are produced, there is less oxidative stress that needs to be attended to by the cell and less cellular damage. Feichtinger et al¹⁹ point out that mitochondrial inefficiency and dysfunction often are overlooked components in several skin diseases, and based on the studies discussed above, these diseases may be aided with a ketogenic diet.

Patient Applications

Clearly, a ketogenic diet is therapeutic, and there are many promising potential roles it may play in the treatment of a wide variety of health and disease states through hormonal normalization, antioxidant effects, anti-inflammatory effects, and improvement of metabolic risk factors. However, there are vast limitations to what is known about the ketogenic diet and how it might be employed, particularly by the dermatologist. First, the ketogenic diet lacks a firm definition. Although processed inflammatory vegetable oils and meats are low in carbohydrates and high in fat by definition, it is impossible to argue that they are healthy options for consumption and disease prevention and treatment. Second, nutrigenomics dictates that there must be an individual role in how the diet is employed (eg, patients who are lactose intolerant will need to stay away from dairy). Third, there are no clear proven clinical results from the ketogenic diet in the realm of dermatology. Fourth, as with everything, there are potential detrimental side effects of the ketogenic diet that must be considered for patients (though there are established screening procedures and prophylactic therapies that are beyond the scope of this article). Further, other diets have shown benefit for many other disease states and health promotion purposes (eg, the Mediterranean diet).²⁰ We do not know yet if the avoidance of certain dietary factors such as processed carbohydrates and fats are more beneficial than adopting a state of ketosis at this time, and therefore we are not claiming superiority of one dietary approach over others that are proven to promote health.

Because there are no large-scale studies of the ketogenic diet, there is no verified standardization of initiating and monitoring it, though certain academic centers do have published methods of doing so.²¹ There are ample anecdotal methods of initiating, maintaining, and monitoring the ketogenic diet.²² In short, drastic restriction of carbohydrate intake and increased fat consumption are the staples of initiating the diet. Medium-chain triglyceride oil supplementation, coffee consumption, intermittent fasting, and low-level aerobic activity also are thought to aid in transition to a ketogenic state. As a result, a dermatologist may recommend that patients interested in this option begin by focusing on fat, fiber, and protein consumption while greatly reducing the amount of carbohydrates in the diet. Morning walks or more intense workouts for fitter patients should be encouraged. Consumption of serum ketone–enhancing foods (eg, coffee, medium-chain triglyceride oil, coconut products) also should be encouraged. A popular beverage known as Bulletproof coffee also may be of interest.²³ A blood ketone meter can be used for biofeedback to reinforce these behaviors by aiming for proper β-hydroxybutyrate levels. Numerous companies and websites exist for supporting those patients wishing to pursue a ketogenic state, some hosted by physicians/researchers with others hosted by laypeople with an interest in the topic; discretion should be used as to the clinical and scientific accuracy of these sites. The dermatologist in particular can follow these patients and assess for changes in severity of skin disease, subjective well-being, need for medications and adjunctive therapies, and status of comorbid conditions.

For more information on the ketogenic diet, consider reading the works of the following physicians and researchers who all have been involved with or are currently conducting research in the medical use of ketones and ketogenic diets: David Perlmutter, MD; Thomas Seyfried, PhD; Dominic D’Agostino, PhD; Terry Wahls, MD; Jeff Volek, PhD; and Peter Attia, MD.

Conclusion

Based on the available data, there is potential for use of the ketogenic diet in an adjunctive manner for dermatologic applications, and studies should be undertaken to establish the efficacy or inefficacy of this diet as a preventive measure or treatment of skin disease. With the large push for complementary and alternative therapies over the last decade, particularly for skin disease, the time for research on the ketogenic diet is ripe. Over the coming years, it is our hope that larger clinical, randomized, controlled trials will be conducted for the benefit of dermatology patients worldwide.

The ketogenic diet has been therapeutically employed by physicians since the times of Hippocrates, primarily for its effect on the nervous system.¹ The neurologic literature is inundated with the uses of this medicinal diet for applications in the treatment of epilepsy, neurodegenerative disease, malignancy, and enzyme deficiencies, among others.² In recent years, physicians and scientists have moved to study the application of a ketogenic diet in the realms of cardiovascular disease,³ autoimmune disease,⁴ management of diabetes mellitus (DM) and obesity,^3,5 and enhancement of sports and combat performance,⁶ all with promising results. Increased interest in alternative therapies among the lay population and the efficacy purported by many adherents has spurred intrigue by health care professionals. Over the last decade, there has seen a boom in so-called holistic approaches to health; included are the Paleo Diet, Primal Blueprint Diet, Bulletproof Diet, and the ketogenic/low-carbohydrate, high-fat diet. The benefits of ketones in these diets—through intermittent fasting or cyclical ketosis—–for cognitive enhancement, overall well-being, amelioration of chronic disease states, and increased health span have been promulgated to the lay population. But to date, there is a large gap in the literature on the applications of ketones as well as the ketogenic diet in dermatology and skin health and disease.

The aim of this article is not to summarize the uses of ketones and the ketogenic diet in dermatologic applications (because, unfortunately, those studies have not been undertaken) but to provide evidence from all available literature to support the need for targeted research and to encourage dermatologists to investigate ketones and their role in treating skin disease, primarily in an adjunctive manner. In doing so, a clearly medicinal diet may gain a foothold in the disease-treatment repertoire and among health-promoting agents of the dermatologist. Given the amount of capital being spent on health care, there is an ever-increasing need for low-cost, safe, and tolerable treatments that can be used for multiple disease processes and to promote health. We believe the ketogenic diet is such an adjunctive therapeutic option, as it has clearly been proven to be tolerable, safe, and efficacious for many people over the last millennia.

We conducted a PubMed search of articles indexed for MEDLINE using varying combinations of the terms ketones, ketogenic, skin, inflammation, metabolic, oxidation, dermatology, and dermatologic and found 12 articles. Herein, we summarize the relevant articles and the works cited by those articles.

Adverse Effects of the Ketogenic Diet

As with all medical therapies, the ketogenic diet is not without risk of adverse effects, which should be communicated at the outset of this article and with patients in the clinic. The only known absolute contraindications to a ketogenic diet are porphyria and pyruvate carboxylase deficiency secondary to underlying metabolic derangements.⁷ Certain metabolic cytopathies and carnitine deficiency are relative contraindications, and patients with these conditions should be cautiously placed on this diet and closely monitored. Dehydration, acidosis, lethargy, hypoglycemia, dyslipidemia, electrolyte imbalances, prurigo pigmentosa, and gastrointestinal distress may be an acute issue, but these effects are transient and can be managed. Chronic adverse effects are nephrolithiasis (there are recommended screening procedures for those at risk and prophylactic therapies, which is beyond the scope of this article) and weight loss.⁷

NLRP3 Inflammasome Suppression

Youm et al⁸ reported their findings in Nature Medicine that β-hydroxybutyrate, a ketone body that naturally circulates in the human body, specifically suppresses activity of the NLRP3 inflammasome. The NLRP3 inflammasome serves as the activating platform for IL-1β.⁸ Aberrant and elevated IL-1β levels cause or are associated with a number of dermatologic diseases—namely, the autoinflammatory syndromes (familial cold autoinflammatory syndrome, Muckle-Wells syndrome, neonatal-onset multisystemic disease/chronic infantile neurological cutaneous articular syndrome), hyperimmunoglobulinemia D with periodic fever syndrome, tumor necrosis factor–receptor associated periodic syndrome, juvenile idiopathic arthritis, relapsing polychondritis, Schnitzler syndrome, Sweet syndrome, Behçet disease, gout, sunburn and contact hypersensitivity, hidradenitis suppurativa, and metastatic melanoma.⁷ Clearly, the ketogenic diet may be employed in a therapeutic manner (though to what degree, we need further study) for these dermatologic conditions based on the interaction with the NRLP3 inflammasome and IL-1β.

Acne

A link between acne and diet has long been suspected, but a lack of well-controlled studies has caused only speculation to remain. Recent literature suggests that the effects of insulin may be a notable driver of acne through effects on sex hormones and subsequent effects on sebum production and inflammation. Cordain et al⁹ discuss the mechanism by which insulin can worsen acne in a valuable article, which Paoli et al¹⁰ later corroborated. Essentially, insulin propagates acne by 2 known mechanisms. First, an increase in serum insulin causes a rise in insulinlike growth factor 1 levels and a decrease in insulinlike growth factor binding protein 3 levels, which directly influences keratinocyte proliferation and reduces retinoic acid receptor/retinoid X receptor activity in the skin, causing hyperkeratinization and concomitant abnormal desquamation of the follicular epithelium.^9,10 Second, this increase in insulinlike growth factor 1 and insulin causes a decrease in sex hormone–binding globulin and leads to increased androgen production and circulation in the skin, which causes an increase in sebum production. These factors combined with skin that is colonized with Cutibacterium acnes lead to an inflammatory response and the disease known as acne vulgaris.^9,10 A ketogenic diet could help ameliorate acne because it results in very little insulin secretion, unlike the typical Western diet, which causes frequent large spikes in insulin levels. Furthermore, the anti-inflammatory effects of ketones would benefit the inflammatory nature of this disease.

DM and Diabetic Skin Disease

Diabetes mellitus carries with it the risk for skin diseases specific to the diabetic disease process, such as increased risk for bacterial and fungal infections, venous stasis, pruritus (secondary to poor circulation), acanthosis nigricans, diabetic dermopathy, necrobiosis lipoidica diabeticorum, digital sclerosis, and bullosis diabeticorum.¹¹ It is well established that better control of DM results in better disease state outcomes.¹² The ketogenic diet has shown itself to be a formidable and successful treatment in the diseases of carbohydrate intolerance (eg, metabolic syndrome, insulin resistance, type 2 DM) because of several known mechanisms, including less glucose entering the body and thus less fat deposition, end-product glycation, and free-radical production (discussed below); enhanced fat loss and metabolic efficiency; increased insulin sensitivity; and decreased inflammation.¹³ Lowering a patient’s insulin resistance through a ketogenic diet may help prevent or treat diabetic skin disease.

Dermatologic Malignancy

A ketogenic diet has been of interest in oncology research as an adjunctive therapy for several reasons: anti-inflammatory effects, antioxidation effects, possible effects on mammalian target of rapamycin (mTOR) regulation,⁷ and exploitation of the Warburg effect.¹⁴ One article discusses how mTOR, a cell-cycle regulator of particular importance in cancer biology, can be influenced by ketones both directly and indirectly through modulating the inflammatory response.⁷ It has been shown that suppressing mTOR activity limits and slows tumor growth and spread. Ketones also may prove to be a unique method of metabolically exploiting cancer physiology. The Warburg effect, which earned Otto Warburg the Nobel Prize in Physiology or Medicine in 1931, is the observation that cancerous cells produce adenosine triphosphate solely through aerobic glycolysis followed by lactic acid fermentation.¹⁴ This phenomenon is the basis of the positron emission tomography scan. There are several small studies of the effects of ketogenic diets on malignancy, and although none of these studies are of substantial size or control, they show that a ketogenic diet can halt or even reverse tumor growth.¹⁵ The hypothesis is that because cancer cells cannot metabolize ketones (but normal cells can), the Warburg effect can be taken advantage of through a ketogenic diet to aid in the treatment of malignant disease.¹⁴ If further studies find it a formidable treatment, it most certainly would be helpful for the dermatologist involved in the treatment of cutaneous cancers.

Oxidative Stress

Oxidative stress, a state brought about when reactive oxygen species (ROS) production exceeds the antioxidant capacity of the cell and causes damage, is known to be a central part of certain skin diseases (eg, acne, psoriasis, cutaneous malignancy, varicose ulcers, cutaneous allergic reactions, and drug-induced skin photosensitivity).⁷ There are 2 proven mechanisms by which a ketogenic diet can augment the body’s innate antioxidation capacity. First, ketones activate a potent antioxidant upregulating protein known as NRF2, which is bound in cytosol and remains inactive until activated by certain stimuli (ie, ketones).¹⁶ Migration to the nucleus causes transcriptional changes in DNA to upregulate, via a myriad of pathways, antioxidant production in the cell; most notably, it results in increased glutathione levels.¹⁷ NRF2 also targets several genes involved in chronic inflammatory skin diseases that cause an increase in the antioxidant capacity.¹⁸ As an aside, several foods encouraged on a ketogenic diet also activate NRF2 independently of ketones (eg, coffee, broccoli).¹⁹ Second, a ketogenic diet results in fewer produced ROS and an increase in the nicotinamide adenine dinucleotide ratio produced by the mitochondria; in short, it is a more efficient way of producing cellular energy while enhancing mitochondrial function. When fewer ROS are produced, there is less oxidative stress that needs to be attended to by the cell and less cellular damage. Feichtinger et al¹⁹ point out that mitochondrial inefficiency and dysfunction often are overlooked components in several skin diseases, and based on the studies discussed above, these diseases may be aided with a ketogenic diet.

Patient Applications

Clearly, a ketogenic diet is therapeutic, and there are many promising potential roles it may play in the treatment of a wide variety of health and disease states through hormonal normalization, antioxidant effects, anti-inflammatory effects, and improvement of metabolic risk factors. However, there are vast limitations to what is known about the ketogenic diet and how it might be employed, particularly by the dermatologist. First, the ketogenic diet lacks a firm definition. Although processed inflammatory vegetable oils and meats are low in carbohydrates and high in fat by definition, it is impossible to argue that they are healthy options for consumption and disease prevention and treatment. Second, nutrigenomics dictates that there must be an individual role in how the diet is employed (eg, patients who are lactose intolerant will need to stay away from dairy). Third, there are no clear proven clinical results from the ketogenic diet in the realm of dermatology. Fourth, as with everything, there are potential detrimental side effects of the ketogenic diet that must be considered for patients (though there are established screening procedures and prophylactic therapies that are beyond the scope of this article). Further, other diets have shown benefit for many other disease states and health promotion purposes (eg, the Mediterranean diet).²⁰ We do not know yet if the avoidance of certain dietary factors such as processed carbohydrates and fats are more beneficial than adopting a state of ketosis at this time, and therefore we are not claiming superiority of one dietary approach over others that are proven to promote health.

Because there are no large-scale studies of the ketogenic diet, there is no verified standardization of initiating and monitoring it, though certain academic centers do have published methods of doing so.²¹ There are ample anecdotal methods of initiating, maintaining, and monitoring the ketogenic diet.²² In short, drastic restriction of carbohydrate intake and increased fat consumption are the staples of initiating the diet. Medium-chain triglyceride oil supplementation, coffee consumption, intermittent fasting, and low-level aerobic activity also are thought to aid in transition to a ketogenic state. As a result, a dermatologist may recommend that patients interested in this option begin by focusing on fat, fiber, and protein consumption while greatly reducing the amount of carbohydrates in the diet. Morning walks or more intense workouts for fitter patients should be encouraged. Consumption of serum ketone–enhancing foods (eg, coffee, medium-chain triglyceride oil, coconut products) also should be encouraged. A popular beverage known as Bulletproof coffee also may be of interest.²³ A blood ketone meter can be used for biofeedback to reinforce these behaviors by aiming for proper β-hydroxybutyrate levels. Numerous companies and websites exist for supporting those patients wishing to pursue a ketogenic state, some hosted by physicians/researchers with others hosted by laypeople with an interest in the topic; discretion should be used as to the clinical and scientific accuracy of these sites. The dermatologist in particular can follow these patients and assess for changes in severity of skin disease, subjective well-being, need for medications and adjunctive therapies, and status of comorbid conditions.

For more information on the ketogenic diet, consider reading the works of the following physicians and researchers who all have been involved with or are currently conducting research in the medical use of ketones and ketogenic diets: David Perlmutter, MD; Thomas Seyfried, PhD; Dominic D’Agostino, PhD; Terry Wahls, MD; Jeff Volek, PhD; and Peter Attia, MD.

Conclusion

Based on the available data, there is potential for use of the ketogenic diet in an adjunctive manner for dermatologic applications, and studies should be undertaken to establish the efficacy or inefficacy of this diet as a preventive measure or treatment of skin disease. With the large push for complementary and alternative therapies over the last decade, particularly for skin disease, the time for research on the ketogenic diet is ripe. Over the coming years, it is our hope that larger clinical, randomized, controlled trials will be conducted for the benefit of dermatology patients worldwide.

The ketogenic diet has been therapeutically employed by physicians since the times of Hippocrates, primarily for its effect on the nervous system.¹ The neurologic literature is inundated with the uses of this medicinal diet for applications in the treatment of epilepsy, neurodegenerative disease, malignancy, and enzyme deficiencies, among others.² In recent years, physicians and scientists have moved to study the application of a ketogenic diet in the realms of cardiovascular disease,³ autoimmune disease,⁴ management of diabetes mellitus (DM) and obesity,^3,5 and enhancement of sports and combat performance,⁶ all with promising results. Increased interest in alternative therapies among the lay population and the efficacy purported by many adherents has spurred intrigue by health care professionals. Over the last decade, there has seen a boom in so-called holistic approaches to health; included are the Paleo Diet, Primal Blueprint Diet, Bulletproof Diet, and the ketogenic/low-carbohydrate, high-fat diet. The benefits of ketones in these diets—through intermittent fasting or cyclical ketosis—–for cognitive enhancement, overall well-being, amelioration of chronic disease states, and increased health span have been promulgated to the lay population. But to date, there is a large gap in the literature on the applications of ketones as well as the ketogenic diet in dermatology and skin health and disease.

The aim of this article is not to summarize the uses of ketones and the ketogenic diet in dermatologic applications (because, unfortunately, those studies have not been undertaken) but to provide evidence from all available literature to support the need for targeted research and to encourage dermatologists to investigate ketones and their role in treating skin disease, primarily in an adjunctive manner. In doing so, a clearly medicinal diet may gain a foothold in the disease-treatment repertoire and among health-promoting agents of the dermatologist. Given the amount of capital being spent on health care, there is an ever-increasing need for low-cost, safe, and tolerable treatments that can be used for multiple disease processes and to promote health. We believe the ketogenic diet is such an adjunctive therapeutic option, as it has clearly been proven to be tolerable, safe, and efficacious for many people over the last millennia.

We conducted a PubMed search of articles indexed for MEDLINE using varying combinations of the terms ketones, ketogenic, skin, inflammation, metabolic, oxidation, dermatology, and dermatologic and found 12 articles. Herein, we summarize the relevant articles and the works cited by those articles.

Adverse Effects of the Ketogenic Diet

As with all medical therapies, the ketogenic diet is not without risk of adverse effects, which should be communicated at the outset of this article and with patients in the clinic. The only known absolute contraindications to a ketogenic diet are porphyria and pyruvate carboxylase deficiency secondary to underlying metabolic derangements.⁷ Certain metabolic cytopathies and carnitine deficiency are relative contraindications, and patients with these conditions should be cautiously placed on this diet and closely monitored. Dehydration, acidosis, lethargy, hypoglycemia, dyslipidemia, electrolyte imbalances, prurigo pigmentosa, and gastrointestinal distress may be an acute issue, but these effects are transient and can be managed. Chronic adverse effects are nephrolithiasis (there are recommended screening procedures for those at risk and prophylactic therapies, which is beyond the scope of this article) and weight loss.⁷

NLRP3 Inflammasome Suppression

Youm et al⁸ reported their findings in Nature Medicine that β-hydroxybutyrate, a ketone body that naturally circulates in the human body, specifically suppresses activity of the NLRP3 inflammasome. The NLRP3 inflammasome serves as the activating platform for IL-1β.⁸ Aberrant and elevated IL-1β levels cause or are associated with a number of dermatologic diseases—namely, the autoinflammatory syndromes (familial cold autoinflammatory syndrome, Muckle-Wells syndrome, neonatal-onset multisystemic disease/chronic infantile neurological cutaneous articular syndrome), hyperimmunoglobulinemia D with periodic fever syndrome, tumor necrosis factor–receptor associated periodic syndrome, juvenile idiopathic arthritis, relapsing polychondritis, Schnitzler syndrome, Sweet syndrome, Behçet disease, gout, sunburn and contact hypersensitivity, hidradenitis suppurativa, and metastatic melanoma.⁷ Clearly, the ketogenic diet may be employed in a therapeutic manner (though to what degree, we need further study) for these dermatologic conditions based on the interaction with the NRLP3 inflammasome and IL-1β.

Acne

A link between acne and diet has long been suspected, but a lack of well-controlled studies has caused only speculation to remain. Recent literature suggests that the effects of insulin may be a notable driver of acne through effects on sex hormones and subsequent effects on sebum production and inflammation. Cordain et al⁹ discuss the mechanism by which insulin can worsen acne in a valuable article, which Paoli et al¹⁰ later corroborated. Essentially, insulin propagates acne by 2 known mechanisms. First, an increase in serum insulin causes a rise in insulinlike growth factor 1 levels and a decrease in insulinlike growth factor binding protein 3 levels, which directly influences keratinocyte proliferation and reduces retinoic acid receptor/retinoid X receptor activity in the skin, causing hyperkeratinization and concomitant abnormal desquamation of the follicular epithelium.^9,10 Second, this increase in insulinlike growth factor 1 and insulin causes a decrease in sex hormone–binding globulin and leads to increased androgen production and circulation in the skin, which causes an increase in sebum production. These factors combined with skin that is colonized with Cutibacterium acnes lead to an inflammatory response and the disease known as acne vulgaris.^9,10 A ketogenic diet could help ameliorate acne because it results in very little insulin secretion, unlike the typical Western diet, which causes frequent large spikes in insulin levels. Furthermore, the anti-inflammatory effects of ketones would benefit the inflammatory nature of this disease.

DM and Diabetic Skin Disease

Diabetes mellitus carries with it the risk for skin diseases specific to the diabetic disease process, such as increased risk for bacterial and fungal infections, venous stasis, pruritus (secondary to poor circulation), acanthosis nigricans, diabetic dermopathy, necrobiosis lipoidica diabeticorum, digital sclerosis, and bullosis diabeticorum.¹¹ It is well established that better control of DM results in better disease state outcomes.¹² The ketogenic diet has shown itself to be a formidable and successful treatment in the diseases of carbohydrate intolerance (eg, metabolic syndrome, insulin resistance, type 2 DM) because of several known mechanisms, including less glucose entering the body and thus less fat deposition, end-product glycation, and free-radical production (discussed below); enhanced fat loss and metabolic efficiency; increased insulin sensitivity; and decreased inflammation.¹³ Lowering a patient’s insulin resistance through a ketogenic diet may help prevent or treat diabetic skin disease.

Dermatologic Malignancy

A ketogenic diet has been of interest in oncology research as an adjunctive therapy for several reasons: anti-inflammatory effects, antioxidation effects, possible effects on mammalian target of rapamycin (mTOR) regulation,⁷ and exploitation of the Warburg effect.¹⁴ One article discusses how mTOR, a cell-cycle regulator of particular importance in cancer biology, can be influenced by ketones both directly and indirectly through modulating the inflammatory response.⁷ It has been shown that suppressing mTOR activity limits and slows tumor growth and spread. Ketones also may prove to be a unique method of metabolically exploiting cancer physiology. The Warburg effect, which earned Otto Warburg the Nobel Prize in Physiology or Medicine in 1931, is the observation that cancerous cells produce adenosine triphosphate solely through aerobic glycolysis followed by lactic acid fermentation.¹⁴ This phenomenon is the basis of the positron emission tomography scan. There are several small studies of the effects of ketogenic diets on malignancy, and although none of these studies are of substantial size or control, they show that a ketogenic diet can halt or even reverse tumor growth.¹⁵ The hypothesis is that because cancer cells cannot metabolize ketones (but normal cells can), the Warburg effect can be taken advantage of through a ketogenic diet to aid in the treatment of malignant disease.¹⁴ If further studies find it a formidable treatment, it most certainly would be helpful for the dermatologist involved in the treatment of cutaneous cancers.

Oxidative Stress

Oxidative stress, a state brought about when reactive oxygen species (ROS) production exceeds the antioxidant capacity of the cell and causes damage, is known to be a central part of certain skin diseases (eg, acne, psoriasis, cutaneous malignancy, varicose ulcers, cutaneous allergic reactions, and drug-induced skin photosensitivity).⁷ There are 2 proven mechanisms by which a ketogenic diet can augment the body’s innate antioxidation capacity. First, ketones activate a potent antioxidant upregulating protein known as NRF2, which is bound in cytosol and remains inactive until activated by certain stimuli (ie, ketones).¹⁶ Migration to the nucleus causes transcriptional changes in DNA to upregulate, via a myriad of pathways, antioxidant production in the cell; most notably, it results in increased glutathione levels.¹⁷ NRF2 also targets several genes involved in chronic inflammatory skin diseases that cause an increase in the antioxidant capacity.¹⁸ As an aside, several foods encouraged on a ketogenic diet also activate NRF2 independently of ketones (eg, coffee, broccoli).¹⁹ Second, a ketogenic diet results in fewer produced ROS and an increase in the nicotinamide adenine dinucleotide ratio produced by the mitochondria; in short, it is a more efficient way of producing cellular energy while enhancing mitochondrial function. When fewer ROS are produced, there is less oxidative stress that needs to be attended to by the cell and less cellular damage. Feichtinger et al¹⁹ point out that mitochondrial inefficiency and dysfunction often are overlooked components in several skin diseases, and based on the studies discussed above, these diseases may be aided with a ketogenic diet.

Patient Applications

Clearly, a ketogenic diet is therapeutic, and there are many promising potential roles it may play in the treatment of a wide variety of health and disease states through hormonal normalization, antioxidant effects, anti-inflammatory effects, and improvement of metabolic risk factors. However, there are vast limitations to what is known about the ketogenic diet and how it might be employed, particularly by the dermatologist. First, the ketogenic diet lacks a firm definition. Although processed inflammatory vegetable oils and meats are low in carbohydrates and high in fat by definition, it is impossible to argue that they are healthy options for consumption and disease prevention and treatment. Second, nutrigenomics dictates that there must be an individual role in how the diet is employed (eg, patients who are lactose intolerant will need to stay away from dairy). Third, there are no clear proven clinical results from the ketogenic diet in the realm of dermatology. Fourth, as with everything, there are potential detrimental side effects of the ketogenic diet that must be considered for patients (though there are established screening procedures and prophylactic therapies that are beyond the scope of this article). Further, other diets have shown benefit for many other disease states and health promotion purposes (eg, the Mediterranean diet).²⁰ We do not know yet if the avoidance of certain dietary factors such as processed carbohydrates and fats are more beneficial than adopting a state of ketosis at this time, and therefore we are not claiming superiority of one dietary approach over others that are proven to promote health.

Because there are no large-scale studies of the ketogenic diet, there is no verified standardization of initiating and monitoring it, though certain academic centers do have published methods of doing so.²¹ There are ample anecdotal methods of initiating, maintaining, and monitoring the ketogenic diet.²² In short, drastic restriction of carbohydrate intake and increased fat consumption are the staples of initiating the diet. Medium-chain triglyceride oil supplementation, coffee consumption, intermittent fasting, and low-level aerobic activity also are thought to aid in transition to a ketogenic state. As a result, a dermatologist may recommend that patients interested in this option begin by focusing on fat, fiber, and protein consumption while greatly reducing the amount of carbohydrates in the diet. Morning walks or more intense workouts for fitter patients should be encouraged. Consumption of serum ketone–enhancing foods (eg, coffee, medium-chain triglyceride oil, coconut products) also should be encouraged. A popular beverage known as Bulletproof coffee also may be of interest.²³ A blood ketone meter can be used for biofeedback to reinforce these behaviors by aiming for proper β-hydroxybutyrate levels. Numerous companies and websites exist for supporting those patients wishing to pursue a ketogenic state, some hosted by physicians/researchers with others hosted by laypeople with an interest in the topic; discretion should be used as to the clinical and scientific accuracy of these sites. The dermatologist in particular can follow these patients and assess for changes in severity of skin disease, subjective well-being, need for medications and adjunctive therapies, and status of comorbid conditions.

For more information on the ketogenic diet, consider reading the works of the following physicians and researchers who all have been involved with or are currently conducting research in the medical use of ketones and ketogenic diets: David Perlmutter, MD; Thomas Seyfried, PhD; Dominic D’Agostino, PhD; Terry Wahls, MD; Jeff Volek, PhD; and Peter Attia, MD.

Conclusion

Based on the available data, there is potential for use of the ketogenic diet in an adjunctive manner for dermatologic applications, and studies should be undertaken to establish the efficacy or inefficacy of this diet as a preventive measure or treatment of skin disease. With the large push for complementary and alternative therapies over the last decade, particularly for skin disease, the time for research on the ketogenic diet is ripe. Over the coming years, it is our hope that larger clinical, randomized, controlled trials will be conducted for the benefit of dermatology patients worldwide.

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

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

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

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].

Psoriasis is a chronic inflammatory skin disorder that affects patients’ quality of life and social interactions.¹ Several studies have shown a strong consistent association between psoriasis and depression as well as possible suicidal ideation and behavior (SIB).^1-13 Notable findings from a 2018 review found depression prevalence ranged from 2.1% to 33.7% among patients with psoriasis vs 0% to 22.7% among unaffected patients.⁷ In a 2017 meta-analysis, Singh et al² found increased odds of SIB (odds ratio [OR], 2.05), attempted suicide (OR, 1.32), and completed suicide (OR, 1.20) in patients with psoriasis compared to those without psoriasis. In 2018, Wu and colleagues⁷ reported that odds of SIB among patients with psoriasis ranged from 1.01 to 1.94 times those of patients without psoriasis, and SIB and suicide attempts were more common than in patients with other dermatologic conditions. Koo and colleagues¹ reached similar conclusions. At the same time, the occurrence of attempted and completed suicides among patients in psoriasis clinical trials has raised concerns about whether psoriasis medications also may increase the risk for SIB.⁷

We review research on the effects of psoriasis treatment on patients’ symptoms of depression and SIB, with a focus on recent analyses of depressive symptoms and SIB among patients with psoriasis who received brodalumab in clinical trials. Finally, we suggest approaches clinicians may consider when caring for patients with psoriasis who may be at risk for depression and SIB.

MATERIALS AND METHODS

We reviewed research on the effects of biologic therapy for psoriasis on depression and SIB, with a primary focus on recent large meta-analyses. Published findings on the pattern of SIB in brodalumab clinical trials and effects of brodalumab treatment on symptoms of depression and anxiety are summarized. The most recent evidence (January 2014–December 2018) regarding the mental health comorbidities of psoriasis was assessed using published English-language research data and review articles according to a PubMed search of articles indexed for MEDLINE using the following terms: depression, anxiety, suicide, suicidal ideation and behavior, SIB, brodalumab, or psoriasis. We also reviewed citations within articles to identify relevant sources. Implications for clinical care of patients with psoriasis are discussed based on expert recommendations and the authors’ clinical experience.

RESULTS

Effects of Psoriasis Treatment on Symptoms of Depression and Suicidality

Occurrences of attempted suicide and completed suicide have been reported during treatment with several psoriasis medications,^7,9 raising concerns about whether these medications increase the risk for depression and SIB in an already vulnerable population. Wu and colleagues⁷ reviewed 11 studies published from 2006 to 2017 reporting the effects of medications for the treatment of psoriasis—adalimumab, apremilast, brodalumab, etanercept, and ustekinumab—on measures of depression and anxiety such as the Beck Depression Inventory, the Hospital Anxiety and Depression Scale (HADS), and the Patient Health Questionnaire (PHQ) 8. In each of the 11 studies, symptoms of depression improved after treatment, over time, or compared to placebo. Notably, the magnitude of improvement in symptoms of depression was not strongly linked to the magnitude of clinical improvement.⁷ Other recent studies have reported reductions in symptoms of depression with biologic therapies, including adalimumab, etanercept, guselkumab, ixekizumab, secukinumab, and ustekinumab.^14-21

With respect to suicidality, an analysis of publicly available data found low rates of completed and attempted suicides (point estimates of 0.0–0.15 per 100 patient-years) in clinical development programs of apremilast, brodalumab, ixekizumab, and secukinumab. Patient suicidality in these trials often occurred in the context of risk factors or stressors such as work, financial difficulties, depression, and substance abuse.⁷ In a detailed 2016 analysis of suicidal behaviors during clinical trials of apremilast, brodalumab, etanercept, infliximab, ixekizumab, secukinumab, tofacitinib, ustekinumab, and other investigational agents, Gooderham and colleagues⁹ concluded that the behaviors may have resulted from the disease or patients’ psychosocial status rather than from treatment and that treatment with biologics does not increase the risk for SIB. Improvements in symptoms of depression during treatment suggest the potential to improve patients’ psychiatric outcomes with biologic treatment.⁹

Evidence From Brodalumab Studies

Intensive efforts have been made to assess the effect of brodalumab, a fully human anti–IL-17RA monoclonal antibody shown to be efficacious in the treatment of moderate to severe plaque psoriasis, on symptoms of depression and to understand the incidence of SIB among patients receiving brodalumab in clinical trials.^22-27

Depression and Anxiety in Studies of Brodalumab
To examine the effects of brodalumab on symptoms of depression, the HADS questionnaire²⁸ was administered to patients in 1 of 3 phase 3 clinical trials of brodalumab.²³ A HADS score of 0 to 7 is considered normal, 8 to 10 is mild, 11 to 14 is moderate, and 15 to 21 is severe.²³ The HADS questionnaire was administered to evaluate the presence and severity of depression and anxiety symptoms at baseline and at weeks 12, 24, 36, and 52.²⁵ This scale was not used in the other 2 phase 3 studies of brodalumab because at the time those studies were initiated, there was no indication to include mental health screenings as part of the study protocol.

Patients were initially randomized to placebo (n=220), brodalumab 140 mg every 2 weeks (Q2W; n=219), or brodalumab 210 mg Q2W (the eventual approved dose; n=222) for 12 weeks.²³ At week 12, patients initially randomized to placebo were switched to brodalumab through week 52. Patients initially randomized to brodalumab 210 mg Q2W were re-randomized to either placebo or brodalumab 210 mg Q2W.²³ Depression and anxiety were common at baseline. Based on HADS scores, depression occurred among 27% and 26% of patients randomized to brodalumab and placebo, respectively; anxiety occurred in 36% of patients in each group.²² Among patients receiving brodalumab 210 mg Q2W from baseline to week 12, HADS depression scores improved in 67% of patients and worsened in 19%. In contrast, the proportion of patients receiving placebo whose depression scores improved (45%) was similar to the proportion whose scores worsened (38%). Hospital Anxiety and Depression Scale anxiety scores also improved more often with brodalumab than with placebo.²²

Furthermore, among patients who had moderate or severe depression or anxiety at baseline, a greater percentage experienced improvement with brodalumab than placebo.²³ Among 30 patients with moderate to severe HADS depression scores at baseline who were treated with brodalumab 210 mg Q2W, 22 (73%) improved by at least 1 depression category by week 12; in the placebo group, 10 of 22 (45%) improved. Among patients with moderate or severe anxiety scores, 28 of 42 patients (67%) treated with brodalumab 210 mg Q2W improved by at least 1 anxiety category compared to 8 of 27 (30%) placebo-treated patients.²³

Over 52 weeks, HADS depression and anxiety scores continued to show a pattern of improvement among patients receiving brodalumab vs placebo.²⁵ Among patients initially receiving placebo, mean HADS depression scores were unchanged from baseline (5.3) to week 12 (5.5). After patients were switched to brodalumab 210 mg Q2W, there was a trend toward improvement between week 12 (5.4) and week 52 (3.1). Among patients initially treated with brodalumab 210 mg Q2W, mean depression scores fell from baseline (5.5) to week 12 (3.4), then rose again between weeks 12 (2.9) and 52 (3.5) in patients switched to placebo (Figure, A). The pattern of findings was similar for HADS anxiety scores (Figure, B).²⁵ Overall, brodalumab treatment appears to improve symptoms of depression and anxiety in patients being treated for psoriasis. This finding is consistent with the effects reported for other biologic therapies previously discussed.

SIB in Studies of Brodalumab
In addition to assessing the effect of brodalumab treatment on symptoms of depression and anxiety in patients with psoriasis, the brodalumab clinical trial program also tracked patterns of SIB among enrolled patients. In contrast with other clinical trials in which patients with a history of psychiatric disorders or substance abuse were excluded, clinical trials of brodalumab did not exclude patients with psychiatric disorders (eg, SIB, depression) and were therefore reflective of the real-world population of patients with moderate to severe psoriasis.²²

In a recently published, detailed analysis of psychiatric adverse events (AEs) in the brodalumab clinical trials, data related to SIB in patients with moderate to severe psoriasis were analyzed from the placebo-controlled phases and open-label, long-term extensions of a placebo-controlled phase 2 clinical trial and from the previously mentioned 3 phase 3 clinical trials.²² From the initiation of the clinical trial program, AEs were monitored during all trials. In response to completed suicides during some studies, additional SIB evaluations were later added at the request of the US Food and Drug Administration, including the Columbia Suicide Severity Rating Scale, the PHQ-8, and the Columbia Classification Algorithm for Suicide Assessment, to independently adjudicate SIB events.²²

In total, 4464 patients in the brodalumab clinical trials received at least 1 dose of brodalumab, and 4126 of these patients received at least 1 dose of brodalumab 210 mg Q2W.²² Total exposure was 9174 patient-years of brodalumab, and mean exposure was 23 months. During the 52-week controlled phases of the clinical trials, 7 patients receiving brodalumab experienced any form of SIB event, representing a time-adjusted incidence rate of 0.20 events (95% confidence interval [CI], 0.08-0.41 events) per 100 patient-years of exposure. During the same 52-week period, patients receiving the comparator drug ustekinumab had an SIB rate of 0.60 events (95% CI, 0.12-1.74 events) per 100 patient-years, which was numerically higher than the rate with brodalumab. Inferential statistical analyses were not performed, but overlapping 95% CIs around these point estimates imply a similar level of SIB risk associated with each agent in these studies. During controlled and uncontrolled treatment periods in all studies, the SIB rate among brodalumab-treated patients was 0.37 events per 100 patient-years.²²

Over all study phases, 3 completed suicides and 1 case adjudicated as indeterminate by the Columbia Classification Algorithm for Suicide Assessment review board were reported.²² All occurred in men aged 39 to 59 years. Of 6 patients with an AE of suicide attempt, all patients had at least 1 SIB risk factor and 3 had a history of SIB. The rate of SIB events was greater in patients with a history of depression (1.42) or suicidality (3.21) compared to those without any history of depression or suicidality (0.21 and 0.20, respectively).²² An examination of the regions in which the brodalumab studies were conducted showed generally consistent SIB incidence rates: 0.52, 0.29, 0.77, and 0 events per 100 patient-years in North America, Europe, Australia, and Russia, respectively.²⁴

As previously described, depression and other risk factors for SIB are prevalent among patients with psoriasis. In addition, the rate of suicide mortality has increased substantially over the last decade in the general population, particularly among middle-aged white men,²⁹ who made up much of the brodalumab clinical trial population.²² Therefore, even without treatment, it would not be surprising that SIB events occurred during the brodalumab trials. Most patients with SIB events during the trials had a history of predisposing risk factors.²² Prescribing information for brodalumab in the United States includes a boxed warning advising physicians to be aware of the risk of SIB as well as a statement that a causal relationship between SIB and brodalumab treatment has not been established.²⁷

COMMENT

This review indicates that depression is increased among patients with psoriasis regardless of treatment regimen⁷; however, the association between psoriasis and suicidality is unclear. In clinical trials of brodalumab, treatment resulted in improved symptoms of depression and anxiety among patients with psoriasis and was associated with lower rates of SIB compared to ustekinumab.^22,23

Despite the boxed warning in the brodalumab package insert concerning suicidality, a causal relationship between brodalumab treatment and increased risk of SIB has not been firmly established.²⁷ The US boxed warning is based on 3 completed suicides and 1 case adjudicated as indeterminate among more than 4000 patients who received at least 1 dose of brodalumab during global clinical trials (0.07% [3/4464]). Compliance in the Risk Evaluation and Mitigation Strategy (REMS) program is mandatory, and patient screening and counseling should not be minimized.²⁷ The 3 completed suicides occurred in patients who reported a history of financial stressors, legal difficulties, or depression and anxiety, and they occurred at least 140 days after initiation of treatment with brodalumab, a chronology that does not support a strong association between brodalumab exposure and SIB.²² Taking into consideration the increased risk for depression among individuals with psoriasis and the details surrounding the 3 completed suicides, an evidence-based causal relationship between brodalumab and increased risk for suicidality cannot be concluded. However, physicians must assess risks and benefits of any therapy in the context of the individual patient’s preferences, risk factors, and response to treatment.

Dermatologists who are aware of the comorbidity between psoriasis and mood disorders play an important role in evaluating patients with psoriasis for psychiatric risk factors.^30-32 The dermatologist should discuss with patients the relationship between psoriasis and depression, assess for any history of depression and SIB, and evaluate for signs and symptoms of depression and current SIB.³³ Screening tools, including the HADS or the short, easily administered PHQ-2³⁴ or PHQ-4,³⁵ can be used to assess whether patients have symptoms of depression.^1,36,37 Patients at risk for depression or SIB should be referred to their primary care physician or a mental health care practitioner.³⁷ Currently, there is a gap in knowledge in screening patients for psychiatric issues within the dermatology community^33,38; however, health care providers can give support to help bridge this gap.

Acknowledgments
This study was sponsored by Amgen Inc. Medical writing support was provided under the direction of the authors by Lisa Baker, PhD, and Rebecca E. Slager, PhD, of MedThink SciCom (Cary, North Carolina) and funded by Ortho Dermatologics, a division of Bausch Health US, LLC.

Psoriasis is a chronic inflammatory skin disorder that affects patients’ quality of life and social interactions.¹ Several studies have shown a strong consistent association between psoriasis and depression as well as possible suicidal ideation and behavior (SIB).^1-13 Notable findings from a 2018 review found depression prevalence ranged from 2.1% to 33.7% among patients with psoriasis vs 0% to 22.7% among unaffected patients.⁷ In a 2017 meta-analysis, Singh et al² found increased odds of SIB (odds ratio [OR], 2.05), attempted suicide (OR, 1.32), and completed suicide (OR, 1.20) in patients with psoriasis compared to those without psoriasis. In 2018, Wu and colleagues⁷ reported that odds of SIB among patients with psoriasis ranged from 1.01 to 1.94 times those of patients without psoriasis, and SIB and suicide attempts were more common than in patients with other dermatologic conditions. Koo and colleagues¹ reached similar conclusions. At the same time, the occurrence of attempted and completed suicides among patients in psoriasis clinical trials has raised concerns about whether psoriasis medications also may increase the risk for SIB.⁷

We review research on the effects of psoriasis treatment on patients’ symptoms of depression and SIB, with a focus on recent analyses of depressive symptoms and SIB among patients with psoriasis who received brodalumab in clinical trials. Finally, we suggest approaches clinicians may consider when caring for patients with psoriasis who may be at risk for depression and SIB.

MATERIALS AND METHODS

We reviewed research on the effects of biologic therapy for psoriasis on depression and SIB, with a primary focus on recent large meta-analyses. Published findings on the pattern of SIB in brodalumab clinical trials and effects of brodalumab treatment on symptoms of depression and anxiety are summarized. The most recent evidence (January 2014–December 2018) regarding the mental health comorbidities of psoriasis was assessed using published English-language research data and review articles according to a PubMed search of articles indexed for MEDLINE using the following terms: depression, anxiety, suicide, suicidal ideation and behavior, SIB, brodalumab, or psoriasis. We also reviewed citations within articles to identify relevant sources. Implications for clinical care of patients with psoriasis are discussed based on expert recommendations and the authors’ clinical experience.

RESULTS

Effects of Psoriasis Treatment on Symptoms of Depression and Suicidality

Occurrences of attempted suicide and completed suicide have been reported during treatment with several psoriasis medications,^7,9 raising concerns about whether these medications increase the risk for depression and SIB in an already vulnerable population. Wu and colleagues⁷ reviewed 11 studies published from 2006 to 2017 reporting the effects of medications for the treatment of psoriasis—adalimumab, apremilast, brodalumab, etanercept, and ustekinumab—on measures of depression and anxiety such as the Beck Depression Inventory, the Hospital Anxiety and Depression Scale (HADS), and the Patient Health Questionnaire (PHQ) 8. In each of the 11 studies, symptoms of depression improved after treatment, over time, or compared to placebo. Notably, the magnitude of improvement in symptoms of depression was not strongly linked to the magnitude of clinical improvement.⁷ Other recent studies have reported reductions in symptoms of depression with biologic therapies, including adalimumab, etanercept, guselkumab, ixekizumab, secukinumab, and ustekinumab.^14-21

With respect to suicidality, an analysis of publicly available data found low rates of completed and attempted suicides (point estimates of 0.0–0.15 per 100 patient-years) in clinical development programs of apremilast, brodalumab, ixekizumab, and secukinumab. Patient suicidality in these trials often occurred in the context of risk factors or stressors such as work, financial difficulties, depression, and substance abuse.⁷ In a detailed 2016 analysis of suicidal behaviors during clinical trials of apremilast, brodalumab, etanercept, infliximab, ixekizumab, secukinumab, tofacitinib, ustekinumab, and other investigational agents, Gooderham and colleagues⁹ concluded that the behaviors may have resulted from the disease or patients’ psychosocial status rather than from treatment and that treatment with biologics does not increase the risk for SIB. Improvements in symptoms of depression during treatment suggest the potential to improve patients’ psychiatric outcomes with biologic treatment.⁹

Evidence From Brodalumab Studies

Intensive efforts have been made to assess the effect of brodalumab, a fully human anti–IL-17RA monoclonal antibody shown to be efficacious in the treatment of moderate to severe plaque psoriasis, on symptoms of depression and to understand the incidence of SIB among patients receiving brodalumab in clinical trials.^22-27

Depression and Anxiety in Studies of Brodalumab
To examine the effects of brodalumab on symptoms of depression, the HADS questionnaire²⁸ was administered to patients in 1 of 3 phase 3 clinical trials of brodalumab.²³ A HADS score of 0 to 7 is considered normal, 8 to 10 is mild, 11 to 14 is moderate, and 15 to 21 is severe.²³ The HADS questionnaire was administered to evaluate the presence and severity of depression and anxiety symptoms at baseline and at weeks 12, 24, 36, and 52.²⁵ This scale was not used in the other 2 phase 3 studies of brodalumab because at the time those studies were initiated, there was no indication to include mental health screenings as part of the study protocol.

Patients were initially randomized to placebo (n=220), brodalumab 140 mg every 2 weeks (Q2W; n=219), or brodalumab 210 mg Q2W (the eventual approved dose; n=222) for 12 weeks.²³ At week 12, patients initially randomized to placebo were switched to brodalumab through week 52. Patients initially randomized to brodalumab 210 mg Q2W were re-randomized to either placebo or brodalumab 210 mg Q2W.²³ Depression and anxiety were common at baseline. Based on HADS scores, depression occurred among 27% and 26% of patients randomized to brodalumab and placebo, respectively; anxiety occurred in 36% of patients in each group.²² Among patients receiving brodalumab 210 mg Q2W from baseline to week 12, HADS depression scores improved in 67% of patients and worsened in 19%. In contrast, the proportion of patients receiving placebo whose depression scores improved (45%) was similar to the proportion whose scores worsened (38%). Hospital Anxiety and Depression Scale anxiety scores also improved more often with brodalumab than with placebo.²²

Furthermore, among patients who had moderate or severe depression or anxiety at baseline, a greater percentage experienced improvement with brodalumab than placebo.²³ Among 30 patients with moderate to severe HADS depression scores at baseline who were treated with brodalumab 210 mg Q2W, 22 (73%) improved by at least 1 depression category by week 12; in the placebo group, 10 of 22 (45%) improved. Among patients with moderate or severe anxiety scores, 28 of 42 patients (67%) treated with brodalumab 210 mg Q2W improved by at least 1 anxiety category compared to 8 of 27 (30%) placebo-treated patients.²³

Over 52 weeks, HADS depression and anxiety scores continued to show a pattern of improvement among patients receiving brodalumab vs placebo.²⁵ Among patients initially receiving placebo, mean HADS depression scores were unchanged from baseline (5.3) to week 12 (5.5). After patients were switched to brodalumab 210 mg Q2W, there was a trend toward improvement between week 12 (5.4) and week 52 (3.1). Among patients initially treated with brodalumab 210 mg Q2W, mean depression scores fell from baseline (5.5) to week 12 (3.4), then rose again between weeks 12 (2.9) and 52 (3.5) in patients switched to placebo (Figure, A). The pattern of findings was similar for HADS anxiety scores (Figure, B).²⁵ Overall, brodalumab treatment appears to improve symptoms of depression and anxiety in patients being treated for psoriasis. This finding is consistent with the effects reported for other biologic therapies previously discussed.

SIB in Studies of Brodalumab
In addition to assessing the effect of brodalumab treatment on symptoms of depression and anxiety in patients with psoriasis, the brodalumab clinical trial program also tracked patterns of SIB among enrolled patients. In contrast with other clinical trials in which patients with a history of psychiatric disorders or substance abuse were excluded, clinical trials of brodalumab did not exclude patients with psychiatric disorders (eg, SIB, depression) and were therefore reflective of the real-world population of patients with moderate to severe psoriasis.²²

In a recently published, detailed analysis of psychiatric adverse events (AEs) in the brodalumab clinical trials, data related to SIB in patients with moderate to severe psoriasis were analyzed from the placebo-controlled phases and open-label, long-term extensions of a placebo-controlled phase 2 clinical trial and from the previously mentioned 3 phase 3 clinical trials.²² From the initiation of the clinical trial program, AEs were monitored during all trials. In response to completed suicides during some studies, additional SIB evaluations were later added at the request of the US Food and Drug Administration, including the Columbia Suicide Severity Rating Scale, the PHQ-8, and the Columbia Classification Algorithm for Suicide Assessment, to independently adjudicate SIB events.²²

In total, 4464 patients in the brodalumab clinical trials received at least 1 dose of brodalumab, and 4126 of these patients received at least 1 dose of brodalumab 210 mg Q2W.²² Total exposure was 9174 patient-years of brodalumab, and mean exposure was 23 months. During the 52-week controlled phases of the clinical trials, 7 patients receiving brodalumab experienced any form of SIB event, representing a time-adjusted incidence rate of 0.20 events (95% confidence interval [CI], 0.08-0.41 events) per 100 patient-years of exposure. During the same 52-week period, patients receiving the comparator drug ustekinumab had an SIB rate of 0.60 events (95% CI, 0.12-1.74 events) per 100 patient-years, which was numerically higher than the rate with brodalumab. Inferential statistical analyses were not performed, but overlapping 95% CIs around these point estimates imply a similar level of SIB risk associated with each agent in these studies. During controlled and uncontrolled treatment periods in all studies, the SIB rate among brodalumab-treated patients was 0.37 events per 100 patient-years.²²

Over all study phases, 3 completed suicides and 1 case adjudicated as indeterminate by the Columbia Classification Algorithm for Suicide Assessment review board were reported.²² All occurred in men aged 39 to 59 years. Of 6 patients with an AE of suicide attempt, all patients had at least 1 SIB risk factor and 3 had a history of SIB. The rate of SIB events was greater in patients with a history of depression (1.42) or suicidality (3.21) compared to those without any history of depression or suicidality (0.21 and 0.20, respectively).²² An examination of the regions in which the brodalumab studies were conducted showed generally consistent SIB incidence rates: 0.52, 0.29, 0.77, and 0 events per 100 patient-years in North America, Europe, Australia, and Russia, respectively.²⁴

As previously described, depression and other risk factors for SIB are prevalent among patients with psoriasis. In addition, the rate of suicide mortality has increased substantially over the last decade in the general population, particularly among middle-aged white men,²⁹ who made up much of the brodalumab clinical trial population.²² Therefore, even without treatment, it would not be surprising that SIB events occurred during the brodalumab trials. Most patients with SIB events during the trials had a history of predisposing risk factors.²² Prescribing information for brodalumab in the United States includes a boxed warning advising physicians to be aware of the risk of SIB as well as a statement that a causal relationship between SIB and brodalumab treatment has not been established.²⁷

COMMENT

This review indicates that depression is increased among patients with psoriasis regardless of treatment regimen⁷; however, the association between psoriasis and suicidality is unclear. In clinical trials of brodalumab, treatment resulted in improved symptoms of depression and anxiety among patients with psoriasis and was associated with lower rates of SIB compared to ustekinumab.^22,23

Despite the boxed warning in the brodalumab package insert concerning suicidality, a causal relationship between brodalumab treatment and increased risk of SIB has not been firmly established.²⁷ The US boxed warning is based on 3 completed suicides and 1 case adjudicated as indeterminate among more than 4000 patients who received at least 1 dose of brodalumab during global clinical trials (0.07% [3/4464]). Compliance in the Risk Evaluation and Mitigation Strategy (REMS) program is mandatory, and patient screening and counseling should not be minimized.²⁷ The 3 completed suicides occurred in patients who reported a history of financial stressors, legal difficulties, or depression and anxiety, and they occurred at least 140 days after initiation of treatment with brodalumab, a chronology that does not support a strong association between brodalumab exposure and SIB.²² Taking into consideration the increased risk for depression among individuals with psoriasis and the details surrounding the 3 completed suicides, an evidence-based causal relationship between brodalumab and increased risk for suicidality cannot be concluded. However, physicians must assess risks and benefits of any therapy in the context of the individual patient’s preferences, risk factors, and response to treatment.

Dermatologists who are aware of the comorbidity between psoriasis and mood disorders play an important role in evaluating patients with psoriasis for psychiatric risk factors.^30-32 The dermatologist should discuss with patients the relationship between psoriasis and depression, assess for any history of depression and SIB, and evaluate for signs and symptoms of depression and current SIB.³³ Screening tools, including the HADS or the short, easily administered PHQ-2³⁴ or PHQ-4,³⁵ can be used to assess whether patients have symptoms of depression.^1,36,37 Patients at risk for depression or SIB should be referred to their primary care physician or a mental health care practitioner.³⁷ Currently, there is a gap in knowledge in screening patients for psychiatric issues within the dermatology community^33,38; however, health care providers can give support to help bridge this gap.

Acknowledgments
This study was sponsored by Amgen Inc. Medical writing support was provided under the direction of the authors by Lisa Baker, PhD, and Rebecca E. Slager, PhD, of MedThink SciCom (Cary, North Carolina) and funded by Ortho Dermatologics, a division of Bausch Health US, LLC.

Psoriasis is a chronic inflammatory skin disorder that affects patients’ quality of life and social interactions.¹ Several studies have shown a strong consistent association between psoriasis and depression as well as possible suicidal ideation and behavior (SIB).^1-13 Notable findings from a 2018 review found depression prevalence ranged from 2.1% to 33.7% among patients with psoriasis vs 0% to 22.7% among unaffected patients.⁷ In a 2017 meta-analysis, Singh et al² found increased odds of SIB (odds ratio [OR], 2.05), attempted suicide (OR, 1.32), and completed suicide (OR, 1.20) in patients with psoriasis compared to those without psoriasis. In 2018, Wu and colleagues⁷ reported that odds of SIB among patients with psoriasis ranged from 1.01 to 1.94 times those of patients without psoriasis, and SIB and suicide attempts were more common than in patients with other dermatologic conditions. Koo and colleagues¹ reached similar conclusions. At the same time, the occurrence of attempted and completed suicides among patients in psoriasis clinical trials has raised concerns about whether psoriasis medications also may increase the risk for SIB.⁷

We review research on the effects of psoriasis treatment on patients’ symptoms of depression and SIB, with a focus on recent analyses of depressive symptoms and SIB among patients with psoriasis who received brodalumab in clinical trials. Finally, we suggest approaches clinicians may consider when caring for patients with psoriasis who may be at risk for depression and SIB.

MATERIALS AND METHODS

We reviewed research on the effects of biologic therapy for psoriasis on depression and SIB, with a primary focus on recent large meta-analyses. Published findings on the pattern of SIB in brodalumab clinical trials and effects of brodalumab treatment on symptoms of depression and anxiety are summarized. The most recent evidence (January 2014–December 2018) regarding the mental health comorbidities of psoriasis was assessed using published English-language research data and review articles according to a PubMed search of articles indexed for MEDLINE using the following terms: depression, anxiety, suicide, suicidal ideation and behavior, SIB, brodalumab, or psoriasis. We also reviewed citations within articles to identify relevant sources. Implications for clinical care of patients with psoriasis are discussed based on expert recommendations and the authors’ clinical experience.

RESULTS

Effects of Psoriasis Treatment on Symptoms of Depression and Suicidality

Occurrences of attempted suicide and completed suicide have been reported during treatment with several psoriasis medications,^7,9 raising concerns about whether these medications increase the risk for depression and SIB in an already vulnerable population. Wu and colleagues⁷ reviewed 11 studies published from 2006 to 2017 reporting the effects of medications for the treatment of psoriasis—adalimumab, apremilast, brodalumab, etanercept, and ustekinumab—on measures of depression and anxiety such as the Beck Depression Inventory, the Hospital Anxiety and Depression Scale (HADS), and the Patient Health Questionnaire (PHQ) 8. In each of the 11 studies, symptoms of depression improved after treatment, over time, or compared to placebo. Notably, the magnitude of improvement in symptoms of depression was not strongly linked to the magnitude of clinical improvement.⁷ Other recent studies have reported reductions in symptoms of depression with biologic therapies, including adalimumab, etanercept, guselkumab, ixekizumab, secukinumab, and ustekinumab.^14-21

With respect to suicidality, an analysis of publicly available data found low rates of completed and attempted suicides (point estimates of 0.0–0.15 per 100 patient-years) in clinical development programs of apremilast, brodalumab, ixekizumab, and secukinumab. Patient suicidality in these trials often occurred in the context of risk factors or stressors such as work, financial difficulties, depression, and substance abuse.⁷ In a detailed 2016 analysis of suicidal behaviors during clinical trials of apremilast, brodalumab, etanercept, infliximab, ixekizumab, secukinumab, tofacitinib, ustekinumab, and other investigational agents, Gooderham and colleagues⁹ concluded that the behaviors may have resulted from the disease or patients’ psychosocial status rather than from treatment and that treatment with biologics does not increase the risk for SIB. Improvements in symptoms of depression during treatment suggest the potential to improve patients’ psychiatric outcomes with biologic treatment.⁹

Evidence From Brodalumab Studies

Intensive efforts have been made to assess the effect of brodalumab, a fully human anti–IL-17RA monoclonal antibody shown to be efficacious in the treatment of moderate to severe plaque psoriasis, on symptoms of depression and to understand the incidence of SIB among patients receiving brodalumab in clinical trials.^22-27

Depression and Anxiety in Studies of Brodalumab
To examine the effects of brodalumab on symptoms of depression, the HADS questionnaire²⁸ was administered to patients in 1 of 3 phase 3 clinical trials of brodalumab.²³ A HADS score of 0 to 7 is considered normal, 8 to 10 is mild, 11 to 14 is moderate, and 15 to 21 is severe.²³ The HADS questionnaire was administered to evaluate the presence and severity of depression and anxiety symptoms at baseline and at weeks 12, 24, 36, and 52.²⁵ This scale was not used in the other 2 phase 3 studies of brodalumab because at the time those studies were initiated, there was no indication to include mental health screenings as part of the study protocol.

Patients were initially randomized to placebo (n=220), brodalumab 140 mg every 2 weeks (Q2W; n=219), or brodalumab 210 mg Q2W (the eventual approved dose; n=222) for 12 weeks.²³ At week 12, patients initially randomized to placebo were switched to brodalumab through week 52. Patients initially randomized to brodalumab 210 mg Q2W were re-randomized to either placebo or brodalumab 210 mg Q2W.²³ Depression and anxiety were common at baseline. Based on HADS scores, depression occurred among 27% and 26% of patients randomized to brodalumab and placebo, respectively; anxiety occurred in 36% of patients in each group.²² Among patients receiving brodalumab 210 mg Q2W from baseline to week 12, HADS depression scores improved in 67% of patients and worsened in 19%. In contrast, the proportion of patients receiving placebo whose depression scores improved (45%) was similar to the proportion whose scores worsened (38%). Hospital Anxiety and Depression Scale anxiety scores also improved more often with brodalumab than with placebo.²²

Furthermore, among patients who had moderate or severe depression or anxiety at baseline, a greater percentage experienced improvement with brodalumab than placebo.²³ Among 30 patients with moderate to severe HADS depression scores at baseline who were treated with brodalumab 210 mg Q2W, 22 (73%) improved by at least 1 depression category by week 12; in the placebo group, 10 of 22 (45%) improved. Among patients with moderate or severe anxiety scores, 28 of 42 patients (67%) treated with brodalumab 210 mg Q2W improved by at least 1 anxiety category compared to 8 of 27 (30%) placebo-treated patients.²³

Over 52 weeks, HADS depression and anxiety scores continued to show a pattern of improvement among patients receiving brodalumab vs placebo.²⁵ Among patients initially receiving placebo, mean HADS depression scores were unchanged from baseline (5.3) to week 12 (5.5). After patients were switched to brodalumab 210 mg Q2W, there was a trend toward improvement between week 12 (5.4) and week 52 (3.1). Among patients initially treated with brodalumab 210 mg Q2W, mean depression scores fell from baseline (5.5) to week 12 (3.4), then rose again between weeks 12 (2.9) and 52 (3.5) in patients switched to placebo (Figure, A). The pattern of findings was similar for HADS anxiety scores (Figure, B).²⁵ Overall, brodalumab treatment appears to improve symptoms of depression and anxiety in patients being treated for psoriasis. This finding is consistent with the effects reported for other biologic therapies previously discussed.

SIB in Studies of Brodalumab
In addition to assessing the effect of brodalumab treatment on symptoms of depression and anxiety in patients with psoriasis, the brodalumab clinical trial program also tracked patterns of SIB among enrolled patients. In contrast with other clinical trials in which patients with a history of psychiatric disorders or substance abuse were excluded, clinical trials of brodalumab did not exclude patients with psychiatric disorders (eg, SIB, depression) and were therefore reflective of the real-world population of patients with moderate to severe psoriasis.²²

In a recently published, detailed analysis of psychiatric adverse events (AEs) in the brodalumab clinical trials, data related to SIB in patients with moderate to severe psoriasis were analyzed from the placebo-controlled phases and open-label, long-term extensions of a placebo-controlled phase 2 clinical trial and from the previously mentioned 3 phase 3 clinical trials.²² From the initiation of the clinical trial program, AEs were monitored during all trials. In response to completed suicides during some studies, additional SIB evaluations were later added at the request of the US Food and Drug Administration, including the Columbia Suicide Severity Rating Scale, the PHQ-8, and the Columbia Classification Algorithm for Suicide Assessment, to independently adjudicate SIB events.²²

In total, 4464 patients in the brodalumab clinical trials received at least 1 dose of brodalumab, and 4126 of these patients received at least 1 dose of brodalumab 210 mg Q2W.²² Total exposure was 9174 patient-years of brodalumab, and mean exposure was 23 months. During the 52-week controlled phases of the clinical trials, 7 patients receiving brodalumab experienced any form of SIB event, representing a time-adjusted incidence rate of 0.20 events (95% confidence interval [CI], 0.08-0.41 events) per 100 patient-years of exposure. During the same 52-week period, patients receiving the comparator drug ustekinumab had an SIB rate of 0.60 events (95% CI, 0.12-1.74 events) per 100 patient-years, which was numerically higher than the rate with brodalumab. Inferential statistical analyses were not performed, but overlapping 95% CIs around these point estimates imply a similar level of SIB risk associated with each agent in these studies. During controlled and uncontrolled treatment periods in all studies, the SIB rate among brodalumab-treated patients was 0.37 events per 100 patient-years.²²

Over all study phases, 3 completed suicides and 1 case adjudicated as indeterminate by the Columbia Classification Algorithm for Suicide Assessment review board were reported.²² All occurred in men aged 39 to 59 years. Of 6 patients with an AE of suicide attempt, all patients had at least 1 SIB risk factor and 3 had a history of SIB. The rate of SIB events was greater in patients with a history of depression (1.42) or suicidality (3.21) compared to those without any history of depression or suicidality (0.21 and 0.20, respectively).²² An examination of the regions in which the brodalumab studies were conducted showed generally consistent SIB incidence rates: 0.52, 0.29, 0.77, and 0 events per 100 patient-years in North America, Europe, Australia, and Russia, respectively.²⁴

As previously described, depression and other risk factors for SIB are prevalent among patients with psoriasis. In addition, the rate of suicide mortality has increased substantially over the last decade in the general population, particularly among middle-aged white men,²⁹ who made up much of the brodalumab clinical trial population.²² Therefore, even without treatment, it would not be surprising that SIB events occurred during the brodalumab trials. Most patients with SIB events during the trials had a history of predisposing risk factors.²² Prescribing information for brodalumab in the United States includes a boxed warning advising physicians to be aware of the risk of SIB as well as a statement that a causal relationship between SIB and brodalumab treatment has not been established.²⁷

COMMENT

This review indicates that depression is increased among patients with psoriasis regardless of treatment regimen⁷; however, the association between psoriasis and suicidality is unclear. In clinical trials of brodalumab, treatment resulted in improved symptoms of depression and anxiety among patients with psoriasis and was associated with lower rates of SIB compared to ustekinumab.^22,23

Despite the boxed warning in the brodalumab package insert concerning suicidality, a causal relationship between brodalumab treatment and increased risk of SIB has not been firmly established.²⁷ The US boxed warning is based on 3 completed suicides and 1 case adjudicated as indeterminate among more than 4000 patients who received at least 1 dose of brodalumab during global clinical trials (0.07% [3/4464]). Compliance in the Risk Evaluation and Mitigation Strategy (REMS) program is mandatory, and patient screening and counseling should not be minimized.²⁷ The 3 completed suicides occurred in patients who reported a history of financial stressors, legal difficulties, or depression and anxiety, and they occurred at least 140 days after initiation of treatment with brodalumab, a chronology that does not support a strong association between brodalumab exposure and SIB.²² Taking into consideration the increased risk for depression among individuals with psoriasis and the details surrounding the 3 completed suicides, an evidence-based causal relationship between brodalumab and increased risk for suicidality cannot be concluded. However, physicians must assess risks and benefits of any therapy in the context of the individual patient’s preferences, risk factors, and response to treatment.

Dermatologists who are aware of the comorbidity between psoriasis and mood disorders play an important role in evaluating patients with psoriasis for psychiatric risk factors.^30-32 The dermatologist should discuss with patients the relationship between psoriasis and depression, assess for any history of depression and SIB, and evaluate for signs and symptoms of depression and current SIB.³³ Screening tools, including the HADS or the short, easily administered PHQ-2³⁴ or PHQ-4,³⁵ can be used to assess whether patients have symptoms of depression.^1,36,37 Patients at risk for depression or SIB should be referred to their primary care physician or a mental health care practitioner.³⁷ Currently, there is a gap in knowledge in screening patients for psychiatric issues within the dermatology community^33,38; however, health care providers can give support to help bridge this gap.

Acknowledgments
This study was sponsored by Amgen Inc. Medical writing support was provided under the direction of the authors by Lisa Baker, PhD, and Rebecca E. Slager, PhD, of MedThink SciCom (Cary, North Carolina) and funded by Ortho Dermatologics, a division of Bausch Health US, LLC.

Obstetricians face the potential practice dilemma of having withdrawn from the market the only drug approved by the US Food and Drug Administration (FDA) for the prevention of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. In the recently published PROLONG (Progestin's Role in Optimizing Neonatal Gestation) study by Blackwell and colleagues, the trial results revealed that there were no significant differences in preterm birth between women treated with 17 α-hydroxyprogesterone caproate (17P; Makena) and those who received placebo.¹ For study details and comments, see "Progesterone supplementation does not PROLONG pregnancy in women at risk for preterm birth: What do we do now?" by Michael House, MD, and Errol Norwitz, MD, PhD, MBA. Subsequently, the FDA's Bone, Reproductive and Urologic Drugs Advisory Committee voted 9-7 to recommend pursuit of approval withdrawal for 17P. 

To assess how experienced obstetricians would manage women with previous preterm birth if 17P became unavailable, OBG Management conducted an informal survey. Here, 4 experts respond to the question, "What are you going to do in your practice for women with a history of a previous preterm birth if 17P is no longer an option?"

Not ready to leave behind 17P for recurrent preterm delivery

Patrick Duff, MD 

Preterm delivery is arguably the most important problem in perinatal medicine. It occurs in 10% to 12% of all obstetric patients in the United States, and complications of prematurity account for the majority of neonatal deaths. A major risk factor for recurrent preterm delivery is a prior history of spontaneous preterm delivery, with or without preterm premature rupture of membranes. Clearly, prevention of recurrence is of paramount importance. 

In the Maternal-Fetal Medicine Units (MFMU) Network trial, Meis and colleagues demonstrated a 34% reduction (relative risk [RR], 0.66; 95% confidence interval [CI], 0.54-0.81) in the risk of recurrent preterm delivery in women who received weekly 250-mg injections of 17P (also called 17-OHPC). After publication of that trial, use of 17P became accepted practice in the United States.² 

The PROLONG study by Blackwell and colleagues questions the value of 17P.¹ In that international trial, which included 1,708 women from 41 centers in the United States and 52 outside the United States, the authors were unable to show any significant difference in the frequency of preterm delivery < 35 weeks (11.0% in the women receiving 17P and 11.5% in women receiving placebo; RR, 0.95; 95% CI, 0.71-1.26). Even when they examined the subset of women treated at US medical centers, they could not demonstrate any significant difference in treatment outcome.  

At least 2 major explanations account for the discrepancy between the MFMU and the Blackwell studies. First, the participants in the PROLONG trial were clearly not at the same increased risk for recurrent preterm delivery as those in the MFMU trial. Second, in the PROLONG trial only the minority of participants were from the United States. In fact, given the relatively low rate of recurrent preterm delivery in the PROLONG trial, the study was underpowered to detect meaningful differences in maternal outcome. Therefore, I am not ready to abandon the use of progesterone supplementation in women at risk for recurrent preterm delivery. 

Continue to: If the FDA removes 17P from the market...

If the FDA removes 17P from the market, my approach with at-risk patients will be as follows: 

• I will encourage all at-risk women to eliminate obvious risk factors, such as smoking, illicit drug use, and excessive physical activity. 
• I will encourage optimal nutrition and appropriate weight gain. 
• I will test all patients for chlamydia, gonorrhea, and bacterial vaginosis and treat women who are infected. 
• After the patient completes the first trimester, I will treat her with micronized progesterone, 200 mg daily, intravaginally. I will continue this medication until 36 to 37 weeks. 
• I will perform an assessment of cervical length at 16, 20, and 24 weeks' gestation. In patients with demonstrable cervical shortening, I will perform a cerclage.

Rational management options for reducing risk of preterm delivery

Alex C. Vidaeff, MD, MPH 

Most women who experience a spontaneous preterm delivery (sPTD) do not deliver prematurely in subsequent pregnancies.³ Two recent systematic reviews, in 2014 and 2017, found an overall risk of recurrent sPTD of 20.2% and 30%, respectively.^4,5 These numbers are closer to the background event rate of 21.9% in the PROLONG trial, while only a few women have a recurrence risk of more than 50%, as in the Meis MFMU trial.^1,2 A public health recommendation cannot be made for an intervention that is expected to work only in rare cases and fail in a majority of cases. Therefore, 17P is no longer a viable option for preventing recurrence in pregnant women with a history of sPTD, with only rare possible exceptions.

What evidence-based alternatives can be offered to pregnant women who had a previous sPTD?

Ultrasound assessment of cervical length has emerged as an effective prognosticator for recurrence in women with a prior sPTD, being able to predict 65.4% of sPTDs at a false-positive rate of 5%.^6,7 Furthermore, sonographic cervical length measurements identify high-risk women who may not need any intervention. It has been shown that, among women with prior sPTD who maintain a normal cervical length up to 24 weeks, more than 90% will deliver at 35 weeks or after without intervention.⁸  

In the United States, interventions to reduce sPTD, once a short cervix has been identified, include vaginal progesterone supplementation and cerclage. The benefit from vaginal progesterone has been documented by an individual patient data meta-analysis, while the benefit of cerclage has been highlighted in a Cochrane Review.^9,10 The results of an adjusted indirect comparison meta-analysis suggest that both interventions are equally effective.¹¹ Therefore, the decision on how best to minimize the risk of recurrent sPTD must be individualized based on historical and clinical circumstances, as well as the woman's informed choice.  

Based on current data, the following approach appears rational to me: 

• Cervical ultrasound surveillance between 16 and 24 weeks' gestation to identify the subgroup of women at significantly increased risk of sPTD recurrence. 
• With cervical length ≤ 25 mm, vaginal progesterone supplementation may be considered. Preferential consideration for progesterone may be given when lower genital tract inflammation is suspected, given the possible anti-inflammatory action of progesterone.^12,13 
• If cervical shortening progresses to 15 to 20 mm, cerclage may be considered. Waiting for a cervix < 15 mm may be unadvisable. In conditions of a very short cervix, frequently dilated, with exposure of the fetal membranes, ascending subclinical intra-amniotic infection already may be present, reducing the efficacy of cerclage. Preferential consideration for cerclage also may be given with 2 sPTDs or mid-trimester losses or with a history of a successful cerclage. 

Continue to: Screen cervical length early, and use cerclage or vaginal progesterone as appropriate...

Screen cervical length early, and use cerclage or vaginal progesterone as appropriate

Michael G. Ross, MD, MPH

In patients with a history of a previous preterm birth, if 17P is no longer an option, I would revert to screening for short cervix with transvaginal ultrasound.  

Screen all high-risk patients at the first prenatal visit, so as not to miss a short cervix before 16 weeks' gestation. Then, beginning at 16 weeks, screen every 2 weeks until approximately 24 weeks.  

If the cervix shortens to 25 mm or less, offer cerclage or vaginal progesterone. If the cervix shortens to 20 mm or less, I would strongly support cerclage or vaginal progesterone. 

Use of 17P is still an option, for now 

Errol R. Norwitz, MD, PhD, MBA 

The way in which 17P was handled by the FDA is exactly the way the system is designed to work; this should be seen as a success, not a failure.  

Given the urgent need for an intervention to prevent preterm birth, the lack of any alternative, and a single, well-designed randomized controlled trial that confirmed safety and suggested some benefit, the FDA approved 17P supplementation in February 2011 for a limited indication only—one or more prior unexplained sPTD—using the expedited review mechanism.² Under this mechanism, a follow-up clinical trial is required to confirm efficacy. This was the PROLONG trial, which failed to show any significant benefit of 17P supplementation in terms of either preterm birth prevention or neonatal outcome.¹ 

In October 2019, an FDA advisory committee met again to review these and other data. After presentations from a range of stakeholders and a robust discussion, the advisory committee voted to pursue approval withdrawal of 17P due to the lack of consistent evidence of benefit (it is important to note that this was not because of safety concerns). This is exactly the way the process is designed to work. 

Where does this leave physicians and patients? It is clear that progesterone supplementation is not a panacea for preterm birth prevention and is not indicated for all women at high risk, even those with one or more prior unexplained sPTDs. Given that preterm birth is a syndrome and not a single diagnosis, it is still possible that there is a subgroup of women who may benefit from this intervention. For this reason—and because there is no clear alternative and no known downside to the administration of this drug (other than cost)—physicians still may choose to discuss this option with their patients and, after counseling, patients still may choose to accept it. If in doubt, engage the "shared decision-making model"; talk to your patients.  

Obstetricians face the potential practice dilemma of having withdrawn from the market the only drug approved by the US Food and Drug Administration (FDA) for the prevention of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. In the recently published PROLONG (Progestin's Role in Optimizing Neonatal Gestation) study by Blackwell and colleagues, the trial results revealed that there were no significant differences in preterm birth between women treated with 17 α-hydroxyprogesterone caproate (17P; Makena) and those who received placebo.¹ For study details and comments, see "Progesterone supplementation does not PROLONG pregnancy in women at risk for preterm birth: What do we do now?" by Michael House, MD, and Errol Norwitz, MD, PhD, MBA. Subsequently, the FDA's Bone, Reproductive and Urologic Drugs Advisory Committee voted 9-7 to recommend pursuit of approval withdrawal for 17P. 

To assess how experienced obstetricians would manage women with previous preterm birth if 17P became unavailable, OBG Management conducted an informal survey. Here, 4 experts respond to the question, "What are you going to do in your practice for women with a history of a previous preterm birth if 17P is no longer an option?"

Not ready to leave behind 17P for recurrent preterm delivery

Patrick Duff, MD 

Preterm delivery is arguably the most important problem in perinatal medicine. It occurs in 10% to 12% of all obstetric patients in the United States, and complications of prematurity account for the majority of neonatal deaths. A major risk factor for recurrent preterm delivery is a prior history of spontaneous preterm delivery, with or without preterm premature rupture of membranes. Clearly, prevention of recurrence is of paramount importance. 

In the Maternal-Fetal Medicine Units (MFMU) Network trial, Meis and colleagues demonstrated a 34% reduction (relative risk [RR], 0.66; 95% confidence interval [CI], 0.54-0.81) in the risk of recurrent preterm delivery in women who received weekly 250-mg injections of 17P (also called 17-OHPC). After publication of that trial, use of 17P became accepted practice in the United States.² 

The PROLONG study by Blackwell and colleagues questions the value of 17P.¹ In that international trial, which included 1,708 women from 41 centers in the United States and 52 outside the United States, the authors were unable to show any significant difference in the frequency of preterm delivery < 35 weeks (11.0% in the women receiving 17P and 11.5% in women receiving placebo; RR, 0.95; 95% CI, 0.71-1.26). Even when they examined the subset of women treated at US medical centers, they could not demonstrate any significant difference in treatment outcome.  

At least 2 major explanations account for the discrepancy between the MFMU and the Blackwell studies. First, the participants in the PROLONG trial were clearly not at the same increased risk for recurrent preterm delivery as those in the MFMU trial. Second, in the PROLONG trial only the minority of participants were from the United States. In fact, given the relatively low rate of recurrent preterm delivery in the PROLONG trial, the study was underpowered to detect meaningful differences in maternal outcome. Therefore, I am not ready to abandon the use of progesterone supplementation in women at risk for recurrent preterm delivery. 

Continue to: If the FDA removes 17P from the market...

If the FDA removes 17P from the market, my approach with at-risk patients will be as follows: 

• I will encourage all at-risk women to eliminate obvious risk factors, such as smoking, illicit drug use, and excessive physical activity. 
• I will encourage optimal nutrition and appropriate weight gain. 
• I will test all patients for chlamydia, gonorrhea, and bacterial vaginosis and treat women who are infected. 
• After the patient completes the first trimester, I will treat her with micronized progesterone, 200 mg daily, intravaginally. I will continue this medication until 36 to 37 weeks. 
• I will perform an assessment of cervical length at 16, 20, and 24 weeks' gestation. In patients with demonstrable cervical shortening, I will perform a cerclage.

Rational management options for reducing risk of preterm delivery

Alex C. Vidaeff, MD, MPH 

Most women who experience a spontaneous preterm delivery (sPTD) do not deliver prematurely in subsequent pregnancies.³ Two recent systematic reviews, in 2014 and 2017, found an overall risk of recurrent sPTD of 20.2% and 30%, respectively.^4,5 These numbers are closer to the background event rate of 21.9% in the PROLONG trial, while only a few women have a recurrence risk of more than 50%, as in the Meis MFMU trial.^1,2 A public health recommendation cannot be made for an intervention that is expected to work only in rare cases and fail in a majority of cases. Therefore, 17P is no longer a viable option for preventing recurrence in pregnant women with a history of sPTD, with only rare possible exceptions.

What evidence-based alternatives can be offered to pregnant women who had a previous sPTD?

Ultrasound assessment of cervical length has emerged as an effective prognosticator for recurrence in women with a prior sPTD, being able to predict 65.4% of sPTDs at a false-positive rate of 5%.^6,7 Furthermore, sonographic cervical length measurements identify high-risk women who may not need any intervention. It has been shown that, among women with prior sPTD who maintain a normal cervical length up to 24 weeks, more than 90% will deliver at 35 weeks or after without intervention.⁸  

In the United States, interventions to reduce sPTD, once a short cervix has been identified, include vaginal progesterone supplementation and cerclage. The benefit from vaginal progesterone has been documented by an individual patient data meta-analysis, while the benefit of cerclage has been highlighted in a Cochrane Review.^9,10 The results of an adjusted indirect comparison meta-analysis suggest that both interventions are equally effective.¹¹ Therefore, the decision on how best to minimize the risk of recurrent sPTD must be individualized based on historical and clinical circumstances, as well as the woman's informed choice.  

Based on current data, the following approach appears rational to me: 

• Cervical ultrasound surveillance between 16 and 24 weeks' gestation to identify the subgroup of women at significantly increased risk of sPTD recurrence. 
• With cervical length ≤ 25 mm, vaginal progesterone supplementation may be considered. Preferential consideration for progesterone may be given when lower genital tract inflammation is suspected, given the possible anti-inflammatory action of progesterone.^12,13 
• If cervical shortening progresses to 15 to 20 mm, cerclage may be considered. Waiting for a cervix < 15 mm may be unadvisable. In conditions of a very short cervix, frequently dilated, with exposure of the fetal membranes, ascending subclinical intra-amniotic infection already may be present, reducing the efficacy of cerclage. Preferential consideration for cerclage also may be given with 2 sPTDs or mid-trimester losses or with a history of a successful cerclage. 

Continue to: Screen cervical length early, and use cerclage or vaginal progesterone as appropriate...

Screen cervical length early, and use cerclage or vaginal progesterone as appropriate

Michael G. Ross, MD, MPH

In patients with a history of a previous preterm birth, if 17P is no longer an option, I would revert to screening for short cervix with transvaginal ultrasound.  

Screen all high-risk patients at the first prenatal visit, so as not to miss a short cervix before 16 weeks' gestation. Then, beginning at 16 weeks, screen every 2 weeks until approximately 24 weeks.  

If the cervix shortens to 25 mm or less, offer cerclage or vaginal progesterone. If the cervix shortens to 20 mm or less, I would strongly support cerclage or vaginal progesterone. 

Use of 17P is still an option, for now 

Errol R. Norwitz, MD, PhD, MBA 

The way in which 17P was handled by the FDA is exactly the way the system is designed to work; this should be seen as a success, not a failure.  

Given the urgent need for an intervention to prevent preterm birth, the lack of any alternative, and a single, well-designed randomized controlled trial that confirmed safety and suggested some benefit, the FDA approved 17P supplementation in February 2011 for a limited indication only—one or more prior unexplained sPTD—using the expedited review mechanism.² Under this mechanism, a follow-up clinical trial is required to confirm efficacy. This was the PROLONG trial, which failed to show any significant benefit of 17P supplementation in terms of either preterm birth prevention or neonatal outcome.¹ 

In October 2019, an FDA advisory committee met again to review these and other data. After presentations from a range of stakeholders and a robust discussion, the advisory committee voted to pursue approval withdrawal of 17P due to the lack of consistent evidence of benefit (it is important to note that this was not because of safety concerns). This is exactly the way the process is designed to work. 

Where does this leave physicians and patients? It is clear that progesterone supplementation is not a panacea for preterm birth prevention and is not indicated for all women at high risk, even those with one or more prior unexplained sPTDs. Given that preterm birth is a syndrome and not a single diagnosis, it is still possible that there is a subgroup of women who may benefit from this intervention. For this reason—and because there is no clear alternative and no known downside to the administration of this drug (other than cost)—physicians still may choose to discuss this option with their patients and, after counseling, patients still may choose to accept it. If in doubt, engage the "shared decision-making model"; talk to your patients.  

Obstetricians face the potential practice dilemma of having withdrawn from the market the only drug approved by the US Food and Drug Administration (FDA) for the prevention of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. In the recently published PROLONG (Progestin's Role in Optimizing Neonatal Gestation) study by Blackwell and colleagues, the trial results revealed that there were no significant differences in preterm birth between women treated with 17 α-hydroxyprogesterone caproate (17P; Makena) and those who received placebo.¹ For study details and comments, see "Progesterone supplementation does not PROLONG pregnancy in women at risk for preterm birth: What do we do now?" by Michael House, MD, and Errol Norwitz, MD, PhD, MBA. Subsequently, the FDA's Bone, Reproductive and Urologic Drugs Advisory Committee voted 9-7 to recommend pursuit of approval withdrawal for 17P. 

To assess how experienced obstetricians would manage women with previous preterm birth if 17P became unavailable, OBG Management conducted an informal survey. Here, 4 experts respond to the question, "What are you going to do in your practice for women with a history of a previous preterm birth if 17P is no longer an option?"

Not ready to leave behind 17P for recurrent preterm delivery

Patrick Duff, MD 

Preterm delivery is arguably the most important problem in perinatal medicine. It occurs in 10% to 12% of all obstetric patients in the United States, and complications of prematurity account for the majority of neonatal deaths. A major risk factor for recurrent preterm delivery is a prior history of spontaneous preterm delivery, with or without preterm premature rupture of membranes. Clearly, prevention of recurrence is of paramount importance. 

In the Maternal-Fetal Medicine Units (MFMU) Network trial, Meis and colleagues demonstrated a 34% reduction (relative risk [RR], 0.66; 95% confidence interval [CI], 0.54-0.81) in the risk of recurrent preterm delivery in women who received weekly 250-mg injections of 17P (also called 17-OHPC). After publication of that trial, use of 17P became accepted practice in the United States.² 

The PROLONG study by Blackwell and colleagues questions the value of 17P.¹ In that international trial, which included 1,708 women from 41 centers in the United States and 52 outside the United States, the authors were unable to show any significant difference in the frequency of preterm delivery < 35 weeks (11.0% in the women receiving 17P and 11.5% in women receiving placebo; RR, 0.95; 95% CI, 0.71-1.26). Even when they examined the subset of women treated at US medical centers, they could not demonstrate any significant difference in treatment outcome.  

At least 2 major explanations account for the discrepancy between the MFMU and the Blackwell studies. First, the participants in the PROLONG trial were clearly not at the same increased risk for recurrent preterm delivery as those in the MFMU trial. Second, in the PROLONG trial only the minority of participants were from the United States. In fact, given the relatively low rate of recurrent preterm delivery in the PROLONG trial, the study was underpowered to detect meaningful differences in maternal outcome. Therefore, I am not ready to abandon the use of progesterone supplementation in women at risk for recurrent preterm delivery. 

Continue to: If the FDA removes 17P from the market...

If the FDA removes 17P from the market, my approach with at-risk patients will be as follows: 

• I will encourage all at-risk women to eliminate obvious risk factors, such as smoking, illicit drug use, and excessive physical activity. 
• I will encourage optimal nutrition and appropriate weight gain. 
• I will test all patients for chlamydia, gonorrhea, and bacterial vaginosis and treat women who are infected. 
• After the patient completes the first trimester, I will treat her with micronized progesterone, 200 mg daily, intravaginally. I will continue this medication until 36 to 37 weeks. 
• I will perform an assessment of cervical length at 16, 20, and 24 weeks' gestation. In patients with demonstrable cervical shortening, I will perform a cerclage.

Rational management options for reducing risk of preterm delivery

Alex C. Vidaeff, MD, MPH 

Most women who experience a spontaneous preterm delivery (sPTD) do not deliver prematurely in subsequent pregnancies.³ Two recent systematic reviews, in 2014 and 2017, found an overall risk of recurrent sPTD of 20.2% and 30%, respectively.^4,5 These numbers are closer to the background event rate of 21.9% in the PROLONG trial, while only a few women have a recurrence risk of more than 50%, as in the Meis MFMU trial.^1,2 A public health recommendation cannot be made for an intervention that is expected to work only in rare cases and fail in a majority of cases. Therefore, 17P is no longer a viable option for preventing recurrence in pregnant women with a history of sPTD, with only rare possible exceptions.

What evidence-based alternatives can be offered to pregnant women who had a previous sPTD?

Ultrasound assessment of cervical length has emerged as an effective prognosticator for recurrence in women with a prior sPTD, being able to predict 65.4% of sPTDs at a false-positive rate of 5%.^6,7 Furthermore, sonographic cervical length measurements identify high-risk women who may not need any intervention. It has been shown that, among women with prior sPTD who maintain a normal cervical length up to 24 weeks, more than 90% will deliver at 35 weeks or after without intervention.⁸  

In the United States, interventions to reduce sPTD, once a short cervix has been identified, include vaginal progesterone supplementation and cerclage. The benefit from vaginal progesterone has been documented by an individual patient data meta-analysis, while the benefit of cerclage has been highlighted in a Cochrane Review.^9,10 The results of an adjusted indirect comparison meta-analysis suggest that both interventions are equally effective.¹¹ Therefore, the decision on how best to minimize the risk of recurrent sPTD must be individualized based on historical and clinical circumstances, as well as the woman's informed choice.  

Based on current data, the following approach appears rational to me: 

• Cervical ultrasound surveillance between 16 and 24 weeks' gestation to identify the subgroup of women at significantly increased risk of sPTD recurrence. 
• With cervical length ≤ 25 mm, vaginal progesterone supplementation may be considered. Preferential consideration for progesterone may be given when lower genital tract inflammation is suspected, given the possible anti-inflammatory action of progesterone.^12,13 
• If cervical shortening progresses to 15 to 20 mm, cerclage may be considered. Waiting for a cervix < 15 mm may be unadvisable. In conditions of a very short cervix, frequently dilated, with exposure of the fetal membranes, ascending subclinical intra-amniotic infection already may be present, reducing the efficacy of cerclage. Preferential consideration for cerclage also may be given with 2 sPTDs or mid-trimester losses or with a history of a successful cerclage. 

Continue to: Screen cervical length early, and use cerclage or vaginal progesterone as appropriate...

Screen cervical length early, and use cerclage or vaginal progesterone as appropriate

Michael G. Ross, MD, MPH

In patients with a history of a previous preterm birth, if 17P is no longer an option, I would revert to screening for short cervix with transvaginal ultrasound.  

Screen all high-risk patients at the first prenatal visit, so as not to miss a short cervix before 16 weeks' gestation. Then, beginning at 16 weeks, screen every 2 weeks until approximately 24 weeks.  

If the cervix shortens to 25 mm or less, offer cerclage or vaginal progesterone. If the cervix shortens to 20 mm or less, I would strongly support cerclage or vaginal progesterone. 

Use of 17P is still an option, for now 

Errol R. Norwitz, MD, PhD, MBA 

The way in which 17P was handled by the FDA is exactly the way the system is designed to work; this should be seen as a success, not a failure.  

Given the urgent need for an intervention to prevent preterm birth, the lack of any alternative, and a single, well-designed randomized controlled trial that confirmed safety and suggested some benefit, the FDA approved 17P supplementation in February 2011 for a limited indication only—one or more prior unexplained sPTD—using the expedited review mechanism.² Under this mechanism, a follow-up clinical trial is required to confirm efficacy. This was the PROLONG trial, which failed to show any significant benefit of 17P supplementation in terms of either preterm birth prevention or neonatal outcome.¹ 

In October 2019, an FDA advisory committee met again to review these and other data. After presentations from a range of stakeholders and a robust discussion, the advisory committee voted to pursue approval withdrawal of 17P due to the lack of consistent evidence of benefit (it is important to note that this was not because of safety concerns). This is exactly the way the process is designed to work. 

Where does this leave physicians and patients? It is clear that progesterone supplementation is not a panacea for preterm birth prevention and is not indicated for all women at high risk, even those with one or more prior unexplained sPTDs. Given that preterm birth is a syndrome and not a single diagnosis, it is still possible that there is a subgroup of women who may benefit from this intervention. For this reason—and because there is no clear alternative and no known downside to the administration of this drug (other than cost)—physicians still may choose to discuss this option with their patients and, after counseling, patients still may choose to accept it. If in doubt, engage the "shared decision-making model"; talk to your patients.  

Prior to last year, this column was titled “Update on osteoporosis.” My observation, however, is that too many ObGyn providers simply measure bone mass (known as bone mineral density, or BMD), label a patient as normal, osteopenic, or osteoporotic, and then consider pharmacotherapy. The FRAX fracture prediction algorithm, which incorporates age, weight, height, history of any previous fracture, family history of hip fracture, current smoking, use of glucocorticoid medications, and any history of rheumatoid arthritis, has refined the screening process somewhat, if and when it is utilized. As clinicians, we should never lose sight of our goal: to prevent fragility fractures. Having osteoporosis increases that risk, but not having osteoporosis does not eliminate it.

In this Update, I highlight various ways in which work published this past year may help us to improve our patients’ bone health and reduce fragility fractures.

Updated ISCD guidance emphasizes appropriate BMD testing, use of the
Z-score, and terminology 

International Society for Clinical Densitometry. 2019 ISCD Official Positions-Adult. June 2019.  https://www.iscd.org/official-positions/2019-ISCD-official-positions-adult. 

Continue to: Indications for BMD testing...

Indications for BMD testing 

The ISCD's indications for BMD testing remain for women age 65 and older. For postmenopausal women younger than age 65, a BMD test is indicated if they have a risk factor for low bone mass, such as 1) low body weight, 2) prior fracture, 3) high-risk medication use, or 4) a disease or condition associated with bone loss. A BMD test also is indicated for women during the menopausal transition with clinical risk factors for fracture, such as low body weight, prior fracture, or high-risk medication use. Interestingly, the ISCD recommendation for men is similar but uses age 70 for this group. 

In addition, the ISCD recommends BMD testing in adults with a fragility fracture, with a disease or condition associated with low bone mass, or taking medications associated with low bone mass, as well as for anyone being considered for pharmacologic therapy, being treated (to monitor treatment effect), not receiving therapy in whom evidence of bone loss would lead to treatment, and in women discontinuing estrogen who should be considered for BMD testing according to the indications already mentioned. 

Sites to assess for osteoporosis. The World Health Organization international reference standard for osteoporosis diagnosis is a T-score of -2.5 or less at the femoral neck. The reference standard, from which the T-score is calculated, is for white women aged 20 to 29 years of age from the database of the Third National Health and Nutrition Examination Survey. Osteoporosis also may be diagnosed in postmenopausal women if the T-score of the lumbar spine, total hip, or femoral neck is -2.5 or less. In certain circumstances, the 33% radius (also called the one-third radius) may be utilized. Other hip regions of interest, including Ward's area and the greater trochanter, should not be used for diagnosis. 

The skeletal sites at which to measure BMD include the anteroposterior of the spine and hip in all patients. In terms of the spine, use L1-L4 for spine BMD measurement. However, exclude vertebrae that are affected by local structural changes or artifact. Use 3 vertebrae if 4 cannot be used, and 2 if 3 cannot be used. BMD-based diagnostic classification should not be made using a single vertebra. Anatomically abnormal vertebrae may be excluded from analysis if they are clearly abnormal and nonassessable within the resolution of the system, or if there is more than a 1.0 T-score difference between the vertebra in question and adjacent vertebrae. When vertebrae are excluded, the BMD of the remaining vertebrae are used to derive the T-score. 

For BMD measurement at the hip, the femoral neck or total proximal femur—whichever is lowest—should be used. Either hip may be measured. Data are insufficient on whether mean T-scores for bilateral hip BMD should be used for diagnosis. 

Terminology. While the ISCD retains the term osteopenia, the term low bone mass or low bone density is preferred. People with low bone mass or density are not necessarily at high fracture risk. 

Concerning BMD reporting in women prior to menopause, Z-scores, not T-scores, are preferred. A Z-score of -2.0 or lower is defined as "below the expected range for age"; a Z-score above -2.0 is "within the expected range for age." 

Use of serial BMD testing 

Finally, regarding serial BMD measurements, such testing in combination with clinical assessment of fracture risk can be used to determine whether treatment should be initiated in untreated patients. Furthermore, serial BMD testing can monitor a patient's response to therapy by finding an increase or stability of bone density. It should be used to monitor individuals following cessation of osteoporosis drug therapy. Serial BMD testing can detect loss of bone density, indicating the need to assess treatment adherence, evaluate possible secondary causes of osteoporosis, and possibly re-evaluate therapeutic options. 

Intervals between BMD testing should be determined according to each patient's clinical status. Typically, 1 year after initiating or changing therapy is appropriate, with longer intervals once therapeutic effect is established.

Continue to: Dyspareunia drug has positive effects on bone...

Dyspareunia drug has positive effects on bone 

de Villiers TJ, Altomare C, Particco M, et al. Effects of ospemifene on bone in postmenopausal women. Climacteric. 2019;22:442-447. 

Previously, ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to that of estradiol and raloxifene.³ Clinical data from 3 phase 1 or 2 clinical trials found that ospemifene 60 mg/day had a positive effect on biochemical markers for bone turnover in healthy postmenopausal women, with significant improvements relative to placebo and effects comparable to those of raloxifene.⁴ 

Effects on bone formation/resorption biomarkers 

In a recent study, de Villiers and colleagues reported the first phase 3 trial that looked at markers of bone formation and bone resorption.⁵ A total of 316 women were randomly assigned to receive ospemifene, and 315 received placebo.

Demographic and baseline characteristics were similar between treatment groups. Participants' mean age was approximately 60 years, mean body mass index (BMI) was 27.2 kg/m2, and mean duration of VVA was 8 to 9 years. Serum levels of 9 bone biomarkers were similar between groups at baseline. 

At week 12, all 5 markers of bone resorption improved with ospemifene treatment, and 3 of the 5 (NTX, CTX, and TRACP-5b) did so in a statistically significant fashion compared with placebo (P≤.02). In addition, at week 12, all 4 markers of bone formation improved with ospemifene treatment compared with placebo (P≤.008). Furthermore, lower bone resorption markers with ospemifene were observed regardless of time since menopause (≤ 5 years or
> 5 years) or baseline BMD, whether normal, osteopenic, or osteoporotic. 

Interpret results cautiously 

The authors caution that the data are limited to biochemical markers rather than fracture or BMD. It is known that there is good correlation between biochemical markers for bone turnover and the occurrence of fracture.⁶ 

Continue to: Sarcopenia adds to osteoporotic risk for fractures...

Sarcopenia adds to osteoporotic risk for fractures 

Lima RM, de Oliveira RJ, Raposo R, et al. Stages of sarcopenia, bone mineral density, and the prevalence of osteoporosis in older women. Arch Osteoporos. 2019;14:38. 

In 1989, the term sarcopenia was introduced to refer to the age-related decline in skeletal muscle mass.⁸ Currently, sarcopenia is defined as a progressive decline in muscle mass, strength, and physical function, thus increasing the risk for various adverse outcomes, including osteoporosis.⁹ Although muscle and bone tissues differ morphologically, their functioning is closely interconnected. 

The sarcopenia-osteoporosis connection 

Lima and colleagues sought to investigate the relationship between sarcopenia and osteoporosis.¹⁰ They measured women's fat free mass with dual-energy x-ray absorptiometry (DXA) scanning, muscle strength using a dynamometer to measure knee extension torque while participants were seated, and functional performance using the timed "up and go test" in which participants were timed as they got up from a chair, walked 3 meters around a cone, and returned to sit in the chair.^10,11 

The authors used definitions from the European Working Group on Sarcopenia in Older People (EWGSOP). Participants who had normal results in all 3 domains were considered nonsarcopenic. Presarcopenia was defined as having low fat free mass on DXA scanning but normal strength and function. Participants who had low fat free mass and either low strength or low function were labeled as having sarcopenia. Severe sarcopenia was defined as abnormal results in all 3 domains. 

Two hundred thirty-four women (mean age, 68.3 years; range, 60-80) underwent BMD testing and were evaluated according to the 3 domains of possible sarcopenia. All were community dwelling and did not have cognitive impairment or functional dependency. 

The rates of osteoporosis were 15.8%, 19.2%, 35.3%, and 46.2% for nonsarcopenia, presarcopenia, sarcopenia, and severe sarcopenia, respectively (P=.002). Whole-body and femoral neck BMD values were significantly lower among all sarcopenia stages when compared with nonsarcopenia (P<.05). The severe sarcopenia group showed the lowest lumbar spine T-scores (P<.05). When clustered, sarcopenia and severe sarcopenia presented a significantly higher risk for osteoporosis (odds ratio, 3.4; 95% confidence interval [CI], 1.5-7.8). 

Consider sarcopenia a risk factor 

The authors concluded that these "results provide support for the concept that a dose-response relationship exists between sarcopenia stages, BMD, and the presence of osteoporosis. These findings strengthen the clinical significance of the EWGSOP sarcopenia definitions and indicate that severe sarcopenia should be viewed with attention by healthcare professionals." 

Continue to: Certain characteristics may offset fracture risk in aromatase inhibitor users...

Certain characteristics may offset fracture risk in aromatase inhibitor users 

Leslie WD, Morin SN, Lix LM, et al. Fracture risk in women with breast cancer initiating aromatase inhibitor therapy: a registry-based cohort study. Oncologist. 2019;24:1432-1438. 

The use of AIs increases bone turnover and induces bone loss at trabecular-rich bone sites at an average rate of 1% to 3% per year, with reports of up to a threefold increased fracture incidence.¹³ By contrast, a large nationwide population-based cohort study using US Medicare data identified minimal fracture risk from AI use compared with tamoxifen use (11% higher for nonvertebral fractures, not significantly increased for hip fractures).¹⁴ 

An article published previously in this column reported that women on AIs treated with intravenous zoledronic acid had improvements in BMD, while women treated with denosumab had statistically significant fewer fractures compared with those receiving placebo, whether they had normal bone mass, osteopenia, or osteoporosis at
baseline.^15-17
 

Data derived from a population-based BMD registry 

In a recent cohort study, Leslie and colleagues offer the opinion that "observations in the clinical trial setting may differ from routine clinical practice."¹⁸ The authors examined fracture outcomes using a large clinical registry of BMD results from women in Manitoba, Canada. They identified women at least 40 years of age initiating AI therapy for breast cancer (n = 1,775), women with breast cancer not receiving AI therapy (n = 1,016), and women from the general population without breast cancer (n = 34,205). 

Fracture outcomes were assessed after a mean of 6.2 years for the AI users, all of whom had at least 12 months of AI exposure. At baseline, AI users had higher BMI, higher BMD, lower osteoporosis prevalence, and fewer prior fractures than women from the general population or women with breast cancer without AI use (all P<.001). After adjusting for all covariates, AI users were not at significantly greater risk for major osteoporotic fractures (hazard ratio [HR], 1.15; 95% CI, 0.93-1.42), hip fracture (HR, 0.90; 95% CI, 0.56-1.43), or any fracture (HR, 1.06; 95% CI, 0.88-1.28) compared with the general population. 

Results challenge prevailing view 

Thus, the authors concluded that higher baseline BMI, BMD, and lower prevalence of prior fracture at baseline may offset the adverse effects of AI exposure. Although confirmatory data from large cohort studies are required, the authors stated that their findings challenge the view that all women with breast cancer initiating AI therapy should be considered at high risk for fracture.  

Prior to last year, this column was titled “Update on osteoporosis.” My observation, however, is that too many ObGyn providers simply measure bone mass (known as bone mineral density, or BMD), label a patient as normal, osteopenic, or osteoporotic, and then consider pharmacotherapy. The FRAX fracture prediction algorithm, which incorporates age, weight, height, history of any previous fracture, family history of hip fracture, current smoking, use of glucocorticoid medications, and any history of rheumatoid arthritis, has refined the screening process somewhat, if and when it is utilized. As clinicians, we should never lose sight of our goal: to prevent fragility fractures. Having osteoporosis increases that risk, but not having osteoporosis does not eliminate it.

In this Update, I highlight various ways in which work published this past year may help us to improve our patients’ bone health and reduce fragility fractures.

Updated ISCD guidance emphasizes appropriate BMD testing, use of the
Z-score, and terminology 

International Society for Clinical Densitometry. 2019 ISCD Official Positions-Adult. June 2019.  https://www.iscd.org/official-positions/2019-ISCD-official-positions-adult. 

Continue to: Indications for BMD testing...

Indications for BMD testing 

The ISCD's indications for BMD testing remain for women age 65 and older. For postmenopausal women younger than age 65, a BMD test is indicated if they have a risk factor for low bone mass, such as 1) low body weight, 2) prior fracture, 3) high-risk medication use, or 4) a disease or condition associated with bone loss. A BMD test also is indicated for women during the menopausal transition with clinical risk factors for fracture, such as low body weight, prior fracture, or high-risk medication use. Interestingly, the ISCD recommendation for men is similar but uses age 70 for this group. 

In addition, the ISCD recommends BMD testing in adults with a fragility fracture, with a disease or condition associated with low bone mass, or taking medications associated with low bone mass, as well as for anyone being considered for pharmacologic therapy, being treated (to monitor treatment effect), not receiving therapy in whom evidence of bone loss would lead to treatment, and in women discontinuing estrogen who should be considered for BMD testing according to the indications already mentioned. 

Sites to assess for osteoporosis. The World Health Organization international reference standard for osteoporosis diagnosis is a T-score of -2.5 or less at the femoral neck. The reference standard, from which the T-score is calculated, is for white women aged 20 to 29 years of age from the database of the Third National Health and Nutrition Examination Survey. Osteoporosis also may be diagnosed in postmenopausal women if the T-score of the lumbar spine, total hip, or femoral neck is -2.5 or less. In certain circumstances, the 33% radius (also called the one-third radius) may be utilized. Other hip regions of interest, including Ward's area and the greater trochanter, should not be used for diagnosis. 

The skeletal sites at which to measure BMD include the anteroposterior of the spine and hip in all patients. In terms of the spine, use L1-L4 for spine BMD measurement. However, exclude vertebrae that are affected by local structural changes or artifact. Use 3 vertebrae if 4 cannot be used, and 2 if 3 cannot be used. BMD-based diagnostic classification should not be made using a single vertebra. Anatomically abnormal vertebrae may be excluded from analysis if they are clearly abnormal and nonassessable within the resolution of the system, or if there is more than a 1.0 T-score difference between the vertebra in question and adjacent vertebrae. When vertebrae are excluded, the BMD of the remaining vertebrae are used to derive the T-score. 

For BMD measurement at the hip, the femoral neck or total proximal femur—whichever is lowest—should be used. Either hip may be measured. Data are insufficient on whether mean T-scores for bilateral hip BMD should be used for diagnosis. 

Terminology. While the ISCD retains the term osteopenia, the term low bone mass or low bone density is preferred. People with low bone mass or density are not necessarily at high fracture risk. 

Concerning BMD reporting in women prior to menopause, Z-scores, not T-scores, are preferred. A Z-score of -2.0 or lower is defined as "below the expected range for age"; a Z-score above -2.0 is "within the expected range for age." 

Use of serial BMD testing 

Finally, regarding serial BMD measurements, such testing in combination with clinical assessment of fracture risk can be used to determine whether treatment should be initiated in untreated patients. Furthermore, serial BMD testing can monitor a patient's response to therapy by finding an increase or stability of bone density. It should be used to monitor individuals following cessation of osteoporosis drug therapy. Serial BMD testing can detect loss of bone density, indicating the need to assess treatment adherence, evaluate possible secondary causes of osteoporosis, and possibly re-evaluate therapeutic options. 

Intervals between BMD testing should be determined according to each patient's clinical status. Typically, 1 year after initiating or changing therapy is appropriate, with longer intervals once therapeutic effect is established.

Continue to: Dyspareunia drug has positive effects on bone...

Dyspareunia drug has positive effects on bone 

de Villiers TJ, Altomare C, Particco M, et al. Effects of ospemifene on bone in postmenopausal women. Climacteric. 2019;22:442-447. 

Previously, ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to that of estradiol and raloxifene.³ Clinical data from 3 phase 1 or 2 clinical trials found that ospemifene 60 mg/day had a positive effect on biochemical markers for bone turnover in healthy postmenopausal women, with significant improvements relative to placebo and effects comparable to those of raloxifene.⁴ 

Effects on bone formation/resorption biomarkers 

In a recent study, de Villiers and colleagues reported the first phase 3 trial that looked at markers of bone formation and bone resorption.⁵ A total of 316 women were randomly assigned to receive ospemifene, and 315 received placebo.

Demographic and baseline characteristics were similar between treatment groups. Participants' mean age was approximately 60 years, mean body mass index (BMI) was 27.2 kg/m2, and mean duration of VVA was 8 to 9 years. Serum levels of 9 bone biomarkers were similar between groups at baseline. 

At week 12, all 5 markers of bone resorption improved with ospemifene treatment, and 3 of the 5 (NTX, CTX, and TRACP-5b) did so in a statistically significant fashion compared with placebo (P≤.02). In addition, at week 12, all 4 markers of bone formation improved with ospemifene treatment compared with placebo (P≤.008). Furthermore, lower bone resorption markers with ospemifene were observed regardless of time since menopause (≤ 5 years or
> 5 years) or baseline BMD, whether normal, osteopenic, or osteoporotic. 

Interpret results cautiously 

The authors caution that the data are limited to biochemical markers rather than fracture or BMD. It is known that there is good correlation between biochemical markers for bone turnover and the occurrence of fracture.⁶ 

Continue to: Sarcopenia adds to osteoporotic risk for fractures...

Sarcopenia adds to osteoporotic risk for fractures 

Lima RM, de Oliveira RJ, Raposo R, et al. Stages of sarcopenia, bone mineral density, and the prevalence of osteoporosis in older women. Arch Osteoporos. 2019;14:38. 

In 1989, the term sarcopenia was introduced to refer to the age-related decline in skeletal muscle mass.⁸ Currently, sarcopenia is defined as a progressive decline in muscle mass, strength, and physical function, thus increasing the risk for various adverse outcomes, including osteoporosis.⁹ Although muscle and bone tissues differ morphologically, their functioning is closely interconnected. 

The sarcopenia-osteoporosis connection 

Lima and colleagues sought to investigate the relationship between sarcopenia and osteoporosis.¹⁰ They measured women's fat free mass with dual-energy x-ray absorptiometry (DXA) scanning, muscle strength using a dynamometer to measure knee extension torque while participants were seated, and functional performance using the timed "up and go test" in which participants were timed as they got up from a chair, walked 3 meters around a cone, and returned to sit in the chair.^10,11 

The authors used definitions from the European Working Group on Sarcopenia in Older People (EWGSOP). Participants who had normal results in all 3 domains were considered nonsarcopenic. Presarcopenia was defined as having low fat free mass on DXA scanning but normal strength and function. Participants who had low fat free mass and either low strength or low function were labeled as having sarcopenia. Severe sarcopenia was defined as abnormal results in all 3 domains. 

Two hundred thirty-four women (mean age, 68.3 years; range, 60-80) underwent BMD testing and were evaluated according to the 3 domains of possible sarcopenia. All were community dwelling and did not have cognitive impairment or functional dependency. 

The rates of osteoporosis were 15.8%, 19.2%, 35.3%, and 46.2% for nonsarcopenia, presarcopenia, sarcopenia, and severe sarcopenia, respectively (P=.002). Whole-body and femoral neck BMD values were significantly lower among all sarcopenia stages when compared with nonsarcopenia (P<.05). The severe sarcopenia group showed the lowest lumbar spine T-scores (P<.05). When clustered, sarcopenia and severe sarcopenia presented a significantly higher risk for osteoporosis (odds ratio, 3.4; 95% confidence interval [CI], 1.5-7.8). 

Consider sarcopenia a risk factor 

The authors concluded that these "results provide support for the concept that a dose-response relationship exists between sarcopenia stages, BMD, and the presence of osteoporosis. These findings strengthen the clinical significance of the EWGSOP sarcopenia definitions and indicate that severe sarcopenia should be viewed with attention by healthcare professionals." 

Continue to: Certain characteristics may offset fracture risk in aromatase inhibitor users...

Certain characteristics may offset fracture risk in aromatase inhibitor users 

Leslie WD, Morin SN, Lix LM, et al. Fracture risk in women with breast cancer initiating aromatase inhibitor therapy: a registry-based cohort study. Oncologist. 2019;24:1432-1438. 

The use of AIs increases bone turnover and induces bone loss at trabecular-rich bone sites at an average rate of 1% to 3% per year, with reports of up to a threefold increased fracture incidence.¹³ By contrast, a large nationwide population-based cohort study using US Medicare data identified minimal fracture risk from AI use compared with tamoxifen use (11% higher for nonvertebral fractures, not significantly increased for hip fractures).¹⁴ 

An article published previously in this column reported that women on AIs treated with intravenous zoledronic acid had improvements in BMD, while women treated with denosumab had statistically significant fewer fractures compared with those receiving placebo, whether they had normal bone mass, osteopenia, or osteoporosis at
baseline.^15-17
 

Data derived from a population-based BMD registry 

In a recent cohort study, Leslie and colleagues offer the opinion that "observations in the clinical trial setting may differ from routine clinical practice."¹⁸ The authors examined fracture outcomes using a large clinical registry of BMD results from women in Manitoba, Canada. They identified women at least 40 years of age initiating AI therapy for breast cancer (n = 1,775), women with breast cancer not receiving AI therapy (n = 1,016), and women from the general population without breast cancer (n = 34,205). 

Fracture outcomes were assessed after a mean of 6.2 years for the AI users, all of whom had at least 12 months of AI exposure. At baseline, AI users had higher BMI, higher BMD, lower osteoporosis prevalence, and fewer prior fractures than women from the general population or women with breast cancer without AI use (all P<.001). After adjusting for all covariates, AI users were not at significantly greater risk for major osteoporotic fractures (hazard ratio [HR], 1.15; 95% CI, 0.93-1.42), hip fracture (HR, 0.90; 95% CI, 0.56-1.43), or any fracture (HR, 1.06; 95% CI, 0.88-1.28) compared with the general population. 

Results challenge prevailing view 

Thus, the authors concluded that higher baseline BMI, BMD, and lower prevalence of prior fracture at baseline may offset the adverse effects of AI exposure. Although confirmatory data from large cohort studies are required, the authors stated that their findings challenge the view that all women with breast cancer initiating AI therapy should be considered at high risk for fracture.  

Prior to last year, this column was titled “Update on osteoporosis.” My observation, however, is that too many ObGyn providers simply measure bone mass (known as bone mineral density, or BMD), label a patient as normal, osteopenic, or osteoporotic, and then consider pharmacotherapy. The FRAX fracture prediction algorithm, which incorporates age, weight, height, history of any previous fracture, family history of hip fracture, current smoking, use of glucocorticoid medications, and any history of rheumatoid arthritis, has refined the screening process somewhat, if and when it is utilized. As clinicians, we should never lose sight of our goal: to prevent fragility fractures. Having osteoporosis increases that risk, but not having osteoporosis does not eliminate it.

In this Update, I highlight various ways in which work published this past year may help us to improve our patients’ bone health and reduce fragility fractures.

Updated ISCD guidance emphasizes appropriate BMD testing, use of the
Z-score, and terminology 

International Society for Clinical Densitometry. 2019 ISCD Official Positions-Adult. June 2019.  https://www.iscd.org/official-positions/2019-ISCD-official-positions-adult. 

Continue to: Indications for BMD testing...

Indications for BMD testing 

The ISCD's indications for BMD testing remain for women age 65 and older. For postmenopausal women younger than age 65, a BMD test is indicated if they have a risk factor for low bone mass, such as 1) low body weight, 2) prior fracture, 3) high-risk medication use, or 4) a disease or condition associated with bone loss. A BMD test also is indicated for women during the menopausal transition with clinical risk factors for fracture, such as low body weight, prior fracture, or high-risk medication use. Interestingly, the ISCD recommendation for men is similar but uses age 70 for this group. 

In addition, the ISCD recommends BMD testing in adults with a fragility fracture, with a disease or condition associated with low bone mass, or taking medications associated with low bone mass, as well as for anyone being considered for pharmacologic therapy, being treated (to monitor treatment effect), not receiving therapy in whom evidence of bone loss would lead to treatment, and in women discontinuing estrogen who should be considered for BMD testing according to the indications already mentioned. 

Sites to assess for osteoporosis. The World Health Organization international reference standard for osteoporosis diagnosis is a T-score of -2.5 or less at the femoral neck. The reference standard, from which the T-score is calculated, is for white women aged 20 to 29 years of age from the database of the Third National Health and Nutrition Examination Survey. Osteoporosis also may be diagnosed in postmenopausal women if the T-score of the lumbar spine, total hip, or femoral neck is -2.5 or less. In certain circumstances, the 33% radius (also called the one-third radius) may be utilized. Other hip regions of interest, including Ward's area and the greater trochanter, should not be used for diagnosis. 

The skeletal sites at which to measure BMD include the anteroposterior of the spine and hip in all patients. In terms of the spine, use L1-L4 for spine BMD measurement. However, exclude vertebrae that are affected by local structural changes or artifact. Use 3 vertebrae if 4 cannot be used, and 2 if 3 cannot be used. BMD-based diagnostic classification should not be made using a single vertebra. Anatomically abnormal vertebrae may be excluded from analysis if they are clearly abnormal and nonassessable within the resolution of the system, or if there is more than a 1.0 T-score difference between the vertebra in question and adjacent vertebrae. When vertebrae are excluded, the BMD of the remaining vertebrae are used to derive the T-score. 

For BMD measurement at the hip, the femoral neck or total proximal femur—whichever is lowest—should be used. Either hip may be measured. Data are insufficient on whether mean T-scores for bilateral hip BMD should be used for diagnosis. 

Terminology. While the ISCD retains the term osteopenia, the term low bone mass or low bone density is preferred. People with low bone mass or density are not necessarily at high fracture risk. 

Concerning BMD reporting in women prior to menopause, Z-scores, not T-scores, are preferred. A Z-score of -2.0 or lower is defined as "below the expected range for age"; a Z-score above -2.0 is "within the expected range for age." 

Use of serial BMD testing 

Finally, regarding serial BMD measurements, such testing in combination with clinical assessment of fracture risk can be used to determine whether treatment should be initiated in untreated patients. Furthermore, serial BMD testing can monitor a patient's response to therapy by finding an increase or stability of bone density. It should be used to monitor individuals following cessation of osteoporosis drug therapy. Serial BMD testing can detect loss of bone density, indicating the need to assess treatment adherence, evaluate possible secondary causes of osteoporosis, and possibly re-evaluate therapeutic options. 

Intervals between BMD testing should be determined according to each patient's clinical status. Typically, 1 year after initiating or changing therapy is appropriate, with longer intervals once therapeutic effect is established.

Continue to: Dyspareunia drug has positive effects on bone...

Dyspareunia drug has positive effects on bone 

de Villiers TJ, Altomare C, Particco M, et al. Effects of ospemifene on bone in postmenopausal women. Climacteric. 2019;22:442-447. 

Previously, ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to that of estradiol and raloxifene.³ Clinical data from 3 phase 1 or 2 clinical trials found that ospemifene 60 mg/day had a positive effect on biochemical markers for bone turnover in healthy postmenopausal women, with significant improvements relative to placebo and effects comparable to those of raloxifene.⁴ 

Effects on bone formation/resorption biomarkers 

In a recent study, de Villiers and colleagues reported the first phase 3 trial that looked at markers of bone formation and bone resorption.⁵ A total of 316 women were randomly assigned to receive ospemifene, and 315 received placebo.

Demographic and baseline characteristics were similar between treatment groups. Participants' mean age was approximately 60 years, mean body mass index (BMI) was 27.2 kg/m2, and mean duration of VVA was 8 to 9 years. Serum levels of 9 bone biomarkers were similar between groups at baseline. 

At week 12, all 5 markers of bone resorption improved with ospemifene treatment, and 3 of the 5 (NTX, CTX, and TRACP-5b) did so in a statistically significant fashion compared with placebo (P≤.02). In addition, at week 12, all 4 markers of bone formation improved with ospemifene treatment compared with placebo (P≤.008). Furthermore, lower bone resorption markers with ospemifene were observed regardless of time since menopause (≤ 5 years or
> 5 years) or baseline BMD, whether normal, osteopenic, or osteoporotic. 

Interpret results cautiously 

The authors caution that the data are limited to biochemical markers rather than fracture or BMD. It is known that there is good correlation between biochemical markers for bone turnover and the occurrence of fracture.⁶ 

Continue to: Sarcopenia adds to osteoporotic risk for fractures...

Sarcopenia adds to osteoporotic risk for fractures 

Lima RM, de Oliveira RJ, Raposo R, et al. Stages of sarcopenia, bone mineral density, and the prevalence of osteoporosis in older women. Arch Osteoporos. 2019;14:38. 

In 1989, the term sarcopenia was introduced to refer to the age-related decline in skeletal muscle mass.⁸ Currently, sarcopenia is defined as a progressive decline in muscle mass, strength, and physical function, thus increasing the risk for various adverse outcomes, including osteoporosis.⁹ Although muscle and bone tissues differ morphologically, their functioning is closely interconnected. 

The sarcopenia-osteoporosis connection 

Lima and colleagues sought to investigate the relationship between sarcopenia and osteoporosis.¹⁰ They measured women's fat free mass with dual-energy x-ray absorptiometry (DXA) scanning, muscle strength using a dynamometer to measure knee extension torque while participants were seated, and functional performance using the timed "up and go test" in which participants were timed as they got up from a chair, walked 3 meters around a cone, and returned to sit in the chair.^10,11 

The authors used definitions from the European Working Group on Sarcopenia in Older People (EWGSOP). Participants who had normal results in all 3 domains were considered nonsarcopenic. Presarcopenia was defined as having low fat free mass on DXA scanning but normal strength and function. Participants who had low fat free mass and either low strength or low function were labeled as having sarcopenia. Severe sarcopenia was defined as abnormal results in all 3 domains. 

Two hundred thirty-four women (mean age, 68.3 years; range, 60-80) underwent BMD testing and were evaluated according to the 3 domains of possible sarcopenia. All were community dwelling and did not have cognitive impairment or functional dependency. 

The rates of osteoporosis were 15.8%, 19.2%, 35.3%, and 46.2% for nonsarcopenia, presarcopenia, sarcopenia, and severe sarcopenia, respectively (P=.002). Whole-body and femoral neck BMD values were significantly lower among all sarcopenia stages when compared with nonsarcopenia (P<.05). The severe sarcopenia group showed the lowest lumbar spine T-scores (P<.05). When clustered, sarcopenia and severe sarcopenia presented a significantly higher risk for osteoporosis (odds ratio, 3.4; 95% confidence interval [CI], 1.5-7.8). 

Consider sarcopenia a risk factor 

The authors concluded that these "results provide support for the concept that a dose-response relationship exists between sarcopenia stages, BMD, and the presence of osteoporosis. These findings strengthen the clinical significance of the EWGSOP sarcopenia definitions and indicate that severe sarcopenia should be viewed with attention by healthcare professionals." 

Continue to: Certain characteristics may offset fracture risk in aromatase inhibitor users...

Certain characteristics may offset fracture risk in aromatase inhibitor users 

Leslie WD, Morin SN, Lix LM, et al. Fracture risk in women with breast cancer initiating aromatase inhibitor therapy: a registry-based cohort study. Oncologist. 2019;24:1432-1438. 

The use of AIs increases bone turnover and induces bone loss at trabecular-rich bone sites at an average rate of 1% to 3% per year, with reports of up to a threefold increased fracture incidence.¹³ By contrast, a large nationwide population-based cohort study using US Medicare data identified minimal fracture risk from AI use compared with tamoxifen use (11% higher for nonvertebral fractures, not significantly increased for hip fractures).¹⁴ 

An article published previously in this column reported that women on AIs treated with intravenous zoledronic acid had improvements in BMD, while women treated with denosumab had statistically significant fewer fractures compared with those receiving placebo, whether they had normal bone mass, osteopenia, or osteoporosis at
baseline.^15-17
 

Data derived from a population-based BMD registry 

In a recent cohort study, Leslie and colleagues offer the opinion that "observations in the clinical trial setting may differ from routine clinical practice."¹⁸ The authors examined fracture outcomes using a large clinical registry of BMD results from women in Manitoba, Canada. They identified women at least 40 years of age initiating AI therapy for breast cancer (n = 1,775), women with breast cancer not receiving AI therapy (n = 1,016), and women from the general population without breast cancer (n = 34,205). 

Fracture outcomes were assessed after a mean of 6.2 years for the AI users, all of whom had at least 12 months of AI exposure. At baseline, AI users had higher BMI, higher BMD, lower osteoporosis prevalence, and fewer prior fractures than women from the general population or women with breast cancer without AI use (all P<.001). After adjusting for all covariates, AI users were not at significantly greater risk for major osteoporotic fractures (hazard ratio [HR], 1.15; 95% CI, 0.93-1.42), hip fracture (HR, 0.90; 95% CI, 0.56-1.43), or any fracture (HR, 1.06; 95% CI, 0.88-1.28) compared with the general population. 

Results challenge prevailing view 

Thus, the authors concluded that higher baseline BMI, BMD, and lower prevalence of prior fracture at baseline may offset the adverse effects of AI exposure. Although confirmatory data from large cohort studies are required, the authors stated that their findings challenge the view that all women with breast cancer initiating AI therapy should be considered at high risk for fracture.  

The Korean War lasted from June 25, 1950 through July 27, 1953. Although many veterans of the Korean War experienced traumas during extremely stressful combat conditions. However, they would not have been diagnosed with posttraumatic stress disorder (PTSD) at the time because the latter did not exist as a formal diagnosis until the publication of the third edition of the Diagnostic and Statistical Manual (DSM) in 1980.¹ Prior to 1980, psychiatric syndromes resulting from war and combat exposure where known by numerous other terms including shell shock, chronic traumatic war neurosis, and combat fatigue/combat exhaustion.^2,3 Military psychiatrists attended to combat fatigue during the course of the Korean War, but as was true of World War I and II, the focus was on returning soldiers to duty. Combat fatigue was generally viewed as a transient condition.^4-8

Although now octo- and nonagenarians, in 2019 there are 1.2 million living Korean War veterans in the US, representing 6.7% of all current veterans.⁹ Understanding their war experiences and the nature of their current and past presentation of PTSD is relevant not only in formal mental health settings, but in primary care settings, including home-based primary care, as well as community living centers, skilled nursing facilities and assisted living facilities. Older adults with PTSD often present with somatic concerns rather than spontaneously reporting mental health symptoms.¹⁰ Beyond the short-term clinical management of Korean War veterans with PTSD, consideration of their experiences also has long-term relevance for the appropriate treatment of other veteran cohorts as they age in coming decades.

The purpose of this article is to provide a clinically focused overview of PTSD in Korean War veterans, to help promote understanding of this often-forgotten group of veterans, and to foster optimized personalized care. This overview will include a description of the Korean War veteran population and the Korean War itself, the manifestations and identification of PTSD among Korean War veterans, and treatment approaches using evidence-based psychotherapies and pharmacotherapies. Finally, we provide recommendations for future research to address present empirical gaps in the understanding and treatment of Korean War veterans with PTSD.

Causes and Course of the Korean War

When working with Korean War veterans it is important to consider the special nature of that specific conflict. Space considerations limit our ability to do justice to the complex history and numerous battles of the Korean War, but information in the following summary was gleaned from several excellent histories.^11-13

The Korean War has been referred to as The Forgotten War, a concern expressed even during the latter parts of the war.^14,15 But the war and its veterans warrant remembering. The root and proximal causes of the Korean War are complex and not fully agreed upon by the main participants.^16-19 In part this may reflect the fact that there was no clear victor in the Korean War, so that the different protagonists have developed their own versions of the history of the conflict. Also, US involvement and the public reaction to the war must be viewed within the larger historical context of that time. This context included the recent end of 4 years of US involvement in World War II (1941-1945) and the subsequent rapid rise of Cold War tensions between the US and the Soviet Union. The latter also included a worldwide fear of nuclear war and the US fear of the global spread of communism. These fears were fueled by the Soviet-led Berlin Blockade from June 1948 through May 1949, the Soviet Union’s successful atomic bomb test in August 1949, the founding of the People’s Republic of China in October 1949, and the February 1950 Sino-Soviet Treaty of Friendship and Alliance.¹³

In the closing days of World War II, the US and Soviet Union agreed to a temporary division of Korea along the 38th parallel to facilitate timely and efficient surrender of Japanese troops. But as Cold War tensions rose, the temporary division became permanent, and Soviet- and US-backed governments of the north and south, respectively, were officially established on the Korean peninsula in 1948. Although by 1949 the Soviets and US had withdrawn most troops from the peninsula, tensions between the north and south continued to mount and hostilities increased. To this day the exact causes of the eruption of war remain disputed, although it is clear that ideological as well as economic factors played a role, and both leaders of North and South Korea were pledging to reunite the peninsula under their respective leadership.^16-19 The tension culminated on June 25, 1950, when North Korean troops crossed the 38th parallel and invaded South Korea. On June 27, 1950, President Truman ordered US naval and air forces to support South Korea and then ordered the involvement of ground troops on June 30.^16,17,19

Although several other member countries of the United Nations (UN) provided troops, 90% of the troops were from the US. About 5.7 million US military personnel served during the war, including about 1.8 million in Korea itself. The US forces experienced approximately 34,000 battle-related deaths, 103,000 were wounded, and 7,000 were prisoners of war (POWs).^11,20-22 The nature and events of the Korean War made it particularly stressful and traumatizing for the soldiers, sailors, and marines involved throughout its entire course. These included near defeat in the early months, a widely alternating war front along the north/south axis during the first year, and subsequently, not only intense constant battles on the fronts, but also a demanding and exhausting guerrilla war in the south, which lasted throughout the remainder of the conflict.^11,15 The US troops during the initial months of the war have been described as outnumbered and underprepared, as many in the initial phase were reassigned from peace-time occupation duty in Japan.⁷

The first year of war was characterized by a repeated north-to-south/south-to-north shifts in control of territory. During the first 3 months, the North Korean forces overwhelmed the South and captured control of all but 2 South Korean cities in the far southeastern region (Pusan, now Busan; and Daegu), and US and UN forces were forced to retreat to the perimeter around Pusan. The intense Battle of Pusan Perimeter lasted from August 4, 1950 to September 18, 1950, and resulted in massive causalities as well as a flood of civilian refugees.

The course of the war began to change in early September 1950 with the landing of amphibious US/UN forces at Inchon, behind North Korean lines, which cut off southern supply routes for the North Korean troops.¹¹ US/UN forces soon crossed to the north of the 38th parallel and captured the North Korean capital, Pyongyang, on October 19, 1950. They continued to push north and approached the Yalu River border with China by late November 1950, but then the Chinese introduced their own troops forcing a southward retreat of US/UN troops during which there were again numerous US/UN casualties. Chinese troops retook Seoul in late December 1950/early January 1951. However, the US/UN forces soon recaptured Seoul and advanced back to the 38th parallel. This back-and-forth across the 38th parallel continued until July 1951 when the front line of battle stabilized there. Although the line stabilized, intense battles and casualties continued for 2 more years. During this period US/UN troops also had to deal with guerrilla warfare behind the front lines due to the actions of communist partisans and isolated North Korean troops. This situation continued until the armistice was signed July 27, 1953.

Trauma and Characteristic Stresses of the War

There were many factors that made the Korean War experience different from previous wars, particularly World War II. For example, in contrast to the strong public support during and after World War II, public support for the Korean War in the US was low, particularly during its final year.²³ In public opinion polls from October 1952 through April 1953, only 23% to 39% reported feeling that the war was worth fighting.²³ A retrospective 1985 survey also found that 70% of World War II veterans, but only 33% of Korean War veterans reported feeling appreciated by the US public on their return from the war.²⁴

Those fighting in the initial months of the war faced a particularly grim situation. According to LTC Philip Smith, who served as Division Psychiatrist on the Masan Front (Pusan Perimeter) during August and September of 1950, “Fighting was almost continuous and all available troops were on the fighting front… For the most part these soldiers were soft from occupation duty, many had not received adequate combat basic training, no refresher combat training in Korea had as yet been instituted,” he reported.⁷ “The extremes of climate coupled with the generally rugged mountainous terrain in Korea were physical factors of importance…These men were psychologically unprepared for the horrors and isolation of war.” LTC Smith noted that the change in status from civilian or occupation life to the marked deprivation of the war in Korea had been “too abrupt to allow as yet for a reasonable adjustment to the new setting” and that as a result “the highest rate of wounded and neuropsychiatric casualties in the Korean campaign resulted.”⁷

Even after this initial period, the nature of the shifting war, the challenging terrain, the high military casualty rate, and the high rate of civilian casualties and displacement continued throughout the war. The climate was also harsh; Korean War veterans were more likely than were those in World War II or Vietnam to experience injuries related to exposure to extreme cold during the winters (frostbite was among the most common service disabilities).¹⁴ During the Chosin Reservoir Campaign in late 1950, temperatures were as low as -50° F with a wind chill as low as -100° F.²⁵ In addition to cold injuries, other physical health concerns for Korean War veterans were noise injuries from gunfire and explosions and occupational hazards, such as exposure to asbestos, radiation, and polychlorinated biphenyls (PCBs).²⁶

PTSD in Korean War Veterans

It is clear that Korean War combat veterans were exposed to traumatic events. It is unknown how many developed PTSD. While notions of psychological distress and disability related to combat trauma exposure have existed for centuries, Korean War and World War II veterans are a remaining link to pre-DSM PTSD mental health in the military. Military/forward psychiatry—psychiatric services near the battle zone rather than requiring evacuation of patients—was present in Korea from the early months of the war, but the focus of forward psychiatry was to reduce psychiatric causalities from combat fatigue and maximize rapid return-to-duty.^4-6 With no real conception of PTSD, there were limited treatments available, and evidenced-based trauma-focused treatments for PTSD would not be introduced for at least another 4 decades.^27-29

Skinner and Kaplick conducted a historical review of case descriptions of trauma-related conditions from World War I through the Vietnam War and noted the consistent inclusion of hyperarousal and intrusive symptoms, although there also was a greater emphasis on somatic conversion or hysteria symptoms in the earlier descriptions.³⁰ By the Korean War, descriptions of combat fatigue included a number of symptoms that overlap with PTSD, including preoccupation with the traumatic stressor, nightmares, irritability/anger, increased startle, and hyperarousal.³¹ But following the acute phases, attention to any chronic problems associated with these conditions waned. As was acknowledged by a military psychiatrist in a 1954 talk, studies of the long-term adjustment of those who had “broken down in combat” were sorely needed.⁶ In a small 1965 study reported by Archibald and Tuddenham, persistent symptoms of combat fatigue among Korean War veterans were definitely present, and there was even a suggestion that the symptoms had increased over the decade since the war.³²

Given the stoicism that typified cultural expectations for military men during this period, Korean War veterans may also have been reluctant to seek mental health treatment either at the time or later. In short, it is likely that a nontrivial proportion of Korean War veterans with PTSD were underdiagnosed and received suboptimal or no mental health treatment for decades following their war experiences.³³ Although the nature of the war, deployment, and public support were distinct in World War II vs the Korean War, the absence of attention to the long-term effects of disorders related to combat trauma and the cultural expectations for stoicism suggest that PTSD among aging World War II veterans may also have gone underrecognized and undertreated.

Apart from the lack of interest in chronic effects of stressors, another problem that has plagued the limited empirical research on Korean War veterans has been the propensity to combine Korean War with World War II veteran samples in studies. Because World War II veterans have outnumbered Korean War veterans until recently, combined samples tended to have relatively few Korean War veterans. Nevertheless, from those studies that have been reported in which 2 groups were compared, important differences have been revealed. Specifically, although precise estimates of the prevalence of PTSD among Korean War combat veterans have varied depending on sampling and method, studies from the 1990s and early 2000s suggested that the prevalence of PTSD and other mental health concerns as well as the severity of symptoms, suicide risk, and psychosocial adjustment difficulties were worse among Korean War combat veterans relative to those among World War II combat veterans; however, both groups had lower prevalence than did Vietnam War combat veterans.^21,34-37 Several authors speculated that these differences in outcome were at least partially due to differences in public support for the respective wars.^36,37

Although there has been a paucity of research on psychiatric issues and PTSD in Korean War veterans, POWs who were very likely to have been exposed to extreme psychological traumas have received some attention. There have been comparisons of mortality and morbidity among POWs from the Korean War (PWK), World War II Pacific Theater (PWJ), and Europe (PWE).³⁸ Among measures that were administered to the former POWs, the overall pattern seen from survey data in the mid-1960s revealed significantly worse health and functioning among the PWK and PWJ groups relative to the PWE group, with psychiatric difficulties being the most commonly reported impairments among the former 2 groups. This pattern was found most strongly with regards to objective measures, such as hospitalizations for “psychoneuroses,” and US Department of Veterans Affairs (VA) disability records, as well as based on self-reported psychosocial/recreational difficulties measured using the Cornell Medical Index (CMI).³⁸

Gold and colleagues reported a follow-up study of more than 700 former POWs who were reinterviewed between 1989 and 1992.³⁹ Although there was no scale of PTSD symptoms prior to formulation of the diagnosis in 1980, the CMI was a self-reported checklist that included a large range of both medical as well as behavioral and psychiatric symptoms. Thus, using CMI survey responses from 1965, the authors examined the factor structure (ie, the correlational relationships between multiple scale items and subgroupings of items) of the CMI relative to diagnosis of PTSD in 1989 to 1992 based on results from the Structured Clinical Interview for the DSM-III-R (SCID). The intent was to help discern whether the component domains of PTSD were present and intercorrelated in a pattern similar to that of the contemporary diagnosis. The investigators examined the factor structure of 20 psychological items from the CMI that appeared relevant to PTSD criteria using the 1965 data. Three factors (subgroups of highly intercorrelated items) were found: irritability (31% of variance), fearfulness/anxiousness (9% of the variance), and social withdrawal (7% of the variance). Although these did not directly correspond to, or fully cover, DSM PTSD domains or criteria, there does appear to be a thematic resemblance of the CMI findings with PTSD, including alterations in arousal and mood, vigilance, and startle.

Identification and Treatment of PTSD in Older Veterans

Of the 1.2 million living Korean War veterans in the US, 36.3% use VA provided health care.⁴⁰ There are a number of complicating factors to consider in the current identification and treatment of PTSD in this cohort, including their advanced age; physical, cognitive, and social changes associated with normal aging; the associated medical and cognitive comorbidities; and the specific social-contextual factors in that age cohort. Any combination of these factors may complicate recognition, diagnosis, and treatment. It is also important to be cognizant of the additional stressors that may have been experienced by ethnic minorites and women serving in Korea, which are poorly documented and studied. Racial integration of the US military began during the Korean War, but the general pattern was for African American soldiers to be assigned to all-white units, rather than the reverse.^14,41,42 And although the majority of military personnel serving in Korea were male, there were women serving in health care positions at mobile army surgical hospital (MASH) units, medical air evacuation (Medevac) aircraft, and off-shore hospital ships.

The clinical presentation of PTSD in older adults has varied, which may partially relate to the time elapsed since the index trauma. For example, older veterans in general may show less avoidance behavior as a part of PTSD, but in those who experience trauma later in life there may actually be greater avoidance.^43,44 There have also been discrepant reports of intrusion or reexperiencing of symptoms, with these also potentially reduced in older veterans.^43,44 However, sleep disturbances seem to be very common among elderly combat veterans, and attention should be paid to the possible presence of sleep apnea, which may be more common in veterans with PTSD in general.^43,45,46

PTSD symptoms may reemerge after decades of remission or quiescence during retirement and/or with the emergence of neurocognitive impairment, such as Alzheimer disease or dementia. These individuals may have more difficulty engaging in distracting activities and work and spend more time engaging in reminiscence about the past, which can include increased focus on traumatic memories.^45,47 Davison and colleagues have suggested a concept they call later-adulthood trauma reengagement (LATR) where later in life combat veterans may “confront and rework their wartime memories in an effort to find meaning and build coherence.”⁴⁸ This process can be a double-edged sword, leading at times positively to enhanced personal growth or negatively to increased symptoms; preventive interventions may be able foster a more positive outcome.⁴⁸

There is some evidence supporting the validity of the Clinician Administered PTSD Scale (CAPS) for the evaluation of PTSD in older adults, although this was based on the DSM-III-revised criteria for PTSD and an earlier version of CAPS.⁴⁹ Bhattarai and colleagues examined responses to the 35-item Mississippi Scale for Combat-Related PTSD (M-PTSD) using VA clinical data collected between 2008 and 2015 on veterans of each combat era from World War II through the post-9/11.⁵⁰ Strong internal consistency and test-retest reliability of the M-PTSD was observed within each veteran era sample. However, using chart diagnosis of PTSD as the criterion standard, the cut-scores for optimal balance of sensitivity and specificity of the M-PTSD scores were substantially lower for the older cohorts (World War II and Korean War veterans) relative to those for Vietnam and more recent veteran cohorts. The authors concluded that M-PTSD can be validly used to screen for PTSD in veterans within each of these cohorts but recommended using lower than standard cut-scores for Korean War and World War II veterans.⁵⁰

This is also consistent with reports that suggest the use of lower cut-scores on self-administered PTSD symptom screens.^43,44 For the clinician interested in quantifying the severity of PTSD, the most recent tools available are the CAPS-5 and the PCL-5, which have both been created in accordance with the DSM-5. The CAPS-5 is a rater-administered tool, and the PCL-5 is self-administered by the veteran. Although there has been little research using these newer tools in geriatric populations, they can currently serve as a means of tracking the severity of PTSD while we await measures that are better validated in Korean War and other older veterans.

Beyond specific empirical guidance, VA clinicians must presently rely on clinical observations and experience. Patients from the Korean War cohort often present at the insistence of a family member for changes in sleep, mood, behavior, or cognition. When the veterans themselves present, older adults with PTSD often focus more on somatic concerns (including pain, sleep, and gastrointestinal disturbance) than psychiatric problems per se. The latter tendency may in part be due to the salience of such symptoms for them, but perhaps also due to considerable stigma of mental health care that is still largely present in this group.^43,44

Psychotherapy

Current VA treatment guidelines recommend trauma-focused therapies, with the strongest evidence base for prolonged exposure (PE), cognitive processing therapy (CPT), and eye movement desensitization and reprocessing (EMDR) therapies.⁵¹Unfortunately, there is a dearth of published empirical data to evaluate the risks and effectiveness of these therapies not just in the context of Korean War veterans, but among any older adult with PTSD population.^33,44,52,53 Recently, Thorp and colleagues published the first randomized controlled trial comparing PE to a relaxation training (RT) therapy among older veterans (83% were from the Vietnam era).⁵⁴ RT is frequently used as a control condition for RCTs involving trauma-focused therapies. They found PE as well as RT to be well-tolerated by participants. They also found some evidence for superior efficacy in PE relative to RT, although the persistence of that improvement was less for self-rated vs clinician-rated symptoms. As the investigators noted, only 35% of those receiving PE exhibited clinically significant change, and 77% still met diagnostic criteria for PTSD, suggesting a persistence of symptom distress and need for further intervention research to advance treatment for PTSD in older adults.

There have been several excellent prior reviews discussing treatment of PTSD in older adults generally.^10,43,44,52 These reviews have invariably expressed concern about the lack of sufficient empirical studies, but based on evidence from studies and case reports, there seems to be tentative support that trauma-focused therapies are acceptable and efficacious for use with older adults with PTSD. In their recent scoping review, Pless Kaiser and colleagues made several recommendations for trauma-focused therapy with older adults, including slow/careful pacing and use of compensatory aids for cognitive and sensory deficits.⁴⁴ When cognitive impairment has exacerbated PTSD symptoms, they suggest therapists consider using an adapted form of CPT completed without a trauma narrative. For PE they recommend extending content across sessions and involving spouse or caregivers to assist with in vivo exposure and homework completion.⁴⁴

Recent studies suggest that PTSD may be a risk factor for the later development of neurodegenerative disorders, and it is often during assessments for dementia that a revelation of PTSD occurs.^10,43,47,55 Cognitive impairment may also be of relevance in deciding on the type of psychotherapy to be implemented, as it may have more adverse effects on the effectiveness of CPT than of exposure-based treatments (PE or EMDR). It may be useful to perform a cognitive assessment prior to initiation of a cognitive-based therapy, although extensive cognitive testing may not be practical or may be contraindicated because of fatigue. A brief screening tool such as the Montreal Cognitive Assessment or the Mini-Mental State Examinationmay be helpful.^{56, 57}

Prolonged exposure has been reported by many clinicians to be effective in older adults with PTSD; however, due consideration should be given to the needs of individuals, as many have functioned for decades by suppressing memories. Cognitive impairment may be important, as cognitive resources may have been utilized to cope with earlier traumas, and there may be a recrudescence or exacerbation of PTSD symptoms as these resources are compromised. There may therefore be a reemergence of symptoms that are more amenable to an exposure-based treatment. Veterans with PTSD and dementia can present particularly difficult treatment dilemmas because with progression of the dementia, standard PTSD treatments, including exposure-based treatments, may cease to be viable. Instead, the focus of intervention may need to be on specific environmental triggers and behavioral approaches that may also be designed to aid caregivers.

Apart from the treatment needs for specific PTSD symptoms, the decades-long effects of poor sleep, irritability, hypervigilance, and dissociation also have social consequences for patients, including marital discord and divorce, and social and family isolation that should be addressed in therapy when appropriate. In addition, many Korean War veterans, like all veterans, sought postmilitary employment in professions that are associated with higher rates of exposure to psychological trauma, such as police or fire departments, and this may have an exacerbating effect on PTSD.⁵⁸

Pharmacotherapy

There is very little empirical evidence guiding pharmacologic approaches to PTSD in older veterans. This population is at increased risk for many comorbidities, and pharmacologic treatments many require dosage adjustments, as is the case for any geriatric patient. Selective serotonin reuptake inhibitor (SSRI) and serotonin norepinephrine reuptake inhibitor (SNRI) medications have been proposed for some cases of PTSD.^59,60 Health care providers may consider the SSRIs escitalopram or sertraline preferentially given their decreased potential for drug-drug interactions, anticholinergic effects, or cardiac toxicity compared with that of other drugs in this class.^60,61 As venlafaxine can increase blood pressure, especially at higher doses, prescribers may choose duloxetine as an alternative if a SNRI is indicated.⁶⁰ For veterans when prazosin is being considered for nightmare control, monitoring for hypotension, orthostasis, and the administration of other antihypertensives or prostatic hypertrophy medications is necessary.⁶¹ The use of benzodiazepines, while not recommended for PTSD, should be viewed with even greater trepidation in a geriatric population given enhanced risk of falls and confusion in the geriatric veteran population.^60,62

Conclusions

Many of the oldest veterans (aged > 80 years) are from the Korean War era. The harsh and unique nature of the war, as well as the differences in context and support from the US public, and the outcome of the war, may have all contributed to and elevation of “combat fatigue” and PTSD among combat veterans from the Korean War. As the “forgotten war” cohort also has been forgotten by researchers, relatively little is known about posttraumatic stress sequelae of these veterans in the decades following the war.

From available evidence, we can readily surmise that problems were underrecognized and suboptimally diagnosed and treated. There is tentative evidence supporting the use of standard interviews and rating scales, such as the CAPS, M-PTSD, and PCL, but lower cut-scores than applied with Vietnam and later veteran cohorts are generally recommended to avoid excessive false negative errors. In terms of psychotherapy treatment, there is again a stark paucity of systematic research, but the limited evidence from studies of PTSD treatment in older adults from the general population tentatively support the acceptability and potential efficacy of recognized evidence-based trauma-focused psychotherapies for PTSD. Research on medication treatment is similarly lacking, but the general recommendations for the use of SSRI or SNRI medications seem to be valid, at least in our clinical experience, and the general rules for geriatric psychopharmacology definitely apply here—start low, go slow.

There are several important avenues for future research. Most pressing among these are establishing the effectiveness of existing treatments, and the modifications that may be needed in the broader context of the above factors, as well as the physical and cognitive changes associated with advanced age. Further research on the phenomenologic aspects of PTSD among Korean War and subsequent cohorts are also needed, as the information obtained will not only guide more effective personalized treatment of the Korean War veterans who remain with us, but also inform future generations of care in terms of the degree and dimensions of variability that may present between cohorts and within cohorts over the life span.

The Korean War lasted from June 25, 1950 through July 27, 1953. Although many veterans of the Korean War experienced traumas during extremely stressful combat conditions. However, they would not have been diagnosed with posttraumatic stress disorder (PTSD) at the time because the latter did not exist as a formal diagnosis until the publication of the third edition of the Diagnostic and Statistical Manual (DSM) in 1980.¹ Prior to 1980, psychiatric syndromes resulting from war and combat exposure where known by numerous other terms including shell shock, chronic traumatic war neurosis, and combat fatigue/combat exhaustion.^2,3 Military psychiatrists attended to combat fatigue during the course of the Korean War, but as was true of World War I and II, the focus was on returning soldiers to duty. Combat fatigue was generally viewed as a transient condition.^4-8

Although now octo- and nonagenarians, in 2019 there are 1.2 million living Korean War veterans in the US, representing 6.7% of all current veterans.⁹ Understanding their war experiences and the nature of their current and past presentation of PTSD is relevant not only in formal mental health settings, but in primary care settings, including home-based primary care, as well as community living centers, skilled nursing facilities and assisted living facilities. Older adults with PTSD often present with somatic concerns rather than spontaneously reporting mental health symptoms.¹⁰ Beyond the short-term clinical management of Korean War veterans with PTSD, consideration of their experiences also has long-term relevance for the appropriate treatment of other veteran cohorts as they age in coming decades.

The purpose of this article is to provide a clinically focused overview of PTSD in Korean War veterans, to help promote understanding of this often-forgotten group of veterans, and to foster optimized personalized care. This overview will include a description of the Korean War veteran population and the Korean War itself, the manifestations and identification of PTSD among Korean War veterans, and treatment approaches using evidence-based psychotherapies and pharmacotherapies. Finally, we provide recommendations for future research to address present empirical gaps in the understanding and treatment of Korean War veterans with PTSD.

Causes and Course of the Korean War

When working with Korean War veterans it is important to consider the special nature of that specific conflict. Space considerations limit our ability to do justice to the complex history and numerous battles of the Korean War, but information in the following summary was gleaned from several excellent histories.^11-13

The Korean War has been referred to as The Forgotten War, a concern expressed even during the latter parts of the war.^14,15 But the war and its veterans warrant remembering. The root and proximal causes of the Korean War are complex and not fully agreed upon by the main participants.^16-19 In part this may reflect the fact that there was no clear victor in the Korean War, so that the different protagonists have developed their own versions of the history of the conflict. Also, US involvement and the public reaction to the war must be viewed within the larger historical context of that time. This context included the recent end of 4 years of US involvement in World War II (1941-1945) and the subsequent rapid rise of Cold War tensions between the US and the Soviet Union. The latter also included a worldwide fear of nuclear war and the US fear of the global spread of communism. These fears were fueled by the Soviet-led Berlin Blockade from June 1948 through May 1949, the Soviet Union’s successful atomic bomb test in August 1949, the founding of the People’s Republic of China in October 1949, and the February 1950 Sino-Soviet Treaty of Friendship and Alliance.¹³

In the closing days of World War II, the US and Soviet Union agreed to a temporary division of Korea along the 38th parallel to facilitate timely and efficient surrender of Japanese troops. But as Cold War tensions rose, the temporary division became permanent, and Soviet- and US-backed governments of the north and south, respectively, were officially established on the Korean peninsula in 1948. Although by 1949 the Soviets and US had withdrawn most troops from the peninsula, tensions between the north and south continued to mount and hostilities increased. To this day the exact causes of the eruption of war remain disputed, although it is clear that ideological as well as economic factors played a role, and both leaders of North and South Korea were pledging to reunite the peninsula under their respective leadership.^16-19 The tension culminated on June 25, 1950, when North Korean troops crossed the 38th parallel and invaded South Korea. On June 27, 1950, President Truman ordered US naval and air forces to support South Korea and then ordered the involvement of ground troops on June 30.^16,17,19

Although several other member countries of the United Nations (UN) provided troops, 90% of the troops were from the US. About 5.7 million US military personnel served during the war, including about 1.8 million in Korea itself. The US forces experienced approximately 34,000 battle-related deaths, 103,000 were wounded, and 7,000 were prisoners of war (POWs).^11,20-22 The nature and events of the Korean War made it particularly stressful and traumatizing for the soldiers, sailors, and marines involved throughout its entire course. These included near defeat in the early months, a widely alternating war front along the north/south axis during the first year, and subsequently, not only intense constant battles on the fronts, but also a demanding and exhausting guerrilla war in the south, which lasted throughout the remainder of the conflict.^11,15 The US troops during the initial months of the war have been described as outnumbered and underprepared, as many in the initial phase were reassigned from peace-time occupation duty in Japan.⁷

The first year of war was characterized by a repeated north-to-south/south-to-north shifts in control of territory. During the first 3 months, the North Korean forces overwhelmed the South and captured control of all but 2 South Korean cities in the far southeastern region (Pusan, now Busan; and Daegu), and US and UN forces were forced to retreat to the perimeter around Pusan. The intense Battle of Pusan Perimeter lasted from August 4, 1950 to September 18, 1950, and resulted in massive causalities as well as a flood of civilian refugees.

The course of the war began to change in early September 1950 with the landing of amphibious US/UN forces at Inchon, behind North Korean lines, which cut off southern supply routes for the North Korean troops.¹¹ US/UN forces soon crossed to the north of the 38th parallel and captured the North Korean capital, Pyongyang, on October 19, 1950. They continued to push north and approached the Yalu River border with China by late November 1950, but then the Chinese introduced their own troops forcing a southward retreat of US/UN troops during which there were again numerous US/UN casualties. Chinese troops retook Seoul in late December 1950/early January 1951. However, the US/UN forces soon recaptured Seoul and advanced back to the 38th parallel. This back-and-forth across the 38th parallel continued until July 1951 when the front line of battle stabilized there. Although the line stabilized, intense battles and casualties continued for 2 more years. During this period US/UN troops also had to deal with guerrilla warfare behind the front lines due to the actions of communist partisans and isolated North Korean troops. This situation continued until the armistice was signed July 27, 1953.

Trauma and Characteristic Stresses of the War

There were many factors that made the Korean War experience different from previous wars, particularly World War II. For example, in contrast to the strong public support during and after World War II, public support for the Korean War in the US was low, particularly during its final year.²³ In public opinion polls from October 1952 through April 1953, only 23% to 39% reported feeling that the war was worth fighting.²³ A retrospective 1985 survey also found that 70% of World War II veterans, but only 33% of Korean War veterans reported feeling appreciated by the US public on their return from the war.²⁴

Those fighting in the initial months of the war faced a particularly grim situation. According to LTC Philip Smith, who served as Division Psychiatrist on the Masan Front (Pusan Perimeter) during August and September of 1950, “Fighting was almost continuous and all available troops were on the fighting front… For the most part these soldiers were soft from occupation duty, many had not received adequate combat basic training, no refresher combat training in Korea had as yet been instituted,” he reported.⁷ “The extremes of climate coupled with the generally rugged mountainous terrain in Korea were physical factors of importance…These men were psychologically unprepared for the horrors and isolation of war.” LTC Smith noted that the change in status from civilian or occupation life to the marked deprivation of the war in Korea had been “too abrupt to allow as yet for a reasonable adjustment to the new setting” and that as a result “the highest rate of wounded and neuropsychiatric casualties in the Korean campaign resulted.”⁷

Even after this initial period, the nature of the shifting war, the challenging terrain, the high military casualty rate, and the high rate of civilian casualties and displacement continued throughout the war. The climate was also harsh; Korean War veterans were more likely than were those in World War II or Vietnam to experience injuries related to exposure to extreme cold during the winters (frostbite was among the most common service disabilities).¹⁴ During the Chosin Reservoir Campaign in late 1950, temperatures were as low as -50° F with a wind chill as low as -100° F.²⁵ In addition to cold injuries, other physical health concerns for Korean War veterans were noise injuries from gunfire and explosions and occupational hazards, such as exposure to asbestos, radiation, and polychlorinated biphenyls (PCBs).²⁶

PTSD in Korean War Veterans

It is clear that Korean War combat veterans were exposed to traumatic events. It is unknown how many developed PTSD. While notions of psychological distress and disability related to combat trauma exposure have existed for centuries, Korean War and World War II veterans are a remaining link to pre-DSM PTSD mental health in the military. Military/forward psychiatry—psychiatric services near the battle zone rather than requiring evacuation of patients—was present in Korea from the early months of the war, but the focus of forward psychiatry was to reduce psychiatric causalities from combat fatigue and maximize rapid return-to-duty.^4-6 With no real conception of PTSD, there were limited treatments available, and evidenced-based trauma-focused treatments for PTSD would not be introduced for at least another 4 decades.^27-29

Skinner and Kaplick conducted a historical review of case descriptions of trauma-related conditions from World War I through the Vietnam War and noted the consistent inclusion of hyperarousal and intrusive symptoms, although there also was a greater emphasis on somatic conversion or hysteria symptoms in the earlier descriptions.³⁰ By the Korean War, descriptions of combat fatigue included a number of symptoms that overlap with PTSD, including preoccupation with the traumatic stressor, nightmares, irritability/anger, increased startle, and hyperarousal.³¹ But following the acute phases, attention to any chronic problems associated with these conditions waned. As was acknowledged by a military psychiatrist in a 1954 talk, studies of the long-term adjustment of those who had “broken down in combat” were sorely needed.⁶ In a small 1965 study reported by Archibald and Tuddenham, persistent symptoms of combat fatigue among Korean War veterans were definitely present, and there was even a suggestion that the symptoms had increased over the decade since the war.³²

Given the stoicism that typified cultural expectations for military men during this period, Korean War veterans may also have been reluctant to seek mental health treatment either at the time or later. In short, it is likely that a nontrivial proportion of Korean War veterans with PTSD were underdiagnosed and received suboptimal or no mental health treatment for decades following their war experiences.³³ Although the nature of the war, deployment, and public support were distinct in World War II vs the Korean War, the absence of attention to the long-term effects of disorders related to combat trauma and the cultural expectations for stoicism suggest that PTSD among aging World War II veterans may also have gone underrecognized and undertreated.

Apart from the lack of interest in chronic effects of stressors, another problem that has plagued the limited empirical research on Korean War veterans has been the propensity to combine Korean War with World War II veteran samples in studies. Because World War II veterans have outnumbered Korean War veterans until recently, combined samples tended to have relatively few Korean War veterans. Nevertheless, from those studies that have been reported in which 2 groups were compared, important differences have been revealed. Specifically, although precise estimates of the prevalence of PTSD among Korean War combat veterans have varied depending on sampling and method, studies from the 1990s and early 2000s suggested that the prevalence of PTSD and other mental health concerns as well as the severity of symptoms, suicide risk, and psychosocial adjustment difficulties were worse among Korean War combat veterans relative to those among World War II combat veterans; however, both groups had lower prevalence than did Vietnam War combat veterans.^21,34-37 Several authors speculated that these differences in outcome were at least partially due to differences in public support for the respective wars.^36,37

Although there has been a paucity of research on psychiatric issues and PTSD in Korean War veterans, POWs who were very likely to have been exposed to extreme psychological traumas have received some attention. There have been comparisons of mortality and morbidity among POWs from the Korean War (PWK), World War II Pacific Theater (PWJ), and Europe (PWE).³⁸ Among measures that were administered to the former POWs, the overall pattern seen from survey data in the mid-1960s revealed significantly worse health and functioning among the PWK and PWJ groups relative to the PWE group, with psychiatric difficulties being the most commonly reported impairments among the former 2 groups. This pattern was found most strongly with regards to objective measures, such as hospitalizations for “psychoneuroses,” and US Department of Veterans Affairs (VA) disability records, as well as based on self-reported psychosocial/recreational difficulties measured using the Cornell Medical Index (CMI).³⁸

Gold and colleagues reported a follow-up study of more than 700 former POWs who were reinterviewed between 1989 and 1992.³⁹ Although there was no scale of PTSD symptoms prior to formulation of the diagnosis in 1980, the CMI was a self-reported checklist that included a large range of both medical as well as behavioral and psychiatric symptoms. Thus, using CMI survey responses from 1965, the authors examined the factor structure (ie, the correlational relationships between multiple scale items and subgroupings of items) of the CMI relative to diagnosis of PTSD in 1989 to 1992 based on results from the Structured Clinical Interview for the DSM-III-R (SCID). The intent was to help discern whether the component domains of PTSD were present and intercorrelated in a pattern similar to that of the contemporary diagnosis. The investigators examined the factor structure of 20 psychological items from the CMI that appeared relevant to PTSD criteria using the 1965 data. Three factors (subgroups of highly intercorrelated items) were found: irritability (31% of variance), fearfulness/anxiousness (9% of the variance), and social withdrawal (7% of the variance). Although these did not directly correspond to, or fully cover, DSM PTSD domains or criteria, there does appear to be a thematic resemblance of the CMI findings with PTSD, including alterations in arousal and mood, vigilance, and startle.

Identification and Treatment of PTSD in Older Veterans

Of the 1.2 million living Korean War veterans in the US, 36.3% use VA provided health care.⁴⁰ There are a number of complicating factors to consider in the current identification and treatment of PTSD in this cohort, including their advanced age; physical, cognitive, and social changes associated with normal aging; the associated medical and cognitive comorbidities; and the specific social-contextual factors in that age cohort. Any combination of these factors may complicate recognition, diagnosis, and treatment. It is also important to be cognizant of the additional stressors that may have been experienced by ethnic minorites and women serving in Korea, which are poorly documented and studied. Racial integration of the US military began during the Korean War, but the general pattern was for African American soldiers to be assigned to all-white units, rather than the reverse.^14,41,42 And although the majority of military personnel serving in Korea were male, there were women serving in health care positions at mobile army surgical hospital (MASH) units, medical air evacuation (Medevac) aircraft, and off-shore hospital ships.

The clinical presentation of PTSD in older adults has varied, which may partially relate to the time elapsed since the index trauma. For example, older veterans in general may show less avoidance behavior as a part of PTSD, but in those who experience trauma later in life there may actually be greater avoidance.^43,44 There have also been discrepant reports of intrusion or reexperiencing of symptoms, with these also potentially reduced in older veterans.^43,44 However, sleep disturbances seem to be very common among elderly combat veterans, and attention should be paid to the possible presence of sleep apnea, which may be more common in veterans with PTSD in general.^43,45,46

PTSD symptoms may reemerge after decades of remission or quiescence during retirement and/or with the emergence of neurocognitive impairment, such as Alzheimer disease or dementia. These individuals may have more difficulty engaging in distracting activities and work and spend more time engaging in reminiscence about the past, which can include increased focus on traumatic memories.^45,47 Davison and colleagues have suggested a concept they call later-adulthood trauma reengagement (LATR) where later in life combat veterans may “confront and rework their wartime memories in an effort to find meaning and build coherence.”⁴⁸ This process can be a double-edged sword, leading at times positively to enhanced personal growth or negatively to increased symptoms; preventive interventions may be able foster a more positive outcome.⁴⁸

There is some evidence supporting the validity of the Clinician Administered PTSD Scale (CAPS) for the evaluation of PTSD in older adults, although this was based on the DSM-III-revised criteria for PTSD and an earlier version of CAPS.⁴⁹ Bhattarai and colleagues examined responses to the 35-item Mississippi Scale for Combat-Related PTSD (M-PTSD) using VA clinical data collected between 2008 and 2015 on veterans of each combat era from World War II through the post-9/11.⁵⁰ Strong internal consistency and test-retest reliability of the M-PTSD was observed within each veteran era sample. However, using chart diagnosis of PTSD as the criterion standard, the cut-scores for optimal balance of sensitivity and specificity of the M-PTSD scores were substantially lower for the older cohorts (World War II and Korean War veterans) relative to those for Vietnam and more recent veteran cohorts. The authors concluded that M-PTSD can be validly used to screen for PTSD in veterans within each of these cohorts but recommended using lower than standard cut-scores for Korean War and World War II veterans.⁵⁰

This is also consistent with reports that suggest the use of lower cut-scores on self-administered PTSD symptom screens.^43,44 For the clinician interested in quantifying the severity of PTSD, the most recent tools available are the CAPS-5 and the PCL-5, which have both been created in accordance with the DSM-5. The CAPS-5 is a rater-administered tool, and the PCL-5 is self-administered by the veteran. Although there has been little research using these newer tools in geriatric populations, they can currently serve as a means of tracking the severity of PTSD while we await measures that are better validated in Korean War and other older veterans.

Beyond specific empirical guidance, VA clinicians must presently rely on clinical observations and experience. Patients from the Korean War cohort often present at the insistence of a family member for changes in sleep, mood, behavior, or cognition. When the veterans themselves present, older adults with PTSD often focus more on somatic concerns (including pain, sleep, and gastrointestinal disturbance) than psychiatric problems per se. The latter tendency may in part be due to the salience of such symptoms for them, but perhaps also due to considerable stigma of mental health care that is still largely present in this group.^43,44

Psychotherapy

Current VA treatment guidelines recommend trauma-focused therapies, with the strongest evidence base for prolonged exposure (PE), cognitive processing therapy (CPT), and eye movement desensitization and reprocessing (EMDR) therapies.⁵¹Unfortunately, there is a dearth of published empirical data to evaluate the risks and effectiveness of these therapies not just in the context of Korean War veterans, but among any older adult with PTSD population.^33,44,52,53 Recently, Thorp and colleagues published the first randomized controlled trial comparing PE to a relaxation training (RT) therapy among older veterans (83% were from the Vietnam era).⁵⁴ RT is frequently used as a control condition for RCTs involving trauma-focused therapies. They found PE as well as RT to be well-tolerated by participants. They also found some evidence for superior efficacy in PE relative to RT, although the persistence of that improvement was less for self-rated vs clinician-rated symptoms. As the investigators noted, only 35% of those receiving PE exhibited clinically significant change, and 77% still met diagnostic criteria for PTSD, suggesting a persistence of symptom distress and need for further intervention research to advance treatment for PTSD in older adults.

There have been several excellent prior reviews discussing treatment of PTSD in older adults generally.^10,43,44,52 These reviews have invariably expressed concern about the lack of sufficient empirical studies, but based on evidence from studies and case reports, there seems to be tentative support that trauma-focused therapies are acceptable and efficacious for use with older adults with PTSD. In their recent scoping review, Pless Kaiser and colleagues made several recommendations for trauma-focused therapy with older adults, including slow/careful pacing and use of compensatory aids for cognitive and sensory deficits.⁴⁴ When cognitive impairment has exacerbated PTSD symptoms, they suggest therapists consider using an adapted form of CPT completed without a trauma narrative. For PE they recommend extending content across sessions and involving spouse or caregivers to assist with in vivo exposure and homework completion.⁴⁴

Recent studies suggest that PTSD may be a risk factor for the later development of neurodegenerative disorders, and it is often during assessments for dementia that a revelation of PTSD occurs.^10,43,47,55 Cognitive impairment may also be of relevance in deciding on the type of psychotherapy to be implemented, as it may have more adverse effects on the effectiveness of CPT than of exposure-based treatments (PE or EMDR). It may be useful to perform a cognitive assessment prior to initiation of a cognitive-based therapy, although extensive cognitive testing may not be practical or may be contraindicated because of fatigue. A brief screening tool such as the Montreal Cognitive Assessment or the Mini-Mental State Examinationmay be helpful.^{56, 57}

Prolonged exposure has been reported by many clinicians to be effective in older adults with PTSD; however, due consideration should be given to the needs of individuals, as many have functioned for decades by suppressing memories. Cognitive impairment may be important, as cognitive resources may have been utilized to cope with earlier traumas, and there may be a recrudescence or exacerbation of PTSD symptoms as these resources are compromised. There may therefore be a reemergence of symptoms that are more amenable to an exposure-based treatment. Veterans with PTSD and dementia can present particularly difficult treatment dilemmas because with progression of the dementia, standard PTSD treatments, including exposure-based treatments, may cease to be viable. Instead, the focus of intervention may need to be on specific environmental triggers and behavioral approaches that may also be designed to aid caregivers.

Apart from the treatment needs for specific PTSD symptoms, the decades-long effects of poor sleep, irritability, hypervigilance, and dissociation also have social consequences for patients, including marital discord and divorce, and social and family isolation that should be addressed in therapy when appropriate. In addition, many Korean War veterans, like all veterans, sought postmilitary employment in professions that are associated with higher rates of exposure to psychological trauma, such as police or fire departments, and this may have an exacerbating effect on PTSD.⁵⁸

Pharmacotherapy

There is very little empirical evidence guiding pharmacologic approaches to PTSD in older veterans. This population is at increased risk for many comorbidities, and pharmacologic treatments many require dosage adjustments, as is the case for any geriatric patient. Selective serotonin reuptake inhibitor (SSRI) and serotonin norepinephrine reuptake inhibitor (SNRI) medications have been proposed for some cases of PTSD.^59,60 Health care providers may consider the SSRIs escitalopram or sertraline preferentially given their decreased potential for drug-drug interactions, anticholinergic effects, or cardiac toxicity compared with that of other drugs in this class.^60,61 As venlafaxine can increase blood pressure, especially at higher doses, prescribers may choose duloxetine as an alternative if a SNRI is indicated.⁶⁰ For veterans when prazosin is being considered for nightmare control, monitoring for hypotension, orthostasis, and the administration of other antihypertensives or prostatic hypertrophy medications is necessary.⁶¹ The use of benzodiazepines, while not recommended for PTSD, should be viewed with even greater trepidation in a geriatric population given enhanced risk of falls and confusion in the geriatric veteran population.^60,62

Conclusions

Many of the oldest veterans (aged > 80 years) are from the Korean War era. The harsh and unique nature of the war, as well as the differences in context and support from the US public, and the outcome of the war, may have all contributed to and elevation of “combat fatigue” and PTSD among combat veterans from the Korean War. As the “forgotten war” cohort also has been forgotten by researchers, relatively little is known about posttraumatic stress sequelae of these veterans in the decades following the war.

From available evidence, we can readily surmise that problems were underrecognized and suboptimally diagnosed and treated. There is tentative evidence supporting the use of standard interviews and rating scales, such as the CAPS, M-PTSD, and PCL, but lower cut-scores than applied with Vietnam and later veteran cohorts are generally recommended to avoid excessive false negative errors. In terms of psychotherapy treatment, there is again a stark paucity of systematic research, but the limited evidence from studies of PTSD treatment in older adults from the general population tentatively support the acceptability and potential efficacy of recognized evidence-based trauma-focused psychotherapies for PTSD. Research on medication treatment is similarly lacking, but the general recommendations for the use of SSRI or SNRI medications seem to be valid, at least in our clinical experience, and the general rules for geriatric psychopharmacology definitely apply here—start low, go slow.

There are several important avenues for future research. Most pressing among these are establishing the effectiveness of existing treatments, and the modifications that may be needed in the broader context of the above factors, as well as the physical and cognitive changes associated with advanced age. Further research on the phenomenologic aspects of PTSD among Korean War and subsequent cohorts are also needed, as the information obtained will not only guide more effective personalized treatment of the Korean War veterans who remain with us, but also inform future generations of care in terms of the degree and dimensions of variability that may present between cohorts and within cohorts over the life span.

The Korean War lasted from June 25, 1950 through July 27, 1953. Although many veterans of the Korean War experienced traumas during extremely stressful combat conditions. However, they would not have been diagnosed with posttraumatic stress disorder (PTSD) at the time because the latter did not exist as a formal diagnosis until the publication of the third edition of the Diagnostic and Statistical Manual (DSM) in 1980.¹ Prior to 1980, psychiatric syndromes resulting from war and combat exposure where known by numerous other terms including shell shock, chronic traumatic war neurosis, and combat fatigue/combat exhaustion.^2,3 Military psychiatrists attended to combat fatigue during the course of the Korean War, but as was true of World War I and II, the focus was on returning soldiers to duty. Combat fatigue was generally viewed as a transient condition.^4-8

Although now octo- and nonagenarians, in 2019 there are 1.2 million living Korean War veterans in the US, representing 6.7% of all current veterans.⁹ Understanding their war experiences and the nature of their current and past presentation of PTSD is relevant not only in formal mental health settings, but in primary care settings, including home-based primary care, as well as community living centers, skilled nursing facilities and assisted living facilities. Older adults with PTSD often present with somatic concerns rather than spontaneously reporting mental health symptoms.¹⁰ Beyond the short-term clinical management of Korean War veterans with PTSD, consideration of their experiences also has long-term relevance for the appropriate treatment of other veteran cohorts as they age in coming decades.

The purpose of this article is to provide a clinically focused overview of PTSD in Korean War veterans, to help promote understanding of this often-forgotten group of veterans, and to foster optimized personalized care. This overview will include a description of the Korean War veteran population and the Korean War itself, the manifestations and identification of PTSD among Korean War veterans, and treatment approaches using evidence-based psychotherapies and pharmacotherapies. Finally, we provide recommendations for future research to address present empirical gaps in the understanding and treatment of Korean War veterans with PTSD.

Causes and Course of the Korean War

When working with Korean War veterans it is important to consider the special nature of that specific conflict. Space considerations limit our ability to do justice to the complex history and numerous battles of the Korean War, but information in the following summary was gleaned from several excellent histories.^11-13

The Korean War has been referred to as The Forgotten War, a concern expressed even during the latter parts of the war.^14,15 But the war and its veterans warrant remembering. The root and proximal causes of the Korean War are complex and not fully agreed upon by the main participants.^16-19 In part this may reflect the fact that there was no clear victor in the Korean War, so that the different protagonists have developed their own versions of the history of the conflict. Also, US involvement and the public reaction to the war must be viewed within the larger historical context of that time. This context included the recent end of 4 years of US involvement in World War II (1941-1945) and the subsequent rapid rise of Cold War tensions between the US and the Soviet Union. The latter also included a worldwide fear of nuclear war and the US fear of the global spread of communism. These fears were fueled by the Soviet-led Berlin Blockade from June 1948 through May 1949, the Soviet Union’s successful atomic bomb test in August 1949, the founding of the People’s Republic of China in October 1949, and the February 1950 Sino-Soviet Treaty of Friendship and Alliance.¹³

In the closing days of World War II, the US and Soviet Union agreed to a temporary division of Korea along the 38th parallel to facilitate timely and efficient surrender of Japanese troops. But as Cold War tensions rose, the temporary division became permanent, and Soviet- and US-backed governments of the north and south, respectively, were officially established on the Korean peninsula in 1948. Although by 1949 the Soviets and US had withdrawn most troops from the peninsula, tensions between the north and south continued to mount and hostilities increased. To this day the exact causes of the eruption of war remain disputed, although it is clear that ideological as well as economic factors played a role, and both leaders of North and South Korea were pledging to reunite the peninsula under their respective leadership.^16-19 The tension culminated on June 25, 1950, when North Korean troops crossed the 38th parallel and invaded South Korea. On June 27, 1950, President Truman ordered US naval and air forces to support South Korea and then ordered the involvement of ground troops on June 30.^16,17,19

Although several other member countries of the United Nations (UN) provided troops, 90% of the troops were from the US. About 5.7 million US military personnel served during the war, including about 1.8 million in Korea itself. The US forces experienced approximately 34,000 battle-related deaths, 103,000 were wounded, and 7,000 were prisoners of war (POWs).^11,20-22 The nature and events of the Korean War made it particularly stressful and traumatizing for the soldiers, sailors, and marines involved throughout its entire course. These included near defeat in the early months, a widely alternating war front along the north/south axis during the first year, and subsequently, not only intense constant battles on the fronts, but also a demanding and exhausting guerrilla war in the south, which lasted throughout the remainder of the conflict.^11,15 The US troops during the initial months of the war have been described as outnumbered and underprepared, as many in the initial phase were reassigned from peace-time occupation duty in Japan.⁷

The first year of war was characterized by a repeated north-to-south/south-to-north shifts in control of territory. During the first 3 months, the North Korean forces overwhelmed the South and captured control of all but 2 South Korean cities in the far southeastern region (Pusan, now Busan; and Daegu), and US and UN forces were forced to retreat to the perimeter around Pusan. The intense Battle of Pusan Perimeter lasted from August 4, 1950 to September 18, 1950, and resulted in massive causalities as well as a flood of civilian refugees.

The course of the war began to change in early September 1950 with the landing of amphibious US/UN forces at Inchon, behind North Korean lines, which cut off southern supply routes for the North Korean troops.¹¹ US/UN forces soon crossed to the north of the 38th parallel and captured the North Korean capital, Pyongyang, on October 19, 1950. They continued to push north and approached the Yalu River border with China by late November 1950, but then the Chinese introduced their own troops forcing a southward retreat of US/UN troops during which there were again numerous US/UN casualties. Chinese troops retook Seoul in late December 1950/early January 1951. However, the US/UN forces soon recaptured Seoul and advanced back to the 38th parallel. This back-and-forth across the 38th parallel continued until July 1951 when the front line of battle stabilized there. Although the line stabilized, intense battles and casualties continued for 2 more years. During this period US/UN troops also had to deal with guerrilla warfare behind the front lines due to the actions of communist partisans and isolated North Korean troops. This situation continued until the armistice was signed July 27, 1953.

Trauma and Characteristic Stresses of the War

There were many factors that made the Korean War experience different from previous wars, particularly World War II. For example, in contrast to the strong public support during and after World War II, public support for the Korean War in the US was low, particularly during its final year.²³ In public opinion polls from October 1952 through April 1953, only 23% to 39% reported feeling that the war was worth fighting.²³ A retrospective 1985 survey also found that 70% of World War II veterans, but only 33% of Korean War veterans reported feeling appreciated by the US public on their return from the war.²⁴

Those fighting in the initial months of the war faced a particularly grim situation. According to LTC Philip Smith, who served as Division Psychiatrist on the Masan Front (Pusan Perimeter) during August and September of 1950, “Fighting was almost continuous and all available troops were on the fighting front… For the most part these soldiers were soft from occupation duty, many had not received adequate combat basic training, no refresher combat training in Korea had as yet been instituted,” he reported.⁷ “The extremes of climate coupled with the generally rugged mountainous terrain in Korea were physical factors of importance…These men were psychologically unprepared for the horrors and isolation of war.” LTC Smith noted that the change in status from civilian or occupation life to the marked deprivation of the war in Korea had been “too abrupt to allow as yet for a reasonable adjustment to the new setting” and that as a result “the highest rate of wounded and neuropsychiatric casualties in the Korean campaign resulted.”⁷

Even after this initial period, the nature of the shifting war, the challenging terrain, the high military casualty rate, and the high rate of civilian casualties and displacement continued throughout the war. The climate was also harsh; Korean War veterans were more likely than were those in World War II or Vietnam to experience injuries related to exposure to extreme cold during the winters (frostbite was among the most common service disabilities).¹⁴ During the Chosin Reservoir Campaign in late 1950, temperatures were as low as -50° F with a wind chill as low as -100° F.²⁵ In addition to cold injuries, other physical health concerns for Korean War veterans were noise injuries from gunfire and explosions and occupational hazards, such as exposure to asbestos, radiation, and polychlorinated biphenyls (PCBs).²⁶

PTSD in Korean War Veterans

It is clear that Korean War combat veterans were exposed to traumatic events. It is unknown how many developed PTSD. While notions of psychological distress and disability related to combat trauma exposure have existed for centuries, Korean War and World War II veterans are a remaining link to pre-DSM PTSD mental health in the military. Military/forward psychiatry—psychiatric services near the battle zone rather than requiring evacuation of patients—was present in Korea from the early months of the war, but the focus of forward psychiatry was to reduce psychiatric causalities from combat fatigue and maximize rapid return-to-duty.^4-6 With no real conception of PTSD, there were limited treatments available, and evidenced-based trauma-focused treatments for PTSD would not be introduced for at least another 4 decades.^27-29

Skinner and Kaplick conducted a historical review of case descriptions of trauma-related conditions from World War I through the Vietnam War and noted the consistent inclusion of hyperarousal and intrusive symptoms, although there also was a greater emphasis on somatic conversion or hysteria symptoms in the earlier descriptions.³⁰ By the Korean War, descriptions of combat fatigue included a number of symptoms that overlap with PTSD, including preoccupation with the traumatic stressor, nightmares, irritability/anger, increased startle, and hyperarousal.³¹ But following the acute phases, attention to any chronic problems associated with these conditions waned. As was acknowledged by a military psychiatrist in a 1954 talk, studies of the long-term adjustment of those who had “broken down in combat” were sorely needed.⁶ In a small 1965 study reported by Archibald and Tuddenham, persistent symptoms of combat fatigue among Korean War veterans were definitely present, and there was even a suggestion that the symptoms had increased over the decade since the war.³²

Given the stoicism that typified cultural expectations for military men during this period, Korean War veterans may also have been reluctant to seek mental health treatment either at the time or later. In short, it is likely that a nontrivial proportion of Korean War veterans with PTSD were underdiagnosed and received suboptimal or no mental health treatment for decades following their war experiences.³³ Although the nature of the war, deployment, and public support were distinct in World War II vs the Korean War, the absence of attention to the long-term effects of disorders related to combat trauma and the cultural expectations for stoicism suggest that PTSD among aging World War II veterans may also have gone underrecognized and undertreated.

Apart from the lack of interest in chronic effects of stressors, another problem that has plagued the limited empirical research on Korean War veterans has been the propensity to combine Korean War with World War II veteran samples in studies. Because World War II veterans have outnumbered Korean War veterans until recently, combined samples tended to have relatively few Korean War veterans. Nevertheless, from those studies that have been reported in which 2 groups were compared, important differences have been revealed. Specifically, although precise estimates of the prevalence of PTSD among Korean War combat veterans have varied depending on sampling and method, studies from the 1990s and early 2000s suggested that the prevalence of PTSD and other mental health concerns as well as the severity of symptoms, suicide risk, and psychosocial adjustment difficulties were worse among Korean War combat veterans relative to those among World War II combat veterans; however, both groups had lower prevalence than did Vietnam War combat veterans.^21,34-37 Several authors speculated that these differences in outcome were at least partially due to differences in public support for the respective wars.^36,37

Although there has been a paucity of research on psychiatric issues and PTSD in Korean War veterans, POWs who were very likely to have been exposed to extreme psychological traumas have received some attention. There have been comparisons of mortality and morbidity among POWs from the Korean War (PWK), World War II Pacific Theater (PWJ), and Europe (PWE).³⁸ Among measures that were administered to the former POWs, the overall pattern seen from survey data in the mid-1960s revealed significantly worse health and functioning among the PWK and PWJ groups relative to the PWE group, with psychiatric difficulties being the most commonly reported impairments among the former 2 groups. This pattern was found most strongly with regards to objective measures, such as hospitalizations for “psychoneuroses,” and US Department of Veterans Affairs (VA) disability records, as well as based on self-reported psychosocial/recreational difficulties measured using the Cornell Medical Index (CMI).³⁸

Gold and colleagues reported a follow-up study of more than 700 former POWs who were reinterviewed between 1989 and 1992.³⁹ Although there was no scale of PTSD symptoms prior to formulation of the diagnosis in 1980, the CMI was a self-reported checklist that included a large range of both medical as well as behavioral and psychiatric symptoms. Thus, using CMI survey responses from 1965, the authors examined the factor structure (ie, the correlational relationships between multiple scale items and subgroupings of items) of the CMI relative to diagnosis of PTSD in 1989 to 1992 based on results from the Structured Clinical Interview for the DSM-III-R (SCID). The intent was to help discern whether the component domains of PTSD were present and intercorrelated in a pattern similar to that of the contemporary diagnosis. The investigators examined the factor structure of 20 psychological items from the CMI that appeared relevant to PTSD criteria using the 1965 data. Three factors (subgroups of highly intercorrelated items) were found: irritability (31% of variance), fearfulness/anxiousness (9% of the variance), and social withdrawal (7% of the variance). Although these did not directly correspond to, or fully cover, DSM PTSD domains or criteria, there does appear to be a thematic resemblance of the CMI findings with PTSD, including alterations in arousal and mood, vigilance, and startle.

Identification and Treatment of PTSD in Older Veterans

Of the 1.2 million living Korean War veterans in the US, 36.3% use VA provided health care.⁴⁰ There are a number of complicating factors to consider in the current identification and treatment of PTSD in this cohort, including their advanced age; physical, cognitive, and social changes associated with normal aging; the associated medical and cognitive comorbidities; and the specific social-contextual factors in that age cohort. Any combination of these factors may complicate recognition, diagnosis, and treatment. It is also important to be cognizant of the additional stressors that may have been experienced by ethnic minorites and women serving in Korea, which are poorly documented and studied. Racial integration of the US military began during the Korean War, but the general pattern was for African American soldiers to be assigned to all-white units, rather than the reverse.^14,41,42 And although the majority of military personnel serving in Korea were male, there were women serving in health care positions at mobile army surgical hospital (MASH) units, medical air evacuation (Medevac) aircraft, and off-shore hospital ships.

The clinical presentation of PTSD in older adults has varied, which may partially relate to the time elapsed since the index trauma. For example, older veterans in general may show less avoidance behavior as a part of PTSD, but in those who experience trauma later in life there may actually be greater avoidance.^43,44 There have also been discrepant reports of intrusion or reexperiencing of symptoms, with these also potentially reduced in older veterans.^43,44 However, sleep disturbances seem to be very common among elderly combat veterans, and attention should be paid to the possible presence of sleep apnea, which may be more common in veterans with PTSD in general.^43,45,46

PTSD symptoms may reemerge after decades of remission or quiescence during retirement and/or with the emergence of neurocognitive impairment, such as Alzheimer disease or dementia. These individuals may have more difficulty engaging in distracting activities and work and spend more time engaging in reminiscence about the past, which can include increased focus on traumatic memories.^45,47 Davison and colleagues have suggested a concept they call later-adulthood trauma reengagement (LATR) where later in life combat veterans may “confront and rework their wartime memories in an effort to find meaning and build coherence.”⁴⁸ This process can be a double-edged sword, leading at times positively to enhanced personal growth or negatively to increased symptoms; preventive interventions may be able foster a more positive outcome.⁴⁸

There is some evidence supporting the validity of the Clinician Administered PTSD Scale (CAPS) for the evaluation of PTSD in older adults, although this was based on the DSM-III-revised criteria for PTSD and an earlier version of CAPS.⁴⁹ Bhattarai and colleagues examined responses to the 35-item Mississippi Scale for Combat-Related PTSD (M-PTSD) using VA clinical data collected between 2008 and 2015 on veterans of each combat era from World War II through the post-9/11.⁵⁰ Strong internal consistency and test-retest reliability of the M-PTSD was observed within each veteran era sample. However, using chart diagnosis of PTSD as the criterion standard, the cut-scores for optimal balance of sensitivity and specificity of the M-PTSD scores were substantially lower for the older cohorts (World War II and Korean War veterans) relative to those for Vietnam and more recent veteran cohorts. The authors concluded that M-PTSD can be validly used to screen for PTSD in veterans within each of these cohorts but recommended using lower than standard cut-scores for Korean War and World War II veterans.⁵⁰

This is also consistent with reports that suggest the use of lower cut-scores on self-administered PTSD symptom screens.^43,44 For the clinician interested in quantifying the severity of PTSD, the most recent tools available are the CAPS-5 and the PCL-5, which have both been created in accordance with the DSM-5. The CAPS-5 is a rater-administered tool, and the PCL-5 is self-administered by the veteran. Although there has been little research using these newer tools in geriatric populations, they can currently serve as a means of tracking the severity of PTSD while we await measures that are better validated in Korean War and other older veterans.

Beyond specific empirical guidance, VA clinicians must presently rely on clinical observations and experience. Patients from the Korean War cohort often present at the insistence of a family member for changes in sleep, mood, behavior, or cognition. When the veterans themselves present, older adults with PTSD often focus more on somatic concerns (including pain, sleep, and gastrointestinal disturbance) than psychiatric problems per se. The latter tendency may in part be due to the salience of such symptoms for them, but perhaps also due to considerable stigma of mental health care that is still largely present in this group.^43,44

Psychotherapy

Current VA treatment guidelines recommend trauma-focused therapies, with the strongest evidence base for prolonged exposure (PE), cognitive processing therapy (CPT), and eye movement desensitization and reprocessing (EMDR) therapies.⁵¹Unfortunately, there is a dearth of published empirical data to evaluate the risks and effectiveness of these therapies not just in the context of Korean War veterans, but among any older adult with PTSD population.^33,44,52,53 Recently, Thorp and colleagues published the first randomized controlled trial comparing PE to a relaxation training (RT) therapy among older veterans (83% were from the Vietnam era).⁵⁴ RT is frequently used as a control condition for RCTs involving trauma-focused therapies. They found PE as well as RT to be well-tolerated by participants. They also found some evidence for superior efficacy in PE relative to RT, although the persistence of that improvement was less for self-rated vs clinician-rated symptoms. As the investigators noted, only 35% of those receiving PE exhibited clinically significant change, and 77% still met diagnostic criteria for PTSD, suggesting a persistence of symptom distress and need for further intervention research to advance treatment for PTSD in older adults.

There have been several excellent prior reviews discussing treatment of PTSD in older adults generally.^10,43,44,52 These reviews have invariably expressed concern about the lack of sufficient empirical studies, but based on evidence from studies and case reports, there seems to be tentative support that trauma-focused therapies are acceptable and efficacious for use with older adults with PTSD. In their recent scoping review, Pless Kaiser and colleagues made several recommendations for trauma-focused therapy with older adults, including slow/careful pacing and use of compensatory aids for cognitive and sensory deficits.⁴⁴ When cognitive impairment has exacerbated PTSD symptoms, they suggest therapists consider using an adapted form of CPT completed without a trauma narrative. For PE they recommend extending content across sessions and involving spouse or caregivers to assist with in vivo exposure and homework completion.⁴⁴

Recent studies suggest that PTSD may be a risk factor for the later development of neurodegenerative disorders, and it is often during assessments for dementia that a revelation of PTSD occurs.^10,43,47,55 Cognitive impairment may also be of relevance in deciding on the type of psychotherapy to be implemented, as it may have more adverse effects on the effectiveness of CPT than of exposure-based treatments (PE or EMDR). It may be useful to perform a cognitive assessment prior to initiation of a cognitive-based therapy, although extensive cognitive testing may not be practical or may be contraindicated because of fatigue. A brief screening tool such as the Montreal Cognitive Assessment or the Mini-Mental State Examinationmay be helpful.^{56, 57}

Prolonged exposure has been reported by many clinicians to be effective in older adults with PTSD; however, due consideration should be given to the needs of individuals, as many have functioned for decades by suppressing memories. Cognitive impairment may be important, as cognitive resources may have been utilized to cope with earlier traumas, and there may be a recrudescence or exacerbation of PTSD symptoms as these resources are compromised. There may therefore be a reemergence of symptoms that are more amenable to an exposure-based treatment. Veterans with PTSD and dementia can present particularly difficult treatment dilemmas because with progression of the dementia, standard PTSD treatments, including exposure-based treatments, may cease to be viable. Instead, the focus of intervention may need to be on specific environmental triggers and behavioral approaches that may also be designed to aid caregivers.

Apart from the treatment needs for specific PTSD symptoms, the decades-long effects of poor sleep, irritability, hypervigilance, and dissociation also have social consequences for patients, including marital discord and divorce, and social and family isolation that should be addressed in therapy when appropriate. In addition, many Korean War veterans, like all veterans, sought postmilitary employment in professions that are associated with higher rates of exposure to psychological trauma, such as police or fire departments, and this may have an exacerbating effect on PTSD.⁵⁸

Pharmacotherapy

There is very little empirical evidence guiding pharmacologic approaches to PTSD in older veterans. This population is at increased risk for many comorbidities, and pharmacologic treatments many require dosage adjustments, as is the case for any geriatric patient. Selective serotonin reuptake inhibitor (SSRI) and serotonin norepinephrine reuptake inhibitor (SNRI) medications have been proposed for some cases of PTSD.^59,60 Health care providers may consider the SSRIs escitalopram or sertraline preferentially given their decreased potential for drug-drug interactions, anticholinergic effects, or cardiac toxicity compared with that of other drugs in this class.^60,61 As venlafaxine can increase blood pressure, especially at higher doses, prescribers may choose duloxetine as an alternative if a SNRI is indicated.⁶⁰ For veterans when prazosin is being considered for nightmare control, monitoring for hypotension, orthostasis, and the administration of other antihypertensives or prostatic hypertrophy medications is necessary.⁶¹ The use of benzodiazepines, while not recommended for PTSD, should be viewed with even greater trepidation in a geriatric population given enhanced risk of falls and confusion in the geriatric veteran population.^60,62

Conclusions

Many of the oldest veterans (aged > 80 years) are from the Korean War era. The harsh and unique nature of the war, as well as the differences in context and support from the US public, and the outcome of the war, may have all contributed to and elevation of “combat fatigue” and PTSD among combat veterans from the Korean War. As the “forgotten war” cohort also has been forgotten by researchers, relatively little is known about posttraumatic stress sequelae of these veterans in the decades following the war.

From available evidence, we can readily surmise that problems were underrecognized and suboptimally diagnosed and treated. There is tentative evidence supporting the use of standard interviews and rating scales, such as the CAPS, M-PTSD, and PCL, but lower cut-scores than applied with Vietnam and later veteran cohorts are generally recommended to avoid excessive false negative errors. In terms of psychotherapy treatment, there is again a stark paucity of systematic research, but the limited evidence from studies of PTSD treatment in older adults from the general population tentatively support the acceptability and potential efficacy of recognized evidence-based trauma-focused psychotherapies for PTSD. Research on medication treatment is similarly lacking, but the general recommendations for the use of SSRI or SNRI medications seem to be valid, at least in our clinical experience, and the general rules for geriatric psychopharmacology definitely apply here—start low, go slow.

There are several important avenues for future research. Most pressing among these are establishing the effectiveness of existing treatments, and the modifications that may be needed in the broader context of the above factors, as well as the physical and cognitive changes associated with advanced age. Further research on the phenomenologic aspects of PTSD among Korean War and subsequent cohorts are also needed, as the information obtained will not only guide more effective personalized treatment of the Korean War veterans who remain with us, but also inform future generations of care in terms of the degree and dimensions of variability that may present between cohorts and within cohorts over the life span.