Clinical Review

DOES PEANUT EXPOSURE INCREASE ALLERGY RISK?
Du Toit G, Roberts G, Sayre PH, et al; LEAP Study Team. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015;372(9):803-813. doi: 10.1056/NEJMoa1414850.

Among children at high risk for peanut allergy, early introduction of peanuts significantly reduced the risk for allergy, according to a randomized controlled trial of 640 infants with severe eczema, egg allergy, or both.

Participants ages 4 to 11 months who were high risk—based on severe atopy or allergy to eggs—were tested for sensitivity to peanut extract at baseline and then assigned to either avoid or consume peanuts.

At 60 months of age, skin allergy testing was repeated; the resulting prevalence of peanut allergy was as follows

A greater percentage of the consumption group showed an increase in levels of peanut-specific IgG4 antibody; the avoidance group, elevated titers of peanut specific IgE antibody.

COMMENTARY
The prevalence of peanut allergy in the United States has increased from 0.4% in 1997 to more than 2% in 2010.¹ In 2000, the American Academy of Pediatrics recommended peanut avoidance until age 3 in children at high risk for atopic disease; then in 2008, based on emerging evidence that early introduction of allergenic foods, including peanuts, may decrease the development of allergy, the recommendations were retracted.^2,3 The present study, using a randomized trial design, confirms the paradigm-changing hypothesis that early introduction of allergenic foods decreases the subsequent development of food allergies. The authors of the accompanying editorial state that these data are incontrovertible and that children at high risk for peanut allergy should, under supervision of an allergist, be tested and if skin-prick–­negative for peanut allergy, be started on a peanut protein–containing diet.¹—NS

1. Gruchalla RS, Sampson HA. Preventing peanut allergy through early consumption ready for prime time? N Engl J Med. 2015;372:875-876.
2. Du Toit G, Katz Y, Sasieni P, et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin Immunol. 2008;122:984-991.
3. Katz Y, Rajuan N, Goldberg MR, et al. Early exposure to cow’s milk protein is protective against IgE-mediated cow’s milk protein allergy. J Allergy Clin Immunol. 2010;126:77-82. 

Continue for Anaphylaxis guideline from AAAAI/ACAAI >>

ANAPHYLAXIS GUIDELINE FROM AAAAI/ACAAI
Campbell RL, Li JT, Nicklas RA, Sadosty AT. Emergency department diagnosis and treatment of anaphylaxis: a practice parameter. Ann Allergy Asthma Immunol. 2014;113(6):599-608. doi: 10.1016/j.anai.2014.10.007.

The American Academy of Allergy, Asthma & Immunology and the American College of Allergy, Asthma, and Immunology guideline for emergency department diagnosis and treatment of anaphylaxis includes the following recommendations
• Carefully and immediately triage and monitor patients who have signs and symptoms of ­anaphylaxis in preparation for epinephrine administration.
• First-line treatment for patients experiencing anaphylaxis is epinephrine. It should be administered intramuscularly in the anterolateral thigh immediately after the diagnosis is made. Epinephrine can be administered every 5 to 15 minutes as needed to control symptoms.
• Do not substitute for epinephrine in the treatment of anaphylaxis. Antihistamines and corticosteroids can be administered in conjunction with epinephrine, not in place of it.
• Determine whether the patient has risk factors for severe and potentially fatal anaphylaxis, such as delayed administration of epinephrine, asthma, a history of biphasic reactions, or cardiovascular disease.
• For anaphylaxis patients with bronchospasms, administer a β-agonist.
• Patients should be observed for 4 to 8 hours (longer for those with a history of risk factors for severe anaphylaxis).
• Refer patients to an allergist–immunologist upon discharge.

COMMENTARY
Identification of anaphylaxis requires judgment. Abbreviated criteria for anaphylaxis include essentially two organ systems of involvement: skin manifestations of pruritus, flushing, hives, or angioedema; respiratory manifestations of wheezing or stridor; decreased blood pressure; and GI symptoms of vomiting, cramping abdominal pain, or diarrhea. Quick identification and treatment of anaphylaxis is important, as the median time to respiratory or cardiac arrest in food-induced anaphylaxis is only 30 minutes. All offices should stock epinephrine in an obvious place; you may consider use of a prefilled pen, so it is easy to find and to give the correct dose. —NS

Continue for Updated practice parameter: Diagnosing and treating food allergies >>

UPDATED PRACTICE PARAMETER: DIAGNOSING AND TREATING FOOD ALLERGIES
Sampson HA, Aceves S, Bock SA, et al. Food allergy: a practice parameter update—2014. J Allergy Clin Immunol. 2014. pii: S0091-6749(14)00672-1. doi: 10.1016/j.jaci.2014.05.013. [Epub ahead of print]

Over the past decade, health care providers have been confronted with a growing number of patients with suspected food allergies, but data supporting an increase in confirmed allergy cases is limited.

The 2014 practice parameter update on food allergies from the American Academy of Allergy, Asthma & Immunology advises clinicians to keep in mind that self-reported food allergy is more common than proven food allergy; that allergy is more common in children and in patients with other atopic conditions; and that the majority of allergic reactions are from peanuts, tree nuts, fish, shellfish, milk, eggs, wheat, soy, and seeds.

The update of the 2006 guidelines includes 64 new summary statements. Highlights include
• Clinicians should advise patients about the risk for cross-reactions from foods similar to their allergens, such as other tree nuts, vertebrate fish, crustaceans, or milk from cows, goats, or other mammals.
• Patients with a seafood allergy should be advised that they are not at increased risk for a reaction to radiocontrast media.
• Patients with food allergies do not need to be concerned about eating genetically modified foods (GMO), due to current FDA screening requirements to rule out allergenicity.
• Patients with chronic idiopathic urticaria or hyperactivity/attention-deficit disorder should not routinely be advised to avoid food additives.
• Patients with asthma should not routinely be advised to avoid sulfates, unless they have had a previous reaction to them.

The guidelines also include a new section on diagnosing and treating non-IgE-mediated food allergies, such as food-protein–induced enterocolitis syndrome, allergic proctocolitis, enteropathy, eosinophilic esophagitis, and gastroenteritis. 

COMMENTARY
Food allergies are a commonly encountered and difficult area of practice for those of us in primary care. They can be life threatening; yet many patients who are concerned about the possibility of food allergy do not actually have a food allergy, so making an accurate diagnosis is important. Allergic evaluation starts with a careful history, and then laboratory testing can begin with specific IgE testing to foods suspected to have caused the clinical reaction of concern. The IgE results need to be carefully interpreted in light of the clinical context in which they were ordered. Oral food challenge can be helpful in addition to IgE testing. Consultation with an allergy-immunology specialist is often helpful as well. —NS

DOES PEANUT EXPOSURE INCREASE ALLERGY RISK?
Du Toit G, Roberts G, Sayre PH, et al; LEAP Study Team. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015;372(9):803-813. doi: 10.1056/NEJMoa1414850.

Among children at high risk for peanut allergy, early introduction of peanuts significantly reduced the risk for allergy, according to a randomized controlled trial of 640 infants with severe eczema, egg allergy, or both.

Participants ages 4 to 11 months who were high risk—based on severe atopy or allergy to eggs—were tested for sensitivity to peanut extract at baseline and then assigned to either avoid or consume peanuts.

At 60 months of age, skin allergy testing was repeated; the resulting prevalence of peanut allergy was as follows

A greater percentage of the consumption group showed an increase in levels of peanut-specific IgG4 antibody; the avoidance group, elevated titers of peanut specific IgE antibody.

COMMENTARY
The prevalence of peanut allergy in the United States has increased from 0.4% in 1997 to more than 2% in 2010.¹ In 2000, the American Academy of Pediatrics recommended peanut avoidance until age 3 in children at high risk for atopic disease; then in 2008, based on emerging evidence that early introduction of allergenic foods, including peanuts, may decrease the development of allergy, the recommendations were retracted.^2,3 The present study, using a randomized trial design, confirms the paradigm-changing hypothesis that early introduction of allergenic foods decreases the subsequent development of food allergies. The authors of the accompanying editorial state that these data are incontrovertible and that children at high risk for peanut allergy should, under supervision of an allergist, be tested and if skin-prick–­negative for peanut allergy, be started on a peanut protein–containing diet.¹—NS

1. Gruchalla RS, Sampson HA. Preventing peanut allergy through early consumption ready for prime time? N Engl J Med. 2015;372:875-876.
2. Du Toit G, Katz Y, Sasieni P, et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin Immunol. 2008;122:984-991.
3. Katz Y, Rajuan N, Goldberg MR, et al. Early exposure to cow’s milk protein is protective against IgE-mediated cow’s milk protein allergy. J Allergy Clin Immunol. 2010;126:77-82. 

Continue for Anaphylaxis guideline from AAAAI/ACAAI >>

ANAPHYLAXIS GUIDELINE FROM AAAAI/ACAAI
Campbell RL, Li JT, Nicklas RA, Sadosty AT. Emergency department diagnosis and treatment of anaphylaxis: a practice parameter. Ann Allergy Asthma Immunol. 2014;113(6):599-608. doi: 10.1016/j.anai.2014.10.007.

The American Academy of Allergy, Asthma & Immunology and the American College of Allergy, Asthma, and Immunology guideline for emergency department diagnosis and treatment of anaphylaxis includes the following recommendations
• Carefully and immediately triage and monitor patients who have signs and symptoms of ­anaphylaxis in preparation for epinephrine administration.
• First-line treatment for patients experiencing anaphylaxis is epinephrine. It should be administered intramuscularly in the anterolateral thigh immediately after the diagnosis is made. Epinephrine can be administered every 5 to 15 minutes as needed to control symptoms.
• Do not substitute for epinephrine in the treatment of anaphylaxis. Antihistamines and corticosteroids can be administered in conjunction with epinephrine, not in place of it.
• Determine whether the patient has risk factors for severe and potentially fatal anaphylaxis, such as delayed administration of epinephrine, asthma, a history of biphasic reactions, or cardiovascular disease.
• For anaphylaxis patients with bronchospasms, administer a β-agonist.
• Patients should be observed for 4 to 8 hours (longer for those with a history of risk factors for severe anaphylaxis).
• Refer patients to an allergist–immunologist upon discharge.

COMMENTARY
Identification of anaphylaxis requires judgment. Abbreviated criteria for anaphylaxis include essentially two organ systems of involvement: skin manifestations of pruritus, flushing, hives, or angioedema; respiratory manifestations of wheezing or stridor; decreased blood pressure; and GI symptoms of vomiting, cramping abdominal pain, or diarrhea. Quick identification and treatment of anaphylaxis is important, as the median time to respiratory or cardiac arrest in food-induced anaphylaxis is only 30 minutes. All offices should stock epinephrine in an obvious place; you may consider use of a prefilled pen, so it is easy to find and to give the correct dose. —NS

Continue for Updated practice parameter: Diagnosing and treating food allergies >>

UPDATED PRACTICE PARAMETER: DIAGNOSING AND TREATING FOOD ALLERGIES
Sampson HA, Aceves S, Bock SA, et al. Food allergy: a practice parameter update—2014. J Allergy Clin Immunol. 2014. pii: S0091-6749(14)00672-1. doi: 10.1016/j.jaci.2014.05.013. [Epub ahead of print]

Over the past decade, health care providers have been confronted with a growing number of patients with suspected food allergies, but data supporting an increase in confirmed allergy cases is limited.

The 2014 practice parameter update on food allergies from the American Academy of Allergy, Asthma & Immunology advises clinicians to keep in mind that self-reported food allergy is more common than proven food allergy; that allergy is more common in children and in patients with other atopic conditions; and that the majority of allergic reactions are from peanuts, tree nuts, fish, shellfish, milk, eggs, wheat, soy, and seeds.

The update of the 2006 guidelines includes 64 new summary statements. Highlights include
• Clinicians should advise patients about the risk for cross-reactions from foods similar to their allergens, such as other tree nuts, vertebrate fish, crustaceans, or milk from cows, goats, or other mammals.
• Patients with a seafood allergy should be advised that they are not at increased risk for a reaction to radiocontrast media.
• Patients with food allergies do not need to be concerned about eating genetically modified foods (GMO), due to current FDA screening requirements to rule out allergenicity.
• Patients with chronic idiopathic urticaria or hyperactivity/attention-deficit disorder should not routinely be advised to avoid food additives.
• Patients with asthma should not routinely be advised to avoid sulfates, unless they have had a previous reaction to them.

The guidelines also include a new section on diagnosing and treating non-IgE-mediated food allergies, such as food-protein–induced enterocolitis syndrome, allergic proctocolitis, enteropathy, eosinophilic esophagitis, and gastroenteritis. 

COMMENTARY
Food allergies are a commonly encountered and difficult area of practice for those of us in primary care. They can be life threatening; yet many patients who are concerned about the possibility of food allergy do not actually have a food allergy, so making an accurate diagnosis is important. Allergic evaluation starts with a careful history, and then laboratory testing can begin with specific IgE testing to foods suspected to have caused the clinical reaction of concern. The IgE results need to be carefully interpreted in light of the clinical context in which they were ordered. Oral food challenge can be helpful in addition to IgE testing. Consultation with an allergy-immunology specialist is often helpful as well. —NS

DOES PEANUT EXPOSURE INCREASE ALLERGY RISK?
Du Toit G, Roberts G, Sayre PH, et al; LEAP Study Team. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015;372(9):803-813. doi: 10.1056/NEJMoa1414850.

Among children at high risk for peanut allergy, early introduction of peanuts significantly reduced the risk for allergy, according to a randomized controlled trial of 640 infants with severe eczema, egg allergy, or both.

Participants ages 4 to 11 months who were high risk—based on severe atopy or allergy to eggs—were tested for sensitivity to peanut extract at baseline and then assigned to either avoid or consume peanuts.

At 60 months of age, skin allergy testing was repeated; the resulting prevalence of peanut allergy was as follows

A greater percentage of the consumption group showed an increase in levels of peanut-specific IgG4 antibody; the avoidance group, elevated titers of peanut specific IgE antibody.

COMMENTARY
The prevalence of peanut allergy in the United States has increased from 0.4% in 1997 to more than 2% in 2010.¹ In 2000, the American Academy of Pediatrics recommended peanut avoidance until age 3 in children at high risk for atopic disease; then in 2008, based on emerging evidence that early introduction of allergenic foods, including peanuts, may decrease the development of allergy, the recommendations were retracted.^2,3 The present study, using a randomized trial design, confirms the paradigm-changing hypothesis that early introduction of allergenic foods decreases the subsequent development of food allergies. The authors of the accompanying editorial state that these data are incontrovertible and that children at high risk for peanut allergy should, under supervision of an allergist, be tested and if skin-prick–­negative for peanut allergy, be started on a peanut protein–containing diet.¹—NS

1. Gruchalla RS, Sampson HA. Preventing peanut allergy through early consumption ready for prime time? N Engl J Med. 2015;372:875-876.
2. Du Toit G, Katz Y, Sasieni P, et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin Immunol. 2008;122:984-991.
3. Katz Y, Rajuan N, Goldberg MR, et al. Early exposure to cow’s milk protein is protective against IgE-mediated cow’s milk protein allergy. J Allergy Clin Immunol. 2010;126:77-82. 

Continue for Anaphylaxis guideline from AAAAI/ACAAI >>

ANAPHYLAXIS GUIDELINE FROM AAAAI/ACAAI
Campbell RL, Li JT, Nicklas RA, Sadosty AT. Emergency department diagnosis and treatment of anaphylaxis: a practice parameter. Ann Allergy Asthma Immunol. 2014;113(6):599-608. doi: 10.1016/j.anai.2014.10.007.

The American Academy of Allergy, Asthma & Immunology and the American College of Allergy, Asthma, and Immunology guideline for emergency department diagnosis and treatment of anaphylaxis includes the following recommendations
• Carefully and immediately triage and monitor patients who have signs and symptoms of ­anaphylaxis in preparation for epinephrine administration.
• First-line treatment for patients experiencing anaphylaxis is epinephrine. It should be administered intramuscularly in the anterolateral thigh immediately after the diagnosis is made. Epinephrine can be administered every 5 to 15 minutes as needed to control symptoms.
• Do not substitute for epinephrine in the treatment of anaphylaxis. Antihistamines and corticosteroids can be administered in conjunction with epinephrine, not in place of it.
• Determine whether the patient has risk factors for severe and potentially fatal anaphylaxis, such as delayed administration of epinephrine, asthma, a history of biphasic reactions, or cardiovascular disease.
• For anaphylaxis patients with bronchospasms, administer a β-agonist.
• Patients should be observed for 4 to 8 hours (longer for those with a history of risk factors for severe anaphylaxis).
• Refer patients to an allergist–immunologist upon discharge.

COMMENTARY
Identification of anaphylaxis requires judgment. Abbreviated criteria for anaphylaxis include essentially two organ systems of involvement: skin manifestations of pruritus, flushing, hives, or angioedema; respiratory manifestations of wheezing or stridor; decreased blood pressure; and GI symptoms of vomiting, cramping abdominal pain, or diarrhea. Quick identification and treatment of anaphylaxis is important, as the median time to respiratory or cardiac arrest in food-induced anaphylaxis is only 30 minutes. All offices should stock epinephrine in an obvious place; you may consider use of a prefilled pen, so it is easy to find and to give the correct dose. —NS

Continue for Updated practice parameter: Diagnosing and treating food allergies >>

UPDATED PRACTICE PARAMETER: DIAGNOSING AND TREATING FOOD ALLERGIES
Sampson HA, Aceves S, Bock SA, et al. Food allergy: a practice parameter update—2014. J Allergy Clin Immunol. 2014. pii: S0091-6749(14)00672-1. doi: 10.1016/j.jaci.2014.05.013. [Epub ahead of print]

Over the past decade, health care providers have been confronted with a growing number of patients with suspected food allergies, but data supporting an increase in confirmed allergy cases is limited.

The 2014 practice parameter update on food allergies from the American Academy of Allergy, Asthma & Immunology advises clinicians to keep in mind that self-reported food allergy is more common than proven food allergy; that allergy is more common in children and in patients with other atopic conditions; and that the majority of allergic reactions are from peanuts, tree nuts, fish, shellfish, milk, eggs, wheat, soy, and seeds.

The update of the 2006 guidelines includes 64 new summary statements. Highlights include
• Clinicians should advise patients about the risk for cross-reactions from foods similar to their allergens, such as other tree nuts, vertebrate fish, crustaceans, or milk from cows, goats, or other mammals.
• Patients with a seafood allergy should be advised that they are not at increased risk for a reaction to radiocontrast media.
• Patients with food allergies do not need to be concerned about eating genetically modified foods (GMO), due to current FDA screening requirements to rule out allergenicity.
• Patients with chronic idiopathic urticaria or hyperactivity/attention-deficit disorder should not routinely be advised to avoid food additives.
• Patients with asthma should not routinely be advised to avoid sulfates, unless they have had a previous reaction to them.

The guidelines also include a new section on diagnosing and treating non-IgE-mediated food allergies, such as food-protein–induced enterocolitis syndrome, allergic proctocolitis, enteropathy, eosinophilic esophagitis, and gastroenteritis. 

COMMENTARY
Food allergies are a commonly encountered and difficult area of practice for those of us in primary care. They can be life threatening; yet many patients who are concerned about the possibility of food allergy do not actually have a food allergy, so making an accurate diagnosis is important. Allergic evaluation starts with a careful history, and then laboratory testing can begin with specific IgE testing to foods suspected to have caused the clinical reaction of concern. The IgE results need to be carefully interpreted in light of the clinical context in which they were ordered. Oral food challenge can be helpful in addition to IgE testing. Consultation with an allergy-immunology specialist is often helpful as well. —NS

CASE 1 › Steve J, age 43, comes to your clinic looking uncharacteristically glum. He was recently downsized from his job and misses his former colleagues. His job loss has caused a financial strain for his family, and he admits to crying in the shower when he thinks about how his life has turned out. Mr. J tells you that he’s gotten a part-time job, but he’s already called in sick several times. On those sick days he “stayed in bed all day and slept.” He says that when he does go to work, he rarely interacts with his coworkers and his concentration is poor. He tells you he wakes up early in the morning on most days and cannot return to sleep, despite being “tired all the time.” He denies suicidal ideation. Mr. J has never felt this way before, which is what prompted his visit today, but he thinks it is “weak to take a pill to feel better.”

What nonpharmacologic options can you offer him?

CASE 2 › Kerri S is a 27-year-old mother of 2 who comes to your clinic to establish care. She tells you about a recent recurrence of depressed mood, which she feels is due to the stress of moving to the area. She is experiencing sleep-onset insomnia and concentration lapses. Her appetite is poor (self-reported 8-lb weight loss in 2 months) and she lacks the motivation to engage in her daily activities, saying, “I wouldn’t even get out of bed if my kids didn’t need me.” She notes that she is constantly irritable and has completely lost her sex drive. Unlike her prior depressive episode, she has not had any suicidal thoughts. Mrs. S was previously successfully treated with paroxetine, 20 mg/d, but she is not interested in restarting her medication because she is still breastfeeding her toddler.

Are there evidence-based options for her care that do not include medication?

Major depressive disorder (MDD) is widespread and often disabling, affecting nearly 8% of people ages 12 and older at any given time.¹ Thus, it’s crucial to be familiar with the diverse array of evidence-based treatment options from which patients can choose. Although medications are an essential treatment option for patients with severe depression, their value for patients with mild to moderate depression is often limited.² In addition, when antidepressants aren’t combined with psychosocial interventions, discontinuing them is associated with relapse.³

Fortunately, research has found that certain nonpharmacologic interventions—including psychotherapies, somatic therapies, and dietary supplements—can have either therapeutic or adjunctive benefits for treating depression, and can be provided in ways that are time- and cost-effective. This article reviews the evidence supporting several options in each of these treatment categories.

Evidence backs several types of psychotherapy

Several recent meta-analyses suggest that a variety of psychotherapeutic treatments may hold promise for your patients with depression.^4,5 When analyses were limited to larger studies in order to decrease the risk of bias, cognitive behavioral therapy (CBT), interpersonal therapy (IPT), and problem-solving therapy (PST) all resulted in moderate to large improvement in depressive symptoms when compared to wait-list controls.⁴ These findings were echoed in a recent systematic review/meta-analysis that focused on depressed primary care patients. Linde et al⁵ found that the number needed to treat (NNT) to achieve one response (≥50% reduction in score on a depression scale) using any type of psychotherapy was 10, and the NNT to achieve one remission (scoring below a predefined score on a depression scale) was 15.

Psychotherapy can be effective when provided in individual and group settings,⁶ as well as via telephone, the Internet, or software programs.⁷ (For a list of self-help, computerized, and Internet-based resources, see TABLE W1 below.)

CBT has been studied for several decades and there’s strong evidence for its efficacy.⁶ Recent investigations have suggested that CBT delivered in less resource-intensive modes (such as via computer program, Internet, telephone, or videoconferencing) can be as effective as face-to-face CBT.^6,8 CBT has been shown to be helpful for a wide range of patients,⁶ improves outcomes over standard primary care treatment,⁹ and provides a useful adjunct to medication in treatment-resistant severe depression.¹⁰

Behavioral activation (BA), which generally is included as a component of CBT, has received support as an independent treatment, and may produce therapeutic results similar to CBT¹¹ and PST (which we’ll discuss in a bit).¹² The core components of BA are scheduling pleasant activities and increasing the patient’s positive interactions with his or her environment by decreasing avoidance, withdrawal, and inactivity.¹¹ Compared to CBT, BA is easier for clinicians to learn and incorporate into primary care visits, and it may be especially useful as an adjunctive or first-step intervention in outpatient clinics.¹¹ Like CBT, BA can be effective in diverse patient groups^13,14 and can be provided using novel delivery modes, such as via the Internet.¹⁵

Compared to cognitive behavioral therapy, behavioral activation is easier for clinicians to learn and incorporate into primary care visits.

IPT is a supportive, structured, brief therapy (12-16 visits) that focuses on helping patients identify and solve current situation- and relationship-based problems that stem from or contribute to their depression.¹⁶ Enhancing the patient’s interpersonal communication—including improving social skills, assertiveness, and appropriate expression of anger—is typically a component of IPT. Like CBT, IPT has been found to be effective for treating depression when administered in person, in group therapy, or via the phone or Internet, and across a broad age range.^17-19

PST involves teaching patients a structured problem-solving process to decrease interpersonal strain and improve positive life experiences.²⁰ Patients are taught to define their problem, generate and evaluate multiple solutions for it, implement a plan for the solution, and evaluate the results. In addition to being used to successfully treat adults,^4,5 PST has been adapted effectively to treat adolescents¹⁶ and older adults.¹⁸

Somatic therapies are also an option

Exercise has long been considered a possible depression treatment due to its activity on endorphin, monoamine, and cortisol levels and via increased social and general activity. A 2013 Cochrane review of 39 randomized control trials (RCTs; N=2326) assessed whether exercise was effective for treating depression in adults.²¹ Thirty-five trials found a moderate effect size when specifically comparing exercise to no treatment or control interventions. The effect size was reduced, however, when analyses were restricted to trials with the highest methodological quality. There was no statistically significant difference when exercise was compared to pharmacologic treatment or psychotherapy.

Although the amount of research is meager, small but statistically significant improvements have also been found for older adults²² and children/adolescents.²³ There is no consensus on the type, frequency, or intensity of exercise needed to achieve benefit. However, because nearly all studies for all age groups have found that exercise has no adverse psychological effects and substantial positive physical effects, exercise should be recommended to all patients with depression unless contraindicated.

Yoga (both exercise-based and meditation-based) has been evaluated both as a sole treatment and as an adjunctive treatment for depression. Several studies have supported the impact of yoga, particularly in pregnant women,²⁴ although the evidence for its efficacy is inconsistent, with yoga frequently failing to improve upon the outcome of waitlist control.²⁵ The evidence for meditation and mindfulness is more consistently positive, with these interventions equaling or exceeding “treatment as usual,” other psychotherapies, and antidepressants in numerous RCTs.²⁵

Electroconvulsive therapy (ECT) has a substantial evidence base supporting its efficacy.²⁶ ECT has been used for decades, although stigma, cardiac and memory risks, and risks of anesthesia often limit its use. Benefits of ECT include a rapid response relative to pharmacotherapy (>50% of patients respond by the end of the first week of ECT)²⁷ and a strong response in older patients.²⁸

More than half of patients receiving electroconvulsive therapy respond to treatment by the end of the first week.

In repetitive transcranial magnetic stimulation (rTMS), electromagnetic coils are placed on a patient’s head to deliver electromagnetic pulses that stimulate areas of the brain that regulate mood. Although rTMS is not widely available, a growing body of evidence supports its use for treating depression, including a meta-analysis of 34 RCTs that included 1383 patients.²⁹ A multisite RCT (N=190) that was not industry-funded reported a 15% response rate and 60% maintenance of remission at 3 months (NNT=12).³⁰ Although ECT is more effective than rTMS, rTMS appears useful for treatment-resistant depression, and can be used as an adjunctive treatment.^29,31

Dietary supplements may be best used as adjuncts

St. John’s wort (Hypericum perforatum), which contains 2 bioactive ingredients (hyperforin and hypericin), has been effectively used to treat depression.³² A 2008 Cochrane review that was limited to high-quality trials involving patients meeting Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria for depression identified 29 trials (N=5489), of which 18 involved comparisons with placebo and 17 with standard antidepressants.³³ Patients’ depression was rated mild to moderate in 19 studies and moderate to severe in 9 studies. Trials examined 4 to 12 weeks of treatment with Hypericum extracts. This study (and several published since) provides strong clinical evidence supporting the efficacy of St. John’s wort for mild to moderate depression. There is insufficient evidence for its use for severe major depression.³³TABLE 1 contains dosing information for St. John’s wort and other supplements used to treat depression.^34-36 

S-adenosyl-L-methionine (SAMe). In a 2003 systematic review,³⁷ 1600 mg/d of oral SAMe was found to significantly benefit patients with depression in 4 of 5 studies, as did parenteral SAMe (7 of 7 trials). Another review of 48 studies found SAMe was safe and effective for depression.³⁸ SAMe has been proposed for use alone or in combination with an antidepressant.

Low folate levels have been associated with a less robust response to antidepressants in patients with major depressive disorder.

Folate and folic acid. Low folate levels have been associated with a less robust response to antidepressants in patients with MDD,³⁹ and higher folate levels appear to be associated with better antidepressant response.⁴⁰ A 2003 Cochrane review suggested folate might have a role in treating depression.³⁹ A 2009 study found folate supplementation could reduce depressive symptoms for patients with normal baseline folate levels as well as those with low levels.⁴¹ Although the evidence is equivocal, folate augmentation may enhance antidepressant efficacy or improve response/remission rates.^41,42

It seems reasonable to check folate levels in depressed patients, and address deficiencies by instructing patients to increase their dietary intake of folate or to take supplements. Augmenting antidepressants with folate appears to be low-risk and possibly helpful in maintaining remission.

Omega-3 fatty acids. There is substantial evidence that omega-3 fatty acids can prevent and treat depression.^43,44 Recent meta-analyses support the use of omega-3 fatty acids as monotherapy and augmentation, but only formulations that contain a high eicosapentaenoic acid (EPA) to docosahexaenoic acid (DHA) ratio (EPA/DHA 2:1).^45,46 Omega-3 supplementation has been used with positive results in older adults, children,⁴⁷ pregnant women,⁴⁸ and women with postpartum depression.⁴⁹ Although initial research into omega-3 treatment of depression appears promising, augmentation of standard antidepressant therapy may be a good conservative option.

Use a validated tool to monitor response to treatment

You can enhance outcomes for your patients with depression if you schedule routine follow-up visits with them to gauge adherence to recommendations, monitor response to treatment, and increase the intensity of care when response is inadequate.⁵⁰ The most important aspect of monitoring response is to use a standardized instrument that quantifies symptoms at every visit.

The PHQ-9—which is free—has been validated for depression screening and monitoring of treatment response in primary care patients.

The Patient Health Questionnaire 9-item depression assessment (PHQ-9)—which is free—has been validated for depression screening and monitoring of treatment response in primary care patients.⁵¹ A decrease of 5 points on the PHQ-9 is the minimum considered to be clinically significant.⁵² Other well-validated, although lengthier, self-report depression assessment and monitoring instruments include the Beck Depression Inventory-revised and the Zung Depression Scale.

CASE 1 › Mr. J is not enjoying his new job or engaging with new coworkers to replace the positive social experiences he had at his previous job. Together, you set a goal of increasing social involvement by having him make plans to see at least one friend per weekend. Because he indicates that he is unlikely to follow through with a therapy referral, you encourage him to try an online CBT program, start an exercise regimen, or take a SAMe supplement. Mr. Jackson agrees to try the CBT and exercise (moderate intensity, 30 minutes 3-4 times per week), but does not want to take SAMe. He agrees to an assessment of his folate levels, which are normal.

Mr. J starts the online CBT program, which reinforces the exercise and social activity prescription you provided. He establishes a regular exercise routine with a good friend. After one month, his mood has started to improve and he has added regular participation in a hobby (woodworking), as well as volunteer work, which he finds fulfilling. You plan to continue monitoring his depression and his adherence to the treatment plan.

CASE 2 › The recent move has decreased Mrs. S’s interactions with family and long-time friends. Because she had previously expressed interest in exercise, you encourage her to join a local “Mommy and Me” exercise and support group for mothers of toddlers. She is willing to participate in psychotherapy, so you provide a referral to a local therapist with expertise in IPT. You also discuss with Mrs. S the possible benefits of omega-3 fatty acid supplementation, which appears to be safe during breastfeeding.³⁴

Mrs. S begins therapy and exercise classes, but can’t motivate herself to continue either of these activities. She becomes discouraged because she’s unable to easily find an omega-3 fatty acid supplement with the ratio you specified (EPA/DHA 2:1). When you see her 2 weeks later, her depression has worsened.

Because you are concerned her suicidality will return, you revisit the pros and cons of taking an antidepressant. Although small amounts of antidepressants can be passed from mother to infant via breastmilk, the amount varies by specific medication, as do the potential risks. Mrs. S decides to resume taking paroxetine 20 mg/d and eventually, once her motivation improves, she’s able to add psychotherapy and exercise to her maintenance/relapse prevention regimen. After you discuss with her the possibility that B vitamin supplementation may assist in maintenance of remission, she adds L-methylfolate 7.5 mg/day to her regimen.

CORRESPONDENCE 
Michele M. Larzelere, PhD; LSUHSC Department of Family Medicine; 200 W. Esplanade Avenue, Suite 409; Kenner, LA 70065; [email protected]

CASE 1 › Steve J, age 43, comes to your clinic looking uncharacteristically glum. He was recently downsized from his job and misses his former colleagues. His job loss has caused a financial strain for his family, and he admits to crying in the shower when he thinks about how his life has turned out. Mr. J tells you that he’s gotten a part-time job, but he’s already called in sick several times. On those sick days he “stayed in bed all day and slept.” He says that when he does go to work, he rarely interacts with his coworkers and his concentration is poor. He tells you he wakes up early in the morning on most days and cannot return to sleep, despite being “tired all the time.” He denies suicidal ideation. Mr. J has never felt this way before, which is what prompted his visit today, but he thinks it is “weak to take a pill to feel better.”

What nonpharmacologic options can you offer him?

CASE 2 › Kerri S is a 27-year-old mother of 2 who comes to your clinic to establish care. She tells you about a recent recurrence of depressed mood, which she feels is due to the stress of moving to the area. She is experiencing sleep-onset insomnia and concentration lapses. Her appetite is poor (self-reported 8-lb weight loss in 2 months) and she lacks the motivation to engage in her daily activities, saying, “I wouldn’t even get out of bed if my kids didn’t need me.” She notes that she is constantly irritable and has completely lost her sex drive. Unlike her prior depressive episode, she has not had any suicidal thoughts. Mrs. S was previously successfully treated with paroxetine, 20 mg/d, but she is not interested in restarting her medication because she is still breastfeeding her toddler.

Are there evidence-based options for her care that do not include medication?

Major depressive disorder (MDD) is widespread and often disabling, affecting nearly 8% of people ages 12 and older at any given time.¹ Thus, it’s crucial to be familiar with the diverse array of evidence-based treatment options from which patients can choose. Although medications are an essential treatment option for patients with severe depression, their value for patients with mild to moderate depression is often limited.² In addition, when antidepressants aren’t combined with psychosocial interventions, discontinuing them is associated with relapse.³

Fortunately, research has found that certain nonpharmacologic interventions—including psychotherapies, somatic therapies, and dietary supplements—can have either therapeutic or adjunctive benefits for treating depression, and can be provided in ways that are time- and cost-effective. This article reviews the evidence supporting several options in each of these treatment categories.

Evidence backs several types of psychotherapy

Several recent meta-analyses suggest that a variety of psychotherapeutic treatments may hold promise for your patients with depression.^4,5 When analyses were limited to larger studies in order to decrease the risk of bias, cognitive behavioral therapy (CBT), interpersonal therapy (IPT), and problem-solving therapy (PST) all resulted in moderate to large improvement in depressive symptoms when compared to wait-list controls.⁴ These findings were echoed in a recent systematic review/meta-analysis that focused on depressed primary care patients. Linde et al⁵ found that the number needed to treat (NNT) to achieve one response (≥50% reduction in score on a depression scale) using any type of psychotherapy was 10, and the NNT to achieve one remission (scoring below a predefined score on a depression scale) was 15.

Psychotherapy can be effective when provided in individual and group settings,⁶ as well as via telephone, the Internet, or software programs.⁷ (For a list of self-help, computerized, and Internet-based resources, see TABLE W1 below.)

CBT has been studied for several decades and there’s strong evidence for its efficacy.⁶ Recent investigations have suggested that CBT delivered in less resource-intensive modes (such as via computer program, Internet, telephone, or videoconferencing) can be as effective as face-to-face CBT.^6,8 CBT has been shown to be helpful for a wide range of patients,⁶ improves outcomes over standard primary care treatment,⁹ and provides a useful adjunct to medication in treatment-resistant severe depression.¹⁰

Behavioral activation (BA), which generally is included as a component of CBT, has received support as an independent treatment, and may produce therapeutic results similar to CBT¹¹ and PST (which we’ll discuss in a bit).¹² The core components of BA are scheduling pleasant activities and increasing the patient’s positive interactions with his or her environment by decreasing avoidance, withdrawal, and inactivity.¹¹ Compared to CBT, BA is easier for clinicians to learn and incorporate into primary care visits, and it may be especially useful as an adjunctive or first-step intervention in outpatient clinics.¹¹ Like CBT, BA can be effective in diverse patient groups^13,14 and can be provided using novel delivery modes, such as via the Internet.¹⁵

Compared to cognitive behavioral therapy, behavioral activation is easier for clinicians to learn and incorporate into primary care visits.

IPT is a supportive, structured, brief therapy (12-16 visits) that focuses on helping patients identify and solve current situation- and relationship-based problems that stem from or contribute to their depression.¹⁶ Enhancing the patient’s interpersonal communication—including improving social skills, assertiveness, and appropriate expression of anger—is typically a component of IPT. Like CBT, IPT has been found to be effective for treating depression when administered in person, in group therapy, or via the phone or Internet, and across a broad age range.^17-19

PST involves teaching patients a structured problem-solving process to decrease interpersonal strain and improve positive life experiences.²⁰ Patients are taught to define their problem, generate and evaluate multiple solutions for it, implement a plan for the solution, and evaluate the results. In addition to being used to successfully treat adults,^4,5 PST has been adapted effectively to treat adolescents¹⁶ and older adults.¹⁸

Somatic therapies are also an option

Exercise has long been considered a possible depression treatment due to its activity on endorphin, monoamine, and cortisol levels and via increased social and general activity. A 2013 Cochrane review of 39 randomized control trials (RCTs; N=2326) assessed whether exercise was effective for treating depression in adults.²¹ Thirty-five trials found a moderate effect size when specifically comparing exercise to no treatment or control interventions. The effect size was reduced, however, when analyses were restricted to trials with the highest methodological quality. There was no statistically significant difference when exercise was compared to pharmacologic treatment or psychotherapy.

Although the amount of research is meager, small but statistically significant improvements have also been found for older adults²² and children/adolescents.²³ There is no consensus on the type, frequency, or intensity of exercise needed to achieve benefit. However, because nearly all studies for all age groups have found that exercise has no adverse psychological effects and substantial positive physical effects, exercise should be recommended to all patients with depression unless contraindicated.

Yoga (both exercise-based and meditation-based) has been evaluated both as a sole treatment and as an adjunctive treatment for depression. Several studies have supported the impact of yoga, particularly in pregnant women,²⁴ although the evidence for its efficacy is inconsistent, with yoga frequently failing to improve upon the outcome of waitlist control.²⁵ The evidence for meditation and mindfulness is more consistently positive, with these interventions equaling or exceeding “treatment as usual,” other psychotherapies, and antidepressants in numerous RCTs.²⁵

Electroconvulsive therapy (ECT) has a substantial evidence base supporting its efficacy.²⁶ ECT has been used for decades, although stigma, cardiac and memory risks, and risks of anesthesia often limit its use. Benefits of ECT include a rapid response relative to pharmacotherapy (>50% of patients respond by the end of the first week of ECT)²⁷ and a strong response in older patients.²⁸

More than half of patients receiving electroconvulsive therapy respond to treatment by the end of the first week.

In repetitive transcranial magnetic stimulation (rTMS), electromagnetic coils are placed on a patient’s head to deliver electromagnetic pulses that stimulate areas of the brain that regulate mood. Although rTMS is not widely available, a growing body of evidence supports its use for treating depression, including a meta-analysis of 34 RCTs that included 1383 patients.²⁹ A multisite RCT (N=190) that was not industry-funded reported a 15% response rate and 60% maintenance of remission at 3 months (NNT=12).³⁰ Although ECT is more effective than rTMS, rTMS appears useful for treatment-resistant depression, and can be used as an adjunctive treatment.^29,31

Dietary supplements may be best used as adjuncts

St. John’s wort (Hypericum perforatum), which contains 2 bioactive ingredients (hyperforin and hypericin), has been effectively used to treat depression.³² A 2008 Cochrane review that was limited to high-quality trials involving patients meeting Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria for depression identified 29 trials (N=5489), of which 18 involved comparisons with placebo and 17 with standard antidepressants.³³ Patients’ depression was rated mild to moderate in 19 studies and moderate to severe in 9 studies. Trials examined 4 to 12 weeks of treatment with Hypericum extracts. This study (and several published since) provides strong clinical evidence supporting the efficacy of St. John’s wort for mild to moderate depression. There is insufficient evidence for its use for severe major depression.³³TABLE 1 contains dosing information for St. John’s wort and other supplements used to treat depression.^34-36 

S-adenosyl-L-methionine (SAMe). In a 2003 systematic review,³⁷ 1600 mg/d of oral SAMe was found to significantly benefit patients with depression in 4 of 5 studies, as did parenteral SAMe (7 of 7 trials). Another review of 48 studies found SAMe was safe and effective for depression.³⁸ SAMe has been proposed for use alone or in combination with an antidepressant.

Low folate levels have been associated with a less robust response to antidepressants in patients with major depressive disorder.

Folate and folic acid. Low folate levels have been associated with a less robust response to antidepressants in patients with MDD,³⁹ and higher folate levels appear to be associated with better antidepressant response.⁴⁰ A 2003 Cochrane review suggested folate might have a role in treating depression.³⁹ A 2009 study found folate supplementation could reduce depressive symptoms for patients with normal baseline folate levels as well as those with low levels.⁴¹ Although the evidence is equivocal, folate augmentation may enhance antidepressant efficacy or improve response/remission rates.^41,42

It seems reasonable to check folate levels in depressed patients, and address deficiencies by instructing patients to increase their dietary intake of folate or to take supplements. Augmenting antidepressants with folate appears to be low-risk and possibly helpful in maintaining remission.

Omega-3 fatty acids. There is substantial evidence that omega-3 fatty acids can prevent and treat depression.^43,44 Recent meta-analyses support the use of omega-3 fatty acids as monotherapy and augmentation, but only formulations that contain a high eicosapentaenoic acid (EPA) to docosahexaenoic acid (DHA) ratio (EPA/DHA 2:1).^45,46 Omega-3 supplementation has been used with positive results in older adults, children,⁴⁷ pregnant women,⁴⁸ and women with postpartum depression.⁴⁹ Although initial research into omega-3 treatment of depression appears promising, augmentation of standard antidepressant therapy may be a good conservative option.

Use a validated tool to monitor response to treatment

You can enhance outcomes for your patients with depression if you schedule routine follow-up visits with them to gauge adherence to recommendations, monitor response to treatment, and increase the intensity of care when response is inadequate.⁵⁰ The most important aspect of monitoring response is to use a standardized instrument that quantifies symptoms at every visit.

The PHQ-9—which is free—has been validated for depression screening and monitoring of treatment response in primary care patients.

The Patient Health Questionnaire 9-item depression assessment (PHQ-9)—which is free—has been validated for depression screening and monitoring of treatment response in primary care patients.⁵¹ A decrease of 5 points on the PHQ-9 is the minimum considered to be clinically significant.⁵² Other well-validated, although lengthier, self-report depression assessment and monitoring instruments include the Beck Depression Inventory-revised and the Zung Depression Scale.

CASE 1 › Mr. J is not enjoying his new job or engaging with new coworkers to replace the positive social experiences he had at his previous job. Together, you set a goal of increasing social involvement by having him make plans to see at least one friend per weekend. Because he indicates that he is unlikely to follow through with a therapy referral, you encourage him to try an online CBT program, start an exercise regimen, or take a SAMe supplement. Mr. Jackson agrees to try the CBT and exercise (moderate intensity, 30 minutes 3-4 times per week), but does not want to take SAMe. He agrees to an assessment of his folate levels, which are normal.

Mr. J starts the online CBT program, which reinforces the exercise and social activity prescription you provided. He establishes a regular exercise routine with a good friend. After one month, his mood has started to improve and he has added regular participation in a hobby (woodworking), as well as volunteer work, which he finds fulfilling. You plan to continue monitoring his depression and his adherence to the treatment plan.

CASE 2 › The recent move has decreased Mrs. S’s interactions with family and long-time friends. Because she had previously expressed interest in exercise, you encourage her to join a local “Mommy and Me” exercise and support group for mothers of toddlers. She is willing to participate in psychotherapy, so you provide a referral to a local therapist with expertise in IPT. You also discuss with Mrs. S the possible benefits of omega-3 fatty acid supplementation, which appears to be safe during breastfeeding.³⁴

Mrs. S begins therapy and exercise classes, but can’t motivate herself to continue either of these activities. She becomes discouraged because she’s unable to easily find an omega-3 fatty acid supplement with the ratio you specified (EPA/DHA 2:1). When you see her 2 weeks later, her depression has worsened.

Because you are concerned her suicidality will return, you revisit the pros and cons of taking an antidepressant. Although small amounts of antidepressants can be passed from mother to infant via breastmilk, the amount varies by specific medication, as do the potential risks. Mrs. S decides to resume taking paroxetine 20 mg/d and eventually, once her motivation improves, she’s able to add psychotherapy and exercise to her maintenance/relapse prevention regimen. After you discuss with her the possibility that B vitamin supplementation may assist in maintenance of remission, she adds L-methylfolate 7.5 mg/day to her regimen.

CORRESPONDENCE 
Michele M. Larzelere, PhD; LSUHSC Department of Family Medicine; 200 W. Esplanade Avenue, Suite 409; Kenner, LA 70065; [email protected]

CASE 1 › Steve J, age 43, comes to your clinic looking uncharacteristically glum. He was recently downsized from his job and misses his former colleagues. His job loss has caused a financial strain for his family, and he admits to crying in the shower when he thinks about how his life has turned out. Mr. J tells you that he’s gotten a part-time job, but he’s already called in sick several times. On those sick days he “stayed in bed all day and slept.” He says that when he does go to work, he rarely interacts with his coworkers and his concentration is poor. He tells you he wakes up early in the morning on most days and cannot return to sleep, despite being “tired all the time.” He denies suicidal ideation. Mr. J has never felt this way before, which is what prompted his visit today, but he thinks it is “weak to take a pill to feel better.”

What nonpharmacologic options can you offer him?

CASE 2 › Kerri S is a 27-year-old mother of 2 who comes to your clinic to establish care. She tells you about a recent recurrence of depressed mood, which she feels is due to the stress of moving to the area. She is experiencing sleep-onset insomnia and concentration lapses. Her appetite is poor (self-reported 8-lb weight loss in 2 months) and she lacks the motivation to engage in her daily activities, saying, “I wouldn’t even get out of bed if my kids didn’t need me.” She notes that she is constantly irritable and has completely lost her sex drive. Unlike her prior depressive episode, she has not had any suicidal thoughts. Mrs. S was previously successfully treated with paroxetine, 20 mg/d, but she is not interested in restarting her medication because she is still breastfeeding her toddler.

Are there evidence-based options for her care that do not include medication?

Major depressive disorder (MDD) is widespread and often disabling, affecting nearly 8% of people ages 12 and older at any given time.¹ Thus, it’s crucial to be familiar with the diverse array of evidence-based treatment options from which patients can choose. Although medications are an essential treatment option for patients with severe depression, their value for patients with mild to moderate depression is often limited.² In addition, when antidepressants aren’t combined with psychosocial interventions, discontinuing them is associated with relapse.³

Fortunately, research has found that certain nonpharmacologic interventions—including psychotherapies, somatic therapies, and dietary supplements—can have either therapeutic or adjunctive benefits for treating depression, and can be provided in ways that are time- and cost-effective. This article reviews the evidence supporting several options in each of these treatment categories.

Evidence backs several types of psychotherapy

Several recent meta-analyses suggest that a variety of psychotherapeutic treatments may hold promise for your patients with depression.^4,5 When analyses were limited to larger studies in order to decrease the risk of bias, cognitive behavioral therapy (CBT), interpersonal therapy (IPT), and problem-solving therapy (PST) all resulted in moderate to large improvement in depressive symptoms when compared to wait-list controls.⁴ These findings were echoed in a recent systematic review/meta-analysis that focused on depressed primary care patients. Linde et al⁵ found that the number needed to treat (NNT) to achieve one response (≥50% reduction in score on a depression scale) using any type of psychotherapy was 10, and the NNT to achieve one remission (scoring below a predefined score on a depression scale) was 15.

Psychotherapy can be effective when provided in individual and group settings,⁶ as well as via telephone, the Internet, or software programs.⁷ (For a list of self-help, computerized, and Internet-based resources, see TABLE W1 below.)

CBT has been studied for several decades and there’s strong evidence for its efficacy.⁶ Recent investigations have suggested that CBT delivered in less resource-intensive modes (such as via computer program, Internet, telephone, or videoconferencing) can be as effective as face-to-face CBT.^6,8 CBT has been shown to be helpful for a wide range of patients,⁶ improves outcomes over standard primary care treatment,⁹ and provides a useful adjunct to medication in treatment-resistant severe depression.¹⁰

Behavioral activation (BA), which generally is included as a component of CBT, has received support as an independent treatment, and may produce therapeutic results similar to CBT¹¹ and PST (which we’ll discuss in a bit).¹² The core components of BA are scheduling pleasant activities and increasing the patient’s positive interactions with his or her environment by decreasing avoidance, withdrawal, and inactivity.¹¹ Compared to CBT, BA is easier for clinicians to learn and incorporate into primary care visits, and it may be especially useful as an adjunctive or first-step intervention in outpatient clinics.¹¹ Like CBT, BA can be effective in diverse patient groups^13,14 and can be provided using novel delivery modes, such as via the Internet.¹⁵

Compared to cognitive behavioral therapy, behavioral activation is easier for clinicians to learn and incorporate into primary care visits.

IPT is a supportive, structured, brief therapy (12-16 visits) that focuses on helping patients identify and solve current situation- and relationship-based problems that stem from or contribute to their depression.¹⁶ Enhancing the patient’s interpersonal communication—including improving social skills, assertiveness, and appropriate expression of anger—is typically a component of IPT. Like CBT, IPT has been found to be effective for treating depression when administered in person, in group therapy, or via the phone or Internet, and across a broad age range.^17-19

PST involves teaching patients a structured problem-solving process to decrease interpersonal strain and improve positive life experiences.²⁰ Patients are taught to define their problem, generate and evaluate multiple solutions for it, implement a plan for the solution, and evaluate the results. In addition to being used to successfully treat adults,^4,5 PST has been adapted effectively to treat adolescents¹⁶ and older adults.¹⁸

Somatic therapies are also an option

Exercise has long been considered a possible depression treatment due to its activity on endorphin, monoamine, and cortisol levels and via increased social and general activity. A 2013 Cochrane review of 39 randomized control trials (RCTs; N=2326) assessed whether exercise was effective for treating depression in adults.²¹ Thirty-five trials found a moderate effect size when specifically comparing exercise to no treatment or control interventions. The effect size was reduced, however, when analyses were restricted to trials with the highest methodological quality. There was no statistically significant difference when exercise was compared to pharmacologic treatment or psychotherapy.

Although the amount of research is meager, small but statistically significant improvements have also been found for older adults²² and children/adolescents.²³ There is no consensus on the type, frequency, or intensity of exercise needed to achieve benefit. However, because nearly all studies for all age groups have found that exercise has no adverse psychological effects and substantial positive physical effects, exercise should be recommended to all patients with depression unless contraindicated.

Yoga (both exercise-based and meditation-based) has been evaluated both as a sole treatment and as an adjunctive treatment for depression. Several studies have supported the impact of yoga, particularly in pregnant women,²⁴ although the evidence for its efficacy is inconsistent, with yoga frequently failing to improve upon the outcome of waitlist control.²⁵ The evidence for meditation and mindfulness is more consistently positive, with these interventions equaling or exceeding “treatment as usual,” other psychotherapies, and antidepressants in numerous RCTs.²⁵

Electroconvulsive therapy (ECT) has a substantial evidence base supporting its efficacy.²⁶ ECT has been used for decades, although stigma, cardiac and memory risks, and risks of anesthesia often limit its use. Benefits of ECT include a rapid response relative to pharmacotherapy (>50% of patients respond by the end of the first week of ECT)²⁷ and a strong response in older patients.²⁸

More than half of patients receiving electroconvulsive therapy respond to treatment by the end of the first week.

In repetitive transcranial magnetic stimulation (rTMS), electromagnetic coils are placed on a patient’s head to deliver electromagnetic pulses that stimulate areas of the brain that regulate mood. Although rTMS is not widely available, a growing body of evidence supports its use for treating depression, including a meta-analysis of 34 RCTs that included 1383 patients.²⁹ A multisite RCT (N=190) that was not industry-funded reported a 15% response rate and 60% maintenance of remission at 3 months (NNT=12).³⁰ Although ECT is more effective than rTMS, rTMS appears useful for treatment-resistant depression, and can be used as an adjunctive treatment.^29,31

Dietary supplements may be best used as adjuncts

St. John’s wort (Hypericum perforatum), which contains 2 bioactive ingredients (hyperforin and hypericin), has been effectively used to treat depression.³² A 2008 Cochrane review that was limited to high-quality trials involving patients meeting Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria for depression identified 29 trials (N=5489), of which 18 involved comparisons with placebo and 17 with standard antidepressants.³³ Patients’ depression was rated mild to moderate in 19 studies and moderate to severe in 9 studies. Trials examined 4 to 12 weeks of treatment with Hypericum extracts. This study (and several published since) provides strong clinical evidence supporting the efficacy of St. John’s wort for mild to moderate depression. There is insufficient evidence for its use for severe major depression.³³TABLE 1 contains dosing information for St. John’s wort and other supplements used to treat depression.^34-36 

S-adenosyl-L-methionine (SAMe). In a 2003 systematic review,³⁷ 1600 mg/d of oral SAMe was found to significantly benefit patients with depression in 4 of 5 studies, as did parenteral SAMe (7 of 7 trials). Another review of 48 studies found SAMe was safe and effective for depression.³⁸ SAMe has been proposed for use alone or in combination with an antidepressant.

Low folate levels have been associated with a less robust response to antidepressants in patients with major depressive disorder.

Folate and folic acid. Low folate levels have been associated with a less robust response to antidepressants in patients with MDD,³⁹ and higher folate levels appear to be associated with better antidepressant response.⁴⁰ A 2003 Cochrane review suggested folate might have a role in treating depression.³⁹ A 2009 study found folate supplementation could reduce depressive symptoms for patients with normal baseline folate levels as well as those with low levels.⁴¹ Although the evidence is equivocal, folate augmentation may enhance antidepressant efficacy or improve response/remission rates.^41,42

It seems reasonable to check folate levels in depressed patients, and address deficiencies by instructing patients to increase their dietary intake of folate or to take supplements. Augmenting antidepressants with folate appears to be low-risk and possibly helpful in maintaining remission.

Omega-3 fatty acids. There is substantial evidence that omega-3 fatty acids can prevent and treat depression.^43,44 Recent meta-analyses support the use of omega-3 fatty acids as monotherapy and augmentation, but only formulations that contain a high eicosapentaenoic acid (EPA) to docosahexaenoic acid (DHA) ratio (EPA/DHA 2:1).^45,46 Omega-3 supplementation has been used with positive results in older adults, children,⁴⁷ pregnant women,⁴⁸ and women with postpartum depression.⁴⁹ Although initial research into omega-3 treatment of depression appears promising, augmentation of standard antidepressant therapy may be a good conservative option.

Use a validated tool to monitor response to treatment

You can enhance outcomes for your patients with depression if you schedule routine follow-up visits with them to gauge adherence to recommendations, monitor response to treatment, and increase the intensity of care when response is inadequate.⁵⁰ The most important aspect of monitoring response is to use a standardized instrument that quantifies symptoms at every visit.

The PHQ-9—which is free—has been validated for depression screening and monitoring of treatment response in primary care patients.

The Patient Health Questionnaire 9-item depression assessment (PHQ-9)—which is free—has been validated for depression screening and monitoring of treatment response in primary care patients.⁵¹ A decrease of 5 points on the PHQ-9 is the minimum considered to be clinically significant.⁵² Other well-validated, although lengthier, self-report depression assessment and monitoring instruments include the Beck Depression Inventory-revised and the Zung Depression Scale.

CASE 1 › Mr. J is not enjoying his new job or engaging with new coworkers to replace the positive social experiences he had at his previous job. Together, you set a goal of increasing social involvement by having him make plans to see at least one friend per weekend. Because he indicates that he is unlikely to follow through with a therapy referral, you encourage him to try an online CBT program, start an exercise regimen, or take a SAMe supplement. Mr. Jackson agrees to try the CBT and exercise (moderate intensity, 30 minutes 3-4 times per week), but does not want to take SAMe. He agrees to an assessment of his folate levels, which are normal.

Mr. J starts the online CBT program, which reinforces the exercise and social activity prescription you provided. He establishes a regular exercise routine with a good friend. After one month, his mood has started to improve and he has added regular participation in a hobby (woodworking), as well as volunteer work, which he finds fulfilling. You plan to continue monitoring his depression and his adherence to the treatment plan.

CASE 2 › The recent move has decreased Mrs. S’s interactions with family and long-time friends. Because she had previously expressed interest in exercise, you encourage her to join a local “Mommy and Me” exercise and support group for mothers of toddlers. She is willing to participate in psychotherapy, so you provide a referral to a local therapist with expertise in IPT. You also discuss with Mrs. S the possible benefits of omega-3 fatty acid supplementation, which appears to be safe during breastfeeding.³⁴

Mrs. S begins therapy and exercise classes, but can’t motivate herself to continue either of these activities. She becomes discouraged because she’s unable to easily find an omega-3 fatty acid supplement with the ratio you specified (EPA/DHA 2:1). When you see her 2 weeks later, her depression has worsened.

Because you are concerned her suicidality will return, you revisit the pros and cons of taking an antidepressant. Although small amounts of antidepressants can be passed from mother to infant via breastmilk, the amount varies by specific medication, as do the potential risks. Mrs. S decides to resume taking paroxetine 20 mg/d and eventually, once her motivation improves, she’s able to add psychotherapy and exercise to her maintenance/relapse prevention regimen. After you discuss with her the possibility that B vitamin supplementation may assist in maintenance of remission, she adds L-methylfolate 7.5 mg/day to her regimen.

CORRESPONDENCE 
Michele M. Larzelere, PhD; LSUHSC Department of Family Medicine; 200 W. Esplanade Avenue, Suite 409; Kenner, LA 70065; [email protected]

A 6-year-old girl was brought to the emergency department (ED) by her mother after the child bumped her head while playing. While the physician examined the child’s head, the mother remarked that her daughter had recently developed bruises that appeared suddenly and only after minor, if any, known trauma. The ED physician determined that the child’s bump to the head was nothing to worry about, attributed the bruising to the child being a “healthy, active 6-year-old,” and sent her home.

Two days later, the child was brought to our office because the mother was still concerned about her daughter’s easy bruising. The mother pointed out ecchymosis scattered across her daughter’s extremities and torso. The child denied any pain or other complaints, including any active or recurrent bleeding. Upon further questioning, the mother mentioned that her daughter had recovered from a coldlike illness several weeks earlier.

THE DIAGNOSIS
We ordered a complete blood count (CBC) and peripheral smear, which were normal except for the platelet count, which was 7,000/μL (normal, 150,000-450,000/μL). Based on the child’s easy bruising and isolated thrombocytopenia, we diagnosed immune thrombocytopenia, which is also known as idiopathic thrombocytopenic purpura (ITP).

DISCUSSION
In ITP, autoantibodies are directed against platelets, leading to their sequestration and destruction in the spleen and a resultant drop in platelet count.¹ Children with ITP typically present between the ages of 2 and 10, with a peak incidence between 2 and 5.² The incidence is estimated to be as high as 8 per 100,000 children.³ However, this estimate primarily reflects symptomatic children, and the true incidence of childhood ITP may be much higher because asymptomatic children may not be brought in to see a doctor.

For the majority of patients, ITP resolves within three months. However, for 20% to 30% of patients, thrombocytopenia will last beyond six months, with or without treatment.⁴ In 1% of cases, patients will have a recurrence of ITP.³

In addition to easy bruising, nearly all patients who present with possible ITP will complain of cutaneous bleeding, typically a nose bleed or bleeding in the oral cavity.² Upon questioning, 60% of patients will report a history of recent infection.⁴ Not surprisingly, bleeding severity correlates inversely with platelet count; severe bleeding is seen in patients with a platelet count < 10,000/μL.

While rare, the more worrisome complications include intracranial hemorrhage (incidence, 0.1% to 0.8%) and other serious hemorrhages that would require transfusion (estimated incidence, 2.9%).²

Vast differential seen in child bruising
When a child presents with bruising, perform a thorough history, including birth and prenatal course, as well as a physical to exclude other potential causes, such as physical abuse, use of herbal remedies or other natural supplements that may not be disclosed as medication, or even environmental exposure. When bruising is present in a child who has isolated thrombocytopenia, the diagnosis of ITP may be straightforward. However, many conditions share thrombocytopenia in their disease process and should be considered in the differential diagnosis of a child who you suspect may have ITP.
• Suspect physical abuse in a bruised child who does not have thrombocytopenia, whose mood is flat or depressed, or who has experienced recurrent injuries or bruising.
• Leukemia, particularly acute lymphoblastic leukemia (ALL), the predominant leukemia found in children, should be ruled out as well. Symptoms that may distinguish a child with ALL from one with ITP include fever, weight loss, and joint pain, as well as signs such as lymphadenopathy, hepatosplenomegaly, anemia, and leukocytosis. A peripheral smear may be ordered to help confirm or exclude a diagnosis of ALL, should any of the above be present in a child with thrombocytopenia.⁵ It may show lymphoblasts and/or atypical cells in a patient with ALL.⁵
• Infections should also be included in a differential when a patient is suspected of having ITP, particularly if he or she has systemic symptoms. Viral infections that may cause thrombocytopenia include mononucleosis, dengue virus, human herpesvirus-6, and HIV.^6,7

ITP often follows an infection, and the incidence of ITP may be higher during winter months, when infections are more common. However, infection may not always be the cause of ITP. Sepsis may also lead to thrombocytopenia, but a child with sepsis would present very differently from one who has only ITP. A septic child would present with acute illness and signs and symptoms of severe systemic illness, such as high fever, altered mental status, tachycardia, pallor, diaphoresis, and hypotension.
• Drug-induced thrombocytopenia (DIT) should be considered in any child who is taking or recently took a medication that may cause thrombocytopenia. Medications that can cause thrombocytopenia include heparin, quinine, vancomycin, trimethoprim-sulfamethoxazole, rifampin, carbamazepine, phenytoin, piperacillin, linezolid, and valproic acid.8 The measles, mumps, and rubella vaccine also can cause thrombocytopenia.8 A careful medication history may determine if the child is at risk for DIT.
• To narrow the differential, obtain a CBC and peripheral smear when evaluating a patient you suspect may have ITP5 (strength of recommendation [SOR]: A). A CBC will determine the patient’s platelet count, and a peripheral smear should be obtained to exclude other possible diagnoses.⁵

If there are any questions regarding the results of a peripheral smear, it may be necessary to perform a bone marrow aspiration. This, however, is not usually necessary in an otherwise typical case of ITP.9 Bone marrow aspiration may, however, be necessary to reevaluate the initial diagnosis for a child who does not respond to treatment for ITP.

Continue for corticosteroids, IVIg are usually effective >>

Corticosteroids, IVIg are usually effective
The first step in treating a patient with ITP is to limit the risk for further injury or bleeding by stopping NSAIDs or ending participation in contact sports^2,9 (SOR: C). The next step is to determine if pharmacologic therapy is warranted.

Medication, if necessary, is the mainstay of treatment for patients with ITP, particularly those experiencing significant bleeding.² Corticosteroids, intravenous (IV) immunoglobulin (IVIg), and IV Rho(D) immune globulin (also known as anti-D) are the medications typically used to treat a child with ITP, depending on availability of the drugs, bleeding or bleeding risk, and convenience of dosing. For example, corticosteroids can be used orally or IV, whereas IVIg and IV Rho(D) may not be readily available in some treatment settings.

Corticosteroids have been shown to more rapidly increase platelet count compared to placebo and appear to have a dose-related effect.^10,11 Oral prednisone can be dosed at 1 to 2 mg/kg/d for 14 days and then tapered over the course of one week^10,11 or one may prescribe 4 mg/kg/d for four days.^10,11 IV methylprednisolone typically is given at 30 mg/kg/d for three to four days.⁹

IVIg may have greater efficacy than corticosteroids in treating ITP, but it may also cause adverse effects, including nausea, headache, and fever. IVIg can be administered as a single 800 to 1,000 mg/kg dose, or as a daily 400 mg/kg dose form five days; higher doses should be reserved for patients with severe bleeding.¹²

If ITP persists despite the use of corticosteroids or IVIg, IV Rho(D) Ig may be used in patients with Rho(D)-positive blood at a single dose of 25 to 50 μg/kg, with additional doses administered on separate days as required to elevate platelet count. However, only Rho(D)-positive patients are eligible for anti-D treatment.

The response rates/times and adverse effects of common treatments for ITP are summarized in the Table.⁹ A small randomized study found that oral methylprednisolone 30 mg/kg/d for three days followed by 20 mg/kg/d for an additional four days was comparable to IVIg 0.4 g/kg/d for five days.¹¹ A different study that compared oral methylprednisolone (30 mg/kg/d or 50 mg/kg/d for seven days) and IVIg (0.5 g/kg/d for five days) found no difference in outcomes among the three treatments.¹³ One advantage, though, of IVIg is that it can be administered as a single IV dose, rather than multiple doses over several weeks, as is the case with oral prednisone.^9,11-13
• Follow platelet counts closely. Patients with ITP should have their platelet counts monitored at least once weekly and as often as twice weekly. The frequency of monitoring may be tapered depending on an individual patient’s response to treatment and the severity of the thrombocytopenia.¹⁴
• We referred our patient to a nearby children’s hospital, where a repeat CBC  showed her platelets had decreased to 3,000/μL. She received a six-hour infusion of IVIg and was discharged with instructions to have her CBC closely monitored. Her platelets remained stable until four weeks later, when they decreased from 102,000/μL to 71,000/μL. She received a second infusion of IVIg as an outpatient.

Soon after, she presented to our ED with a headache, nausea, and fever of 102°F. CT of her head was normal; a repeat CBC showed no elevation in white blood cells, but her hemoglobin had decreased from 11.9 g/dL to 9.7 g/dL. (Her platelets were 254,000/μL.) The patient’s complaints were likely adverse effects of the IVIg. The CBC abnormalities, fever, headache, and malaise resolved shortly thereafter, and the patient remains asymptomatic with no recurrence of ITP.

Continue for the takeaway >>

THE TAKEAWAY
Suspect ITP in a child who bruises easily and who also has thrombocytopenia. Order a CBC and peripheral blood smear to rule out other potential illnesses. Pharmacotherapy, if needed, typically consists of an oral or IV corticosteroid or IVIg; IV Rho(D) Ig may be used in Rho(D)-positive patients who don’t respond to other treatments. Patients with ITP should have their platelet count monitored at least once weekly until platelets have increased to 150,000/μL or higher. Frequency of monitoring may be reduced as the clinical picture improves and the patient remains stable. More frequent monitoring may be necessary based on severity, complications, and response to treatment.

REFERENCES
1. Johnsen J. Pathogenesis in immune thrombocytopenia: new insights. Hematology Am Soc Hematol Educ Program. 2012;2012:306-312.
2. Kühne T, Buchanan GR, Zimmerman S, et al; Intercontinental Childhood ITP Study Group. A prospective comparative study of 2540 infants and children with newly diagnosed idiopathic thrombocytopenic purpura (ITP) from the Intercontinental Childhood ITP Study Group. J Pediatr. 2003;143:605-608.
3. Kurtzberg J, Stockman JA III. Idiopathic autoimmune thrombocytopenic purpura. Adv Pediatr. 1994;41:111-134.
4. Zeller B, Rajantie J, Hedlund-Treutiger I, et al. Childhood idiopathic thrombocytopenic purpura in the Nordic countries: epidemiology and predictors of chronic disease. Acta Paediatr. 2005;94:178-184.
5. Margolin JF, Steuber CP, Poplack DG. Acute lymphoblastic leukemia. In: Pizzo PA, Poplack DG, eds. Principles and Practice of Pediatric Oncology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:317-321.
6. Hashimoto H, Maruyama H, Fujimoto K, et al. Hematologic findings associated with thrombocytopenia during the acute phase of exanthem subitum confirmed by primary human herpesvirus-6 infection. J Pediatr Hematol Oncol. 2002;24:211-214.
7. La Russa VF, Innis BL. Mechanisms of dengue virus-induced bone marrow suppression. Baillieres Clin Haematol. 1995;8:249-270.
8. Aster RH, Curtis BR, McFarland JG, et al. Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management. Thromb Haemost. 2009;7:911-918.
9. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115:168-186.
10. Bellucci S, Charpak Y, Chastang C, et al. Low doses v conventional doses of corticoids in immune thrombocytopenic purpura (ITP): results of a randomized clinical trial in 160 children, 223 adults. Blood. 1988;71:1165-1169.
11. Ozsoylu S, Sayli TR, Oztürk G. Oral megadose methylprednisolone versus intravenous immunoglobulin for acute childhood idiopathic thrombocytopenic purpura. Pediatr Hematol Oncol. 1993;10:317-321.
12. Beck CE, Nathan PC, Parkin PC, et al. Corticosteroids versus intravenous immune globulin for the treatment of acute immune thrombocytopenic purpura in children: a systematic review and meta-analysis of randomized controlled trials. J Pediatr. 2005;147:521-527.
13. Albayrak D, Islek I, Kalaycí AG, et al. Acute immune thrombocytopenic purpura: a comparative study of very high oral doses of methylprednisolone and intravenously administered immune globulin. J Pediatr. 1994;125(6 pt 1):1004-1007.
14. Tarantino MD, Madden RM, Fennewald DL, et al. Treatment of childhood acute immune thrombocytopenic purpura with anti-D immune globulin or pooled immune globulin. J Pediatr. 1999;134:21-26.

A 6-year-old girl was brought to the emergency department (ED) by her mother after the child bumped her head while playing. While the physician examined the child’s head, the mother remarked that her daughter had recently developed bruises that appeared suddenly and only after minor, if any, known trauma. The ED physician determined that the child’s bump to the head was nothing to worry about, attributed the bruising to the child being a “healthy, active 6-year-old,” and sent her home.

Two days later, the child was brought to our office because the mother was still concerned about her daughter’s easy bruising. The mother pointed out ecchymosis scattered across her daughter’s extremities and torso. The child denied any pain or other complaints, including any active or recurrent bleeding. Upon further questioning, the mother mentioned that her daughter had recovered from a coldlike illness several weeks earlier.

THE DIAGNOSIS
We ordered a complete blood count (CBC) and peripheral smear, which were normal except for the platelet count, which was 7,000/μL (normal, 150,000-450,000/μL). Based on the child’s easy bruising and isolated thrombocytopenia, we diagnosed immune thrombocytopenia, which is also known as idiopathic thrombocytopenic purpura (ITP).

DISCUSSION
In ITP, autoantibodies are directed against platelets, leading to their sequestration and destruction in the spleen and a resultant drop in platelet count.¹ Children with ITP typically present between the ages of 2 and 10, with a peak incidence between 2 and 5.² The incidence is estimated to be as high as 8 per 100,000 children.³ However, this estimate primarily reflects symptomatic children, and the true incidence of childhood ITP may be much higher because asymptomatic children may not be brought in to see a doctor.

For the majority of patients, ITP resolves within three months. However, for 20% to 30% of patients, thrombocytopenia will last beyond six months, with or without treatment.⁴ In 1% of cases, patients will have a recurrence of ITP.³

In addition to easy bruising, nearly all patients who present with possible ITP will complain of cutaneous bleeding, typically a nose bleed or bleeding in the oral cavity.² Upon questioning, 60% of patients will report a history of recent infection.⁴ Not surprisingly, bleeding severity correlates inversely with platelet count; severe bleeding is seen in patients with a platelet count < 10,000/μL.

While rare, the more worrisome complications include intracranial hemorrhage (incidence, 0.1% to 0.8%) and other serious hemorrhages that would require transfusion (estimated incidence, 2.9%).²

Vast differential seen in child bruising
When a child presents with bruising, perform a thorough history, including birth and prenatal course, as well as a physical to exclude other potential causes, such as physical abuse, use of herbal remedies or other natural supplements that may not be disclosed as medication, or even environmental exposure. When bruising is present in a child who has isolated thrombocytopenia, the diagnosis of ITP may be straightforward. However, many conditions share thrombocytopenia in their disease process and should be considered in the differential diagnosis of a child who you suspect may have ITP.
• Suspect physical abuse in a bruised child who does not have thrombocytopenia, whose mood is flat or depressed, or who has experienced recurrent injuries or bruising.
• Leukemia, particularly acute lymphoblastic leukemia (ALL), the predominant leukemia found in children, should be ruled out as well. Symptoms that may distinguish a child with ALL from one with ITP include fever, weight loss, and joint pain, as well as signs such as lymphadenopathy, hepatosplenomegaly, anemia, and leukocytosis. A peripheral smear may be ordered to help confirm or exclude a diagnosis of ALL, should any of the above be present in a child with thrombocytopenia.⁵ It may show lymphoblasts and/or atypical cells in a patient with ALL.⁵
• Infections should also be included in a differential when a patient is suspected of having ITP, particularly if he or she has systemic symptoms. Viral infections that may cause thrombocytopenia include mononucleosis, dengue virus, human herpesvirus-6, and HIV.^6,7

ITP often follows an infection, and the incidence of ITP may be higher during winter months, when infections are more common. However, infection may not always be the cause of ITP. Sepsis may also lead to thrombocytopenia, but a child with sepsis would present very differently from one who has only ITP. A septic child would present with acute illness and signs and symptoms of severe systemic illness, such as high fever, altered mental status, tachycardia, pallor, diaphoresis, and hypotension.
• Drug-induced thrombocytopenia (DIT) should be considered in any child who is taking or recently took a medication that may cause thrombocytopenia. Medications that can cause thrombocytopenia include heparin, quinine, vancomycin, trimethoprim-sulfamethoxazole, rifampin, carbamazepine, phenytoin, piperacillin, linezolid, and valproic acid.8 The measles, mumps, and rubella vaccine also can cause thrombocytopenia.8 A careful medication history may determine if the child is at risk for DIT.
• To narrow the differential, obtain a CBC and peripheral smear when evaluating a patient you suspect may have ITP5 (strength of recommendation [SOR]: A). A CBC will determine the patient’s platelet count, and a peripheral smear should be obtained to exclude other possible diagnoses.⁵

If there are any questions regarding the results of a peripheral smear, it may be necessary to perform a bone marrow aspiration. This, however, is not usually necessary in an otherwise typical case of ITP.9 Bone marrow aspiration may, however, be necessary to reevaluate the initial diagnosis for a child who does not respond to treatment for ITP.

Continue for corticosteroids, IVIg are usually effective >>

Corticosteroids, IVIg are usually effective
The first step in treating a patient with ITP is to limit the risk for further injury or bleeding by stopping NSAIDs or ending participation in contact sports^2,9 (SOR: C). The next step is to determine if pharmacologic therapy is warranted.

Medication, if necessary, is the mainstay of treatment for patients with ITP, particularly those experiencing significant bleeding.² Corticosteroids, intravenous (IV) immunoglobulin (IVIg), and IV Rho(D) immune globulin (also known as anti-D) are the medications typically used to treat a child with ITP, depending on availability of the drugs, bleeding or bleeding risk, and convenience of dosing. For example, corticosteroids can be used orally or IV, whereas IVIg and IV Rho(D) may not be readily available in some treatment settings.

Corticosteroids have been shown to more rapidly increase platelet count compared to placebo and appear to have a dose-related effect.^10,11 Oral prednisone can be dosed at 1 to 2 mg/kg/d for 14 days and then tapered over the course of one week^10,11 or one may prescribe 4 mg/kg/d for four days.^10,11 IV methylprednisolone typically is given at 30 mg/kg/d for three to four days.⁹

IVIg may have greater efficacy than corticosteroids in treating ITP, but it may also cause adverse effects, including nausea, headache, and fever. IVIg can be administered as a single 800 to 1,000 mg/kg dose, or as a daily 400 mg/kg dose form five days; higher doses should be reserved for patients with severe bleeding.¹²

If ITP persists despite the use of corticosteroids or IVIg, IV Rho(D) Ig may be used in patients with Rho(D)-positive blood at a single dose of 25 to 50 μg/kg, with additional doses administered on separate days as required to elevate platelet count. However, only Rho(D)-positive patients are eligible for anti-D treatment.

The response rates/times and adverse effects of common treatments for ITP are summarized in the Table.⁹ A small randomized study found that oral methylprednisolone 30 mg/kg/d for three days followed by 20 mg/kg/d for an additional four days was comparable to IVIg 0.4 g/kg/d for five days.¹¹ A different study that compared oral methylprednisolone (30 mg/kg/d or 50 mg/kg/d for seven days) and IVIg (0.5 g/kg/d for five days) found no difference in outcomes among the three treatments.¹³ One advantage, though, of IVIg is that it can be administered as a single IV dose, rather than multiple doses over several weeks, as is the case with oral prednisone.^9,11-13
• Follow platelet counts closely. Patients with ITP should have their platelet counts monitored at least once weekly and as often as twice weekly. The frequency of monitoring may be tapered depending on an individual patient’s response to treatment and the severity of the thrombocytopenia.¹⁴
• We referred our patient to a nearby children’s hospital, where a repeat CBC  showed her platelets had decreased to 3,000/μL. She received a six-hour infusion of IVIg and was discharged with instructions to have her CBC closely monitored. Her platelets remained stable until four weeks later, when they decreased from 102,000/μL to 71,000/μL. She received a second infusion of IVIg as an outpatient.

Soon after, she presented to our ED with a headache, nausea, and fever of 102°F. CT of her head was normal; a repeat CBC showed no elevation in white blood cells, but her hemoglobin had decreased from 11.9 g/dL to 9.7 g/dL. (Her platelets were 254,000/μL.) The patient’s complaints were likely adverse effects of the IVIg. The CBC abnormalities, fever, headache, and malaise resolved shortly thereafter, and the patient remains asymptomatic with no recurrence of ITP.

Continue for the takeaway >>

THE TAKEAWAY
Suspect ITP in a child who bruises easily and who also has thrombocytopenia. Order a CBC and peripheral blood smear to rule out other potential illnesses. Pharmacotherapy, if needed, typically consists of an oral or IV corticosteroid or IVIg; IV Rho(D) Ig may be used in Rho(D)-positive patients who don’t respond to other treatments. Patients with ITP should have their platelet count monitored at least once weekly until platelets have increased to 150,000/μL or higher. Frequency of monitoring may be reduced as the clinical picture improves and the patient remains stable. More frequent monitoring may be necessary based on severity, complications, and response to treatment.

REFERENCES
1. Johnsen J. Pathogenesis in immune thrombocytopenia: new insights. Hematology Am Soc Hematol Educ Program. 2012;2012:306-312.
2. Kühne T, Buchanan GR, Zimmerman S, et al; Intercontinental Childhood ITP Study Group. A prospective comparative study of 2540 infants and children with newly diagnosed idiopathic thrombocytopenic purpura (ITP) from the Intercontinental Childhood ITP Study Group. J Pediatr. 2003;143:605-608.
3. Kurtzberg J, Stockman JA III. Idiopathic autoimmune thrombocytopenic purpura. Adv Pediatr. 1994;41:111-134.
4. Zeller B, Rajantie J, Hedlund-Treutiger I, et al. Childhood idiopathic thrombocytopenic purpura in the Nordic countries: epidemiology and predictors of chronic disease. Acta Paediatr. 2005;94:178-184.
5. Margolin JF, Steuber CP, Poplack DG. Acute lymphoblastic leukemia. In: Pizzo PA, Poplack DG, eds. Principles and Practice of Pediatric Oncology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:317-321.
6. Hashimoto H, Maruyama H, Fujimoto K, et al. Hematologic findings associated with thrombocytopenia during the acute phase of exanthem subitum confirmed by primary human herpesvirus-6 infection. J Pediatr Hematol Oncol. 2002;24:211-214.
7. La Russa VF, Innis BL. Mechanisms of dengue virus-induced bone marrow suppression. Baillieres Clin Haematol. 1995;8:249-270.
8. Aster RH, Curtis BR, McFarland JG, et al. Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management. Thromb Haemost. 2009;7:911-918.
9. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115:168-186.
10. Bellucci S, Charpak Y, Chastang C, et al. Low doses v conventional doses of corticoids in immune thrombocytopenic purpura (ITP): results of a randomized clinical trial in 160 children, 223 adults. Blood. 1988;71:1165-1169.
11. Ozsoylu S, Sayli TR, Oztürk G. Oral megadose methylprednisolone versus intravenous immunoglobulin for acute childhood idiopathic thrombocytopenic purpura. Pediatr Hematol Oncol. 1993;10:317-321.
12. Beck CE, Nathan PC, Parkin PC, et al. Corticosteroids versus intravenous immune globulin for the treatment of acute immune thrombocytopenic purpura in children: a systematic review and meta-analysis of randomized controlled trials. J Pediatr. 2005;147:521-527.
13. Albayrak D, Islek I, Kalaycí AG, et al. Acute immune thrombocytopenic purpura: a comparative study of very high oral doses of methylprednisolone and intravenously administered immune globulin. J Pediatr. 1994;125(6 pt 1):1004-1007.
14. Tarantino MD, Madden RM, Fennewald DL, et al. Treatment of childhood acute immune thrombocytopenic purpura with anti-D immune globulin or pooled immune globulin. J Pediatr. 1999;134:21-26.

A 6-year-old girl was brought to the emergency department (ED) by her mother after the child bumped her head while playing. While the physician examined the child’s head, the mother remarked that her daughter had recently developed bruises that appeared suddenly and only after minor, if any, known trauma. The ED physician determined that the child’s bump to the head was nothing to worry about, attributed the bruising to the child being a “healthy, active 6-year-old,” and sent her home.

Two days later, the child was brought to our office because the mother was still concerned about her daughter’s easy bruising. The mother pointed out ecchymosis scattered across her daughter’s extremities and torso. The child denied any pain or other complaints, including any active or recurrent bleeding. Upon further questioning, the mother mentioned that her daughter had recovered from a coldlike illness several weeks earlier.

THE DIAGNOSIS
We ordered a complete blood count (CBC) and peripheral smear, which were normal except for the platelet count, which was 7,000/μL (normal, 150,000-450,000/μL). Based on the child’s easy bruising and isolated thrombocytopenia, we diagnosed immune thrombocytopenia, which is also known as idiopathic thrombocytopenic purpura (ITP).

DISCUSSION
In ITP, autoantibodies are directed against platelets, leading to their sequestration and destruction in the spleen and a resultant drop in platelet count.¹ Children with ITP typically present between the ages of 2 and 10, with a peak incidence between 2 and 5.² The incidence is estimated to be as high as 8 per 100,000 children.³ However, this estimate primarily reflects symptomatic children, and the true incidence of childhood ITP may be much higher because asymptomatic children may not be brought in to see a doctor.

For the majority of patients, ITP resolves within three months. However, for 20% to 30% of patients, thrombocytopenia will last beyond six months, with or without treatment.⁴ In 1% of cases, patients will have a recurrence of ITP.³

In addition to easy bruising, nearly all patients who present with possible ITP will complain of cutaneous bleeding, typically a nose bleed or bleeding in the oral cavity.² Upon questioning, 60% of patients will report a history of recent infection.⁴ Not surprisingly, bleeding severity correlates inversely with platelet count; severe bleeding is seen in patients with a platelet count < 10,000/μL.

While rare, the more worrisome complications include intracranial hemorrhage (incidence, 0.1% to 0.8%) and other serious hemorrhages that would require transfusion (estimated incidence, 2.9%).²

Vast differential seen in child bruising
When a child presents with bruising, perform a thorough history, including birth and prenatal course, as well as a physical to exclude other potential causes, such as physical abuse, use of herbal remedies or other natural supplements that may not be disclosed as medication, or even environmental exposure. When bruising is present in a child who has isolated thrombocytopenia, the diagnosis of ITP may be straightforward. However, many conditions share thrombocytopenia in their disease process and should be considered in the differential diagnosis of a child who you suspect may have ITP.
• Suspect physical abuse in a bruised child who does not have thrombocytopenia, whose mood is flat or depressed, or who has experienced recurrent injuries or bruising.
• Leukemia, particularly acute lymphoblastic leukemia (ALL), the predominant leukemia found in children, should be ruled out as well. Symptoms that may distinguish a child with ALL from one with ITP include fever, weight loss, and joint pain, as well as signs such as lymphadenopathy, hepatosplenomegaly, anemia, and leukocytosis. A peripheral smear may be ordered to help confirm or exclude a diagnosis of ALL, should any of the above be present in a child with thrombocytopenia.⁵ It may show lymphoblasts and/or atypical cells in a patient with ALL.⁵
• Infections should also be included in a differential when a patient is suspected of having ITP, particularly if he or she has systemic symptoms. Viral infections that may cause thrombocytopenia include mononucleosis, dengue virus, human herpesvirus-6, and HIV.^6,7

ITP often follows an infection, and the incidence of ITP may be higher during winter months, when infections are more common. However, infection may not always be the cause of ITP. Sepsis may also lead to thrombocytopenia, but a child with sepsis would present very differently from one who has only ITP. A septic child would present with acute illness and signs and symptoms of severe systemic illness, such as high fever, altered mental status, tachycardia, pallor, diaphoresis, and hypotension.
• Drug-induced thrombocytopenia (DIT) should be considered in any child who is taking or recently took a medication that may cause thrombocytopenia. Medications that can cause thrombocytopenia include heparin, quinine, vancomycin, trimethoprim-sulfamethoxazole, rifampin, carbamazepine, phenytoin, piperacillin, linezolid, and valproic acid.8 The measles, mumps, and rubella vaccine also can cause thrombocytopenia.8 A careful medication history may determine if the child is at risk for DIT.
• To narrow the differential, obtain a CBC and peripheral smear when evaluating a patient you suspect may have ITP5 (strength of recommendation [SOR]: A). A CBC will determine the patient’s platelet count, and a peripheral smear should be obtained to exclude other possible diagnoses.⁵

If there are any questions regarding the results of a peripheral smear, it may be necessary to perform a bone marrow aspiration. This, however, is not usually necessary in an otherwise typical case of ITP.9 Bone marrow aspiration may, however, be necessary to reevaluate the initial diagnosis for a child who does not respond to treatment for ITP.

Continue for corticosteroids, IVIg are usually effective >>

Corticosteroids, IVIg are usually effective
The first step in treating a patient with ITP is to limit the risk for further injury or bleeding by stopping NSAIDs or ending participation in contact sports^2,9 (SOR: C). The next step is to determine if pharmacologic therapy is warranted.

Medication, if necessary, is the mainstay of treatment for patients with ITP, particularly those experiencing significant bleeding.² Corticosteroids, intravenous (IV) immunoglobulin (IVIg), and IV Rho(D) immune globulin (also known as anti-D) are the medications typically used to treat a child with ITP, depending on availability of the drugs, bleeding or bleeding risk, and convenience of dosing. For example, corticosteroids can be used orally or IV, whereas IVIg and IV Rho(D) may not be readily available in some treatment settings.

Corticosteroids have been shown to more rapidly increase platelet count compared to placebo and appear to have a dose-related effect.^10,11 Oral prednisone can be dosed at 1 to 2 mg/kg/d for 14 days and then tapered over the course of one week^10,11 or one may prescribe 4 mg/kg/d for four days.^10,11 IV methylprednisolone typically is given at 30 mg/kg/d for three to four days.⁹

IVIg may have greater efficacy than corticosteroids in treating ITP, but it may also cause adverse effects, including nausea, headache, and fever. IVIg can be administered as a single 800 to 1,000 mg/kg dose, or as a daily 400 mg/kg dose form five days; higher doses should be reserved for patients with severe bleeding.¹²

If ITP persists despite the use of corticosteroids or IVIg, IV Rho(D) Ig may be used in patients with Rho(D)-positive blood at a single dose of 25 to 50 μg/kg, with additional doses administered on separate days as required to elevate platelet count. However, only Rho(D)-positive patients are eligible for anti-D treatment.

The response rates/times and adverse effects of common treatments for ITP are summarized in the Table.⁹ A small randomized study found that oral methylprednisolone 30 mg/kg/d for three days followed by 20 mg/kg/d for an additional four days was comparable to IVIg 0.4 g/kg/d for five days.¹¹ A different study that compared oral methylprednisolone (30 mg/kg/d or 50 mg/kg/d for seven days) and IVIg (0.5 g/kg/d for five days) found no difference in outcomes among the three treatments.¹³ One advantage, though, of IVIg is that it can be administered as a single IV dose, rather than multiple doses over several weeks, as is the case with oral prednisone.^9,11-13
• Follow platelet counts closely. Patients with ITP should have their platelet counts monitored at least once weekly and as often as twice weekly. The frequency of monitoring may be tapered depending on an individual patient’s response to treatment and the severity of the thrombocytopenia.¹⁴
• We referred our patient to a nearby children’s hospital, where a repeat CBC  showed her platelets had decreased to 3,000/μL. She received a six-hour infusion of IVIg and was discharged with instructions to have her CBC closely monitored. Her platelets remained stable until four weeks later, when they decreased from 102,000/μL to 71,000/μL. She received a second infusion of IVIg as an outpatient.

Soon after, she presented to our ED with a headache, nausea, and fever of 102°F. CT of her head was normal; a repeat CBC showed no elevation in white blood cells, but her hemoglobin had decreased from 11.9 g/dL to 9.7 g/dL. (Her platelets were 254,000/μL.) The patient’s complaints were likely adverse effects of the IVIg. The CBC abnormalities, fever, headache, and malaise resolved shortly thereafter, and the patient remains asymptomatic with no recurrence of ITP.

Continue for the takeaway >>

THE TAKEAWAY
Suspect ITP in a child who bruises easily and who also has thrombocytopenia. Order a CBC and peripheral blood smear to rule out other potential illnesses. Pharmacotherapy, if needed, typically consists of an oral or IV corticosteroid or IVIg; IV Rho(D) Ig may be used in Rho(D)-positive patients who don’t respond to other treatments. Patients with ITP should have their platelet count monitored at least once weekly until platelets have increased to 150,000/μL or higher. Frequency of monitoring may be reduced as the clinical picture improves and the patient remains stable. More frequent monitoring may be necessary based on severity, complications, and response to treatment.

REFERENCES
1. Johnsen J. Pathogenesis in immune thrombocytopenia: new insights. Hematology Am Soc Hematol Educ Program. 2012;2012:306-312.
2. Kühne T, Buchanan GR, Zimmerman S, et al; Intercontinental Childhood ITP Study Group. A prospective comparative study of 2540 infants and children with newly diagnosed idiopathic thrombocytopenic purpura (ITP) from the Intercontinental Childhood ITP Study Group. J Pediatr. 2003;143:605-608.
3. Kurtzberg J, Stockman JA III. Idiopathic autoimmune thrombocytopenic purpura. Adv Pediatr. 1994;41:111-134.
4. Zeller B, Rajantie J, Hedlund-Treutiger I, et al. Childhood idiopathic thrombocytopenic purpura in the Nordic countries: epidemiology and predictors of chronic disease. Acta Paediatr. 2005;94:178-184.
5. Margolin JF, Steuber CP, Poplack DG. Acute lymphoblastic leukemia. In: Pizzo PA, Poplack DG, eds. Principles and Practice of Pediatric Oncology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001:317-321.
6. Hashimoto H, Maruyama H, Fujimoto K, et al. Hematologic findings associated with thrombocytopenia during the acute phase of exanthem subitum confirmed by primary human herpesvirus-6 infection. J Pediatr Hematol Oncol. 2002;24:211-214.
7. La Russa VF, Innis BL. Mechanisms of dengue virus-induced bone marrow suppression. Baillieres Clin Haematol. 1995;8:249-270.
8. Aster RH, Curtis BR, McFarland JG, et al. Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management. Thromb Haemost. 2009;7:911-918.
9. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115:168-186.
10. Bellucci S, Charpak Y, Chastang C, et al. Low doses v conventional doses of corticoids in immune thrombocytopenic purpura (ITP): results of a randomized clinical trial in 160 children, 223 adults. Blood. 1988;71:1165-1169.
11. Ozsoylu S, Sayli TR, Oztürk G. Oral megadose methylprednisolone versus intravenous immunoglobulin for acute childhood idiopathic thrombocytopenic purpura. Pediatr Hematol Oncol. 1993;10:317-321.
12. Beck CE, Nathan PC, Parkin PC, et al. Corticosteroids versus intravenous immune globulin for the treatment of acute immune thrombocytopenic purpura in children: a systematic review and meta-analysis of randomized controlled trials. J Pediatr. 2005;147:521-527.
13. Albayrak D, Islek I, Kalaycí AG, et al. Acute immune thrombocytopenic purpura: a comparative study of very high oral doses of methylprednisolone and intravenously administered immune globulin. J Pediatr. 1994;125(6 pt 1):1004-1007.
14. Tarantino MD, Madden RM, Fennewald DL, et al. Treatment of childhood acute immune thrombocytopenic purpura with anti-D immune globulin or pooled immune globulin. J Pediatr. 1999;134:21-26.

Overview

Palliative medicine in the ED represents a paradigm shift for the emergency physician (EP)—from identifying and stabilizing acute medical and surgical conditions to providing symptomatic comfort care to a dying patient. When the ED became the “safety net” for patients who have serious, life-limiting illnesses,^1-3 it also became the most frequent place where such care is initially sought⁴—although not considered an ideal place to begin such care.

In one study, approximately 40% of dying patients presented to the ED during their final 2 weeks of life.⁵ With the ED becoming more recognized as a location for palliative care, the EP plays a key role in the care of these patients. The 2013 Model of the Clinical Practice of Emergency Medi­cine explicitly lists palliative medicine within the EP’s scope of practice.⁶ Further support for providing palliative care in emergency medicine includes the cosponsorship of Hospice and Palliative Medicine subspecialty board certification by the American Board of Emergency Medicine in 2008. Finally, palliative care medicine principles have been endorsed in the “Choosing Wisely” initiative of the American College of Emergency Physicians.

Essential Palliative Care Skills

Quest et al⁷ have identified the following 12 primary palliative care skills in which every EP should be competent:

1. Assessment of illness trajectory;
2. Determination of prognosis;
3. Communication of bad news;
4. Interpretation and formation of an advance care plan;
5. Allowance of family presence during resuscitation;
6. Symptom management (both pain and nonpain);
7. Withholding and withdrawal of life-sustaining treatments;
8. Management of imminently dying patients;
9. Identification and implementation of hospice and palliative care plans;
10. Understanding of ethical and legal issues pertinent to end-of-life care;
11. Display of spiritual and cultural competency; and
12. Management of the dying child.

Although all of the above are important skills, this paper focuses on the symptom management of pain and nonpain (skill 6) in patients presenting to the ED with a life-limiting illness. The evidence base for these treatments is limited due to the many methodological challenges faced when studying symptoms in patients who are at end of life.

Pharmacologic Management of Symptoms

Recent research has found that symptom burden is high at end of life. Despite the increase in attention to these patients and their needs, symptoms including pain, depression, and delirium have repeatedly increased between 1998 and 2010.⁸ A 2013 study recommended that a minimum of four classes of medications be considered for patients who are at end of life: opioid (for pain); benzodiazepine (for anxiety); antipsychotic (for delirium and nausea); and antimuscarinic (for excessive secretions).⁹ The role and indications for each of these drug classes will be discussed.

Palliative Care Intervention

Though EPs frequently request specialty and subspecialty consultation for ED patients, they usually do not consider a palliative care medicine consult for the dying patient. Palliative care medicine utilizes an interdisciplinary, collaborative, team-based approach to decrease the pain and suffering of patients with advanced illness.¹⁰

Benefits from early palliative care intervention in the ED include improved symptom management, improved patient and family satisfaction, improved outcomes, decreased length of stay, less use of intensive care units, and less costs.⁴

Pain Management

Pain is one of the most devastating symptoms that a patient can experience, and its management is an integral component of palliative care medicine. Initial evaluation must include appropriate assessment of the pain and its impact on a patient’s function and quality of life.

The general approach to pain management follows the World Health Organization pain ladder. For mild to moderate pain, step 1 begins with acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID), with or without an adjuvant such as an antidepressant or anticonvulsant. If pain persists, step 2 involves the addition of an opioid. For moderate to severe pain, step 3 involves the addition of stronger opioids, such as hydromorphone, morphine, and oxycodone. Typically, a patient with a serious, life-limiting illness who presents to the ED for help will likely require treatment with strong opioids (step 3).

Opioids

In patients requiring step 3 management, opioids are the primary medication used to manage pain. An initial equivalent dose of morphine 5 mg intravenously (IV) is appropriate in an opioid-naïve patient. The adage of “starting low and going slow” is important to follow; however, an important corollary is “…and use enough.” If a patient’s pain is not controlled with initial dosages, additional bolus doses of 50% to 100% increments will be necessary. Because opioids do not have a ceiling effect, it is important to understand that dosages may seem very high for some patients compared to others. In this population, ensuring baseline pain control, with either an oral long-acting formulation or a continuous IV infusion, is important.¹¹

Difficulties clinicians have in determining opioids for the management of pain are multifactorial. One consideration may be the growing public concern for prescription opioid abuse, potentially creating resistance to appropriate use of opioids by clinicians who fear legal or regulatory push back.

General principles in managing severe pain in the opioid-tolerant patient include the following: (1) calculating the morphine equivalent as a daily 24-hour dose; (2) determining the breakthrough dose, which is usually 10% to 15% of the calculated daily dose; (3) titrating doses upward if pain is not controlled, or if more than three breakthrough doses are being required daily; and (4) reducing the calculated conversion dose of a new opioid 25% to 50% when converting to a different opioid.¹²

The EP is frequently required to convert a patient’s oral opioid analgesic to an equivalent IV dose, and hydromorphone and morphine are the two most commonly used. The Table provides an approximation for this conversion.

Equianalgesic Dosing

Equianalgesic dosing is an important concept in pain management, especially for those patients already receiving opioids. There is great variation in the analgesic potency of the different opioids. The dose at which two opioids provide equivalent pain relief is the equianalgesic dose. Usually, this is standardized to 10 mg of parenteral morphine.¹³ Unfortunately, it is not uncommon for patients to be undertreated when switched to another opioid.

Nonpain Symptom Management

Nonpain symptoms that all EPs must know how to manage include constipation, dyspnea, nausea/vomiting, the so-called death rattle, and terminal delirium. In one study of reasons for ED visits by palliative care patients, the most common were dyspnea (26%), nausea/vomiting/constipation (17%), and uncontrolled pain (15%).¹⁴

Constipation

The most important adverse effect of opioids—one that does not improve or change during treatment—is constipation. Constipation in general—not just associated with opioids—has been ranked as one of the 10 most bothersome symptoms in the palliative care population, leading to discomfort, decreased quality of life, and potential small bowel obstruction or perforation.¹⁵ Unless contraindicated, a gastrointestinal stimulant such as senna, or an osmotic laxative such as lactulose, must be prescribed whenever an opioid is initiated. As the author (Galicia-Castillo) often notes, “The hand that writes the prescription for an opioid should be the hand that writes an Rx for a bowel regimen, or it becomes the hand that disimpacts the patient.”

The most recent Cochrane Review for the management of constipation in the palliative care population did not show any differences in the effectiveness among three commonly used laxatives: senna, docusate, and lactulose. This review did not evaluate polyethylene glycol, which is also commonly used.¹⁶ The addition of stool softeners, bisacodyl and nightly prune juice can also be helpful.¹⁰

Dyspnea

Dyspnea, the subjective feeling of breathing discomfort, is a common end-of-life complaint. Similar to pain, self-report is required for adequate assessment of dyspnea. Treatment recommendations include opioids, anxiolytics, and oxygen therapy.¹⁸ Opioids are the most widely studied treatment for dyspnea, demonstrating reduction in breathlessness in patients who have a variety of conditions, such as advanced chronic obstructive pulmonary disease, interstitial lung disease, cancer, and chronic heart failure.¹⁹

While many of the benefits of opioids are widely recognized and understood, the manner in which they improve symptoms of dyspnea is less well known. In addition, the evidence of effectiveness is limited to oral or parenteral morphine and fentanyl, and nebulized opioids have not been well studied. Oxygen treatments have been shown to reduce dyspnea in patients who suffer from hypoxemia; however, no benefit was found for patients who had only mild or no hypoxemia. A majority of dying patients did not experience a change in respiratory comfort after their supplemental oxygen was withdrawn. In these cases, when administration of oxygen is unnecessary, it may potentially introduce further discomfort to end-of-life patients by causing nasal dryness and impaired mobility.²⁰

The use of benzodiazepines as the primary medication to manage dyspnea is unfounded, but may provide some benefit when used in conjunction with opioids.¹¹ When indicated, a longer-acting agent (eg, clonazepam, with an initial starting does of 0.25 mg orally every 12 hours) may be used.⁴

Nausea and Vomiting

Nausea and vomiting have been reported by 16% to 68% of patients who had life-limiting illness, such as cancer, heart failure, renal failure, or acquired immunodeficiency syndrome.²¹ The etiology of nausea and vomiting is multifactorial in a dying patient. Assessment and treatment has been based on understanding how neurotransmitters are involved in the “emetic pathway,”²² but other pathways, such as a cytokine-mediated model of cancer symptoms, may also be important.²³

Nonpharmacologic methods to utilize include avoidance of environmental stimuli, such as fatty, spicy, and salted foods; use of relaxation and distraction; and massage.²² Several medication classes have been utilized to treat nausea and vomiting: prokinetic agents (metoclopramide 10 mg three to four times a day, 30 minutes prior to meals and bedtime); dopamine receptor antagonists (haloperidol 1.5-5 mg two to three times a day); antihistaminic agents (promethazine 25 mg orally or IV every 4-6 hours, with a maximum dose of 100 mg/d); and selective 5 hydroxytryptamine-3 receptor antagonists (ondansetron 4-8 mg once or twice a day). Other agents that have been utilized include corticosteroids, benzodiazepines, octreotide, and cannabinoids.²²

Procedures such as percutaneous endoscopic gastrostomy placement, nasogastric tube placement, and stenting may be necessary for patients who have advanced disease caused by a mechanical obstruction.²²

Death Rattle

The death rattle occurs when secretions accumulate in the pharynx and/or airways when swallowing and cough mechanisms are no longer intact.²⁴ This phenomenon occurs in 23% to 92% of dying patients.²⁵ Generally, death occurs within 48 hours for about 75% of such patients.²⁶ The noise that results from this process is usually more disturbing for those visiting the patients than to the patient themselves. Conservative measures to employ include placing patients on their sides to facilitate secretion drainage and to minimize upper airway sounds, gentle oral and pharyngeal suctioning, and limiting fluid input.¹¹

One recent study reviewing the use of the anticholinergics atropine, scopolamine, and hyoscine demonstrated similar efficacy among the three drugs. Dosages used in this study included atropine 0.5 mg as a subcutaneous bolus, followed by 3 mg every 24 hours subcutaneously; scopolamine as a 0.25 mg subcutaneous bolus, followed by 1.5 mg every 24 hours IV or by subcutaneous infusion; and hyoscine 20 mg as a subcutaneous bolus followed by 60 mg every 24 hours IV or subcutaneous infusion. Glycopyrrolate is often used in the cognitively intact patient, as it does not cross the blood-brain barrier; however, supply concerns at the time of the study prevented a review of its efficiency.²⁷ All of these medications are also available in oral and transdermal formulations.

Terminal Delirium

Delirium is a common complication for patients nearing the end of life, affecting as many as 88% of dying patients.²⁸ It is characterized by an acute onset of cognitive impairment that may manifest as either a hyperactive or hypoactive state. Causes for terminal delirium are multifactorial. Initially, management should include prevention strategies, such as frequently orientating the patient, maintenance of day-night cycles, provision of adequate sleep, and minimization of sensory overload.¹¹ When pharmacological therapy is required to improve quality of life, a neuroleptic medication, namely haloperidol, should be used initially. The addition of a benzodiazepine may help if the initial treatments are ineffective, or if sedation is desired.²⁸

Summary

Emergency physicians have a unique opportunity to improve the quality of life for patients suffering serious illness, especially those who are actively dying. The management of pain and nonpain symptoms in patients who are at end of life, is a particularly important skill for every EP. If available, a consultation with a palliative care medicine consultant may improve both short- and long-term patient care.

Dr Galicia-Castillo is the Sue Faulkner Scribner professor of geriatrics at the Eastern Virginia Medical School Glennan Center for Geriatrics and Gerontology, and Medical Director for Palliative Care Medicine at Sentara Norfolk General Hospital. Dr Counselman is the distinguished professor and chairman of the department of emergency medicine at Eastern Virginia Medical School, Norfolk; and a physician at Emergency Physicians of Tidewater, Norfolk, Virginia. He is also the associate editor in chief of EMERGENCY MEDICINE editorial board.

Overview

Palliative medicine in the ED represents a paradigm shift for the emergency physician (EP)—from identifying and stabilizing acute medical and surgical conditions to providing symptomatic comfort care to a dying patient. When the ED became the “safety net” for patients who have serious, life-limiting illnesses,^1-3 it also became the most frequent place where such care is initially sought⁴—although not considered an ideal place to begin such care.

In one study, approximately 40% of dying patients presented to the ED during their final 2 weeks of life.⁵ With the ED becoming more recognized as a location for palliative care, the EP plays a key role in the care of these patients. The 2013 Model of the Clinical Practice of Emergency Medi­cine explicitly lists palliative medicine within the EP’s scope of practice.⁶ Further support for providing palliative care in emergency medicine includes the cosponsorship of Hospice and Palliative Medicine subspecialty board certification by the American Board of Emergency Medicine in 2008. Finally, palliative care medicine principles have been endorsed in the “Choosing Wisely” initiative of the American College of Emergency Physicians.

Essential Palliative Care Skills

Quest et al⁷ have identified the following 12 primary palliative care skills in which every EP should be competent:

1. Assessment of illness trajectory;
2. Determination of prognosis;
3. Communication of bad news;
4. Interpretation and formation of an advance care plan;
5. Allowance of family presence during resuscitation;
6. Symptom management (both pain and nonpain);
7. Withholding and withdrawal of life-sustaining treatments;
8. Management of imminently dying patients;
9. Identification and implementation of hospice and palliative care plans;
10. Understanding of ethical and legal issues pertinent to end-of-life care;
11. Display of spiritual and cultural competency; and
12. Management of the dying child.

Although all of the above are important skills, this paper focuses on the symptom management of pain and nonpain (skill 6) in patients presenting to the ED with a life-limiting illness. The evidence base for these treatments is limited due to the many methodological challenges faced when studying symptoms in patients who are at end of life.

Pharmacologic Management of Symptoms

Recent research has found that symptom burden is high at end of life. Despite the increase in attention to these patients and their needs, symptoms including pain, depression, and delirium have repeatedly increased between 1998 and 2010.⁸ A 2013 study recommended that a minimum of four classes of medications be considered for patients who are at end of life: opioid (for pain); benzodiazepine (for anxiety); antipsychotic (for delirium and nausea); and antimuscarinic (for excessive secretions).⁹ The role and indications for each of these drug classes will be discussed.

Palliative Care Intervention

Though EPs frequently request specialty and subspecialty consultation for ED patients, they usually do not consider a palliative care medicine consult for the dying patient. Palliative care medicine utilizes an interdisciplinary, collaborative, team-based approach to decrease the pain and suffering of patients with advanced illness.¹⁰

Benefits from early palliative care intervention in the ED include improved symptom management, improved patient and family satisfaction, improved outcomes, decreased length of stay, less use of intensive care units, and less costs.⁴

Pain Management

Pain is one of the most devastating symptoms that a patient can experience, and its management is an integral component of palliative care medicine. Initial evaluation must include appropriate assessment of the pain and its impact on a patient’s function and quality of life.

The general approach to pain management follows the World Health Organization pain ladder. For mild to moderate pain, step 1 begins with acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID), with or without an adjuvant such as an antidepressant or anticonvulsant. If pain persists, step 2 involves the addition of an opioid. For moderate to severe pain, step 3 involves the addition of stronger opioids, such as hydromorphone, morphine, and oxycodone. Typically, a patient with a serious, life-limiting illness who presents to the ED for help will likely require treatment with strong opioids (step 3).

Opioids

In patients requiring step 3 management, opioids are the primary medication used to manage pain. An initial equivalent dose of morphine 5 mg intravenously (IV) is appropriate in an opioid-naïve patient. The adage of “starting low and going slow” is important to follow; however, an important corollary is “…and use enough.” If a patient’s pain is not controlled with initial dosages, additional bolus doses of 50% to 100% increments will be necessary. Because opioids do not have a ceiling effect, it is important to understand that dosages may seem very high for some patients compared to others. In this population, ensuring baseline pain control, with either an oral long-acting formulation or a continuous IV infusion, is important.¹¹

Difficulties clinicians have in determining opioids for the management of pain are multifactorial. One consideration may be the growing public concern for prescription opioid abuse, potentially creating resistance to appropriate use of opioids by clinicians who fear legal or regulatory push back.

General principles in managing severe pain in the opioid-tolerant patient include the following: (1) calculating the morphine equivalent as a daily 24-hour dose; (2) determining the breakthrough dose, which is usually 10% to 15% of the calculated daily dose; (3) titrating doses upward if pain is not controlled, or if more than three breakthrough doses are being required daily; and (4) reducing the calculated conversion dose of a new opioid 25% to 50% when converting to a different opioid.¹²

The EP is frequently required to convert a patient’s oral opioid analgesic to an equivalent IV dose, and hydromorphone and morphine are the two most commonly used. The Table provides an approximation for this conversion.

Equianalgesic Dosing

Equianalgesic dosing is an important concept in pain management, especially for those patients already receiving opioids. There is great variation in the analgesic potency of the different opioids. The dose at which two opioids provide equivalent pain relief is the equianalgesic dose. Usually, this is standardized to 10 mg of parenteral morphine.¹³ Unfortunately, it is not uncommon for patients to be undertreated when switched to another opioid.

Nonpain Symptom Management

Nonpain symptoms that all EPs must know how to manage include constipation, dyspnea, nausea/vomiting, the so-called death rattle, and terminal delirium. In one study of reasons for ED visits by palliative care patients, the most common were dyspnea (26%), nausea/vomiting/constipation (17%), and uncontrolled pain (15%).¹⁴

Constipation

The most important adverse effect of opioids—one that does not improve or change during treatment—is constipation. Constipation in general—not just associated with opioids—has been ranked as one of the 10 most bothersome symptoms in the palliative care population, leading to discomfort, decreased quality of life, and potential small bowel obstruction or perforation.¹⁵ Unless contraindicated, a gastrointestinal stimulant such as senna, or an osmotic laxative such as lactulose, must be prescribed whenever an opioid is initiated. As the author (Galicia-Castillo) often notes, “The hand that writes the prescription for an opioid should be the hand that writes an Rx for a bowel regimen, or it becomes the hand that disimpacts the patient.”

The most recent Cochrane Review for the management of constipation in the palliative care population did not show any differences in the effectiveness among three commonly used laxatives: senna, docusate, and lactulose. This review did not evaluate polyethylene glycol, which is also commonly used.¹⁶ The addition of stool softeners, bisacodyl and nightly prune juice can also be helpful.¹⁰

Dyspnea

Dyspnea, the subjective feeling of breathing discomfort, is a common end-of-life complaint. Similar to pain, self-report is required for adequate assessment of dyspnea. Treatment recommendations include opioids, anxiolytics, and oxygen therapy.¹⁸ Opioids are the most widely studied treatment for dyspnea, demonstrating reduction in breathlessness in patients who have a variety of conditions, such as advanced chronic obstructive pulmonary disease, interstitial lung disease, cancer, and chronic heart failure.¹⁹

While many of the benefits of opioids are widely recognized and understood, the manner in which they improve symptoms of dyspnea is less well known. In addition, the evidence of effectiveness is limited to oral or parenteral morphine and fentanyl, and nebulized opioids have not been well studied. Oxygen treatments have been shown to reduce dyspnea in patients who suffer from hypoxemia; however, no benefit was found for patients who had only mild or no hypoxemia. A majority of dying patients did not experience a change in respiratory comfort after their supplemental oxygen was withdrawn. In these cases, when administration of oxygen is unnecessary, it may potentially introduce further discomfort to end-of-life patients by causing nasal dryness and impaired mobility.²⁰

The use of benzodiazepines as the primary medication to manage dyspnea is unfounded, but may provide some benefit when used in conjunction with opioids.¹¹ When indicated, a longer-acting agent (eg, clonazepam, with an initial starting does of 0.25 mg orally every 12 hours) may be used.⁴

Nausea and Vomiting

Nausea and vomiting have been reported by 16% to 68% of patients who had life-limiting illness, such as cancer, heart failure, renal failure, or acquired immunodeficiency syndrome.²¹ The etiology of nausea and vomiting is multifactorial in a dying patient. Assessment and treatment has been based on understanding how neurotransmitters are involved in the “emetic pathway,”²² but other pathways, such as a cytokine-mediated model of cancer symptoms, may also be important.²³

Nonpharmacologic methods to utilize include avoidance of environmental stimuli, such as fatty, spicy, and salted foods; use of relaxation and distraction; and massage.²² Several medication classes have been utilized to treat nausea and vomiting: prokinetic agents (metoclopramide 10 mg three to four times a day, 30 minutes prior to meals and bedtime); dopamine receptor antagonists (haloperidol 1.5-5 mg two to three times a day); antihistaminic agents (promethazine 25 mg orally or IV every 4-6 hours, with a maximum dose of 100 mg/d); and selective 5 hydroxytryptamine-3 receptor antagonists (ondansetron 4-8 mg once or twice a day). Other agents that have been utilized include corticosteroids, benzodiazepines, octreotide, and cannabinoids.²²

Procedures such as percutaneous endoscopic gastrostomy placement, nasogastric tube placement, and stenting may be necessary for patients who have advanced disease caused by a mechanical obstruction.²²

Death Rattle

The death rattle occurs when secretions accumulate in the pharynx and/or airways when swallowing and cough mechanisms are no longer intact.²⁴ This phenomenon occurs in 23% to 92% of dying patients.²⁵ Generally, death occurs within 48 hours for about 75% of such patients.²⁶ The noise that results from this process is usually more disturbing for those visiting the patients than to the patient themselves. Conservative measures to employ include placing patients on their sides to facilitate secretion drainage and to minimize upper airway sounds, gentle oral and pharyngeal suctioning, and limiting fluid input.¹¹

One recent study reviewing the use of the anticholinergics atropine, scopolamine, and hyoscine demonstrated similar efficacy among the three drugs. Dosages used in this study included atropine 0.5 mg as a subcutaneous bolus, followed by 3 mg every 24 hours subcutaneously; scopolamine as a 0.25 mg subcutaneous bolus, followed by 1.5 mg every 24 hours IV or by subcutaneous infusion; and hyoscine 20 mg as a subcutaneous bolus followed by 60 mg every 24 hours IV or subcutaneous infusion. Glycopyrrolate is often used in the cognitively intact patient, as it does not cross the blood-brain barrier; however, supply concerns at the time of the study prevented a review of its efficiency.²⁷ All of these medications are also available in oral and transdermal formulations.

Terminal Delirium

Delirium is a common complication for patients nearing the end of life, affecting as many as 88% of dying patients.²⁸ It is characterized by an acute onset of cognitive impairment that may manifest as either a hyperactive or hypoactive state. Causes for terminal delirium are multifactorial. Initially, management should include prevention strategies, such as frequently orientating the patient, maintenance of day-night cycles, provision of adequate sleep, and minimization of sensory overload.¹¹ When pharmacological therapy is required to improve quality of life, a neuroleptic medication, namely haloperidol, should be used initially. The addition of a benzodiazepine may help if the initial treatments are ineffective, or if sedation is desired.²⁸

Summary

Emergency physicians have a unique opportunity to improve the quality of life for patients suffering serious illness, especially those who are actively dying. The management of pain and nonpain symptoms in patients who are at end of life, is a particularly important skill for every EP. If available, a consultation with a palliative care medicine consultant may improve both short- and long-term patient care.

Dr Galicia-Castillo is the Sue Faulkner Scribner professor of geriatrics at the Eastern Virginia Medical School Glennan Center for Geriatrics and Gerontology, and Medical Director for Palliative Care Medicine at Sentara Norfolk General Hospital. Dr Counselman is the distinguished professor and chairman of the department of emergency medicine at Eastern Virginia Medical School, Norfolk; and a physician at Emergency Physicians of Tidewater, Norfolk, Virginia. He is also the associate editor in chief of EMERGENCY MEDICINE editorial board.

Overview

Palliative medicine in the ED represents a paradigm shift for the emergency physician (EP)—from identifying and stabilizing acute medical and surgical conditions to providing symptomatic comfort care to a dying patient. When the ED became the “safety net” for patients who have serious, life-limiting illnesses,^1-3 it also became the most frequent place where such care is initially sought⁴—although not considered an ideal place to begin such care.

In one study, approximately 40% of dying patients presented to the ED during their final 2 weeks of life.⁵ With the ED becoming more recognized as a location for palliative care, the EP plays a key role in the care of these patients. The 2013 Model of the Clinical Practice of Emergency Medi­cine explicitly lists palliative medicine within the EP’s scope of practice.⁶ Further support for providing palliative care in emergency medicine includes the cosponsorship of Hospice and Palliative Medicine subspecialty board certification by the American Board of Emergency Medicine in 2008. Finally, palliative care medicine principles have been endorsed in the “Choosing Wisely” initiative of the American College of Emergency Physicians.

Essential Palliative Care Skills

Quest et al⁷ have identified the following 12 primary palliative care skills in which every EP should be competent:

1. Assessment of illness trajectory;
2. Determination of prognosis;
3. Communication of bad news;
4. Interpretation and formation of an advance care plan;
5. Allowance of family presence during resuscitation;
6. Symptom management (both pain and nonpain);
7. Withholding and withdrawal of life-sustaining treatments;
8. Management of imminently dying patients;
9. Identification and implementation of hospice and palliative care plans;
10. Understanding of ethical and legal issues pertinent to end-of-life care;
11. Display of spiritual and cultural competency; and
12. Management of the dying child.

Although all of the above are important skills, this paper focuses on the symptom management of pain and nonpain (skill 6) in patients presenting to the ED with a life-limiting illness. The evidence base for these treatments is limited due to the many methodological challenges faced when studying symptoms in patients who are at end of life.

Pharmacologic Management of Symptoms

Recent research has found that symptom burden is high at end of life. Despite the increase in attention to these patients and their needs, symptoms including pain, depression, and delirium have repeatedly increased between 1998 and 2010.⁸ A 2013 study recommended that a minimum of four classes of medications be considered for patients who are at end of life: opioid (for pain); benzodiazepine (for anxiety); antipsychotic (for delirium and nausea); and antimuscarinic (for excessive secretions).⁹ The role and indications for each of these drug classes will be discussed.

Palliative Care Intervention

Though EPs frequently request specialty and subspecialty consultation for ED patients, they usually do not consider a palliative care medicine consult for the dying patient. Palliative care medicine utilizes an interdisciplinary, collaborative, team-based approach to decrease the pain and suffering of patients with advanced illness.¹⁰

Benefits from early palliative care intervention in the ED include improved symptom management, improved patient and family satisfaction, improved outcomes, decreased length of stay, less use of intensive care units, and less costs.⁴

Pain Management

Pain is one of the most devastating symptoms that a patient can experience, and its management is an integral component of palliative care medicine. Initial evaluation must include appropriate assessment of the pain and its impact on a patient’s function and quality of life.

The general approach to pain management follows the World Health Organization pain ladder. For mild to moderate pain, step 1 begins with acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID), with or without an adjuvant such as an antidepressant or anticonvulsant. If pain persists, step 2 involves the addition of an opioid. For moderate to severe pain, step 3 involves the addition of stronger opioids, such as hydromorphone, morphine, and oxycodone. Typically, a patient with a serious, life-limiting illness who presents to the ED for help will likely require treatment with strong opioids (step 3).

Opioids

In patients requiring step 3 management, opioids are the primary medication used to manage pain. An initial equivalent dose of morphine 5 mg intravenously (IV) is appropriate in an opioid-naïve patient. The adage of “starting low and going slow” is important to follow; however, an important corollary is “…and use enough.” If a patient’s pain is not controlled with initial dosages, additional bolus doses of 50% to 100% increments will be necessary. Because opioids do not have a ceiling effect, it is important to understand that dosages may seem very high for some patients compared to others. In this population, ensuring baseline pain control, with either an oral long-acting formulation or a continuous IV infusion, is important.¹¹

Difficulties clinicians have in determining opioids for the management of pain are multifactorial. One consideration may be the growing public concern for prescription opioid abuse, potentially creating resistance to appropriate use of opioids by clinicians who fear legal or regulatory push back.

General principles in managing severe pain in the opioid-tolerant patient include the following: (1) calculating the morphine equivalent as a daily 24-hour dose; (2) determining the breakthrough dose, which is usually 10% to 15% of the calculated daily dose; (3) titrating doses upward if pain is not controlled, or if more than three breakthrough doses are being required daily; and (4) reducing the calculated conversion dose of a new opioid 25% to 50% when converting to a different opioid.¹²

The EP is frequently required to convert a patient’s oral opioid analgesic to an equivalent IV dose, and hydromorphone and morphine are the two most commonly used. The Table provides an approximation for this conversion.

Equianalgesic Dosing

Equianalgesic dosing is an important concept in pain management, especially for those patients already receiving opioids. There is great variation in the analgesic potency of the different opioids. The dose at which two opioids provide equivalent pain relief is the equianalgesic dose. Usually, this is standardized to 10 mg of parenteral morphine.¹³ Unfortunately, it is not uncommon for patients to be undertreated when switched to another opioid.

Nonpain Symptom Management

Nonpain symptoms that all EPs must know how to manage include constipation, dyspnea, nausea/vomiting, the so-called death rattle, and terminal delirium. In one study of reasons for ED visits by palliative care patients, the most common were dyspnea (26%), nausea/vomiting/constipation (17%), and uncontrolled pain (15%).¹⁴

Constipation

The most important adverse effect of opioids—one that does not improve or change during treatment—is constipation. Constipation in general—not just associated with opioids—has been ranked as one of the 10 most bothersome symptoms in the palliative care population, leading to discomfort, decreased quality of life, and potential small bowel obstruction or perforation.¹⁵ Unless contraindicated, a gastrointestinal stimulant such as senna, or an osmotic laxative such as lactulose, must be prescribed whenever an opioid is initiated. As the author (Galicia-Castillo) often notes, “The hand that writes the prescription for an opioid should be the hand that writes an Rx for a bowel regimen, or it becomes the hand that disimpacts the patient.”

The most recent Cochrane Review for the management of constipation in the palliative care population did not show any differences in the effectiveness among three commonly used laxatives: senna, docusate, and lactulose. This review did not evaluate polyethylene glycol, which is also commonly used.¹⁶ The addition of stool softeners, bisacodyl and nightly prune juice can also be helpful.¹⁰

Dyspnea

Dyspnea, the subjective feeling of breathing discomfort, is a common end-of-life complaint. Similar to pain, self-report is required for adequate assessment of dyspnea. Treatment recommendations include opioids, anxiolytics, and oxygen therapy.¹⁸ Opioids are the most widely studied treatment for dyspnea, demonstrating reduction in breathlessness in patients who have a variety of conditions, such as advanced chronic obstructive pulmonary disease, interstitial lung disease, cancer, and chronic heart failure.¹⁹

While many of the benefits of opioids are widely recognized and understood, the manner in which they improve symptoms of dyspnea is less well known. In addition, the evidence of effectiveness is limited to oral or parenteral morphine and fentanyl, and nebulized opioids have not been well studied. Oxygen treatments have been shown to reduce dyspnea in patients who suffer from hypoxemia; however, no benefit was found for patients who had only mild or no hypoxemia. A majority of dying patients did not experience a change in respiratory comfort after their supplemental oxygen was withdrawn. In these cases, when administration of oxygen is unnecessary, it may potentially introduce further discomfort to end-of-life patients by causing nasal dryness and impaired mobility.²⁰

The use of benzodiazepines as the primary medication to manage dyspnea is unfounded, but may provide some benefit when used in conjunction with opioids.¹¹ When indicated, a longer-acting agent (eg, clonazepam, with an initial starting does of 0.25 mg orally every 12 hours) may be used.⁴

Nausea and Vomiting

Nausea and vomiting have been reported by 16% to 68% of patients who had life-limiting illness, such as cancer, heart failure, renal failure, or acquired immunodeficiency syndrome.²¹ The etiology of nausea and vomiting is multifactorial in a dying patient. Assessment and treatment has been based on understanding how neurotransmitters are involved in the “emetic pathway,”²² but other pathways, such as a cytokine-mediated model of cancer symptoms, may also be important.²³

Nonpharmacologic methods to utilize include avoidance of environmental stimuli, such as fatty, spicy, and salted foods; use of relaxation and distraction; and massage.²² Several medication classes have been utilized to treat nausea and vomiting: prokinetic agents (metoclopramide 10 mg three to four times a day, 30 minutes prior to meals and bedtime); dopamine receptor antagonists (haloperidol 1.5-5 mg two to three times a day); antihistaminic agents (promethazine 25 mg orally or IV every 4-6 hours, with a maximum dose of 100 mg/d); and selective 5 hydroxytryptamine-3 receptor antagonists (ondansetron 4-8 mg once or twice a day). Other agents that have been utilized include corticosteroids, benzodiazepines, octreotide, and cannabinoids.²²

Procedures such as percutaneous endoscopic gastrostomy placement, nasogastric tube placement, and stenting may be necessary for patients who have advanced disease caused by a mechanical obstruction.²²

Death Rattle

The death rattle occurs when secretions accumulate in the pharynx and/or airways when swallowing and cough mechanisms are no longer intact.²⁴ This phenomenon occurs in 23% to 92% of dying patients.²⁵ Generally, death occurs within 48 hours for about 75% of such patients.²⁶ The noise that results from this process is usually more disturbing for those visiting the patients than to the patient themselves. Conservative measures to employ include placing patients on their sides to facilitate secretion drainage and to minimize upper airway sounds, gentle oral and pharyngeal suctioning, and limiting fluid input.¹¹

One recent study reviewing the use of the anticholinergics atropine, scopolamine, and hyoscine demonstrated similar efficacy among the three drugs. Dosages used in this study included atropine 0.5 mg as a subcutaneous bolus, followed by 3 mg every 24 hours subcutaneously; scopolamine as a 0.25 mg subcutaneous bolus, followed by 1.5 mg every 24 hours IV or by subcutaneous infusion; and hyoscine 20 mg as a subcutaneous bolus followed by 60 mg every 24 hours IV or subcutaneous infusion. Glycopyrrolate is often used in the cognitively intact patient, as it does not cross the blood-brain barrier; however, supply concerns at the time of the study prevented a review of its efficiency.²⁷ All of these medications are also available in oral and transdermal formulations.

Terminal Delirium

Delirium is a common complication for patients nearing the end of life, affecting as many as 88% of dying patients.²⁸ It is characterized by an acute onset of cognitive impairment that may manifest as either a hyperactive or hypoactive state. Causes for terminal delirium are multifactorial. Initially, management should include prevention strategies, such as frequently orientating the patient, maintenance of day-night cycles, provision of adequate sleep, and minimization of sensory overload.¹¹ When pharmacological therapy is required to improve quality of life, a neuroleptic medication, namely haloperidol, should be used initially. The addition of a benzodiazepine may help if the initial treatments are ineffective, or if sedation is desired.²⁸

Summary

Emergency physicians have a unique opportunity to improve the quality of life for patients suffering serious illness, especially those who are actively dying. The management of pain and nonpain symptoms in patients who are at end of life, is a particularly important skill for every EP. If available, a consultation with a palliative care medicine consultant may improve both short- and long-term patient care.

Dr Galicia-Castillo is the Sue Faulkner Scribner professor of geriatrics at the Eastern Virginia Medical School Glennan Center for Geriatrics and Gerontology, and Medical Director for Palliative Care Medicine at Sentara Norfolk General Hospital. Dr Counselman is the distinguished professor and chairman of the department of emergency medicine at Eastern Virginia Medical School, Norfolk; and a physician at Emergency Physicians of Tidewater, Norfolk, Virginia. He is also the associate editor in chief of EMERGENCY MEDICINE editorial board.

Introduction

Percutaneous endoscopic gastrostomy (PEG) tubes are a common method employed for long-term feeding in patients who are unable to tolerate oral feedings.¹ Though PEG-tube placement is a common, safe, and well-studied practice, there are known complications, including wound infection, dislodgement, and peritonitis.² Dislodgement and recurrent ED visits are increasingly becoming a burden on both patients and healthcare providers, as up to 12.8% of patients will require ED replacement of a dislodged tube, totaling an estimated $1,200 per visit.³

Newer techniques include Roux-en-Y feeding jejunostomy tubes, which are anticipated to reduce long-term compli­cations.^4,5 However, dislodgement, sinus tracts, and superimposed infections still occur, also leading to ED visits.⁶ Foley catheters are a readily available and low-cost alternative to replace commercial feeding-tubes in the ED, and are commonly used when the original feeding-tube is not suitable for reuse.⁷ In the following presentation, the authors describe a previously unseen case of a fully intussuscepted Foley catheter though a Roux-en-Y jejunostomy.

Case Report

A 69-year-old man, recently diagnosed with invasive squamous cell carcinoma of the distal esophagus, presented to the ED with a chief complaint of “J-tube fell out.” One month prior to presentation, the patient had undergone a laparoscopic Janeway Roux-en-Y nipple jejunostomy. He had been previously evaluated several times in the ED for a displaced J-tube, and his commercial feeding tube had been replaced with a Foley catheter without incident.

On this visit, the patient’s wife reported that the Foley catheter had become displaced 3 days prior to presentation, and she assumed that the patient had accidentally pulled it out. According to the patient’s wife, he had attempted oral feedings, but had difficulty swallowing as well as coughing episodes.

Upon initial evaluation, the patient complained of diffuse abdominal pain and cramping. He denied any nausea or vomiting, and reported normal bowel movements. The physical examination was remarkable for the following: hypotension (blood pressure, 64/46 mm Hg); heart rate, 94 beats/minute; temperature, 96.4°F; cachexia; a diffusely tender abdomen; and viable stoma on the anterior abdominal wall. Purulent and malodorous drainage was noted at the stoma site. There was no Foley catheter or J-tube in place, and neither the patient nor his wife had brought the dislodged tube to the ED.

A computed tomography scan of the patient’s abdomen and pelvis were ordered with IV and oral contrast. The imaging studies revealed multiple dilated, fluid-filled loops of small bowel, and a Foley catheter proximal to the ileocecal valve, with the balloon still inflated (Figure).

The emergency physician notified the original surgical team of the patient’s status. The surgical team placed a new, 14 French (Fr)-Foley catheter through the stoma, sutured it in place, and admitted the patient to their service. The patient was maintained on IV antibiotics and fluids. As he continued to pass flatus and stool, a diet was advanced through the replacement Foley catheter. The intussuscepted Foley was subsequently passed naturally on day 4 of his hospital admission. The patient unfortunately died several days later of hypoxic respiratory failure, which was not thought to be related to the ingested catheter.

Discussion

Percutaneous Foley catheters, either pre- or postpyloric, have been used for decades as permanent feeding tubes for patients unable to tolerate oral feedings. These catheters are well-known to be inexpensive and safe replacements for commercial gastrostomy tubes.⁷ However, a number of complications unique to Foley feeding tubes have been described in case reports, including mechanical obstruction leading to pancreatitis, duodenal obstruction, bowel ischemia secondary to balloon overfilling, pyloric obstruction, bowel infection, as well as broken and digested catheters.^8-10

Interestingly, despite multiple case reports demonstrating tube migration, prospective studies have shown this to be a relatively uncommon complication.¹¹ In 2012, a patient in Israel ingested a Foley catheter via the gastrostomy stoma, resulting in small bowel obstruction relieved only by enterotomy and removal of the catheter. There have been no previous documented reports of ingested tubes via jejunostomy stoma.¹² Significant forces exerted on Foley catheters have been described, resulting in skin necrosis at the hub and stretching of the catheter from the proximal small bowel to the terminal ileum. In this case presentation, bowel peristalsis was able to advance the entire tube through the skin.¹³

Management of feeding-Foley-catheter complications typically involves deflation of the balloon and removal and replacement of the offending catheter—usually with a smaller sized Foley catheter (eg, 12Fr, 14Fr, 16Fr). Complicated cases with catheter malfunction have been successfully managed endoscopically.¹⁴ The patient in this case was likely at higher risk of complication given the abnormally large wound surrounding the stoma and skin breakdown secondary to superimposed infection.

Conclusion

This case highlights the potent peristaltic forces that are exerted upon a feeding Foley catheter and reinforces the importance of proper tube anchorage. Although this patient did well with direct skin suturing of the replacement catheter, previous studies recommend using a plastic retention ring. Placing a mark on the outside of the catheter as a means to continuously visualize its proper anchorage and placement has also been suggested in the literature. Additionally, whenever a patient presents with a displaced feeding tube (Foley catheter or commercial tube), providers should not assume that the tube has been displaced externally and should maintain a low-threshold for advanced imaging and/or endoscopy if the tube cannot otherwise be located.

Dr Lefkove is an attending physician in the department of emergency medicine, DeKalb Medical Center, Atlanta, Georgia. Dr Meloy is an assistant professor of emergency medicine at Emory University School of Medicine, Atlanta, Georgia.

Introduction

Percutaneous endoscopic gastrostomy (PEG) tubes are a common method employed for long-term feeding in patients who are unable to tolerate oral feedings.¹ Though PEG-tube placement is a common, safe, and well-studied practice, there are known complications, including wound infection, dislodgement, and peritonitis.² Dislodgement and recurrent ED visits are increasingly becoming a burden on both patients and healthcare providers, as up to 12.8% of patients will require ED replacement of a dislodged tube, totaling an estimated $1,200 per visit.³

Newer techniques include Roux-en-Y feeding jejunostomy tubes, which are anticipated to reduce long-term compli­cations.^4,5 However, dislodgement, sinus tracts, and superimposed infections still occur, also leading to ED visits.⁶ Foley catheters are a readily available and low-cost alternative to replace commercial feeding-tubes in the ED, and are commonly used when the original feeding-tube is not suitable for reuse.⁷ In the following presentation, the authors describe a previously unseen case of a fully intussuscepted Foley catheter though a Roux-en-Y jejunostomy.

Case Report

A 69-year-old man, recently diagnosed with invasive squamous cell carcinoma of the distal esophagus, presented to the ED with a chief complaint of “J-tube fell out.” One month prior to presentation, the patient had undergone a laparoscopic Janeway Roux-en-Y nipple jejunostomy. He had been previously evaluated several times in the ED for a displaced J-tube, and his commercial feeding tube had been replaced with a Foley catheter without incident.

On this visit, the patient’s wife reported that the Foley catheter had become displaced 3 days prior to presentation, and she assumed that the patient had accidentally pulled it out. According to the patient’s wife, he had attempted oral feedings, but had difficulty swallowing as well as coughing episodes.

Upon initial evaluation, the patient complained of diffuse abdominal pain and cramping. He denied any nausea or vomiting, and reported normal bowel movements. The physical examination was remarkable for the following: hypotension (blood pressure, 64/46 mm Hg); heart rate, 94 beats/minute; temperature, 96.4°F; cachexia; a diffusely tender abdomen; and viable stoma on the anterior abdominal wall. Purulent and malodorous drainage was noted at the stoma site. There was no Foley catheter or J-tube in place, and neither the patient nor his wife had brought the dislodged tube to the ED.

A computed tomography scan of the patient’s abdomen and pelvis were ordered with IV and oral contrast. The imaging studies revealed multiple dilated, fluid-filled loops of small bowel, and a Foley catheter proximal to the ileocecal valve, with the balloon still inflated (Figure).

The emergency physician notified the original surgical team of the patient’s status. The surgical team placed a new, 14 French (Fr)-Foley catheter through the stoma, sutured it in place, and admitted the patient to their service. The patient was maintained on IV antibiotics and fluids. As he continued to pass flatus and stool, a diet was advanced through the replacement Foley catheter. The intussuscepted Foley was subsequently passed naturally on day 4 of his hospital admission. The patient unfortunately died several days later of hypoxic respiratory failure, which was not thought to be related to the ingested catheter.

Discussion

Percutaneous Foley catheters, either pre- or postpyloric, have been used for decades as permanent feeding tubes for patients unable to tolerate oral feedings. These catheters are well-known to be inexpensive and safe replacements for commercial gastrostomy tubes.⁷ However, a number of complications unique to Foley feeding tubes have been described in case reports, including mechanical obstruction leading to pancreatitis, duodenal obstruction, bowel ischemia secondary to balloon overfilling, pyloric obstruction, bowel infection, as well as broken and digested catheters.^8-10

Interestingly, despite multiple case reports demonstrating tube migration, prospective studies have shown this to be a relatively uncommon complication.¹¹ In 2012, a patient in Israel ingested a Foley catheter via the gastrostomy stoma, resulting in small bowel obstruction relieved only by enterotomy and removal of the catheter. There have been no previous documented reports of ingested tubes via jejunostomy stoma.¹² Significant forces exerted on Foley catheters have been described, resulting in skin necrosis at the hub and stretching of the catheter from the proximal small bowel to the terminal ileum. In this case presentation, bowel peristalsis was able to advance the entire tube through the skin.¹³

Management of feeding-Foley-catheter complications typically involves deflation of the balloon and removal and replacement of the offending catheter—usually with a smaller sized Foley catheter (eg, 12Fr, 14Fr, 16Fr). Complicated cases with catheter malfunction have been successfully managed endoscopically.¹⁴ The patient in this case was likely at higher risk of complication given the abnormally large wound surrounding the stoma and skin breakdown secondary to superimposed infection.

Conclusion

This case highlights the potent peristaltic forces that are exerted upon a feeding Foley catheter and reinforces the importance of proper tube anchorage. Although this patient did well with direct skin suturing of the replacement catheter, previous studies recommend using a plastic retention ring. Placing a mark on the outside of the catheter as a means to continuously visualize its proper anchorage and placement has also been suggested in the literature. Additionally, whenever a patient presents with a displaced feeding tube (Foley catheter or commercial tube), providers should not assume that the tube has been displaced externally and should maintain a low-threshold for advanced imaging and/or endoscopy if the tube cannot otherwise be located.

Dr Lefkove is an attending physician in the department of emergency medicine, DeKalb Medical Center, Atlanta, Georgia. Dr Meloy is an assistant professor of emergency medicine at Emory University School of Medicine, Atlanta, Georgia.

Introduction

Percutaneous endoscopic gastrostomy (PEG) tubes are a common method employed for long-term feeding in patients who are unable to tolerate oral feedings.¹ Though PEG-tube placement is a common, safe, and well-studied practice, there are known complications, including wound infection, dislodgement, and peritonitis.² Dislodgement and recurrent ED visits are increasingly becoming a burden on both patients and healthcare providers, as up to 12.8% of patients will require ED replacement of a dislodged tube, totaling an estimated $1,200 per visit.³

Newer techniques include Roux-en-Y feeding jejunostomy tubes, which are anticipated to reduce long-term compli­cations.^4,5 However, dislodgement, sinus tracts, and superimposed infections still occur, also leading to ED visits.⁶ Foley catheters are a readily available and low-cost alternative to replace commercial feeding-tubes in the ED, and are commonly used when the original feeding-tube is not suitable for reuse.⁷ In the following presentation, the authors describe a previously unseen case of a fully intussuscepted Foley catheter though a Roux-en-Y jejunostomy.

Case Report

A 69-year-old man, recently diagnosed with invasive squamous cell carcinoma of the distal esophagus, presented to the ED with a chief complaint of “J-tube fell out.” One month prior to presentation, the patient had undergone a laparoscopic Janeway Roux-en-Y nipple jejunostomy. He had been previously evaluated several times in the ED for a displaced J-tube, and his commercial feeding tube had been replaced with a Foley catheter without incident.

On this visit, the patient’s wife reported that the Foley catheter had become displaced 3 days prior to presentation, and she assumed that the patient had accidentally pulled it out. According to the patient’s wife, he had attempted oral feedings, but had difficulty swallowing as well as coughing episodes.

Upon initial evaluation, the patient complained of diffuse abdominal pain and cramping. He denied any nausea or vomiting, and reported normal bowel movements. The physical examination was remarkable for the following: hypotension (blood pressure, 64/46 mm Hg); heart rate, 94 beats/minute; temperature, 96.4°F; cachexia; a diffusely tender abdomen; and viable stoma on the anterior abdominal wall. Purulent and malodorous drainage was noted at the stoma site. There was no Foley catheter or J-tube in place, and neither the patient nor his wife had brought the dislodged tube to the ED.

A computed tomography scan of the patient’s abdomen and pelvis were ordered with IV and oral contrast. The imaging studies revealed multiple dilated, fluid-filled loops of small bowel, and a Foley catheter proximal to the ileocecal valve, with the balloon still inflated (Figure).

The emergency physician notified the original surgical team of the patient’s status. The surgical team placed a new, 14 French (Fr)-Foley catheter through the stoma, sutured it in place, and admitted the patient to their service. The patient was maintained on IV antibiotics and fluids. As he continued to pass flatus and stool, a diet was advanced through the replacement Foley catheter. The intussuscepted Foley was subsequently passed naturally on day 4 of his hospital admission. The patient unfortunately died several days later of hypoxic respiratory failure, which was not thought to be related to the ingested catheter.

Discussion

Percutaneous Foley catheters, either pre- or postpyloric, have been used for decades as permanent feeding tubes for patients unable to tolerate oral feedings. These catheters are well-known to be inexpensive and safe replacements for commercial gastrostomy tubes.⁷ However, a number of complications unique to Foley feeding tubes have been described in case reports, including mechanical obstruction leading to pancreatitis, duodenal obstruction, bowel ischemia secondary to balloon overfilling, pyloric obstruction, bowel infection, as well as broken and digested catheters.^8-10

Interestingly, despite multiple case reports demonstrating tube migration, prospective studies have shown this to be a relatively uncommon complication.¹¹ In 2012, a patient in Israel ingested a Foley catheter via the gastrostomy stoma, resulting in small bowel obstruction relieved only by enterotomy and removal of the catheter. There have been no previous documented reports of ingested tubes via jejunostomy stoma.¹² Significant forces exerted on Foley catheters have been described, resulting in skin necrosis at the hub and stretching of the catheter from the proximal small bowel to the terminal ileum. In this case presentation, bowel peristalsis was able to advance the entire tube through the skin.¹³

Management of feeding-Foley-catheter complications typically involves deflation of the balloon and removal and replacement of the offending catheter—usually with a smaller sized Foley catheter (eg, 12Fr, 14Fr, 16Fr). Complicated cases with catheter malfunction have been successfully managed endoscopically.¹⁴ The patient in this case was likely at higher risk of complication given the abnormally large wound surrounding the stoma and skin breakdown secondary to superimposed infection.

Conclusion

This case highlights the potent peristaltic forces that are exerted upon a feeding Foley catheter and reinforces the importance of proper tube anchorage. Although this patient did well with direct skin suturing of the replacement catheter, previous studies recommend using a plastic retention ring. Placing a mark on the outside of the catheter as a means to continuously visualize its proper anchorage and placement has also been suggested in the literature. Additionally, whenever a patient presents with a displaced feeding tube (Foley catheter or commercial tube), providers should not assume that the tube has been displaced externally and should maintain a low-threshold for advanced imaging and/or endoscopy if the tube cannot otherwise be located.

Dr Lefkove is an attending physician in the department of emergency medicine, DeKalb Medical Center, Atlanta, Georgia. Dr Meloy is an assistant professor of emergency medicine at Emory University School of Medicine, Atlanta, Georgia.

Anticonvulsants, antidepressants, and opioids are the most frequently prescribed medications for neuropathic pain.¹ But some patients are unable to tolerate the adverse effects of these drugs, and others achieve only partial pain relief. What can you offer them?

Combinations of prescription medications are generally considered more effective than monotherapy for painful peripheral neuropathy,¹ but it is unclear which combinations are best. Alternative therapies—several of which have some evidence of safety and efficacy in treating peripheral neuropathy—are another option. Yet trials with alternative therapies, alone or in combination with prescription drugs, are rarely considered.

In fact, physicians are often unfamiliar with these therapies. Many are concerned about the absence of US Food and Drug Administration approval for alternative therapies and the variability in quality control associated with the lack of oversight, as well. Making recommendations about the duration of therapy also presents a challenge because most studies of supplements are relatively short. What’s more, alternative treatments are rarely covered by third-party payers.

Nonetheless, the therapies detailed in the text and TABLE^2-12 that follow are generally well tolerated and appear to be safe. Adding them to your arsenal of therapeutic choices for patients with painful peripheral neuropathy may increase your ability to provide successful treatment.

Acetyl-L-carnitine (ALC)

ALC occurs naturally in the body as L-carnitine and acetyl-carnitine esters, which are converted to carnitines by intracellular enzymes and cell membrane transporters.² ALC has been studied in patients with neuropathy associated with human immunodeficiency virus (HIV), cancer, and diabetes. Potential mechanisms of action include the correction of a deficiency that may be causing the neuropathy (which sometimes occurs in HIV-positive patients¹³ or those taking anticonvulsants¹⁴), a direct antioxidant effect, or an enhanced response to nerve growth factor.¹³

Adding these generally well-tolerated therapies to your arsenal of therapeutic choices for patients may increase your ability to provide successful treatment.

ALC can be given intramuscularly (IM) or orally in doses of 2000 to 3000 mg/d. In one randomized placebo-controlled trial (N=333), patients with diabetic neuropathy received 1000 mg IM followed by an oral dose of 2000 mg every day for a year.⁶ Mean pain scores decreased by 39%, with 67% of those receiving ALC vs 23% of those on placebo showing moderate to marked improvement.

In a pooled analysis (N=1257) of 2 randomized controlled trials (RCTs), patients with diabetes took 1000 mg ALC 3 times daily or placebo for a year.⁷ Cohort pain scores improved by 40% from baseline in the ALC group compared with a 24% improvement for those in the placebo group.

THE BOTTOM LINE ALC is well tolerated, with minor adverse effects such as headache and nausea reported.^6,7 It should not be given to patients taking acenocoumarol or warfarin, however. A major interaction causing an elevated international normalized ratio has been found to occur when either agent is combined with L-carnitine² and could theoretically occur with ALC, as well. No other drug-drug interactions have been documented.²

Alpha lipoic acid (ALA)

Both a fat- and a water-soluble vitamin that is usually obtained from the diet, ALA regenerates endogenous antioxidants like vitamins C and E and glutathione. It is this regenerative mechanism that it is believed to alleviate diabetic neuropathy.² ALA 600 mg/d appears to be effective, although studies suggest that intravenous (IV) use is more effective than oral administration.

IV administration of alpha lipoic acid is more effective than oral administration, but patients run the risk of an allergic reaction at the injection site.

A meta-analysis of 4 RCTs (N=653), 2 with ALA taken orally and 2 involving IV administration, is a case in point.³ The pooled standardized mean difference estimated from all trials showed a reduction in total symptom scores of −2.26 (95% confidence interval [CI], −3.12 to −1.41; P=.00001), with 0 indicating no symptoms, 3 indicating severe symptoms, and a maximum score of 14.64 if all symptoms were severe and continuous. Subgroup analyses revealed a reduction of −1.78 (95% CI, −2.45 to −1.10; P=.00001) for oral ALA and −2.81 (95% CI, −4.16 to −1.46; P=.0001) for IV administration. Doses >600 mg/d did not improve efficacy, but did increase adverse effects such as nausea, vomiting, and dizziness.

In a multicenter RCT (N=460) of ALA 600 mg/d for 4 years, however, no improvement in the primary endpoint (a composite of neuropathy impairment scores and 7 neurophysiologic tests) was found.¹⁵ Although there was a statistically significant improvement in symptoms of neuropathy (−0.68 with ALA compared with +0.61 with placebo), the change was too small to be considered clinically significant.

ALA did slow the progression of neuropathy, however, with 29% of patients in the treatment group experiencing worsening symptoms compared with 38% of those on placebo. There was no difference in tolerability or discontinuation of treatment between the 2 groups.

A recent observational study (N=101) compared the efficacy of pregabalin, carbamazepine, and ALA over a 21-month period.⁴ Although those taking pregabalin had the best response rate, all 3 treatments led to significant improvement in the burning associated with neuropathic pain.

ALA 100 mg bid has been investigated as part of a 3-drug combination (with pregabalin 75 mg bid and methylcobalamin 750 mcg bid) compared with monotherapy (pregabalin 75 mg bid) in an open randomized study (N=30) for 12 weeks.¹⁶ While there was a trend toward improvement in pain relief, sleep interference, and nerve function in the combination therapy group, no statistically significant difference between the 2 groups was found. Nonetheless, more than a third (36%) had a global assessment rating of “excellent” vs one in 5 (20%) of those on pregabalin alone.

THE BOTTOM LINE Overall, ALA is well tolerated; the most common adverse effects are nausea and skin rash. IV administration is more effective than oral administration, but may cause nausea, headache, and an allergic reaction at the injection site.² ALA does have the potential for an interaction with chemotherapy and thyroid hormone and may decrease the effectiveness of these therapies.²

B vitamins

Deficiencies of vitamin B1 (thiamine), B6 (pyridoxine), B12 (cyanocobalamin), and folate are known causes of neuropathy, and correcting them often improves or eliminates the symptoms.¹³ Vitamin B12 deficiency is commonly seen in patients taking metformin;¹⁴ these patients may benefit from supplementation with B12 1000 mcg/d.

Many of the B vitamins have been studied for treatment of neuropathy, but benfotiamine (a lipid-soluble form of thiamine) is thought to be the best option because it is better absorbed across cell membranes than other B vitamins.⁹ A Cochrane review found that benfotiamine alone may be effective for both diabetic and alcoholic neuropathy and that short-term use of higher doses of vitamin B complex (25 mg B1 or 320 mg benfotiamine + 50-720 mg B6 + 1000 mcg B12 daily) may reduce neuropathic pain.⁹

Vitamin B12 deficiency is common in patients taking metformin; they may benefit from supplementation with B12 1000 mcg/d.

A randomized multicenter trial (N=214) found that adding a supplement containing L-methylfolate 3 mg, pyridoxal 5-phosphate 35 mg, and methylcobalamin 2 mg twice daily to other medications (eg, pregabalin, gabapentin, or duloxetine) improved symptoms of diabetic neuropathy.¹⁰ At 24 weeks, those receiving the combination therapy had a 26% decrease in pain symptoms compared with a 15% decrease for those on medication alone, with no significant adverse effects.

THE BOTTOM LINE Overall, vitamin B supplementation is well tolerated and appears to be more effective in relieving neuropathic pain than medication alone.^9,14 But larger studies are needed before its efficacy in treating patients who do not have a deficiency can be established.

Capsaicin

Capsaicin, an ingredient found in peppers, works by binding to nociceptors to selectively stimulate afferent C fibers. This causes the release of substance P, a neurotransmitter that mediates pain, leading to its depletion and resulting in desensitization.² Several meta-analyses and systematic reviews have found that topical capsaicin can be very effective, both as an adjunctive treatment and as monotherapy for neuropathic pain.^11,17,18 The concentration used in the studies was 0.075% capsaicin cream, applied 3 to 4 times a day for 6 to 12 weeks, compared with placebo creams. In all categories studied, capsaicin was either statistically significant or trending in its favor, with the exception of adverse effects.

Capsaicin led to an improvement in daily activities and ability to sleep and a reduction in pain as measured with a visual analog scale and physician global evaluation.^11,17,18

The most notable adverse effects were a burning sensation on the skin and coughing and sneezing caused by inhalation of dried cream. Although the adverse effects were expected to improve after 2 to 7 days of use, a significant number of participants withdrew from the study.

A 7-study meta-analysis showed the effectiveness of an 8% capsaicin patch for treatment of post-herpetic neuralgia and HIV-associated neuropathy.¹² The patch, available only by prescription, was worn every day for 4 weeks (60 minutes daily for post-herpetic neuralgia and 30 minutes a day for HIV-associated neuropathy). The pooled results were statistically significant, but the patch was less effective for patients ages 18 to 40 years and for those of Asian descent. It can be used with other analgesics or as monotherapy, with few adverse reactions.^12,19

THE BOTTOM LINE Since capsaicin is a topical medication, there are no relevant drug-drug interactions. Patients should be cautioned to wash their hands after application, however, and to avoid contact with eyes and open wounds.

Gamma linolenic acid (GLA)

Also known as evening primrose oil, GLA is an omega-6 fatty acid that’s an important constituent of neuronal cell membranes—and believed to decrease neuropathic pain by having some anti-inflammatory effects.² This suggests that therapy with GLA has the potential to improve neuronal phospholipid structure and microcirculation.²

Two placebo-controlled trials (N=22,111) showed improvement in pain scores and multiple neurophysiologic assessments in patients with diabetes treated with GLA (360-480 mg/d).^20,21 The treatment was well tolerated, but the beneficial effect was more pronounced in those with less severe diabetes.

THE BOTTOM LINE The dose of GLA studied (8 to 12 capsules daily) could lead to problems with patient adherence. In addition, GLA should be used with caution in patients who are taking antiplatelet medication or have seizure disorders.² 

Magnesium (Mg)

Mg is highly involved in multiple enzyme systems throughout the body. Although it is very well absorbed from dietary sources,² patients with diabetes, liver disease, and hormonal imbalances, as well as the elderly, are often deficient in Mg. It is unclear how this affects peripheral neuropathy.¹³

Mg may have an antinociceptive effect by decreasing intracellular calcium influx and antagonizing N-methyl-D-aspartate receptors and associated nerve signaling.²² A small RCT (N=80) showed Mg to decrease the severity of neuropathic back pain.²² Patients received Mg sulfate 1 g IV, given over 4 hours, every day for 2 weeks. The infusion was then replaced with Mg oxide 400 mg plus Mg gluconate 100 mg, taken orally twice daily for 4 weeks. An improvement in mean pain score was seen as early as 2 weeks, and scores had decreased by 2.8 points (on a 0-10-point scale) at 6 months.

Another small RCT (N=45) gave patients with neuropathy of postherpetic, traumatic, or surgical (but not diabetic) origin Mg chloride 838 mg orally 3 times a day for 4 weeks.²³ The supplement was taken with meals. Mean pain scores in the treatment group decreased by 3 points, but this was not significantly different from the improvement seen in those on placebo.

Patients with painful diabetic neuropathy may benefit from magnesium (Mg) gluconate 300 mg/d, but supplementation is unsafe for those with renal dysfunction, cardiac conduction abnormalities, or elevated Mg levels.

In a similar study, patients (N=110) with type 1 diabetes and a normal serum Mg but an insufficiency as measured by erythrocyte Mg were given Mg gluconate 300 mg or placebo daily for 5 years.⁸ The supplement slowed the progression of peripheral neuropathy (only 12% of those receiving Mg gluconate experienced a significant worsening of symptoms over the course of the study, compared with 61% of those in the placebo group), but in most cases, it did not lead to an improvement.

No consistent approach to Mg supplementation has been studied, which makes recommending a particular route, dose, or formulation challenging. There is evidence that oral Mg, particularly in the form of Mg oxide, can cause diarrhea, especially in doses >350 mg/d. Mg gluconate and Mg chloride are better tolerated; Mg carbonate should be avoided due to poor oral absorption.²

BOTTOM LINE Mg supplementation appears to slow the progression of diabetic peripheral neuropathy, but is unsafe for patients with renal dysfunction, cardiac conduction abnormalities, or elevated Mg levels.² Caution is required, too, when considering Mg supplementation for patients taking anticoagulants, bisphosphonates, digoxin, potassium-sparing diuretics, or tetracycline antibiotics.²

CORRESPONDENCE 
Mary Onysko, PharmD, BCPS, University of Wyoming, School of Pharmacy Health Sciences Center, Room 292, 1000 E. University Avenue, Laramie, WY 82071; [email protected]

Anticonvulsants, antidepressants, and opioids are the most frequently prescribed medications for neuropathic pain.¹ But some patients are unable to tolerate the adverse effects of these drugs, and others achieve only partial pain relief. What can you offer them?

Combinations of prescription medications are generally considered more effective than monotherapy for painful peripheral neuropathy,¹ but it is unclear which combinations are best. Alternative therapies—several of which have some evidence of safety and efficacy in treating peripheral neuropathy—are another option. Yet trials with alternative therapies, alone or in combination with prescription drugs, are rarely considered.

In fact, physicians are often unfamiliar with these therapies. Many are concerned about the absence of US Food and Drug Administration approval for alternative therapies and the variability in quality control associated with the lack of oversight, as well. Making recommendations about the duration of therapy also presents a challenge because most studies of supplements are relatively short. What’s more, alternative treatments are rarely covered by third-party payers.

Nonetheless, the therapies detailed in the text and TABLE^2-12 that follow are generally well tolerated and appear to be safe. Adding them to your arsenal of therapeutic choices for patients with painful peripheral neuropathy may increase your ability to provide successful treatment.

Acetyl-L-carnitine (ALC)

ALC occurs naturally in the body as L-carnitine and acetyl-carnitine esters, which are converted to carnitines by intracellular enzymes and cell membrane transporters.² ALC has been studied in patients with neuropathy associated with human immunodeficiency virus (HIV), cancer, and diabetes. Potential mechanisms of action include the correction of a deficiency that may be causing the neuropathy (which sometimes occurs in HIV-positive patients¹³ or those taking anticonvulsants¹⁴), a direct antioxidant effect, or an enhanced response to nerve growth factor.¹³

Adding these generally well-tolerated therapies to your arsenal of therapeutic choices for patients may increase your ability to provide successful treatment.

ALC can be given intramuscularly (IM) or orally in doses of 2000 to 3000 mg/d. In one randomized placebo-controlled trial (N=333), patients with diabetic neuropathy received 1000 mg IM followed by an oral dose of 2000 mg every day for a year.⁶ Mean pain scores decreased by 39%, with 67% of those receiving ALC vs 23% of those on placebo showing moderate to marked improvement.

In a pooled analysis (N=1257) of 2 randomized controlled trials (RCTs), patients with diabetes took 1000 mg ALC 3 times daily or placebo for a year.⁷ Cohort pain scores improved by 40% from baseline in the ALC group compared with a 24% improvement for those in the placebo group.

THE BOTTOM LINE ALC is well tolerated, with minor adverse effects such as headache and nausea reported.^6,7 It should not be given to patients taking acenocoumarol or warfarin, however. A major interaction causing an elevated international normalized ratio has been found to occur when either agent is combined with L-carnitine² and could theoretically occur with ALC, as well. No other drug-drug interactions have been documented.²

Alpha lipoic acid (ALA)

Both a fat- and a water-soluble vitamin that is usually obtained from the diet, ALA regenerates endogenous antioxidants like vitamins C and E and glutathione. It is this regenerative mechanism that it is believed to alleviate diabetic neuropathy.² ALA 600 mg/d appears to be effective, although studies suggest that intravenous (IV) use is more effective than oral administration.

IV administration of alpha lipoic acid is more effective than oral administration, but patients run the risk of an allergic reaction at the injection site.

A meta-analysis of 4 RCTs (N=653), 2 with ALA taken orally and 2 involving IV administration, is a case in point.³ The pooled standardized mean difference estimated from all trials showed a reduction in total symptom scores of −2.26 (95% confidence interval [CI], −3.12 to −1.41; P=.00001), with 0 indicating no symptoms, 3 indicating severe symptoms, and a maximum score of 14.64 if all symptoms were severe and continuous. Subgroup analyses revealed a reduction of −1.78 (95% CI, −2.45 to −1.10; P=.00001) for oral ALA and −2.81 (95% CI, −4.16 to −1.46; P=.0001) for IV administration. Doses >600 mg/d did not improve efficacy, but did increase adverse effects such as nausea, vomiting, and dizziness.

In a multicenter RCT (N=460) of ALA 600 mg/d for 4 years, however, no improvement in the primary endpoint (a composite of neuropathy impairment scores and 7 neurophysiologic tests) was found.¹⁵ Although there was a statistically significant improvement in symptoms of neuropathy (−0.68 with ALA compared with +0.61 with placebo), the change was too small to be considered clinically significant.

ALA did slow the progression of neuropathy, however, with 29% of patients in the treatment group experiencing worsening symptoms compared with 38% of those on placebo. There was no difference in tolerability or discontinuation of treatment between the 2 groups.

A recent observational study (N=101) compared the efficacy of pregabalin, carbamazepine, and ALA over a 21-month period.⁴ Although those taking pregabalin had the best response rate, all 3 treatments led to significant improvement in the burning associated with neuropathic pain.

ALA 100 mg bid has been investigated as part of a 3-drug combination (with pregabalin 75 mg bid and methylcobalamin 750 mcg bid) compared with monotherapy (pregabalin 75 mg bid) in an open randomized study (N=30) for 12 weeks.¹⁶ While there was a trend toward improvement in pain relief, sleep interference, and nerve function in the combination therapy group, no statistically significant difference between the 2 groups was found. Nonetheless, more than a third (36%) had a global assessment rating of “excellent” vs one in 5 (20%) of those on pregabalin alone.

THE BOTTOM LINE Overall, ALA is well tolerated; the most common adverse effects are nausea and skin rash. IV administration is more effective than oral administration, but may cause nausea, headache, and an allergic reaction at the injection site.² ALA does have the potential for an interaction with chemotherapy and thyroid hormone and may decrease the effectiveness of these therapies.²

B vitamins

Deficiencies of vitamin B1 (thiamine), B6 (pyridoxine), B12 (cyanocobalamin), and folate are known causes of neuropathy, and correcting them often improves or eliminates the symptoms.¹³ Vitamin B12 deficiency is commonly seen in patients taking metformin;¹⁴ these patients may benefit from supplementation with B12 1000 mcg/d.

Many of the B vitamins have been studied for treatment of neuropathy, but benfotiamine (a lipid-soluble form of thiamine) is thought to be the best option because it is better absorbed across cell membranes than other B vitamins.⁹ A Cochrane review found that benfotiamine alone may be effective for both diabetic and alcoholic neuropathy and that short-term use of higher doses of vitamin B complex (25 mg B1 or 320 mg benfotiamine + 50-720 mg B6 + 1000 mcg B12 daily) may reduce neuropathic pain.⁹

Vitamin B12 deficiency is common in patients taking metformin; they may benefit from supplementation with B12 1000 mcg/d.

A randomized multicenter trial (N=214) found that adding a supplement containing L-methylfolate 3 mg, pyridoxal 5-phosphate 35 mg, and methylcobalamin 2 mg twice daily to other medications (eg, pregabalin, gabapentin, or duloxetine) improved symptoms of diabetic neuropathy.¹⁰ At 24 weeks, those receiving the combination therapy had a 26% decrease in pain symptoms compared with a 15% decrease for those on medication alone, with no significant adverse effects.

THE BOTTOM LINE Overall, vitamin B supplementation is well tolerated and appears to be more effective in relieving neuropathic pain than medication alone.^9,14 But larger studies are needed before its efficacy in treating patients who do not have a deficiency can be established.

Capsaicin

Capsaicin, an ingredient found in peppers, works by binding to nociceptors to selectively stimulate afferent C fibers. This causes the release of substance P, a neurotransmitter that mediates pain, leading to its depletion and resulting in desensitization.² Several meta-analyses and systematic reviews have found that topical capsaicin can be very effective, both as an adjunctive treatment and as monotherapy for neuropathic pain.^11,17,18 The concentration used in the studies was 0.075% capsaicin cream, applied 3 to 4 times a day for 6 to 12 weeks, compared with placebo creams. In all categories studied, capsaicin was either statistically significant or trending in its favor, with the exception of adverse effects.

Capsaicin led to an improvement in daily activities and ability to sleep and a reduction in pain as measured with a visual analog scale and physician global evaluation.^11,17,18

The most notable adverse effects were a burning sensation on the skin and coughing and sneezing caused by inhalation of dried cream. Although the adverse effects were expected to improve after 2 to 7 days of use, a significant number of participants withdrew from the study.

A 7-study meta-analysis showed the effectiveness of an 8% capsaicin patch for treatment of post-herpetic neuralgia and HIV-associated neuropathy.¹² The patch, available only by prescription, was worn every day for 4 weeks (60 minutes daily for post-herpetic neuralgia and 30 minutes a day for HIV-associated neuropathy). The pooled results were statistically significant, but the patch was less effective for patients ages 18 to 40 years and for those of Asian descent. It can be used with other analgesics or as monotherapy, with few adverse reactions.^12,19

THE BOTTOM LINE Since capsaicin is a topical medication, there are no relevant drug-drug interactions. Patients should be cautioned to wash their hands after application, however, and to avoid contact with eyes and open wounds.

Gamma linolenic acid (GLA)

Also known as evening primrose oil, GLA is an omega-6 fatty acid that’s an important constituent of neuronal cell membranes—and believed to decrease neuropathic pain by having some anti-inflammatory effects.² This suggests that therapy with GLA has the potential to improve neuronal phospholipid structure and microcirculation.²

Two placebo-controlled trials (N=22,111) showed improvement in pain scores and multiple neurophysiologic assessments in patients with diabetes treated with GLA (360-480 mg/d).^20,21 The treatment was well tolerated, but the beneficial effect was more pronounced in those with less severe diabetes.

THE BOTTOM LINE The dose of GLA studied (8 to 12 capsules daily) could lead to problems with patient adherence. In addition, GLA should be used with caution in patients who are taking antiplatelet medication or have seizure disorders.² 

Magnesium (Mg)

Mg is highly involved in multiple enzyme systems throughout the body. Although it is very well absorbed from dietary sources,² patients with diabetes, liver disease, and hormonal imbalances, as well as the elderly, are often deficient in Mg. It is unclear how this affects peripheral neuropathy.¹³

Mg may have an antinociceptive effect by decreasing intracellular calcium influx and antagonizing N-methyl-D-aspartate receptors and associated nerve signaling.²² A small RCT (N=80) showed Mg to decrease the severity of neuropathic back pain.²² Patients received Mg sulfate 1 g IV, given over 4 hours, every day for 2 weeks. The infusion was then replaced with Mg oxide 400 mg plus Mg gluconate 100 mg, taken orally twice daily for 4 weeks. An improvement in mean pain score was seen as early as 2 weeks, and scores had decreased by 2.8 points (on a 0-10-point scale) at 6 months.

Another small RCT (N=45) gave patients with neuropathy of postherpetic, traumatic, or surgical (but not diabetic) origin Mg chloride 838 mg orally 3 times a day for 4 weeks.²³ The supplement was taken with meals. Mean pain scores in the treatment group decreased by 3 points, but this was not significantly different from the improvement seen in those on placebo.

Patients with painful diabetic neuropathy may benefit from magnesium (Mg) gluconate 300 mg/d, but supplementation is unsafe for those with renal dysfunction, cardiac conduction abnormalities, or elevated Mg levels.

In a similar study, patients (N=110) with type 1 diabetes and a normal serum Mg but an insufficiency as measured by erythrocyte Mg were given Mg gluconate 300 mg or placebo daily for 5 years.⁸ The supplement slowed the progression of peripheral neuropathy (only 12% of those receiving Mg gluconate experienced a significant worsening of symptoms over the course of the study, compared with 61% of those in the placebo group), but in most cases, it did not lead to an improvement.

No consistent approach to Mg supplementation has been studied, which makes recommending a particular route, dose, or formulation challenging. There is evidence that oral Mg, particularly in the form of Mg oxide, can cause diarrhea, especially in doses >350 mg/d. Mg gluconate and Mg chloride are better tolerated; Mg carbonate should be avoided due to poor oral absorption.²

BOTTOM LINE Mg supplementation appears to slow the progression of diabetic peripheral neuropathy, but is unsafe for patients with renal dysfunction, cardiac conduction abnormalities, or elevated Mg levels.² Caution is required, too, when considering Mg supplementation for patients taking anticoagulants, bisphosphonates, digoxin, potassium-sparing diuretics, or tetracycline antibiotics.²

CORRESPONDENCE 
Mary Onysko, PharmD, BCPS, University of Wyoming, School of Pharmacy Health Sciences Center, Room 292, 1000 E. University Avenue, Laramie, WY 82071; [email protected]

Anticonvulsants, antidepressants, and opioids are the most frequently prescribed medications for neuropathic pain.¹ But some patients are unable to tolerate the adverse effects of these drugs, and others achieve only partial pain relief. What can you offer them?

Combinations of prescription medications are generally considered more effective than monotherapy for painful peripheral neuropathy,¹ but it is unclear which combinations are best. Alternative therapies—several of which have some evidence of safety and efficacy in treating peripheral neuropathy—are another option. Yet trials with alternative therapies, alone or in combination with prescription drugs, are rarely considered.

In fact, physicians are often unfamiliar with these therapies. Many are concerned about the absence of US Food and Drug Administration approval for alternative therapies and the variability in quality control associated with the lack of oversight, as well. Making recommendations about the duration of therapy also presents a challenge because most studies of supplements are relatively short. What’s more, alternative treatments are rarely covered by third-party payers.

Nonetheless, the therapies detailed in the text and TABLE^2-12 that follow are generally well tolerated and appear to be safe. Adding them to your arsenal of therapeutic choices for patients with painful peripheral neuropathy may increase your ability to provide successful treatment.

Acetyl-L-carnitine (ALC)

ALC occurs naturally in the body as L-carnitine and acetyl-carnitine esters, which are converted to carnitines by intracellular enzymes and cell membrane transporters.² ALC has been studied in patients with neuropathy associated with human immunodeficiency virus (HIV), cancer, and diabetes. Potential mechanisms of action include the correction of a deficiency that may be causing the neuropathy (which sometimes occurs in HIV-positive patients¹³ or those taking anticonvulsants¹⁴), a direct antioxidant effect, or an enhanced response to nerve growth factor.¹³

Adding these generally well-tolerated therapies to your arsenal of therapeutic choices for patients may increase your ability to provide successful treatment.

ALC can be given intramuscularly (IM) or orally in doses of 2000 to 3000 mg/d. In one randomized placebo-controlled trial (N=333), patients with diabetic neuropathy received 1000 mg IM followed by an oral dose of 2000 mg every day for a year.⁶ Mean pain scores decreased by 39%, with 67% of those receiving ALC vs 23% of those on placebo showing moderate to marked improvement.

In a pooled analysis (N=1257) of 2 randomized controlled trials (RCTs), patients with diabetes took 1000 mg ALC 3 times daily or placebo for a year.⁷ Cohort pain scores improved by 40% from baseline in the ALC group compared with a 24% improvement for those in the placebo group.

THE BOTTOM LINE ALC is well tolerated, with minor adverse effects such as headache and nausea reported.^6,7 It should not be given to patients taking acenocoumarol or warfarin, however. A major interaction causing an elevated international normalized ratio has been found to occur when either agent is combined with L-carnitine² and could theoretically occur with ALC, as well. No other drug-drug interactions have been documented.²

Alpha lipoic acid (ALA)

Both a fat- and a water-soluble vitamin that is usually obtained from the diet, ALA regenerates endogenous antioxidants like vitamins C and E and glutathione. It is this regenerative mechanism that it is believed to alleviate diabetic neuropathy.² ALA 600 mg/d appears to be effective, although studies suggest that intravenous (IV) use is more effective than oral administration.

IV administration of alpha lipoic acid is more effective than oral administration, but patients run the risk of an allergic reaction at the injection site.

A meta-analysis of 4 RCTs (N=653), 2 with ALA taken orally and 2 involving IV administration, is a case in point.³ The pooled standardized mean difference estimated from all trials showed a reduction in total symptom scores of −2.26 (95% confidence interval [CI], −3.12 to −1.41; P=.00001), with 0 indicating no symptoms, 3 indicating severe symptoms, and a maximum score of 14.64 if all symptoms were severe and continuous. Subgroup analyses revealed a reduction of −1.78 (95% CI, −2.45 to −1.10; P=.00001) for oral ALA and −2.81 (95% CI, −4.16 to −1.46; P=.0001) for IV administration. Doses >600 mg/d did not improve efficacy, but did increase adverse effects such as nausea, vomiting, and dizziness.

In a multicenter RCT (N=460) of ALA 600 mg/d for 4 years, however, no improvement in the primary endpoint (a composite of neuropathy impairment scores and 7 neurophysiologic tests) was found.¹⁵ Although there was a statistically significant improvement in symptoms of neuropathy (−0.68 with ALA compared with +0.61 with placebo), the change was too small to be considered clinically significant.

ALA did slow the progression of neuropathy, however, with 29% of patients in the treatment group experiencing worsening symptoms compared with 38% of those on placebo. There was no difference in tolerability or discontinuation of treatment between the 2 groups.

A recent observational study (N=101) compared the efficacy of pregabalin, carbamazepine, and ALA over a 21-month period.⁴ Although those taking pregabalin had the best response rate, all 3 treatments led to significant improvement in the burning associated with neuropathic pain.

ALA 100 mg bid has been investigated as part of a 3-drug combination (with pregabalin 75 mg bid and methylcobalamin 750 mcg bid) compared with monotherapy (pregabalin 75 mg bid) in an open randomized study (N=30) for 12 weeks.¹⁶ While there was a trend toward improvement in pain relief, sleep interference, and nerve function in the combination therapy group, no statistically significant difference between the 2 groups was found. Nonetheless, more than a third (36%) had a global assessment rating of “excellent” vs one in 5 (20%) of those on pregabalin alone.

THE BOTTOM LINE Overall, ALA is well tolerated; the most common adverse effects are nausea and skin rash. IV administration is more effective than oral administration, but may cause nausea, headache, and an allergic reaction at the injection site.² ALA does have the potential for an interaction with chemotherapy and thyroid hormone and may decrease the effectiveness of these therapies.²

B vitamins

Deficiencies of vitamin B1 (thiamine), B6 (pyridoxine), B12 (cyanocobalamin), and folate are known causes of neuropathy, and correcting them often improves or eliminates the symptoms.¹³ Vitamin B12 deficiency is commonly seen in patients taking metformin;¹⁴ these patients may benefit from supplementation with B12 1000 mcg/d.

Many of the B vitamins have been studied for treatment of neuropathy, but benfotiamine (a lipid-soluble form of thiamine) is thought to be the best option because it is better absorbed across cell membranes than other B vitamins.⁹ A Cochrane review found that benfotiamine alone may be effective for both diabetic and alcoholic neuropathy and that short-term use of higher doses of vitamin B complex (25 mg B1 or 320 mg benfotiamine + 50-720 mg B6 + 1000 mcg B12 daily) may reduce neuropathic pain.⁹

Vitamin B12 deficiency is common in patients taking metformin; they may benefit from supplementation with B12 1000 mcg/d.

A randomized multicenter trial (N=214) found that adding a supplement containing L-methylfolate 3 mg, pyridoxal 5-phosphate 35 mg, and methylcobalamin 2 mg twice daily to other medications (eg, pregabalin, gabapentin, or duloxetine) improved symptoms of diabetic neuropathy.¹⁰ At 24 weeks, those receiving the combination therapy had a 26% decrease in pain symptoms compared with a 15% decrease for those on medication alone, with no significant adverse effects.

THE BOTTOM LINE Overall, vitamin B supplementation is well tolerated and appears to be more effective in relieving neuropathic pain than medication alone.^9,14 But larger studies are needed before its efficacy in treating patients who do not have a deficiency can be established.

Capsaicin

Capsaicin, an ingredient found in peppers, works by binding to nociceptors to selectively stimulate afferent C fibers. This causes the release of substance P, a neurotransmitter that mediates pain, leading to its depletion and resulting in desensitization.² Several meta-analyses and systematic reviews have found that topical capsaicin can be very effective, both as an adjunctive treatment and as monotherapy for neuropathic pain.^11,17,18 The concentration used in the studies was 0.075% capsaicin cream, applied 3 to 4 times a day for 6 to 12 weeks, compared with placebo creams. In all categories studied, capsaicin was either statistically significant or trending in its favor, with the exception of adverse effects.

Capsaicin led to an improvement in daily activities and ability to sleep and a reduction in pain as measured with a visual analog scale and physician global evaluation.^11,17,18

The most notable adverse effects were a burning sensation on the skin and coughing and sneezing caused by inhalation of dried cream. Although the adverse effects were expected to improve after 2 to 7 days of use, a significant number of participants withdrew from the study.

A 7-study meta-analysis showed the effectiveness of an 8% capsaicin patch for treatment of post-herpetic neuralgia and HIV-associated neuropathy.¹² The patch, available only by prescription, was worn every day for 4 weeks (60 minutes daily for post-herpetic neuralgia and 30 minutes a day for HIV-associated neuropathy). The pooled results were statistically significant, but the patch was less effective for patients ages 18 to 40 years and for those of Asian descent. It can be used with other analgesics or as monotherapy, with few adverse reactions.^12,19

THE BOTTOM LINE Since capsaicin is a topical medication, there are no relevant drug-drug interactions. Patients should be cautioned to wash their hands after application, however, and to avoid contact with eyes and open wounds.

Gamma linolenic acid (GLA)

Also known as evening primrose oil, GLA is an omega-6 fatty acid that’s an important constituent of neuronal cell membranes—and believed to decrease neuropathic pain by having some anti-inflammatory effects.² This suggests that therapy with GLA has the potential to improve neuronal phospholipid structure and microcirculation.²

Two placebo-controlled trials (N=22,111) showed improvement in pain scores and multiple neurophysiologic assessments in patients with diabetes treated with GLA (360-480 mg/d).^20,21 The treatment was well tolerated, but the beneficial effect was more pronounced in those with less severe diabetes.

THE BOTTOM LINE The dose of GLA studied (8 to 12 capsules daily) could lead to problems with patient adherence. In addition, GLA should be used with caution in patients who are taking antiplatelet medication or have seizure disorders.² 

Magnesium (Mg)

Mg is highly involved in multiple enzyme systems throughout the body. Although it is very well absorbed from dietary sources,² patients with diabetes, liver disease, and hormonal imbalances, as well as the elderly, are often deficient in Mg. It is unclear how this affects peripheral neuropathy.¹³

Mg may have an antinociceptive effect by decreasing intracellular calcium influx and antagonizing N-methyl-D-aspartate receptors and associated nerve signaling.²² A small RCT (N=80) showed Mg to decrease the severity of neuropathic back pain.²² Patients received Mg sulfate 1 g IV, given over 4 hours, every day for 2 weeks. The infusion was then replaced with Mg oxide 400 mg plus Mg gluconate 100 mg, taken orally twice daily for 4 weeks. An improvement in mean pain score was seen as early as 2 weeks, and scores had decreased by 2.8 points (on a 0-10-point scale) at 6 months.

Another small RCT (N=45) gave patients with neuropathy of postherpetic, traumatic, or surgical (but not diabetic) origin Mg chloride 838 mg orally 3 times a day for 4 weeks.²³ The supplement was taken with meals. Mean pain scores in the treatment group decreased by 3 points, but this was not significantly different from the improvement seen in those on placebo.

Patients with painful diabetic neuropathy may benefit from magnesium (Mg) gluconate 300 mg/d, but supplementation is unsafe for those with renal dysfunction, cardiac conduction abnormalities, or elevated Mg levels.

In a similar study, patients (N=110) with type 1 diabetes and a normal serum Mg but an insufficiency as measured by erythrocyte Mg were given Mg gluconate 300 mg or placebo daily for 5 years.⁸ The supplement slowed the progression of peripheral neuropathy (only 12% of those receiving Mg gluconate experienced a significant worsening of symptoms over the course of the study, compared with 61% of those in the placebo group), but in most cases, it did not lead to an improvement.

No consistent approach to Mg supplementation has been studied, which makes recommending a particular route, dose, or formulation challenging. There is evidence that oral Mg, particularly in the form of Mg oxide, can cause diarrhea, especially in doses >350 mg/d. Mg gluconate and Mg chloride are better tolerated; Mg carbonate should be avoided due to poor oral absorption.²

BOTTOM LINE Mg supplementation appears to slow the progression of diabetic peripheral neuropathy, but is unsafe for patients with renal dysfunction, cardiac conduction abnormalities, or elevated Mg levels.² Caution is required, too, when considering Mg supplementation for patients taking anticoagulants, bisphosphonates, digoxin, potassium-sparing diuretics, or tetracycline antibiotics.²

CORRESPONDENCE 
Mary Onysko, PharmD, BCPS, University of Wyoming, School of Pharmacy Health Sciences Center, Room 292, 1000 E. University Avenue, Laramie, WY 82071; [email protected]

Unintended pregnancy remains a serious problem in the United States, and the rate continues to increase. Currently, the unintended pregnancy rate is at an all-time high, estimated at 51% of all pregnancies.¹ Sobering statistics reveal that the United States has a significantly higher rate of unintended pregnancy than any other developed country.^2,3

So the question remains: If we have been introducing new contraceptive methods, why do unintended pregnancy rates keep rising in the United States?

The answer: Key barriers prevent women from attaining their desired contraceptive—foremost among them, cost.

The unintended pregnancy rate is highest among women who are poor, young (aged 18–24 years), minorities, or cohabitating.¹ The unintended pregnancy rate among poor women (income below the federal poverty level) of reproductive age has increased over the past few decades, whereas the rate among high-income women (more than twice the federal poverty level) has declined.¹ The unintended pregnancy rate discrepancy between poor women and those with means has increased 77%, from a threefold difference in 1995 to a difference of more than fivefold in 2008 (TABLE 1).^1,4

These data indicate that we are doing well providing contraception to women of means. However, as a society, we need to improve how we deliver contraceptives—especially highly effective methods—to poor women. As one might expect, given these numbers, low-income women have rates of abortion and unplanned birth that are nearly 6 times higher than their higher-income counterparts.¹ The resultant cost to society is substantial, with 68% of unplanned births paid for by public insurance programs such as Medicaid, compared with 38% of planned births.⁵

As women’s health providers, we must work to improve these numbers and advocate for our patients to help them gain access to the contraceptives they need in accordance with their reproductive life plan. In this article, we hope to put this information in context as we:

National and state snapshots reveal shifting proportions of intended, unintended pregnancies
Finer LB, Zolna MR. Shifts in intended and unintended pregnancies in the United States, 2001–2008. Am J Public Health. 2014;104(suppl 1):s43–s48.

Kost K. Unintended pregnancy rates at the state level: estimates for 2010 and trends since 2002. Guttmacher Institute. https://www.guttmacher.org/pubs/StateUP10.pdf. Published January 2015. Accessed June 29, 2015.

Recent studies have demonstrated trends in unplanned pregnancy over the past 2 decades on both a national and statewide level. Data from the National Survey of Family Growth have highlighted trends in abortion and miscarriage, and data from the National Center for Health Statistics have shed light on birth trends. Of 6 million births in 2008, 51% were unintended.¹ Unintended pregnancy was defined as a gestation that was mistimed or unwanted. Intended pregnancy was defined as one that was desired at the time it occurred or sooner.

2008 data focus on the national level
Although the overall pregnancy rate for US women aged 15 to 44 years is relatively unchanged, there is a small change in whether or not the pregnancy was intended. For 2008, as the rate of intended pregnancy dropped slightly, from 54 to 51 pregnancies per 1,000 women, the unintended pregnancy rate increased by 10%, from 49 to 54 pregnancies per 1,000 women. Proportionally, unintended pregnancies that resulted in abortion declined from 47% to 40%, whereas the rate of unintended pregnancies ending in birth increased to 27 births per 1,000 women.¹

2010 data focus on individual states
We now have state-specific data on trends in unintended pregnancy rates from 2002 to 2010 in the United States.⁶ In 28 of 50 states, more than half of all pregnancies were unintended, with rates ranging from 36% to 62%. The median rate was 47 unintended pregnancies per 1,000 women aged 15 to 44, with the lowest unintended pregnancy rate in New Hampshire at 32 per 1,000 women and highest rates in Delaware, Hawaii, and New York at 61 to 62 unintended pregnancies per 1,000 women.⁶

Between 2002 and 2010, unintended pregnancy rates fell 5% or more in 18 states and rose 5% or more in 4 states. In the remaining 12 states for which there are data, unintended pregnancy rates remained unchanged.

Interestingly, 16 states had increases in unintended pregnancy rates of 5% or more between 2002 and 2006. The trend reversed between 2006 and 2010, during which 28 of 41 states with available data experienced decreases of 5% or more and only 1 state experienced an increase of 5% or more. These latest numbers suggest we may be making some progress in reducing the overall rate of unintended pregnancy.

What this EVIDENCE means for practice
Although the rate of unintended pregnancy is declining in some states, the national rate is still increasing. This information emphasizes the need for all providers to consider initiating discussions about pregnancy intentions—a step that may be as important as obtaining blood pressure and weight. When women are seen for any health visit, they should be asked about their reproductive plans. The Centers for Disease Control and Prevention (CDC) has issued a helpful set of questions to guide the discussion of timing and planning pregnancy. It also provides useful information on ways to increase utilization of long-acting reversible contraceptives (LARCs) to help realize the goal of fewer unintended pregnancies. (For more on this discussion, see “How to motivate your patient to create a reproductive life plan,” below.)

How Colorado broke down barriers to highly effective contraception—and saved $42.5 million in 1 year
Ricketts S, Klinger G, Schwalberg R. Game change in Colorado: widespread use of long-acting reversible contraceptives and rapid decline of births among young, low-income women. Perspect Sexual Reprod Health. 2014;46(3):125–132.

The Contraceptive CHOICE Project in St. Louis County, Missouri, is an incredible success story. In it, clinicians made highly effective LARCs readily available and free of charge. When a large percentage of women chose a LARC method, the unintended pregnancy and abortion rates declined.⁷ In Colorado, providers put this study into practice, creating a successful statewide initiative to reduce the unintended pregnancy rate.⁸

The data behind LARC methods
LARC methods are backed by endorsements from the American College of Obstetricians and Gynecologists, the American Academy of Pediatrics, the CDC, and the World Health Organization, which recommend them for adolescents because of their superiority to shorter-acting methods. With LARCs, failure rates are lower and compliance is greater, making them ideal for adolescents, who have high unintended pregnancy rates.¹

However, based on 2011 data, only 2% of LARC users nationwide are aged 20 or younger. A number of barriers prevent young women from obtaining LARCs, including lack of education, limited access to and availability of the contraceptives, and, importantly, cost. Many state plans have adopted ­Medicaid expansions to reduce barriers to LARCs. However, this benefit is still not available in many states, Colorado being 1 of them.

How the Colorado initiative worked
In 2005, 40% of Colorado’s births were ­unintended, and 60% of those unintended births occurred in women aged 15 to 24 years. About three-quarters of women who were using a contraceptive method at the time of unintended pregnancy reported that it was a low-cost, high-failure method such as condoms or withdrawal.

In response, Colorado’s Department of Public Health and Environment and the ­Colorado Family Planning Initiative (CFPI) used private funds from an anonymous foundation to provide LARC products at no cost to the Title X–funded clinics in the state.

The initiative began in 2009 in clinics that served 95% of the state’s total population. The funding provided the products ­themselves (intrauterine device [IUD], implant), as well as training for providers and staff.

Before the initiative began, 52,645 clients received services in these clinics annually. In the third year of the initiative, that number had increased to 64,928 annually. About 55% of clients receiving services both preinitiative and postinitiative were younger than 25 years, and most (92% in 2011) had income below the poverty level.

LARC use increased fourfold over the 3 years of the funded program, from less than 4.5% to 19.4% in the third year. Contraceptive implant use increased tenfold, and IUD use increased by almost threefold. At the same time, oral contraceptive use declined 13%. Before the initiative, only 620 young, low-income women used a LARC method; afterward, 8,435 did.

These changes in contraceptive practice triggered a significant decline in pregnancy rates (TABLE 2) and abortion rates (TABLE 3). Abortion rates increased 8% among 20- to 24-year-olds who were not enrolled in the initiative and decreased 18% among those who were. The proportion of high-risk births (births to unmarried, low-income women with less than a high school education) dropped 24% after the initiative began. The proportion of high-risk births in counties not receiving CFPI funds stayed the same at 7%.

Colorado program saved $42.5 million in public funds
This Colorado program demonstrated that the CHOICE Project can be translated to a statewide initiative. Whereas CHOICE enrolled 9,256 women over 4 years, the Colorado initiative included more than 50,000 clients annually over 3 years. Colorado did not use any state funds for this project, which resulted in significant decreases in the unintended birth rate, abortion rate, and rate of high-risk births.

The Colorado governor’s office estimates that the CFPI saved $5.68 in Medicaid costs for Colorado for every dollar spent on contraceptives. In just 1 year (2010), the program saved approximately $42.5 million in public funds.

Ironically, despite the success of this project, the Colorado legislature denied further funding once the initial financial support ceased.
 

What this EVIDENCE means for practice
The Colorado program demonstrates that we all can provide LARC methods in practice, especially to young women. In this population, use of highly effective contraception resulted in fewer unintended pregnancies, births, and abortions statewide.

We also need to advocate for our patients, particularly those who have less means and rely on public assistance. Public funding of LARC methods clearly improves outcomes at an individual and population level.

A new, more affordable IUD enters the market
Eisenberg DL, Schreiber CA, Turok DK, Teal SB, Westhoff CL, Creinin MD. Three-year efficacy and safety of a new 52-mg levonorgestrel-releasing intrauterine system. Contraception. 2015;92(1):10–16.

Programs such as the Contraceptive CHOICE Project and the Colorado Family Planning Initiative relied on private foundations for financial support, largely because of the high cost of the IUDs and implants currently available in the United States. Even with the Affordable Care Act (ACA) reducing the costs of LARC products and other contraceptives for patients, there are still many women not covered by these programs. For example, “grandfathered” health insurance plans do not need to follow some aspects of the ACA.

Just as important, the high cost of LARC products takes a toll on providers and clinics that must finance the cost per unit to have stock on hand and then wait for months for reimbursement by insurance companies. As a result, some providers do not stock IUDs and implants and only order them as they are needed and approved by insurance for a particular patient. These barriers limit access to LARC methods and reduce the number of women who receive the products.⁸

Liletta is less expensive than other IUDs
Enter Liletta, a new levonorgestrel-releasing, 52-mg intrauterine system (IUS) that has been in clinical trials since 2009.⁹ ACCESS IUS (A Comprehensive Contraceptive Efficacy and Safety Study of an Intrauterine System) was initiated by Medicines360, a unique nonprofit pharmaceutical company committed to ensuring access to reproductive health products for all women (private and public sector).

ACCESS IUS is the largest IUD approval study ever performed exclusively in the United States. The Phase 3, open-label clinical trial was conducted at 29 sites around the United States, enrolling healthy, nonpregnant, sexually active women aged 16 to 45 years with regular menstrual cycles. Both nulliparous and parous women were included, with no weight or body mass index (BMI) restrictions applied. The study is ongoing and will continue for as long as 7 years. Eisenberg and colleagues published the data used for initial approval for 3 years of use in the United States and Europe.⁹

Details of the trial
A total of 1,600 women aged 16 to 35 years comprised the group in which efficacy was evaluated. An additional 151 women aged 36 to 45 years were evaluated for safety only. Of the enrolled women, 1,011 (58%) were nulliparous, making ACCESS IUS the largest product approval study of nulliparous women. In addition, 438 women (25.1%) were obese, and 5% of these women had a BMI greater than 40 kg/m².

Liletta was placed successfully in 1,714 women (97.9%). Fifteen women did not have placement attempted due to uterine factors (the uterus could not be sounded, or the sound was <5.5 cm) or factors unrelated to the product or inserter. In women in whom placement was attempted, the success rate was 98.7%.

The first-year Pearl index for Liletta was 0.15. Life-table pregnancy rates were 0.14 through year 1 and 0.55 through year 3. Four of the 6 pregnancies reported through 3 years of use were ectopic. Adverse events and their incidence, occurring in more than 2% of users, were acne (6%), expulsion (3.5%), dyspareunia (2.8%), and mastalgia (2.0%). The most common adverse events leading to discontinuation were expulsion (3.5%), bleeding complaints (1.5%), acne (1.3%), and mood swings (1.3%).

Uterine perforation with Liletta was diagnosed in 2 participants (0.11%). Expulsion occurred in 62 users (3.5%) and was more frequent among parous than nulliparous women (5.6% vs 2.0%, respectively; P<.001). Most (80.6%) of the expulsions were reported in the first year of product use. Pelvic infection was reported in 10 participants (0.6%), and all cases resolved with outpatient antibiotic treatment.⁹

Keep in mind that this is an ongoing study—not all women have reached a full 3 years of use. Updates on efficacy and adverse events will be published in the future. This current publication demonstrates the high efficacy and safety of the product through 3 years of use, permitting its approval for contraception in the United States.

In Europe, the product is approved for both contraception and the treatment of heavy menstrual bleeding, based on a European study.¹⁰

What this EVIDENCE means for practice
Liletta is a branded product (not generic) designed to be similar to Mirena, with the same size, frame, hormone content, and hormone release rate.¹¹ Medicines360 has entered a groundbreaking marketing partnership with Actavis to make Liletta widely available and affordable. For most public sector providers and clinics in the United States, Liletta costs only $50, significantly less than other LARC methods available in the United States. Actavis also has a program that ensures that any woman lacking insurance coverage for an IUD and not receiving care at a public sector clinic will not be charged more than $75 for her IUD. However, the price of the device is only one aspect of its overall cost, as women still need to pay for any office visit or insertion fees.

For society, this unique business partnership has to include providers and patients as well. Sales of Liletta in the private sector will support the very low price in the public sector. As a health care community, even if we do not directly care for women in public-sector settings, we can all help poor women access very affordable highly effective contraception.

For providers, Liletta is a lower-cost alternative to currently available hormonal IUDs and should perform well over the long term. The highly successful use of Liletta in nulliparous women demonstrates its safety in this population. The 3-year approval is the first step, as the Phase 3 study continues. In the future, Liletta is expected to be approved for 5 years or longer.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Unintended pregnancy remains a serious problem in the United States, and the rate continues to increase. Currently, the unintended pregnancy rate is at an all-time high, estimated at 51% of all pregnancies.¹ Sobering statistics reveal that the United States has a significantly higher rate of unintended pregnancy than any other developed country.^2,3

So the question remains: If we have been introducing new contraceptive methods, why do unintended pregnancy rates keep rising in the United States?

The answer: Key barriers prevent women from attaining their desired contraceptive—foremost among them, cost.

The unintended pregnancy rate is highest among women who are poor, young (aged 18–24 years), minorities, or cohabitating.¹ The unintended pregnancy rate among poor women (income below the federal poverty level) of reproductive age has increased over the past few decades, whereas the rate among high-income women (more than twice the federal poverty level) has declined.¹ The unintended pregnancy rate discrepancy between poor women and those with means has increased 77%, from a threefold difference in 1995 to a difference of more than fivefold in 2008 (TABLE 1).^1,4

These data indicate that we are doing well providing contraception to women of means. However, as a society, we need to improve how we deliver contraceptives—especially highly effective methods—to poor women. As one might expect, given these numbers, low-income women have rates of abortion and unplanned birth that are nearly 6 times higher than their higher-income counterparts.¹ The resultant cost to society is substantial, with 68% of unplanned births paid for by public insurance programs such as Medicaid, compared with 38% of planned births.⁵

As women’s health providers, we must work to improve these numbers and advocate for our patients to help them gain access to the contraceptives they need in accordance with their reproductive life plan. In this article, we hope to put this information in context as we:

National and state snapshots reveal shifting proportions of intended, unintended pregnancies
Finer LB, Zolna MR. Shifts in intended and unintended pregnancies in the United States, 2001–2008. Am J Public Health. 2014;104(suppl 1):s43–s48.

Kost K. Unintended pregnancy rates at the state level: estimates for 2010 and trends since 2002. Guttmacher Institute. https://www.guttmacher.org/pubs/StateUP10.pdf. Published January 2015. Accessed June 29, 2015.

Recent studies have demonstrated trends in unplanned pregnancy over the past 2 decades on both a national and statewide level. Data from the National Survey of Family Growth have highlighted trends in abortion and miscarriage, and data from the National Center for Health Statistics have shed light on birth trends. Of 6 million births in 2008, 51% were unintended.¹ Unintended pregnancy was defined as a gestation that was mistimed or unwanted. Intended pregnancy was defined as one that was desired at the time it occurred or sooner.

2008 data focus on the national level
Although the overall pregnancy rate for US women aged 15 to 44 years is relatively unchanged, there is a small change in whether or not the pregnancy was intended. For 2008, as the rate of intended pregnancy dropped slightly, from 54 to 51 pregnancies per 1,000 women, the unintended pregnancy rate increased by 10%, from 49 to 54 pregnancies per 1,000 women. Proportionally, unintended pregnancies that resulted in abortion declined from 47% to 40%, whereas the rate of unintended pregnancies ending in birth increased to 27 births per 1,000 women.¹

2010 data focus on individual states
We now have state-specific data on trends in unintended pregnancy rates from 2002 to 2010 in the United States.⁶ In 28 of 50 states, more than half of all pregnancies were unintended, with rates ranging from 36% to 62%. The median rate was 47 unintended pregnancies per 1,000 women aged 15 to 44, with the lowest unintended pregnancy rate in New Hampshire at 32 per 1,000 women and highest rates in Delaware, Hawaii, and New York at 61 to 62 unintended pregnancies per 1,000 women.⁶

Between 2002 and 2010, unintended pregnancy rates fell 5% or more in 18 states and rose 5% or more in 4 states. In the remaining 12 states for which there are data, unintended pregnancy rates remained unchanged.

Interestingly, 16 states had increases in unintended pregnancy rates of 5% or more between 2002 and 2006. The trend reversed between 2006 and 2010, during which 28 of 41 states with available data experienced decreases of 5% or more and only 1 state experienced an increase of 5% or more. These latest numbers suggest we may be making some progress in reducing the overall rate of unintended pregnancy.

What this EVIDENCE means for practice
Although the rate of unintended pregnancy is declining in some states, the national rate is still increasing. This information emphasizes the need for all providers to consider initiating discussions about pregnancy intentions—a step that may be as important as obtaining blood pressure and weight. When women are seen for any health visit, they should be asked about their reproductive plans. The Centers for Disease Control and Prevention (CDC) has issued a helpful set of questions to guide the discussion of timing and planning pregnancy. It also provides useful information on ways to increase utilization of long-acting reversible contraceptives (LARCs) to help realize the goal of fewer unintended pregnancies. (For more on this discussion, see “How to motivate your patient to create a reproductive life plan,” below.)

How Colorado broke down barriers to highly effective contraception—and saved $42.5 million in 1 year
Ricketts S, Klinger G, Schwalberg R. Game change in Colorado: widespread use of long-acting reversible contraceptives and rapid decline of births among young, low-income women. Perspect Sexual Reprod Health. 2014;46(3):125–132.

The Contraceptive CHOICE Project in St. Louis County, Missouri, is an incredible success story. In it, clinicians made highly effective LARCs readily available and free of charge. When a large percentage of women chose a LARC method, the unintended pregnancy and abortion rates declined.⁷ In Colorado, providers put this study into practice, creating a successful statewide initiative to reduce the unintended pregnancy rate.⁸

The data behind LARC methods
LARC methods are backed by endorsements from the American College of Obstetricians and Gynecologists, the American Academy of Pediatrics, the CDC, and the World Health Organization, which recommend them for adolescents because of their superiority to shorter-acting methods. With LARCs, failure rates are lower and compliance is greater, making them ideal for adolescents, who have high unintended pregnancy rates.¹

However, based on 2011 data, only 2% of LARC users nationwide are aged 20 or younger. A number of barriers prevent young women from obtaining LARCs, including lack of education, limited access to and availability of the contraceptives, and, importantly, cost. Many state plans have adopted ­Medicaid expansions to reduce barriers to LARCs. However, this benefit is still not available in many states, Colorado being 1 of them.

How the Colorado initiative worked
In 2005, 40% of Colorado’s births were ­unintended, and 60% of those unintended births occurred in women aged 15 to 24 years. About three-quarters of women who were using a contraceptive method at the time of unintended pregnancy reported that it was a low-cost, high-failure method such as condoms or withdrawal.

In response, Colorado’s Department of Public Health and Environment and the ­Colorado Family Planning Initiative (CFPI) used private funds from an anonymous foundation to provide LARC products at no cost to the Title X–funded clinics in the state.

The initiative began in 2009 in clinics that served 95% of the state’s total population. The funding provided the products ­themselves (intrauterine device [IUD], implant), as well as training for providers and staff.

Before the initiative began, 52,645 clients received services in these clinics annually. In the third year of the initiative, that number had increased to 64,928 annually. About 55% of clients receiving services both preinitiative and postinitiative were younger than 25 years, and most (92% in 2011) had income below the poverty level.

LARC use increased fourfold over the 3 years of the funded program, from less than 4.5% to 19.4% in the third year. Contraceptive implant use increased tenfold, and IUD use increased by almost threefold. At the same time, oral contraceptive use declined 13%. Before the initiative, only 620 young, low-income women used a LARC method; afterward, 8,435 did.

These changes in contraceptive practice triggered a significant decline in pregnancy rates (TABLE 2) and abortion rates (TABLE 3). Abortion rates increased 8% among 20- to 24-year-olds who were not enrolled in the initiative and decreased 18% among those who were. The proportion of high-risk births (births to unmarried, low-income women with less than a high school education) dropped 24% after the initiative began. The proportion of high-risk births in counties not receiving CFPI funds stayed the same at 7%.

Colorado program saved $42.5 million in public funds
This Colorado program demonstrated that the CHOICE Project can be translated to a statewide initiative. Whereas CHOICE enrolled 9,256 women over 4 years, the Colorado initiative included more than 50,000 clients annually over 3 years. Colorado did not use any state funds for this project, which resulted in significant decreases in the unintended birth rate, abortion rate, and rate of high-risk births.

The Colorado governor’s office estimates that the CFPI saved $5.68 in Medicaid costs for Colorado for every dollar spent on contraceptives. In just 1 year (2010), the program saved approximately $42.5 million in public funds.

Ironically, despite the success of this project, the Colorado legislature denied further funding once the initial financial support ceased.
 

What this EVIDENCE means for practice
The Colorado program demonstrates that we all can provide LARC methods in practice, especially to young women. In this population, use of highly effective contraception resulted in fewer unintended pregnancies, births, and abortions statewide.

We also need to advocate for our patients, particularly those who have less means and rely on public assistance. Public funding of LARC methods clearly improves outcomes at an individual and population level.

A new, more affordable IUD enters the market
Eisenberg DL, Schreiber CA, Turok DK, Teal SB, Westhoff CL, Creinin MD. Three-year efficacy and safety of a new 52-mg levonorgestrel-releasing intrauterine system. Contraception. 2015;92(1):10–16.

Programs such as the Contraceptive CHOICE Project and the Colorado Family Planning Initiative relied on private foundations for financial support, largely because of the high cost of the IUDs and implants currently available in the United States. Even with the Affordable Care Act (ACA) reducing the costs of LARC products and other contraceptives for patients, there are still many women not covered by these programs. For example, “grandfathered” health insurance plans do not need to follow some aspects of the ACA.

Just as important, the high cost of LARC products takes a toll on providers and clinics that must finance the cost per unit to have stock on hand and then wait for months for reimbursement by insurance companies. As a result, some providers do not stock IUDs and implants and only order them as they are needed and approved by insurance for a particular patient. These barriers limit access to LARC methods and reduce the number of women who receive the products.⁸

Liletta is less expensive than other IUDs
Enter Liletta, a new levonorgestrel-releasing, 52-mg intrauterine system (IUS) that has been in clinical trials since 2009.⁹ ACCESS IUS (A Comprehensive Contraceptive Efficacy and Safety Study of an Intrauterine System) was initiated by Medicines360, a unique nonprofit pharmaceutical company committed to ensuring access to reproductive health products for all women (private and public sector).

ACCESS IUS is the largest IUD approval study ever performed exclusively in the United States. The Phase 3, open-label clinical trial was conducted at 29 sites around the United States, enrolling healthy, nonpregnant, sexually active women aged 16 to 45 years with regular menstrual cycles. Both nulliparous and parous women were included, with no weight or body mass index (BMI) restrictions applied. The study is ongoing and will continue for as long as 7 years. Eisenberg and colleagues published the data used for initial approval for 3 years of use in the United States and Europe.⁹

Details of the trial
A total of 1,600 women aged 16 to 35 years comprised the group in which efficacy was evaluated. An additional 151 women aged 36 to 45 years were evaluated for safety only. Of the enrolled women, 1,011 (58%) were nulliparous, making ACCESS IUS the largest product approval study of nulliparous women. In addition, 438 women (25.1%) were obese, and 5% of these women had a BMI greater than 40 kg/m².

Liletta was placed successfully in 1,714 women (97.9%). Fifteen women did not have placement attempted due to uterine factors (the uterus could not be sounded, or the sound was <5.5 cm) or factors unrelated to the product or inserter. In women in whom placement was attempted, the success rate was 98.7%.

The first-year Pearl index for Liletta was 0.15. Life-table pregnancy rates were 0.14 through year 1 and 0.55 through year 3. Four of the 6 pregnancies reported through 3 years of use were ectopic. Adverse events and their incidence, occurring in more than 2% of users, were acne (6%), expulsion (3.5%), dyspareunia (2.8%), and mastalgia (2.0%). The most common adverse events leading to discontinuation were expulsion (3.5%), bleeding complaints (1.5%), acne (1.3%), and mood swings (1.3%).

Uterine perforation with Liletta was diagnosed in 2 participants (0.11%). Expulsion occurred in 62 users (3.5%) and was more frequent among parous than nulliparous women (5.6% vs 2.0%, respectively; P<.001). Most (80.6%) of the expulsions were reported in the first year of product use. Pelvic infection was reported in 10 participants (0.6%), and all cases resolved with outpatient antibiotic treatment.⁹

Keep in mind that this is an ongoing study—not all women have reached a full 3 years of use. Updates on efficacy and adverse events will be published in the future. This current publication demonstrates the high efficacy and safety of the product through 3 years of use, permitting its approval for contraception in the United States.

In Europe, the product is approved for both contraception and the treatment of heavy menstrual bleeding, based on a European study.¹⁰

What this EVIDENCE means for practice
Liletta is a branded product (not generic) designed to be similar to Mirena, with the same size, frame, hormone content, and hormone release rate.¹¹ Medicines360 has entered a groundbreaking marketing partnership with Actavis to make Liletta widely available and affordable. For most public sector providers and clinics in the United States, Liletta costs only $50, significantly less than other LARC methods available in the United States. Actavis also has a program that ensures that any woman lacking insurance coverage for an IUD and not receiving care at a public sector clinic will not be charged more than $75 for her IUD. However, the price of the device is only one aspect of its overall cost, as women still need to pay for any office visit or insertion fees.

For society, this unique business partnership has to include providers and patients as well. Sales of Liletta in the private sector will support the very low price in the public sector. As a health care community, even if we do not directly care for women in public-sector settings, we can all help poor women access very affordable highly effective contraception.

For providers, Liletta is a lower-cost alternative to currently available hormonal IUDs and should perform well over the long term. The highly successful use of Liletta in nulliparous women demonstrates its safety in this population. The 3-year approval is the first step, as the Phase 3 study continues. In the future, Liletta is expected to be approved for 5 years or longer.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Unintended pregnancy remains a serious problem in the United States, and the rate continues to increase. Currently, the unintended pregnancy rate is at an all-time high, estimated at 51% of all pregnancies.¹ Sobering statistics reveal that the United States has a significantly higher rate of unintended pregnancy than any other developed country.^2,3

So the question remains: If we have been introducing new contraceptive methods, why do unintended pregnancy rates keep rising in the United States?

The answer: Key barriers prevent women from attaining their desired contraceptive—foremost among them, cost.

The unintended pregnancy rate is highest among women who are poor, young (aged 18–24 years), minorities, or cohabitating.¹ The unintended pregnancy rate among poor women (income below the federal poverty level) of reproductive age has increased over the past few decades, whereas the rate among high-income women (more than twice the federal poverty level) has declined.¹ The unintended pregnancy rate discrepancy between poor women and those with means has increased 77%, from a threefold difference in 1995 to a difference of more than fivefold in 2008 (TABLE 1).^1,4

These data indicate that we are doing well providing contraception to women of means. However, as a society, we need to improve how we deliver contraceptives—especially highly effective methods—to poor women. As one might expect, given these numbers, low-income women have rates of abortion and unplanned birth that are nearly 6 times higher than their higher-income counterparts.¹ The resultant cost to society is substantial, with 68% of unplanned births paid for by public insurance programs such as Medicaid, compared with 38% of planned births.⁵

As women’s health providers, we must work to improve these numbers and advocate for our patients to help them gain access to the contraceptives they need in accordance with their reproductive life plan. In this article, we hope to put this information in context as we:

National and state snapshots reveal shifting proportions of intended, unintended pregnancies
Finer LB, Zolna MR. Shifts in intended and unintended pregnancies in the United States, 2001–2008. Am J Public Health. 2014;104(suppl 1):s43–s48.

Kost K. Unintended pregnancy rates at the state level: estimates for 2010 and trends since 2002. Guttmacher Institute. https://www.guttmacher.org/pubs/StateUP10.pdf. Published January 2015. Accessed June 29, 2015.

Recent studies have demonstrated trends in unplanned pregnancy over the past 2 decades on both a national and statewide level. Data from the National Survey of Family Growth have highlighted trends in abortion and miscarriage, and data from the National Center for Health Statistics have shed light on birth trends. Of 6 million births in 2008, 51% were unintended.¹ Unintended pregnancy was defined as a gestation that was mistimed or unwanted. Intended pregnancy was defined as one that was desired at the time it occurred or sooner.

2008 data focus on the national level
Although the overall pregnancy rate for US women aged 15 to 44 years is relatively unchanged, there is a small change in whether or not the pregnancy was intended. For 2008, as the rate of intended pregnancy dropped slightly, from 54 to 51 pregnancies per 1,000 women, the unintended pregnancy rate increased by 10%, from 49 to 54 pregnancies per 1,000 women. Proportionally, unintended pregnancies that resulted in abortion declined from 47% to 40%, whereas the rate of unintended pregnancies ending in birth increased to 27 births per 1,000 women.¹

2010 data focus on individual states
We now have state-specific data on trends in unintended pregnancy rates from 2002 to 2010 in the United States.⁶ In 28 of 50 states, more than half of all pregnancies were unintended, with rates ranging from 36% to 62%. The median rate was 47 unintended pregnancies per 1,000 women aged 15 to 44, with the lowest unintended pregnancy rate in New Hampshire at 32 per 1,000 women and highest rates in Delaware, Hawaii, and New York at 61 to 62 unintended pregnancies per 1,000 women.⁶

Between 2002 and 2010, unintended pregnancy rates fell 5% or more in 18 states and rose 5% or more in 4 states. In the remaining 12 states for which there are data, unintended pregnancy rates remained unchanged.

Interestingly, 16 states had increases in unintended pregnancy rates of 5% or more between 2002 and 2006. The trend reversed between 2006 and 2010, during which 28 of 41 states with available data experienced decreases of 5% or more and only 1 state experienced an increase of 5% or more. These latest numbers suggest we may be making some progress in reducing the overall rate of unintended pregnancy.

What this EVIDENCE means for practice
Although the rate of unintended pregnancy is declining in some states, the national rate is still increasing. This information emphasizes the need for all providers to consider initiating discussions about pregnancy intentions—a step that may be as important as obtaining blood pressure and weight. When women are seen for any health visit, they should be asked about their reproductive plans. The Centers for Disease Control and Prevention (CDC) has issued a helpful set of questions to guide the discussion of timing and planning pregnancy. It also provides useful information on ways to increase utilization of long-acting reversible contraceptives (LARCs) to help realize the goal of fewer unintended pregnancies. (For more on this discussion, see “How to motivate your patient to create a reproductive life plan,” below.)

How Colorado broke down barriers to highly effective contraception—and saved $42.5 million in 1 year
Ricketts S, Klinger G, Schwalberg R. Game change in Colorado: widespread use of long-acting reversible contraceptives and rapid decline of births among young, low-income women. Perspect Sexual Reprod Health. 2014;46(3):125–132.

The Contraceptive CHOICE Project in St. Louis County, Missouri, is an incredible success story. In it, clinicians made highly effective LARCs readily available and free of charge. When a large percentage of women chose a LARC method, the unintended pregnancy and abortion rates declined.⁷ In Colorado, providers put this study into practice, creating a successful statewide initiative to reduce the unintended pregnancy rate.⁸

The data behind LARC methods
LARC methods are backed by endorsements from the American College of Obstetricians and Gynecologists, the American Academy of Pediatrics, the CDC, and the World Health Organization, which recommend them for adolescents because of their superiority to shorter-acting methods. With LARCs, failure rates are lower and compliance is greater, making them ideal for adolescents, who have high unintended pregnancy rates.¹

However, based on 2011 data, only 2% of LARC users nationwide are aged 20 or younger. A number of barriers prevent young women from obtaining LARCs, including lack of education, limited access to and availability of the contraceptives, and, importantly, cost. Many state plans have adopted ­Medicaid expansions to reduce barriers to LARCs. However, this benefit is still not available in many states, Colorado being 1 of them.

How the Colorado initiative worked
In 2005, 40% of Colorado’s births were ­unintended, and 60% of those unintended births occurred in women aged 15 to 24 years. About three-quarters of women who were using a contraceptive method at the time of unintended pregnancy reported that it was a low-cost, high-failure method such as condoms or withdrawal.

In response, Colorado’s Department of Public Health and Environment and the ­Colorado Family Planning Initiative (CFPI) used private funds from an anonymous foundation to provide LARC products at no cost to the Title X–funded clinics in the state.

The initiative began in 2009 in clinics that served 95% of the state’s total population. The funding provided the products ­themselves (intrauterine device [IUD], implant), as well as training for providers and staff.

Before the initiative began, 52,645 clients received services in these clinics annually. In the third year of the initiative, that number had increased to 64,928 annually. About 55% of clients receiving services both preinitiative and postinitiative were younger than 25 years, and most (92% in 2011) had income below the poverty level.

LARC use increased fourfold over the 3 years of the funded program, from less than 4.5% to 19.4% in the third year. Contraceptive implant use increased tenfold, and IUD use increased by almost threefold. At the same time, oral contraceptive use declined 13%. Before the initiative, only 620 young, low-income women used a LARC method; afterward, 8,435 did.

These changes in contraceptive practice triggered a significant decline in pregnancy rates (TABLE 2) and abortion rates (TABLE 3). Abortion rates increased 8% among 20- to 24-year-olds who were not enrolled in the initiative and decreased 18% among those who were. The proportion of high-risk births (births to unmarried, low-income women with less than a high school education) dropped 24% after the initiative began. The proportion of high-risk births in counties not receiving CFPI funds stayed the same at 7%.

Colorado program saved $42.5 million in public funds
This Colorado program demonstrated that the CHOICE Project can be translated to a statewide initiative. Whereas CHOICE enrolled 9,256 women over 4 years, the Colorado initiative included more than 50,000 clients annually over 3 years. Colorado did not use any state funds for this project, which resulted in significant decreases in the unintended birth rate, abortion rate, and rate of high-risk births.

The Colorado governor’s office estimates that the CFPI saved $5.68 in Medicaid costs for Colorado for every dollar spent on contraceptives. In just 1 year (2010), the program saved approximately $42.5 million in public funds.

Ironically, despite the success of this project, the Colorado legislature denied further funding once the initial financial support ceased.
 

What this EVIDENCE means for practice
The Colorado program demonstrates that we all can provide LARC methods in practice, especially to young women. In this population, use of highly effective contraception resulted in fewer unintended pregnancies, births, and abortions statewide.

We also need to advocate for our patients, particularly those who have less means and rely on public assistance. Public funding of LARC methods clearly improves outcomes at an individual and population level.

A new, more affordable IUD enters the market
Eisenberg DL, Schreiber CA, Turok DK, Teal SB, Westhoff CL, Creinin MD. Three-year efficacy and safety of a new 52-mg levonorgestrel-releasing intrauterine system. Contraception. 2015;92(1):10–16.

Programs such as the Contraceptive CHOICE Project and the Colorado Family Planning Initiative relied on private foundations for financial support, largely because of the high cost of the IUDs and implants currently available in the United States. Even with the Affordable Care Act (ACA) reducing the costs of LARC products and other contraceptives for patients, there are still many women not covered by these programs. For example, “grandfathered” health insurance plans do not need to follow some aspects of the ACA.

Just as important, the high cost of LARC products takes a toll on providers and clinics that must finance the cost per unit to have stock on hand and then wait for months for reimbursement by insurance companies. As a result, some providers do not stock IUDs and implants and only order them as they are needed and approved by insurance for a particular patient. These barriers limit access to LARC methods and reduce the number of women who receive the products.⁸

Liletta is less expensive than other IUDs
Enter Liletta, a new levonorgestrel-releasing, 52-mg intrauterine system (IUS) that has been in clinical trials since 2009.⁹ ACCESS IUS (A Comprehensive Contraceptive Efficacy and Safety Study of an Intrauterine System) was initiated by Medicines360, a unique nonprofit pharmaceutical company committed to ensuring access to reproductive health products for all women (private and public sector).

ACCESS IUS is the largest IUD approval study ever performed exclusively in the United States. The Phase 3, open-label clinical trial was conducted at 29 sites around the United States, enrolling healthy, nonpregnant, sexually active women aged 16 to 45 years with regular menstrual cycles. Both nulliparous and parous women were included, with no weight or body mass index (BMI) restrictions applied. The study is ongoing and will continue for as long as 7 years. Eisenberg and colleagues published the data used for initial approval for 3 years of use in the United States and Europe.⁹

Details of the trial
A total of 1,600 women aged 16 to 35 years comprised the group in which efficacy was evaluated. An additional 151 women aged 36 to 45 years were evaluated for safety only. Of the enrolled women, 1,011 (58%) were nulliparous, making ACCESS IUS the largest product approval study of nulliparous women. In addition, 438 women (25.1%) were obese, and 5% of these women had a BMI greater than 40 kg/m².

Liletta was placed successfully in 1,714 women (97.9%). Fifteen women did not have placement attempted due to uterine factors (the uterus could not be sounded, or the sound was <5.5 cm) or factors unrelated to the product or inserter. In women in whom placement was attempted, the success rate was 98.7%.

The first-year Pearl index for Liletta was 0.15. Life-table pregnancy rates were 0.14 through year 1 and 0.55 through year 3. Four of the 6 pregnancies reported through 3 years of use were ectopic. Adverse events and their incidence, occurring in more than 2% of users, were acne (6%), expulsion (3.5%), dyspareunia (2.8%), and mastalgia (2.0%). The most common adverse events leading to discontinuation were expulsion (3.5%), bleeding complaints (1.5%), acne (1.3%), and mood swings (1.3%).

Uterine perforation with Liletta was diagnosed in 2 participants (0.11%). Expulsion occurred in 62 users (3.5%) and was more frequent among parous than nulliparous women (5.6% vs 2.0%, respectively; P<.001). Most (80.6%) of the expulsions were reported in the first year of product use. Pelvic infection was reported in 10 participants (0.6%), and all cases resolved with outpatient antibiotic treatment.⁹

Keep in mind that this is an ongoing study—not all women have reached a full 3 years of use. Updates on efficacy and adverse events will be published in the future. This current publication demonstrates the high efficacy and safety of the product through 3 years of use, permitting its approval for contraception in the United States.

In Europe, the product is approved for both contraception and the treatment of heavy menstrual bleeding, based on a European study.¹⁰

What this EVIDENCE means for practice
Liletta is a branded product (not generic) designed to be similar to Mirena, with the same size, frame, hormone content, and hormone release rate.¹¹ Medicines360 has entered a groundbreaking marketing partnership with Actavis to make Liletta widely available and affordable. For most public sector providers and clinics in the United States, Liletta costs only $50, significantly less than other LARC methods available in the United States. Actavis also has a program that ensures that any woman lacking insurance coverage for an IUD and not receiving care at a public sector clinic will not be charged more than $75 for her IUD. However, the price of the device is only one aspect of its overall cost, as women still need to pay for any office visit or insertion fees.

For society, this unique business partnership has to include providers and patients as well. Sales of Liletta in the private sector will support the very low price in the public sector. As a health care community, even if we do not directly care for women in public-sector settings, we can all help poor women access very affordable highly effective contraception.

For providers, Liletta is a lower-cost alternative to currently available hormonal IUDs and should perform well over the long term. The highly successful use of Liletta in nulliparous women demonstrates its safety in this population. The 3-year approval is the first step, as the Phase 3 study continues. In the future, Liletta is expected to be approved for 5 years or longer.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

“Critical Window” HT Timing Is Revealed
Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368.

After the initial 2002 publication of findings from the WHI trial of women with an intact uterus who were randomized to receive conjugated equine estrogens and medroxyprogesterone acetate or placebo, prominent news headlines claimed that HT causes myocardial infarction (MI) and breast cancer. As a result, millions of women worldwide stopped taking HT. A second impact of the report: Many clinicians became reluctant to prescribe HT.

Although it generated far less media attention, research published in the Journal of the American Medical Association in October 2013 details findings from a 13-year follow-up of WHI HT clinical trial participants and better informs clinicians and our patients about HT’s safety profile.

During the WHI intervention phase, absolute risks were modest
Although HT was associated with a multifaceted pattern of benefits and risks in both the ­estrogen-progestin therapy (EPT) and ­estrogen-only therapy (ET) arms of the WHI, absolute risks, as reflected in an increase or decrease in the number of cases per 10,000 women treated per year, were modest.

For example, the hazard ratio (HR) for coronary heart disease (CHD) ­during the intervention phase, during which ­participants were given HT or placebo (mean 5.2 years for EPT and 6.8 years for ET) was 1.18 in the EPT arm (95% confidence interval [CI], 0.95-1.45) and 0.94 in the ET arm (95% CI, 0.78-1.14). In both arms, women given HT had reduced risk for vasomotor symptoms, hip fractures, and diabetes, and increased risk for stroke, venous thromboembolism (VTE), and gallbladder disease, compared with women receiving placebo.

The results for breast cancer differed markedly between arms. During the intervention period, an elevated risk was observed with EPT while a borderline reduced risk was observed with ET.

Among participants older than 65 at baseline, the risk for cognitive decline was increased in the EPT arm but not in the ET arm.

Post intervention, most risks and benefits attenuated
An elevation in the risk for breast cancer persisted in the EPT arm (cumulative HR over 13 years, 1.28; 95% CI, 1.11-1.48). In contrast, in the ET arm, a significantly reduced risk for breast cancer materialized (HR, 0.79; 95% CI, 0.65-0.97) (see Table).

To put into perspective the elevated risk for breast cancer observed among women randomly allocated to EPT, the attributable risk is less than 1 additional case of breast cancer diagnosed per 1,000 EPT users annually. Another way to frame this elevated risk: An HR of 1.28 is slightly higher than the HR conferred by consuming one glass of wine daily and lower than the HR noted with two glasses daily.¹

Overall, results tended to be more favorable for ET than for EPT. Neither type of HT affected overall mortality rates.

Age differences come to the fore
The WHI findings demonstrate a lower absolute risk for adverse events with HT in younger versus older participants. In addition, age and time since menopause appeared to affect many of the HRs observed in the trial. In the ET arm, more favorable results for all-cause mortality, MI, colorectal cancer, and the global index (CHD, invasive breast cancer, pulmonary embolism, colorectal cancer, and endometrial cancer) were observed in women ages 50 to 59 at baseline. In the EPT arm, the risk for MI was elevated only in women more than 10 years past the onset of menopause at baseline. Both HT regimens, however, were associated with increased risk for stroke, VTE, and gallbladder disease.

EPT increased the risk for breast cancer in all age-groups. However, the lower absolute risks for adverse events, and generally more favorable HRs for many outcomes, in younger women resulted in substantially lower rates of adverse events attributable to HT in the younger age-group, compared with older women.

As far as CHD is concerned, the impact of age (or time since menopause) on the vascular response to HT in women and in nonhuman models has generated support for a “critical window” or timing hypothesis, which postulates that estrogen reduces the development of early stages of atherosclerosis while causing plaque destabilization and other adverse effects when advanced atherosclerotic lesions are present. Recent studies from Scandinavia provide additional support for this hypothesis (see the sidebar).

REFERENCE
1. Chen WY, Rosner B, Hankinson SE, et al. Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk. JAMA. 2011;306(17):1884-190.

Continue for ACOG Guidance on menopausal symptoms >>

ACOG Guidance on Menopausal Symptoms
American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 141: management of menopausal symptoms. Obstet Gynecol. 2014;123(1):202-216.

Despite findings from new studies, optimal ­management of menopausal symptoms remains controversial. In January 2014, ACOG issued ­guidance regarding conventional systemic and vaginal HT, recently approved treatments, and compounded HT.

For the management of vasomotor symptoms, ACOG indicated that systemic HT (including oral and transdermal routes), alone or combined with a progestin, is the most effective treatment for bothersome menopausal vasomotor symptoms. The ACOG Practice Bulletin also pointed out that systemic EPT increases the risk for VTE and breast cancer and that, compared with oral estrogen, transdermal estrogen may carry a lower risk for VTE.

Some insurers deny coverage of HT for women older than 65
A classification of medications from the American Geriatrics Society known as “the Beers List” [the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults] includes oral and transdermal estrogen, with or without a progestin.¹ Along with many of the clinicians reading this update, I routinely receive notices from insurance companies that, based on the Beers List, they will no longer provide reimbursement for systemic HT in patients who are older than 65. In this regard, I believe that one of the most important components of ACOG’s Practice Bulletin is the following text:

“The decision to continue HT should be individualized and be based on a woman’s symptoms and the risk­-benefit ratio, regardless of age. Because some women aged 65 years and older may continue to need systemic HT for the management of vasomotor symptoms, the American College of Obstetricians and Gynecologists recommends against routine discontinuation of systemic estrogen at age 65 years. As with younger women, use of HT and estrogen therapy should be individualized, based on each woman’s risk-benefit ratio and clinical presentation.”

Three new options for menopausal HT
The ACOG Practice Bulletin describes three formulations for the treatment of menopausal symptoms that have recently become available:
• In women with a uterus and with bothersome vasomotor symptoms, an alternative to EPT is oral tablets combining conjugated equine estrogen (0.45 mg) with the selective estrogen receptor modulator (SERM) bazedoxifene (20 mg).
• The oral SERM ospemifene (60 mg) is effective for relief of dyspareunia associated with vulvovaginal atrophy (also known as genitourinary syndrome of menopause).
• Paroxetine mesylate (7.5 mg) is the only FDA-approved nonhormonal formulation for management of vasomotor symptoms and is dosed lower than regimens used to treat psychiatric conditions.

Steer patients clear of compounded formulations
Every week, I encounter patients who have recently visited clinicians who prescribe and sell compounded bioidentical hormones. In addressing this issue, ACOG provides a useful service to women and their clinicians:

“Because of a lack of FDA oversight, most compounded preparations have not undergone any rigorous clinical testing for either safety or efficacy, so the purity, potency, and quality of compounded preparations are a concern. In addition, both underdosage and overdosage are possible because of variable bioavailability and bioactivity. Evidence is lacking to support superiority claims of compounded bioidentical hormones over conventional menopausal HT…. Conventional HT is preferred, given the available data.”

REFERENCE
1. Geriatrics Care Online: Beers Pocket Card. www.americangeriatrics.org/files/documents/beers/PrintableBeersPocketCard.pdf. Accessed July 21, 2015.

Continue for Testosterone improves parameters of sexual function >>

Testosterone Improves Parameters of Sexual Function
Huang G, Basaria S, Travison TG, et al. Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance, and physical function in a randomized trial. Menopause. 2014;21(6):612-623.

No formulation of testosterone is approved by the FDA for use in women. Nonetheless, in the United States, many menopausal women hoping to boost their sexual desire are prescribed, off-label, testosterone formulations indicated for use in men, as well as compounded formulations.¹

Investigators randomly allocated women who had undergone hysterectomy to 12 weeks of transdermal estradiol followed by 24 weekly intramuscular injections of placebo or testosterone enanthate at doses of 3.0, 6.0, 12.5, or 25.0 mg while continuing estrogen. At the outset of the trial, all women had serum free testosterone levels below the range for healthy premenopausal women.

Among the 62 women who received testosterone, serum testosterone levels increased in a dose-related fashion. Among those allocated to the highest dose, serum total testosterone levels at 24 weeks were five to six times higher than values in healthy premenopausal women. Compared with women who received placebo, those who received the highest testosterone dose had better measures of sexual desire, arousal, and frequency of sexual activity. Excess hair growth was significantly more common in women who received the two highest doses of testosterone.

REFERENCE
1. Kingsberg SA, Woodard T. Female sexual dysfunction: focus on low desire. Obstet Gynecol. 2015;125(2):477–486.

Continue to find out if HT is safe in statin users

Is HT Safe in Statin Users?
Berglind IA, Andersen M, Citarella A, Liet al. Hormone therapy and risk of cardiovascular outcomes and mortality in women treated with statins. Menopause. 2015;22(4):369–376. Hodis HN, Mack WJ. Hormone therapy and risk of all-cause mortality in women treated with statins [comment]. Menopause. 2015;22(4):363–364.

Since the initial publication of findings from the WHI, clinicians have been cautioned not to prescribe menopausal HT in women at elevated risk for CVD. In this study from Sweden, investigators enrolled women ages 40 to 74 who initiated statin use between 2006 and 2007 due to known CVD (secondary prevention) or in the absence of known CVD (primary prevention). Women were followed for a mean of four years after beginning statins, until the end of 2011.

Of 40,958 statin users, 7% used HT (mean age of HT users and nonusers was 61 and 62, respectively). Overall, 70% of statin use was for primary prevention. Deaths from CVD occurred in 5 and 18 patients per 10,000 person-years among HT users and nonusers, respectively (HR, 0.38). All-cause mortality occurred in 33 and 87 patients per 10,000 person-years among HT users and non­users, respectively (HR, 0.53). These reduced risks for mortality noted in women who used concomitant statins achieved statistical significance. Whether statins were used for ­primary or secondary prevention, the incidence of cardiovascular events was similar in HT users and nonusers.

Why these findings diverge from those of the WHI
The findings of this large prospective cohort study are consistent with findings from other large observational studies—though they diverge from WHI findings. As Berglind and colleagues note, few WHI participants used statins at baseline. Also in contrast with the WHI, in which all HT was based on conjugated estrogen, all HT users in this Swedish study used oral or transdermal estradiol, as conjugated estrogen is not available in Sweden (and appears to be associated with an elevated risk for CVD, compared with other estrogens¹).

REFERENCE
1. Smith NL, Blondon M, Wiggins KL, et al. Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens. JAMA Intern Med. 2014;174(1):25–31.

“Critical Window” HT Timing Is Revealed
Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368.

After the initial 2002 publication of findings from the WHI trial of women with an intact uterus who were randomized to receive conjugated equine estrogens and medroxyprogesterone acetate or placebo, prominent news headlines claimed that HT causes myocardial infarction (MI) and breast cancer. As a result, millions of women worldwide stopped taking HT. A second impact of the report: Many clinicians became reluctant to prescribe HT.

Although it generated far less media attention, research published in the Journal of the American Medical Association in October 2013 details findings from a 13-year follow-up of WHI HT clinical trial participants and better informs clinicians and our patients about HT’s safety profile.

During the WHI intervention phase, absolute risks were modest
Although HT was associated with a multifaceted pattern of benefits and risks in both the ­estrogen-progestin therapy (EPT) and ­estrogen-only therapy (ET) arms of the WHI, absolute risks, as reflected in an increase or decrease in the number of cases per 10,000 women treated per year, were modest.

For example, the hazard ratio (HR) for coronary heart disease (CHD) ­during the intervention phase, during which ­participants were given HT or placebo (mean 5.2 years for EPT and 6.8 years for ET) was 1.18 in the EPT arm (95% confidence interval [CI], 0.95-1.45) and 0.94 in the ET arm (95% CI, 0.78-1.14). In both arms, women given HT had reduced risk for vasomotor symptoms, hip fractures, and diabetes, and increased risk for stroke, venous thromboembolism (VTE), and gallbladder disease, compared with women receiving placebo.

The results for breast cancer differed markedly between arms. During the intervention period, an elevated risk was observed with EPT while a borderline reduced risk was observed with ET.

Among participants older than 65 at baseline, the risk for cognitive decline was increased in the EPT arm but not in the ET arm.

Post intervention, most risks and benefits attenuated
An elevation in the risk for breast cancer persisted in the EPT arm (cumulative HR over 13 years, 1.28; 95% CI, 1.11-1.48). In contrast, in the ET arm, a significantly reduced risk for breast cancer materialized (HR, 0.79; 95% CI, 0.65-0.97) (see Table).

To put into perspective the elevated risk for breast cancer observed among women randomly allocated to EPT, the attributable risk is less than 1 additional case of breast cancer diagnosed per 1,000 EPT users annually. Another way to frame this elevated risk: An HR of 1.28 is slightly higher than the HR conferred by consuming one glass of wine daily and lower than the HR noted with two glasses daily.¹

Overall, results tended to be more favorable for ET than for EPT. Neither type of HT affected overall mortality rates.

Age differences come to the fore
The WHI findings demonstrate a lower absolute risk for adverse events with HT in younger versus older participants. In addition, age and time since menopause appeared to affect many of the HRs observed in the trial. In the ET arm, more favorable results for all-cause mortality, MI, colorectal cancer, and the global index (CHD, invasive breast cancer, pulmonary embolism, colorectal cancer, and endometrial cancer) were observed in women ages 50 to 59 at baseline. In the EPT arm, the risk for MI was elevated only in women more than 10 years past the onset of menopause at baseline. Both HT regimens, however, were associated with increased risk for stroke, VTE, and gallbladder disease.

EPT increased the risk for breast cancer in all age-groups. However, the lower absolute risks for adverse events, and generally more favorable HRs for many outcomes, in younger women resulted in substantially lower rates of adverse events attributable to HT in the younger age-group, compared with older women.

As far as CHD is concerned, the impact of age (or time since menopause) on the vascular response to HT in women and in nonhuman models has generated support for a “critical window” or timing hypothesis, which postulates that estrogen reduces the development of early stages of atherosclerosis while causing plaque destabilization and other adverse effects when advanced atherosclerotic lesions are present. Recent studies from Scandinavia provide additional support for this hypothesis (see the sidebar).

REFERENCE
1. Chen WY, Rosner B, Hankinson SE, et al. Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk. JAMA. 2011;306(17):1884-190.

Continue for ACOG Guidance on menopausal symptoms >>

ACOG Guidance on Menopausal Symptoms
American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 141: management of menopausal symptoms. Obstet Gynecol. 2014;123(1):202-216.

Despite findings from new studies, optimal ­management of menopausal symptoms remains controversial. In January 2014, ACOG issued ­guidance regarding conventional systemic and vaginal HT, recently approved treatments, and compounded HT.

For the management of vasomotor symptoms, ACOG indicated that systemic HT (including oral and transdermal routes), alone or combined with a progestin, is the most effective treatment for bothersome menopausal vasomotor symptoms. The ACOG Practice Bulletin also pointed out that systemic EPT increases the risk for VTE and breast cancer and that, compared with oral estrogen, transdermal estrogen may carry a lower risk for VTE.

Some insurers deny coverage of HT for women older than 65
A classification of medications from the American Geriatrics Society known as “the Beers List” [the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults] includes oral and transdermal estrogen, with or without a progestin.¹ Along with many of the clinicians reading this update, I routinely receive notices from insurance companies that, based on the Beers List, they will no longer provide reimbursement for systemic HT in patients who are older than 65. In this regard, I believe that one of the most important components of ACOG’s Practice Bulletin is the following text:

“The decision to continue HT should be individualized and be based on a woman’s symptoms and the risk­-benefit ratio, regardless of age. Because some women aged 65 years and older may continue to need systemic HT for the management of vasomotor symptoms, the American College of Obstetricians and Gynecologists recommends against routine discontinuation of systemic estrogen at age 65 years. As with younger women, use of HT and estrogen therapy should be individualized, based on each woman’s risk-benefit ratio and clinical presentation.”

Three new options for menopausal HT
The ACOG Practice Bulletin describes three formulations for the treatment of menopausal symptoms that have recently become available:
• In women with a uterus and with bothersome vasomotor symptoms, an alternative to EPT is oral tablets combining conjugated equine estrogen (0.45 mg) with the selective estrogen receptor modulator (SERM) bazedoxifene (20 mg).
• The oral SERM ospemifene (60 mg) is effective for relief of dyspareunia associated with vulvovaginal atrophy (also known as genitourinary syndrome of menopause).
• Paroxetine mesylate (7.5 mg) is the only FDA-approved nonhormonal formulation for management of vasomotor symptoms and is dosed lower than regimens used to treat psychiatric conditions.

Steer patients clear of compounded formulations
Every week, I encounter patients who have recently visited clinicians who prescribe and sell compounded bioidentical hormones. In addressing this issue, ACOG provides a useful service to women and their clinicians:

“Because of a lack of FDA oversight, most compounded preparations have not undergone any rigorous clinical testing for either safety or efficacy, so the purity, potency, and quality of compounded preparations are a concern. In addition, both underdosage and overdosage are possible because of variable bioavailability and bioactivity. Evidence is lacking to support superiority claims of compounded bioidentical hormones over conventional menopausal HT…. Conventional HT is preferred, given the available data.”

REFERENCE
1. Geriatrics Care Online: Beers Pocket Card. www.americangeriatrics.org/files/documents/beers/PrintableBeersPocketCard.pdf. Accessed July 21, 2015.

Continue for Testosterone improves parameters of sexual function >>

Testosterone Improves Parameters of Sexual Function
Huang G, Basaria S, Travison TG, et al. Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance, and physical function in a randomized trial. Menopause. 2014;21(6):612-623.

No formulation of testosterone is approved by the FDA for use in women. Nonetheless, in the United States, many menopausal women hoping to boost their sexual desire are prescribed, off-label, testosterone formulations indicated for use in men, as well as compounded formulations.¹

Investigators randomly allocated women who had undergone hysterectomy to 12 weeks of transdermal estradiol followed by 24 weekly intramuscular injections of placebo or testosterone enanthate at doses of 3.0, 6.0, 12.5, or 25.0 mg while continuing estrogen. At the outset of the trial, all women had serum free testosterone levels below the range for healthy premenopausal women.

Among the 62 women who received testosterone, serum testosterone levels increased in a dose-related fashion. Among those allocated to the highest dose, serum total testosterone levels at 24 weeks were five to six times higher than values in healthy premenopausal women. Compared with women who received placebo, those who received the highest testosterone dose had better measures of sexual desire, arousal, and frequency of sexual activity. Excess hair growth was significantly more common in women who received the two highest doses of testosterone.

REFERENCE
1. Kingsberg SA, Woodard T. Female sexual dysfunction: focus on low desire. Obstet Gynecol. 2015;125(2):477–486.

Continue to find out if HT is safe in statin users

Is HT Safe in Statin Users?
Berglind IA, Andersen M, Citarella A, Liet al. Hormone therapy and risk of cardiovascular outcomes and mortality in women treated with statins. Menopause. 2015;22(4):369–376. Hodis HN, Mack WJ. Hormone therapy and risk of all-cause mortality in women treated with statins [comment]. Menopause. 2015;22(4):363–364.

Since the initial publication of findings from the WHI, clinicians have been cautioned not to prescribe menopausal HT in women at elevated risk for CVD. In this study from Sweden, investigators enrolled women ages 40 to 74 who initiated statin use between 2006 and 2007 due to known CVD (secondary prevention) or in the absence of known CVD (primary prevention). Women were followed for a mean of four years after beginning statins, until the end of 2011.

Of 40,958 statin users, 7% used HT (mean age of HT users and nonusers was 61 and 62, respectively). Overall, 70% of statin use was for primary prevention. Deaths from CVD occurred in 5 and 18 patients per 10,000 person-years among HT users and nonusers, respectively (HR, 0.38). All-cause mortality occurred in 33 and 87 patients per 10,000 person-years among HT users and non­users, respectively (HR, 0.53). These reduced risks for mortality noted in women who used concomitant statins achieved statistical significance. Whether statins were used for ­primary or secondary prevention, the incidence of cardiovascular events was similar in HT users and nonusers.

Why these findings diverge from those of the WHI
The findings of this large prospective cohort study are consistent with findings from other large observational studies—though they diverge from WHI findings. As Berglind and colleagues note, few WHI participants used statins at baseline. Also in contrast with the WHI, in which all HT was based on conjugated estrogen, all HT users in this Swedish study used oral or transdermal estradiol, as conjugated estrogen is not available in Sweden (and appears to be associated with an elevated risk for CVD, compared with other estrogens¹).

REFERENCE
1. Smith NL, Blondon M, Wiggins KL, et al. Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens. JAMA Intern Med. 2014;174(1):25–31.

“Critical Window” HT Timing Is Revealed
Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353-1368.

After the initial 2002 publication of findings from the WHI trial of women with an intact uterus who were randomized to receive conjugated equine estrogens and medroxyprogesterone acetate or placebo, prominent news headlines claimed that HT causes myocardial infarction (MI) and breast cancer. As a result, millions of women worldwide stopped taking HT. A second impact of the report: Many clinicians became reluctant to prescribe HT.

Although it generated far less media attention, research published in the Journal of the American Medical Association in October 2013 details findings from a 13-year follow-up of WHI HT clinical trial participants and better informs clinicians and our patients about HT’s safety profile.

During the WHI intervention phase, absolute risks were modest
Although HT was associated with a multifaceted pattern of benefits and risks in both the ­estrogen-progestin therapy (EPT) and ­estrogen-only therapy (ET) arms of the WHI, absolute risks, as reflected in an increase or decrease in the number of cases per 10,000 women treated per year, were modest.

For example, the hazard ratio (HR) for coronary heart disease (CHD) ­during the intervention phase, during which ­participants were given HT or placebo (mean 5.2 years for EPT and 6.8 years for ET) was 1.18 in the EPT arm (95% confidence interval [CI], 0.95-1.45) and 0.94 in the ET arm (95% CI, 0.78-1.14). In both arms, women given HT had reduced risk for vasomotor symptoms, hip fractures, and diabetes, and increased risk for stroke, venous thromboembolism (VTE), and gallbladder disease, compared with women receiving placebo.

The results for breast cancer differed markedly between arms. During the intervention period, an elevated risk was observed with EPT while a borderline reduced risk was observed with ET.

Among participants older than 65 at baseline, the risk for cognitive decline was increased in the EPT arm but not in the ET arm.

Post intervention, most risks and benefits attenuated
An elevation in the risk for breast cancer persisted in the EPT arm (cumulative HR over 13 years, 1.28; 95% CI, 1.11-1.48). In contrast, in the ET arm, a significantly reduced risk for breast cancer materialized (HR, 0.79; 95% CI, 0.65-0.97) (see Table).

To put into perspective the elevated risk for breast cancer observed among women randomly allocated to EPT, the attributable risk is less than 1 additional case of breast cancer diagnosed per 1,000 EPT users annually. Another way to frame this elevated risk: An HR of 1.28 is slightly higher than the HR conferred by consuming one glass of wine daily and lower than the HR noted with two glasses daily.¹

Overall, results tended to be more favorable for ET than for EPT. Neither type of HT affected overall mortality rates.

Age differences come to the fore
The WHI findings demonstrate a lower absolute risk for adverse events with HT in younger versus older participants. In addition, age and time since menopause appeared to affect many of the HRs observed in the trial. In the ET arm, more favorable results for all-cause mortality, MI, colorectal cancer, and the global index (CHD, invasive breast cancer, pulmonary embolism, colorectal cancer, and endometrial cancer) were observed in women ages 50 to 59 at baseline. In the EPT arm, the risk for MI was elevated only in women more than 10 years past the onset of menopause at baseline. Both HT regimens, however, were associated with increased risk for stroke, VTE, and gallbladder disease.

EPT increased the risk for breast cancer in all age-groups. However, the lower absolute risks for adverse events, and generally more favorable HRs for many outcomes, in younger women resulted in substantially lower rates of adverse events attributable to HT in the younger age-group, compared with older women.

As far as CHD is concerned, the impact of age (or time since menopause) on the vascular response to HT in women and in nonhuman models has generated support for a “critical window” or timing hypothesis, which postulates that estrogen reduces the development of early stages of atherosclerosis while causing plaque destabilization and other adverse effects when advanced atherosclerotic lesions are present. Recent studies from Scandinavia provide additional support for this hypothesis (see the sidebar).

REFERENCE
1. Chen WY, Rosner B, Hankinson SE, et al. Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk. JAMA. 2011;306(17):1884-190.

Continue for ACOG Guidance on menopausal symptoms >>

ACOG Guidance on Menopausal Symptoms
American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 141: management of menopausal symptoms. Obstet Gynecol. 2014;123(1):202-216.

Despite findings from new studies, optimal ­management of menopausal symptoms remains controversial. In January 2014, ACOG issued ­guidance regarding conventional systemic and vaginal HT, recently approved treatments, and compounded HT.

For the management of vasomotor symptoms, ACOG indicated that systemic HT (including oral and transdermal routes), alone or combined with a progestin, is the most effective treatment for bothersome menopausal vasomotor symptoms. The ACOG Practice Bulletin also pointed out that systemic EPT increases the risk for VTE and breast cancer and that, compared with oral estrogen, transdermal estrogen may carry a lower risk for VTE.

Some insurers deny coverage of HT for women older than 65
A classification of medications from the American Geriatrics Society known as “the Beers List” [the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults] includes oral and transdermal estrogen, with or without a progestin.¹ Along with many of the clinicians reading this update, I routinely receive notices from insurance companies that, based on the Beers List, they will no longer provide reimbursement for systemic HT in patients who are older than 65. In this regard, I believe that one of the most important components of ACOG’s Practice Bulletin is the following text:

“The decision to continue HT should be individualized and be based on a woman’s symptoms and the risk­-benefit ratio, regardless of age. Because some women aged 65 years and older may continue to need systemic HT for the management of vasomotor symptoms, the American College of Obstetricians and Gynecologists recommends against routine discontinuation of systemic estrogen at age 65 years. As with younger women, use of HT and estrogen therapy should be individualized, based on each woman’s risk-benefit ratio and clinical presentation.”

Three new options for menopausal HT
The ACOG Practice Bulletin describes three formulations for the treatment of menopausal symptoms that have recently become available:
• In women with a uterus and with bothersome vasomotor symptoms, an alternative to EPT is oral tablets combining conjugated equine estrogen (0.45 mg) with the selective estrogen receptor modulator (SERM) bazedoxifene (20 mg).
• The oral SERM ospemifene (60 mg) is effective for relief of dyspareunia associated with vulvovaginal atrophy (also known as genitourinary syndrome of menopause).
• Paroxetine mesylate (7.5 mg) is the only FDA-approved nonhormonal formulation for management of vasomotor symptoms and is dosed lower than regimens used to treat psychiatric conditions.

Steer patients clear of compounded formulations
Every week, I encounter patients who have recently visited clinicians who prescribe and sell compounded bioidentical hormones. In addressing this issue, ACOG provides a useful service to women and their clinicians:

“Because of a lack of FDA oversight, most compounded preparations have not undergone any rigorous clinical testing for either safety or efficacy, so the purity, potency, and quality of compounded preparations are a concern. In addition, both underdosage and overdosage are possible because of variable bioavailability and bioactivity. Evidence is lacking to support superiority claims of compounded bioidentical hormones over conventional menopausal HT…. Conventional HT is preferred, given the available data.”

REFERENCE
1. Geriatrics Care Online: Beers Pocket Card. www.americangeriatrics.org/files/documents/beers/PrintableBeersPocketCard.pdf. Accessed July 21, 2015.

Continue for Testosterone improves parameters of sexual function >>

Testosterone Improves Parameters of Sexual Function
Huang G, Basaria S, Travison TG, et al. Testosterone dose-response relationships in hysterectomized women with or without oophorectomy: effects on sexual function, body composition, muscle performance, and physical function in a randomized trial. Menopause. 2014;21(6):612-623.

No formulation of testosterone is approved by the FDA for use in women. Nonetheless, in the United States, many menopausal women hoping to boost their sexual desire are prescribed, off-label, testosterone formulations indicated for use in men, as well as compounded formulations.¹

Investigators randomly allocated women who had undergone hysterectomy to 12 weeks of transdermal estradiol followed by 24 weekly intramuscular injections of placebo or testosterone enanthate at doses of 3.0, 6.0, 12.5, or 25.0 mg while continuing estrogen. At the outset of the trial, all women had serum free testosterone levels below the range for healthy premenopausal women.

Among the 62 women who received testosterone, serum testosterone levels increased in a dose-related fashion. Among those allocated to the highest dose, serum total testosterone levels at 24 weeks were five to six times higher than values in healthy premenopausal women. Compared with women who received placebo, those who received the highest testosterone dose had better measures of sexual desire, arousal, and frequency of sexual activity. Excess hair growth was significantly more common in women who received the two highest doses of testosterone.

REFERENCE
1. Kingsberg SA, Woodard T. Female sexual dysfunction: focus on low desire. Obstet Gynecol. 2015;125(2):477–486.

Continue to find out if HT is safe in statin users

Is HT Safe in Statin Users?
Berglind IA, Andersen M, Citarella A, Liet al. Hormone therapy and risk of cardiovascular outcomes and mortality in women treated with statins. Menopause. 2015;22(4):369–376. Hodis HN, Mack WJ. Hormone therapy and risk of all-cause mortality in women treated with statins [comment]. Menopause. 2015;22(4):363–364.

Since the initial publication of findings from the WHI, clinicians have been cautioned not to prescribe menopausal HT in women at elevated risk for CVD. In this study from Sweden, investigators enrolled women ages 40 to 74 who initiated statin use between 2006 and 2007 due to known CVD (secondary prevention) or in the absence of known CVD (primary prevention). Women were followed for a mean of four years after beginning statins, until the end of 2011.

Of 40,958 statin users, 7% used HT (mean age of HT users and nonusers was 61 and 62, respectively). Overall, 70% of statin use was for primary prevention. Deaths from CVD occurred in 5 and 18 patients per 10,000 person-years among HT users and nonusers, respectively (HR, 0.38). All-cause mortality occurred in 33 and 87 patients per 10,000 person-years among HT users and non­users, respectively (HR, 0.53). These reduced risks for mortality noted in women who used concomitant statins achieved statistical significance. Whether statins were used for ­primary or secondary prevention, the incidence of cardiovascular events was similar in HT users and nonusers.

Why these findings diverge from those of the WHI
The findings of this large prospective cohort study are consistent with findings from other large observational studies—though they diverge from WHI findings. As Berglind and colleagues note, few WHI participants used statins at baseline. Also in contrast with the WHI, in which all HT was based on conjugated estrogen, all HT users in this Swedish study used oral or transdermal estradiol, as conjugated estrogen is not available in Sweden (and appears to be associated with an elevated risk for CVD, compared with other estrogens¹).

REFERENCE
1. Smith NL, Blondon M, Wiggins KL, et al. Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens. JAMA Intern Med. 2014;174(1):25–31.