Symptoms of sleep-disordered breathing range from primary snoring and upper airway resistance to obstructive sleep apnea (OSA). Psychiatric disorders and OSA frequently are comorbid. In a study of veterans with OSA, 22% had depression, 17% had anxiety, 12% had posttraumatic stress disorder, and 5% had psychosis.1 Treatments for OSA include dental devices, positive airway pressure ventilation, and surgery. Treating OSA often improves comorbid psychiatric disorders.2 However, medication-induced weight gain (eg, from antipsychotics) and hypnotics can worsen OSA. The mnemonic ABCDE can help you remember precipitating factors of OSA, associated sleep patterns, and complications of untreated OSA.

Precipitating factors

Age, gender, and race. OSA has a higher prevalence among middle-age men and the incidence of OSA gradually increases in postmenopausal women. African American patients also are at increased risk.

Bulkiness. Obesity is a significant risk factor for OSA, especially among middle-age men. Secondary fat deposition around the neck and decreased muscle tone and lung volume may lead to OSA.

Circumference of the neck. A neck circumference of >16 inches in women and >17 inches in men indicates a greater risk of developing OSA.³

Disrupted air flow. Airway narrowing can be present in patients with a small oropharynx, large tongue or uvula, backward tongue displacement, nasal obstruction, or craniofacial abnormalities.⁴ Certain medications (eg, muscle relaxants), alcohol, or hypothyroidism can reduce muscle tone and lead to OSA.⁵ Gastroesophageal reflux, asthma, pregnancy, stroke, and neuromuscular disease increase susceptibility to OSA. Patients with cardiac failure often have associated central sleep apnea.⁴

Extended family members. Patients with first-degree relatives who have OSA are at an increased risk of developing it themselves.⁵

Associated sleep patterns

Arousals. Intermittent nighttime sleep, non-restorative sleep, restless sleep, and insomnia are common among patients with OSA.⁵

Blocked airway and snoring. Snoring is common in OSA and signifies partial airway obstruction.

Choking, coughing, and gasping for air. As a result of decreased oxygenation, OSA patients usually wake up gasping for air. Associated gastroesophageal reflux also can cause cough.

Dry and/or open mouth. Most OSA patients breathe through their mouth because of obstruction in the upper airway.⁶ Patients often complain of dry mouth and morning thirst.

Excessive daytime sleepiness. Because of lack of nighttime sleep, it is common for individuals with OSA to feel tired during the day or want to nap.

Complications of untreated OSA

Anxiety and depression. There is a strong relationship between untreated OSA and psychiatric disorders, especially anxiety and depression in adults.¹

Body mass index elevation or obesity. Frequent apneas are linked to an increase in leptin and ghrelin levels, which leads to increased appetite.^4,5

Cardiovascular complications. Increased incidences of pulmonary or systemic hypertension, cardiac arrhythmias, myocardial infarctions, and strokes have been associated with untreated OSA.⁵

Daytime tiredness and sleepiness. Attention problems, tardiness, and accidents are common among patients with OSA.

Endocrine abnormalities. Individuals with moderate to severe OSA have a higher risk of developing diabetes mellitus and hypercholesterolemia.⁴

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Symptoms of sleep-disordered breathing range from primary snoring and upper airway resistance to obstructive sleep apnea (OSA). Psychiatric disorders and OSA frequently are comorbid. In a study of veterans with OSA, 22% had depression, 17% had anxiety, 12% had posttraumatic stress disorder, and 5% had psychosis.1 Treatments for OSA include dental devices, positive airway pressure ventilation, and surgery. Treating OSA often improves comorbid psychiatric disorders.2 However, medication-induced weight gain (eg, from antipsychotics) and hypnotics can worsen OSA. The mnemonic ABCDE can help you remember precipitating factors of OSA, associated sleep patterns, and complications of untreated OSA.

Precipitating factors

Age, gender, and race. OSA has a higher prevalence among middle-age men and the incidence of OSA gradually increases in postmenopausal women. African American patients also are at increased risk.

Bulkiness. Obesity is a significant risk factor for OSA, especially among middle-age men. Secondary fat deposition around the neck and decreased muscle tone and lung volume may lead to OSA.

Circumference of the neck. A neck circumference of >16 inches in women and >17 inches in men indicates a greater risk of developing OSA.³

Disrupted air flow. Airway narrowing can be present in patients with a small oropharynx, large tongue or uvula, backward tongue displacement, nasal obstruction, or craniofacial abnormalities.⁴ Certain medications (eg, muscle relaxants), alcohol, or hypothyroidism can reduce muscle tone and lead to OSA.⁵ Gastroesophageal reflux, asthma, pregnancy, stroke, and neuromuscular disease increase susceptibility to OSA. Patients with cardiac failure often have associated central sleep apnea.⁴

Extended family members. Patients with first-degree relatives who have OSA are at an increased risk of developing it themselves.⁵

Associated sleep patterns

Arousals. Intermittent nighttime sleep, non-restorative sleep, restless sleep, and insomnia are common among patients with OSA.⁵

Blocked airway and snoring. Snoring is common in OSA and signifies partial airway obstruction.

Choking, coughing, and gasping for air. As a result of decreased oxygenation, OSA patients usually wake up gasping for air. Associated gastroesophageal reflux also can cause cough.

Dry and/or open mouth. Most OSA patients breathe through their mouth because of obstruction in the upper airway.⁶ Patients often complain of dry mouth and morning thirst.

Excessive daytime sleepiness. Because of lack of nighttime sleep, it is common for individuals with OSA to feel tired during the day or want to nap.

Complications of untreated OSA

Anxiety and depression. There is a strong relationship between untreated OSA and psychiatric disorders, especially anxiety and depression in adults.¹

Body mass index elevation or obesity. Frequent apneas are linked to an increase in leptin and ghrelin levels, which leads to increased appetite.^4,5

Cardiovascular complications. Increased incidences of pulmonary or systemic hypertension, cardiac arrhythmias, myocardial infarctions, and strokes have been associated with untreated OSA.⁵

Daytime tiredness and sleepiness. Attention problems, tardiness, and accidents are common among patients with OSA.

Endocrine abnormalities. Individuals with moderate to severe OSA have a higher risk of developing diabetes mellitus and hypercholesterolemia.⁴

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Symptoms of sleep-disordered breathing range from primary snoring and upper airway resistance to obstructive sleep apnea (OSA). Psychiatric disorders and OSA frequently are comorbid. In a study of veterans with OSA, 22% had depression, 17% had anxiety, 12% had posttraumatic stress disorder, and 5% had psychosis.1 Treatments for OSA include dental devices, positive airway pressure ventilation, and surgery. Treating OSA often improves comorbid psychiatric disorders.2 However, medication-induced weight gain (eg, from antipsychotics) and hypnotics can worsen OSA. The mnemonic ABCDE can help you remember precipitating factors of OSA, associated sleep patterns, and complications of untreated OSA.

Precipitating factors

Age, gender, and race. OSA has a higher prevalence among middle-age men and the incidence of OSA gradually increases in postmenopausal women. African American patients also are at increased risk.

Bulkiness. Obesity is a significant risk factor for OSA, especially among middle-age men. Secondary fat deposition around the neck and decreased muscle tone and lung volume may lead to OSA.

Circumference of the neck. A neck circumference of >16 inches in women and >17 inches in men indicates a greater risk of developing OSA.³

Disrupted air flow. Airway narrowing can be present in patients with a small oropharynx, large tongue or uvula, backward tongue displacement, nasal obstruction, or craniofacial abnormalities.⁴ Certain medications (eg, muscle relaxants), alcohol, or hypothyroidism can reduce muscle tone and lead to OSA.⁵ Gastroesophageal reflux, asthma, pregnancy, stroke, and neuromuscular disease increase susceptibility to OSA. Patients with cardiac failure often have associated central sleep apnea.⁴

Extended family members. Patients with first-degree relatives who have OSA are at an increased risk of developing it themselves.⁵

Associated sleep patterns

Arousals. Intermittent nighttime sleep, non-restorative sleep, restless sleep, and insomnia are common among patients with OSA.⁵

Blocked airway and snoring. Snoring is common in OSA and signifies partial airway obstruction.

Choking, coughing, and gasping for air. As a result of decreased oxygenation, OSA patients usually wake up gasping for air. Associated gastroesophageal reflux also can cause cough.

Dry and/or open mouth. Most OSA patients breathe through their mouth because of obstruction in the upper airway.⁶ Patients often complain of dry mouth and morning thirst.

Excessive daytime sleepiness. Because of lack of nighttime sleep, it is common for individuals with OSA to feel tired during the day or want to nap.

Complications of untreated OSA

Anxiety and depression. There is a strong relationship between untreated OSA and psychiatric disorders, especially anxiety and depression in adults.¹

Body mass index elevation or obesity. Frequent apneas are linked to an increase in leptin and ghrelin levels, which leads to increased appetite.^4,5

Cardiovascular complications. Increased incidences of pulmonary or systemic hypertension, cardiac arrhythmias, myocardial infarctions, and strokes have been associated with untreated OSA.⁵

Daytime tiredness and sleepiness. Attention problems, tardiness, and accidents are common among patients with OSA.

Endocrine abnormalities. Individuals with moderate to severe OSA have a higher risk of developing diabetes mellitus and hypercholesterolemia.⁴

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Second-generation antipsychotics (SGAs) represent 5% of all U.S. drug expenditures.¹ Their use for indications not approved by the FDA (“off-label” use) increased to a total of $6 billion in 2008, $5.4 billion of which was for uses with limited or uncertain evidence.1

Off-label use of antipsychotics usually is based on novel applications of known receptor binding affinities (Table 1).^2-5 For example, antipsychotics with strong antihistamine effects may promote sedation and could be used to treat insomnia. Clinicians also might use antipsychotics to treat a specific symptom of an illness when other treatment options are limited⁶ or when patients do not respond to standard treatments.

Table 1

Possible rationales for antipsychotic use for nonpsychotic conditions

To safely use any medication off-label, clinicians should become familiar with literature on the proposed use. Clinicians should consider off-label use only after carefully weighing the potential therapeutic benefits against the risks. Patients should be aware that the prescribed use is not FDA-approved and informed consent should include a discussion of alternative treatments. The high cost of SGAs may be a limiting factor and should be discussed with patients.

This article reviews the evidence for using antipsychotics to treat insomnia, tics, delirium, and stuttering (Table 2). Click here for a review of the evidence supporting antipsychotics for treating migraine and cluster headaches and nausea

Table 2

Antipsychotics for nonpsychotic disorders: Strength of the evidence

Current use of antipsychotics

Antipsychotics are divided into 2 major classes—first-generation antipsychotics (FGAs) and SGAs—and principally are FDA-approved for treating schizophrenia. Some antipsychotics have received FDA approval for maintenance treatment of schizophrenia and bipolar disorder (BD), and others have been approved to treat tic disorders (haloperidol and pimozide).

To varying degrees, all antipsychotics block D2 receptors, which is thought to be necessary for treating psychosis. However, some SGAs have significant affinity at other receptors—such as 5-HT2A and 5-HT1A—that confer additional properties that are not fully understood (Table 3). For example, it is believed that 5-HT2A blockade in the striatum reduces the potential for extrapyramidal symptoms (EPS).

Each antipsychotic blocks a unique set of receptors in the brain, leading to a specific set of intended and potentially untoward effects. For example, olanzapine’s effect on psychosis largely stems from its action at the D2 receptor, whereas its sedative and anticholinergic properties are a result of activity at histamine (H1) receptors and muscarinic receptors, respectively. Clinicians can make rational use of unintended effects by carefully selecting a medication based on receptor binding profile (eg, using an antipsychotic with sedating properties in a patient who has psychosis and insomnia). This approach can limit use of multiple medications and maximize a medication’s known effects while attempting to minimize side effects.

Table 3

Antipsychotics: Receptor pharmacology and common side effects

Insomnia

Clinicians use FGAs and SGAs to treat insomnia because of their sedating effects, although evidence supporting this use is questionable. Among the FGAs, chlorpromazine produces moderate to severe sedation, whereas haloperidol is only mildly sedating. Clozapine is believed to be the most sedating SGA, whereas quetiapine and olanzapine produce moderate sedation.⁷

Most data on antipsychotics’ sedating effects comes from studies completed for schizophrenia or BD. Few studies have evaluated using antipsychotics to treat primary insomnia or other sleep disorders in otherwise healthy patients.² However, data from phase I studies of antipsychotics has shown that schizophrenia patients tolerate a higher maximum dose compared with healthy volunteers, who often experience more sedation.

An antipsychotic’s potential for sedation is directly related to its affinity at H1 receptors and total drug concentration at the H1 receptor binding site. Because drugs with lower affinity for D2 receptors typically are prescribed at higher doses when treating psychiatric illness, the corresponding concentration at H1 receptors can lead to greater sedation compared with equivalent doses of higher-potency agents.

The same phenomenon is seen with high-potency agents. Haloperidol has a relatively weak binding affinity to the H1 receptor,⁸ but causes more sedation at higher doses. Haloperidol, 20 mg/d, produces sedation in more patients than a moderate dose of risperidone, 2 to 10 mg/d.⁸ These observations correlate with “the high milligram-low-potency” spectrum seen with FGAs.⁷

Among SGAs, a double-blind, placebo-controlled, crossover study of the effects of ziprasidone, 40 mg/d, on sleep in a group of healthy volunteers found a significant increase in total sleep time and sleep efficiency.⁹ A double-blind trial compared patients taking low, medium, or high daily doses of olanzapine with patients receiving haloperidol or placebo.¹⁰ Sedation was reported in 20% of patients taking low doses of olanzapine (5 ± 2.5 mg/d) compared with 29.7% on medium doses (10 ± 2.5 mg/d) and 39.1% on high doses (15 ± 2.5 mg/d).¹⁰

A double-blind, placebo-controlled, crossover study demonstrated that olanzapine produced significant increases in sleep continuity, slow wave sleep, and subjective ratings of sleep quality in healthy men.¹¹ Similarly, a study comparing haloperidol, 12 mg/d, and quetiapine, 75 to 750 mg/d, for treating acute schizophrenia found an 8% to 11% incidence of somnolence in the quetiapine group compared with 6% and 8% in the haloperidol and placebo groups, respectively.¹² Somnolence was reported as an adverse event in these studies, which were designed to examine the drug’s effect on acute schizophrenia and did not evaluate its effect on sleep.

A double-blind, placebo-controlled, crossover study examining quetiapine’s effects on sleep in 14 healthy patients demonstrated a significant difference in total sleep time, sleep period time, and sleep efficiency.¹³ Similarly, an open-label pilot study of quetiapine’s effect on primary insomnia showed significant improvement in total sleep time and sleep efficiency.¹⁴

Studies examining quetiapine’s effects on insomnia in patients with substance abuse¹⁵ and women with localized breast cancer¹⁶ showed improved sleep scores on multiple assessment tools, while an open-label study of quetiapine for Parkinson’s disease demonstrated decreased sleep latency.¹⁷ Adjunctive quetiapine administered over a 6-week, open-label trial in veterans with posttraumatic stress disorder revealed significant improvement from baseline in sleep quality and duration and diminished dreaming.¹⁸

Sedating antipsychotics such as thioridazine and chlorpromazine historically were used off-label for insomnia, but fell out of favor because of their associated cardiac risks. More recently, clinicians have been using SGAs in a similar manner¹⁹ even though SGAs are costly and have significant risks such as metabolic problems.

Studies supporting the use of SGAs for the short-term or long-term treatment of insomnia are limited by small sample sizes or open-label designs.²⁰ In 2005 the National Institutes of Health State-of-the-Science Conference Panel did not recommend using SGAs for treating chronic insomnia.²¹

Tics in Tourette’s disorder

FGAs and SGAs have been used to treat tics associated with Tourette’s disorder (TD).²² Haloperidol is FDA-approved for treating tics in adult and pediatric patients with TD. Many studies have reported the efficacy of haloperidol in this population; however, cognitive blunting, weight gain, lethargy, and akathisia limit its use.²³

Pimozide, the most widely used alternative to haloperidol for treating TD, can cause clinically significant QTc prolongation and sudden death. Penfluridol demonstrated significant symptomatic improvement compared with haloperidol in 1 study, but its carcinogenic potential limits its use.²⁴

A double-blind, placebo-controlled study comparing fluphenazine and trifluoperazine with haloperidol for treating TD showed that both are significantly more effective than placebo, but none was more effective than the others.²⁵ Studies show chlorpromazine, perphenazine, and thioridazine are less effective than haloperidol and their use is limited by photosensitivity, dermatitis, EPS, and blood and liver dyscrasias.²⁶

Risperidone is superior to placebo for treating tics associated with TD.²⁷ A placebo-controlled trial of ziprasidone showed the drug has efficacy similar to risperidone in reducing tics in children and adolescents with TD.²⁸ However, ziprasidone is not FDA-approved for this use.

Evidence supporting the use of other SGAs for treating TD is more limited. Several small studies of olanzapine and aripiprazole had limited but favorable results. Quetiapine has not been studied for treating TD, but several case reports have indicated a positive response. In a double-blind, placebo-controlled trial, clozapine showed no therapeutic benefit for TD.²⁹

Delirium

American Psychiatric Association practice guidelines suggest using psychotropic medications to treat neuropsychiatric symptoms of delirium.³⁰ Antipsychotics are considered first-line agents that lower hospital mortality rates, decrease lengths of hospital stays, and improve delirium symptoms, in some cases before the underlying medical etiologies resolve.^30,31 Available in liquid, oral, IM, and IV formulations, haloperidol is the mainstay of symptomatic treatment of delirium.³¹ Although not FDA-approved, it is recommended by the Society of Critical Care Medicine as a safe, cost-effective, and efficacious therapy for the psychiatric symptoms associated with delirium.

The most extensively studied SGA for treating delirium, risperidone often is used as an alternative to haloperidol. Case reports describe its potential efficacy.³² In a head-to-head study, risperidone was as effective as low-dose haloperidol for acute delirium treatment.³³

Olanzapine was effective in managing delirium in several case studies.³⁴ Also, in a 7-day, randomized, placebo-controlled study, olanzapine and haloperidol showed significantly greater and relatively equivalent improvement compared with placebo; patients treated with olanzapine experienced more rapid improvement in 1 study.³⁵

Case reports and prospective studies also have described quetiapine as effective for treating delirium.^36,37 In a prospective, double-blind, placebo-controlled study, patients taking quetiapine had a faster resolution of delirium with reduced overall duration and less agitation than those taking placebo.³⁷ Mortality, intensive care unit length of stay, and incidence of QTc prolongation did not differ, but patients treated with quetiapine were more likely to have increased somnolence and were more frequently discharged to home or rehabilitation centers. One limitation of the study is that concomitant haloperidol use on an “as needed” basis was permitted.³⁸

Evidence supporting the efficacy of ziprasidone for delirium is limited to case reports.³⁹ In 1 case report, a patient with chronic HIV infection and acute cryptococcal meningitis experienced significant improvement of delirium symptoms but could not continue ziprasidone because of fluctuating QTc intervals.⁴⁰

In 2 patients with delirium, aripiprazole, 15 and 30 mg/d, improved confusion, disorientation, and agitation within 7 days.⁴¹ In another study of delirium, 13 of 14 patients on flexibly dosed aripiprazole (5 to 15 mg/d) showed improvement in Clinical Global Impressions Scale scores, although 3 patients developed prolonged QTc intervals.⁴²

Stuttering or stammering

Stuttering or stammering are age-inappropriate disturbances in normal fluency and time patterning of speech. The evidence for antipsychotics to treat stuttering or stammering speech mainly consists of case reports and does not include disfluency frequency data, which makes it difficult to accept claims of efficacy. Disfluency frequency data describe how often a patient has specific disfluencies (blocks, prolongations, interjection, and repetition of syllables, words, or phrases).

Two FGAs (chlorpromazine and haloperidol) and 2 SGAs (risperidone and olanzapine) have been evaluated for treating stuttering. Children were 2.5 times more likely to demonstrate significant improvement when taking chlorpromazine vs placebo.⁴³ An open-label study of haloperidol lacked disfluency frequency data, therefore casting doubts on haloperidol’s reported efficacy in the study.⁴⁴

In a case report, a 4-year-old boy with severe behavioral dyscontrol showed complete remission of stammering after 1 day of risperidone, 0.25 mg/d.⁴⁵ The patient’s symptoms reappeared several days after the drug was stopped. In a case series of 2 patients with developmental stuttering, 1 patient reported significant improvement in fluency with olanzapine, 2.5 mg/d, and the other showed marked improvement in fluency with 5 mg/d.⁴⁶

Related Resources

• Sipahimalani A, Masand PS. Use of risperidone in delirium: case reports. Ann Clin Psychiatry. 1997;9(2):105-107.
• Shapiro AK, Shapiro E, Wayne HL. Treatment of Tourette’s syndrome with haloperidol: review of 34 cases. Arch Gen Psychiatry. 1973;28(1):92-96.
• Sipahimalani A, Masand PS. Olanzapine in the treatment of delirium. Psychosomatics. 1998;39(5):422-430.

Drug Brand Names

• Aripiprazole • Abilify
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluphenazine • Permitil, Prolixin
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Pimozide • Orap
• Prochlorperazine • Compazine
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Trifluoperazine • Stelazine
• Ziprasidone • Geodon

Disclosure

Dr. Macaluso has received grant or research support from EnVivo Pharmaceuticals, Janssen, L.P., and Pfizer, Inc.

Dr. Tripathi reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Second-generation antipsychotics (SGAs) represent 5% of all U.S. drug expenditures.¹ Their use for indications not approved by the FDA (“off-label” use) increased to a total of $6 billion in 2008, $5.4 billion of which was for uses with limited or uncertain evidence.1

Off-label use of antipsychotics usually is based on novel applications of known receptor binding affinities (Table 1).^2-5 For example, antipsychotics with strong antihistamine effects may promote sedation and could be used to treat insomnia. Clinicians also might use antipsychotics to treat a specific symptom of an illness when other treatment options are limited⁶ or when patients do not respond to standard treatments.

Table 1

Possible rationales for antipsychotic use for nonpsychotic conditions

To safely use any medication off-label, clinicians should become familiar with literature on the proposed use. Clinicians should consider off-label use only after carefully weighing the potential therapeutic benefits against the risks. Patients should be aware that the prescribed use is not FDA-approved and informed consent should include a discussion of alternative treatments. The high cost of SGAs may be a limiting factor and should be discussed with patients.

This article reviews the evidence for using antipsychotics to treat insomnia, tics, delirium, and stuttering (Table 2). Click here for a review of the evidence supporting antipsychotics for treating migraine and cluster headaches and nausea

Table 2

Antipsychotics for nonpsychotic disorders: Strength of the evidence

Current use of antipsychotics

Antipsychotics are divided into 2 major classes—first-generation antipsychotics (FGAs) and SGAs—and principally are FDA-approved for treating schizophrenia. Some antipsychotics have received FDA approval for maintenance treatment of schizophrenia and bipolar disorder (BD), and others have been approved to treat tic disorders (haloperidol and pimozide).

To varying degrees, all antipsychotics block D2 receptors, which is thought to be necessary for treating psychosis. However, some SGAs have significant affinity at other receptors—such as 5-HT2A and 5-HT1A—that confer additional properties that are not fully understood (Table 3). For example, it is believed that 5-HT2A blockade in the striatum reduces the potential for extrapyramidal symptoms (EPS).

Each antipsychotic blocks a unique set of receptors in the brain, leading to a specific set of intended and potentially untoward effects. For example, olanzapine’s effect on psychosis largely stems from its action at the D2 receptor, whereas its sedative and anticholinergic properties are a result of activity at histamine (H1) receptors and muscarinic receptors, respectively. Clinicians can make rational use of unintended effects by carefully selecting a medication based on receptor binding profile (eg, using an antipsychotic with sedating properties in a patient who has psychosis and insomnia). This approach can limit use of multiple medications and maximize a medication’s known effects while attempting to minimize side effects.

Table 3

Antipsychotics: Receptor pharmacology and common side effects

Insomnia

Clinicians use FGAs and SGAs to treat insomnia because of their sedating effects, although evidence supporting this use is questionable. Among the FGAs, chlorpromazine produces moderate to severe sedation, whereas haloperidol is only mildly sedating. Clozapine is believed to be the most sedating SGA, whereas quetiapine and olanzapine produce moderate sedation.⁷

Most data on antipsychotics’ sedating effects comes from studies completed for schizophrenia or BD. Few studies have evaluated using antipsychotics to treat primary insomnia or other sleep disorders in otherwise healthy patients.² However, data from phase I studies of antipsychotics has shown that schizophrenia patients tolerate a higher maximum dose compared with healthy volunteers, who often experience more sedation.

An antipsychotic’s potential for sedation is directly related to its affinity at H1 receptors and total drug concentration at the H1 receptor binding site. Because drugs with lower affinity for D2 receptors typically are prescribed at higher doses when treating psychiatric illness, the corresponding concentration at H1 receptors can lead to greater sedation compared with equivalent doses of higher-potency agents.

The same phenomenon is seen with high-potency agents. Haloperidol has a relatively weak binding affinity to the H1 receptor,⁸ but causes more sedation at higher doses. Haloperidol, 20 mg/d, produces sedation in more patients than a moderate dose of risperidone, 2 to 10 mg/d.⁸ These observations correlate with “the high milligram-low-potency” spectrum seen with FGAs.⁷

Among SGAs, a double-blind, placebo-controlled, crossover study of the effects of ziprasidone, 40 mg/d, on sleep in a group of healthy volunteers found a significant increase in total sleep time and sleep efficiency.⁹ A double-blind trial compared patients taking low, medium, or high daily doses of olanzapine with patients receiving haloperidol or placebo.¹⁰ Sedation was reported in 20% of patients taking low doses of olanzapine (5 ± 2.5 mg/d) compared with 29.7% on medium doses (10 ± 2.5 mg/d) and 39.1% on high doses (15 ± 2.5 mg/d).¹⁰

A double-blind, placebo-controlled, crossover study demonstrated that olanzapine produced significant increases in sleep continuity, slow wave sleep, and subjective ratings of sleep quality in healthy men.¹¹ Similarly, a study comparing haloperidol, 12 mg/d, and quetiapine, 75 to 750 mg/d, for treating acute schizophrenia found an 8% to 11% incidence of somnolence in the quetiapine group compared with 6% and 8% in the haloperidol and placebo groups, respectively.¹² Somnolence was reported as an adverse event in these studies, which were designed to examine the drug’s effect on acute schizophrenia and did not evaluate its effect on sleep.

A double-blind, placebo-controlled, crossover study examining quetiapine’s effects on sleep in 14 healthy patients demonstrated a significant difference in total sleep time, sleep period time, and sleep efficiency.¹³ Similarly, an open-label pilot study of quetiapine’s effect on primary insomnia showed significant improvement in total sleep time and sleep efficiency.¹⁴

Studies examining quetiapine’s effects on insomnia in patients with substance abuse¹⁵ and women with localized breast cancer¹⁶ showed improved sleep scores on multiple assessment tools, while an open-label study of quetiapine for Parkinson’s disease demonstrated decreased sleep latency.¹⁷ Adjunctive quetiapine administered over a 6-week, open-label trial in veterans with posttraumatic stress disorder revealed significant improvement from baseline in sleep quality and duration and diminished dreaming.¹⁸

Sedating antipsychotics such as thioridazine and chlorpromazine historically were used off-label for insomnia, but fell out of favor because of their associated cardiac risks. More recently, clinicians have been using SGAs in a similar manner¹⁹ even though SGAs are costly and have significant risks such as metabolic problems.

Studies supporting the use of SGAs for the short-term or long-term treatment of insomnia are limited by small sample sizes or open-label designs.²⁰ In 2005 the National Institutes of Health State-of-the-Science Conference Panel did not recommend using SGAs for treating chronic insomnia.²¹

Tics in Tourette’s disorder

FGAs and SGAs have been used to treat tics associated with Tourette’s disorder (TD).²² Haloperidol is FDA-approved for treating tics in adult and pediatric patients with TD. Many studies have reported the efficacy of haloperidol in this population; however, cognitive blunting, weight gain, lethargy, and akathisia limit its use.²³

Pimozide, the most widely used alternative to haloperidol for treating TD, can cause clinically significant QTc prolongation and sudden death. Penfluridol demonstrated significant symptomatic improvement compared with haloperidol in 1 study, but its carcinogenic potential limits its use.²⁴

A double-blind, placebo-controlled study comparing fluphenazine and trifluoperazine with haloperidol for treating TD showed that both are significantly more effective than placebo, but none was more effective than the others.²⁵ Studies show chlorpromazine, perphenazine, and thioridazine are less effective than haloperidol and their use is limited by photosensitivity, dermatitis, EPS, and blood and liver dyscrasias.²⁶

Risperidone is superior to placebo for treating tics associated with TD.²⁷ A placebo-controlled trial of ziprasidone showed the drug has efficacy similar to risperidone in reducing tics in children and adolescents with TD.²⁸ However, ziprasidone is not FDA-approved for this use.

Evidence supporting the use of other SGAs for treating TD is more limited. Several small studies of olanzapine and aripiprazole had limited but favorable results. Quetiapine has not been studied for treating TD, but several case reports have indicated a positive response. In a double-blind, placebo-controlled trial, clozapine showed no therapeutic benefit for TD.²⁹

Delirium

American Psychiatric Association practice guidelines suggest using psychotropic medications to treat neuropsychiatric symptoms of delirium.³⁰ Antipsychotics are considered first-line agents that lower hospital mortality rates, decrease lengths of hospital stays, and improve delirium symptoms, in some cases before the underlying medical etiologies resolve.^30,31 Available in liquid, oral, IM, and IV formulations, haloperidol is the mainstay of symptomatic treatment of delirium.³¹ Although not FDA-approved, it is recommended by the Society of Critical Care Medicine as a safe, cost-effective, and efficacious therapy for the psychiatric symptoms associated with delirium.

The most extensively studied SGA for treating delirium, risperidone often is used as an alternative to haloperidol. Case reports describe its potential efficacy.³² In a head-to-head study, risperidone was as effective as low-dose haloperidol for acute delirium treatment.³³

Olanzapine was effective in managing delirium in several case studies.³⁴ Also, in a 7-day, randomized, placebo-controlled study, olanzapine and haloperidol showed significantly greater and relatively equivalent improvement compared with placebo; patients treated with olanzapine experienced more rapid improvement in 1 study.³⁵

Case reports and prospective studies also have described quetiapine as effective for treating delirium.^36,37 In a prospective, double-blind, placebo-controlled study, patients taking quetiapine had a faster resolution of delirium with reduced overall duration and less agitation than those taking placebo.³⁷ Mortality, intensive care unit length of stay, and incidence of QTc prolongation did not differ, but patients treated with quetiapine were more likely to have increased somnolence and were more frequently discharged to home or rehabilitation centers. One limitation of the study is that concomitant haloperidol use on an “as needed” basis was permitted.³⁸

Evidence supporting the efficacy of ziprasidone for delirium is limited to case reports.³⁹ In 1 case report, a patient with chronic HIV infection and acute cryptococcal meningitis experienced significant improvement of delirium symptoms but could not continue ziprasidone because of fluctuating QTc intervals.⁴⁰

In 2 patients with delirium, aripiprazole, 15 and 30 mg/d, improved confusion, disorientation, and agitation within 7 days.⁴¹ In another study of delirium, 13 of 14 patients on flexibly dosed aripiprazole (5 to 15 mg/d) showed improvement in Clinical Global Impressions Scale scores, although 3 patients developed prolonged QTc intervals.⁴²

Stuttering or stammering

Stuttering or stammering are age-inappropriate disturbances in normal fluency and time patterning of speech. The evidence for antipsychotics to treat stuttering or stammering speech mainly consists of case reports and does not include disfluency frequency data, which makes it difficult to accept claims of efficacy. Disfluency frequency data describe how often a patient has specific disfluencies (blocks, prolongations, interjection, and repetition of syllables, words, or phrases).

Two FGAs (chlorpromazine and haloperidol) and 2 SGAs (risperidone and olanzapine) have been evaluated for treating stuttering. Children were 2.5 times more likely to demonstrate significant improvement when taking chlorpromazine vs placebo.⁴³ An open-label study of haloperidol lacked disfluency frequency data, therefore casting doubts on haloperidol’s reported efficacy in the study.⁴⁴

In a case report, a 4-year-old boy with severe behavioral dyscontrol showed complete remission of stammering after 1 day of risperidone, 0.25 mg/d.⁴⁵ The patient’s symptoms reappeared several days after the drug was stopped. In a case series of 2 patients with developmental stuttering, 1 patient reported significant improvement in fluency with olanzapine, 2.5 mg/d, and the other showed marked improvement in fluency with 5 mg/d.⁴⁶

Related Resources

• Sipahimalani A, Masand PS. Use of risperidone in delirium: case reports. Ann Clin Psychiatry. 1997;9(2):105-107.
• Shapiro AK, Shapiro E, Wayne HL. Treatment of Tourette’s syndrome with haloperidol: review of 34 cases. Arch Gen Psychiatry. 1973;28(1):92-96.
• Sipahimalani A, Masand PS. Olanzapine in the treatment of delirium. Psychosomatics. 1998;39(5):422-430.

Drug Brand Names

• Aripiprazole • Abilify
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluphenazine • Permitil, Prolixin
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Pimozide • Orap
• Prochlorperazine • Compazine
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Trifluoperazine • Stelazine
• Ziprasidone • Geodon

Disclosure

Dr. Macaluso has received grant or research support from EnVivo Pharmaceuticals, Janssen, L.P., and Pfizer, Inc.

Dr. Tripathi reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Second-generation antipsychotics (SGAs) represent 5% of all U.S. drug expenditures.¹ Their use for indications not approved by the FDA (“off-label” use) increased to a total of $6 billion in 2008, $5.4 billion of which was for uses with limited or uncertain evidence.1

Off-label use of antipsychotics usually is based on novel applications of known receptor binding affinities (Table 1).^2-5 For example, antipsychotics with strong antihistamine effects may promote sedation and could be used to treat insomnia. Clinicians also might use antipsychotics to treat a specific symptom of an illness when other treatment options are limited⁶ or when patients do not respond to standard treatments.

Table 1

Possible rationales for antipsychotic use for nonpsychotic conditions

To safely use any medication off-label, clinicians should become familiar with literature on the proposed use. Clinicians should consider off-label use only after carefully weighing the potential therapeutic benefits against the risks. Patients should be aware that the prescribed use is not FDA-approved and informed consent should include a discussion of alternative treatments. The high cost of SGAs may be a limiting factor and should be discussed with patients.

This article reviews the evidence for using antipsychotics to treat insomnia, tics, delirium, and stuttering (Table 2). Click here for a review of the evidence supporting antipsychotics for treating migraine and cluster headaches and nausea

Table 2

Antipsychotics for nonpsychotic disorders: Strength of the evidence

Current use of antipsychotics

Antipsychotics are divided into 2 major classes—first-generation antipsychotics (FGAs) and SGAs—and principally are FDA-approved for treating schizophrenia. Some antipsychotics have received FDA approval for maintenance treatment of schizophrenia and bipolar disorder (BD), and others have been approved to treat tic disorders (haloperidol and pimozide).

To varying degrees, all antipsychotics block D2 receptors, which is thought to be necessary for treating psychosis. However, some SGAs have significant affinity at other receptors—such as 5-HT2A and 5-HT1A—that confer additional properties that are not fully understood (Table 3). For example, it is believed that 5-HT2A blockade in the striatum reduces the potential for extrapyramidal symptoms (EPS).

Each antipsychotic blocks a unique set of receptors in the brain, leading to a specific set of intended and potentially untoward effects. For example, olanzapine’s effect on psychosis largely stems from its action at the D2 receptor, whereas its sedative and anticholinergic properties are a result of activity at histamine (H1) receptors and muscarinic receptors, respectively. Clinicians can make rational use of unintended effects by carefully selecting a medication based on receptor binding profile (eg, using an antipsychotic with sedating properties in a patient who has psychosis and insomnia). This approach can limit use of multiple medications and maximize a medication’s known effects while attempting to minimize side effects.

Table 3

Antipsychotics: Receptor pharmacology and common side effects

Insomnia

Clinicians use FGAs and SGAs to treat insomnia because of their sedating effects, although evidence supporting this use is questionable. Among the FGAs, chlorpromazine produces moderate to severe sedation, whereas haloperidol is only mildly sedating. Clozapine is believed to be the most sedating SGA, whereas quetiapine and olanzapine produce moderate sedation.⁷

Most data on antipsychotics’ sedating effects comes from studies completed for schizophrenia or BD. Few studies have evaluated using antipsychotics to treat primary insomnia or other sleep disorders in otherwise healthy patients.² However, data from phase I studies of antipsychotics has shown that schizophrenia patients tolerate a higher maximum dose compared with healthy volunteers, who often experience more sedation.

An antipsychotic’s potential for sedation is directly related to its affinity at H1 receptors and total drug concentration at the H1 receptor binding site. Because drugs with lower affinity for D2 receptors typically are prescribed at higher doses when treating psychiatric illness, the corresponding concentration at H1 receptors can lead to greater sedation compared with equivalent doses of higher-potency agents.

The same phenomenon is seen with high-potency agents. Haloperidol has a relatively weak binding affinity to the H1 receptor,⁸ but causes more sedation at higher doses. Haloperidol, 20 mg/d, produces sedation in more patients than a moderate dose of risperidone, 2 to 10 mg/d.⁸ These observations correlate with “the high milligram-low-potency” spectrum seen with FGAs.⁷

Among SGAs, a double-blind, placebo-controlled, crossover study of the effects of ziprasidone, 40 mg/d, on sleep in a group of healthy volunteers found a significant increase in total sleep time and sleep efficiency.⁹ A double-blind trial compared patients taking low, medium, or high daily doses of olanzapine with patients receiving haloperidol or placebo.¹⁰ Sedation was reported in 20% of patients taking low doses of olanzapine (5 ± 2.5 mg/d) compared with 29.7% on medium doses (10 ± 2.5 mg/d) and 39.1% on high doses (15 ± 2.5 mg/d).¹⁰

A double-blind, placebo-controlled, crossover study demonstrated that olanzapine produced significant increases in sleep continuity, slow wave sleep, and subjective ratings of sleep quality in healthy men.¹¹ Similarly, a study comparing haloperidol, 12 mg/d, and quetiapine, 75 to 750 mg/d, for treating acute schizophrenia found an 8% to 11% incidence of somnolence in the quetiapine group compared with 6% and 8% in the haloperidol and placebo groups, respectively.¹² Somnolence was reported as an adverse event in these studies, which were designed to examine the drug’s effect on acute schizophrenia and did not evaluate its effect on sleep.

A double-blind, placebo-controlled, crossover study examining quetiapine’s effects on sleep in 14 healthy patients demonstrated a significant difference in total sleep time, sleep period time, and sleep efficiency.¹³ Similarly, an open-label pilot study of quetiapine’s effect on primary insomnia showed significant improvement in total sleep time and sleep efficiency.¹⁴

Studies examining quetiapine’s effects on insomnia in patients with substance abuse¹⁵ and women with localized breast cancer¹⁶ showed improved sleep scores on multiple assessment tools, while an open-label study of quetiapine for Parkinson’s disease demonstrated decreased sleep latency.¹⁷ Adjunctive quetiapine administered over a 6-week, open-label trial in veterans with posttraumatic stress disorder revealed significant improvement from baseline in sleep quality and duration and diminished dreaming.¹⁸

Sedating antipsychotics such as thioridazine and chlorpromazine historically were used off-label for insomnia, but fell out of favor because of their associated cardiac risks. More recently, clinicians have been using SGAs in a similar manner¹⁹ even though SGAs are costly and have significant risks such as metabolic problems.

Studies supporting the use of SGAs for the short-term or long-term treatment of insomnia are limited by small sample sizes or open-label designs.²⁰ In 2005 the National Institutes of Health State-of-the-Science Conference Panel did not recommend using SGAs for treating chronic insomnia.²¹

Tics in Tourette’s disorder

FGAs and SGAs have been used to treat tics associated with Tourette’s disorder (TD).²² Haloperidol is FDA-approved for treating tics in adult and pediatric patients with TD. Many studies have reported the efficacy of haloperidol in this population; however, cognitive blunting, weight gain, lethargy, and akathisia limit its use.²³

Pimozide, the most widely used alternative to haloperidol for treating TD, can cause clinically significant QTc prolongation and sudden death. Penfluridol demonstrated significant symptomatic improvement compared with haloperidol in 1 study, but its carcinogenic potential limits its use.²⁴

A double-blind, placebo-controlled study comparing fluphenazine and trifluoperazine with haloperidol for treating TD showed that both are significantly more effective than placebo, but none was more effective than the others.²⁵ Studies show chlorpromazine, perphenazine, and thioridazine are less effective than haloperidol and their use is limited by photosensitivity, dermatitis, EPS, and blood and liver dyscrasias.²⁶

Risperidone is superior to placebo for treating tics associated with TD.²⁷ A placebo-controlled trial of ziprasidone showed the drug has efficacy similar to risperidone in reducing tics in children and adolescents with TD.²⁸ However, ziprasidone is not FDA-approved for this use.

Evidence supporting the use of other SGAs for treating TD is more limited. Several small studies of olanzapine and aripiprazole had limited but favorable results. Quetiapine has not been studied for treating TD, but several case reports have indicated a positive response. In a double-blind, placebo-controlled trial, clozapine showed no therapeutic benefit for TD.²⁹

Delirium

American Psychiatric Association practice guidelines suggest using psychotropic medications to treat neuropsychiatric symptoms of delirium.³⁰ Antipsychotics are considered first-line agents that lower hospital mortality rates, decrease lengths of hospital stays, and improve delirium symptoms, in some cases before the underlying medical etiologies resolve.^30,31 Available in liquid, oral, IM, and IV formulations, haloperidol is the mainstay of symptomatic treatment of delirium.³¹ Although not FDA-approved, it is recommended by the Society of Critical Care Medicine as a safe, cost-effective, and efficacious therapy for the psychiatric symptoms associated with delirium.

The most extensively studied SGA for treating delirium, risperidone often is used as an alternative to haloperidol. Case reports describe its potential efficacy.³² In a head-to-head study, risperidone was as effective as low-dose haloperidol for acute delirium treatment.³³

Olanzapine was effective in managing delirium in several case studies.³⁴ Also, in a 7-day, randomized, placebo-controlled study, olanzapine and haloperidol showed significantly greater and relatively equivalent improvement compared with placebo; patients treated with olanzapine experienced more rapid improvement in 1 study.³⁵

Case reports and prospective studies also have described quetiapine as effective for treating delirium.^36,37 In a prospective, double-blind, placebo-controlled study, patients taking quetiapine had a faster resolution of delirium with reduced overall duration and less agitation than those taking placebo.³⁷ Mortality, intensive care unit length of stay, and incidence of QTc prolongation did not differ, but patients treated with quetiapine were more likely to have increased somnolence and were more frequently discharged to home or rehabilitation centers. One limitation of the study is that concomitant haloperidol use on an “as needed” basis was permitted.³⁸

Evidence supporting the efficacy of ziprasidone for delirium is limited to case reports.³⁹ In 1 case report, a patient with chronic HIV infection and acute cryptococcal meningitis experienced significant improvement of delirium symptoms but could not continue ziprasidone because of fluctuating QTc intervals.⁴⁰

In 2 patients with delirium, aripiprazole, 15 and 30 mg/d, improved confusion, disorientation, and agitation within 7 days.⁴¹ In another study of delirium, 13 of 14 patients on flexibly dosed aripiprazole (5 to 15 mg/d) showed improvement in Clinical Global Impressions Scale scores, although 3 patients developed prolonged QTc intervals.⁴²

Stuttering or stammering

Stuttering or stammering are age-inappropriate disturbances in normal fluency and time patterning of speech. The evidence for antipsychotics to treat stuttering or stammering speech mainly consists of case reports and does not include disfluency frequency data, which makes it difficult to accept claims of efficacy. Disfluency frequency data describe how often a patient has specific disfluencies (blocks, prolongations, interjection, and repetition of syllables, words, or phrases).

Two FGAs (chlorpromazine and haloperidol) and 2 SGAs (risperidone and olanzapine) have been evaluated for treating stuttering. Children were 2.5 times more likely to demonstrate significant improvement when taking chlorpromazine vs placebo.⁴³ An open-label study of haloperidol lacked disfluency frequency data, therefore casting doubts on haloperidol’s reported efficacy in the study.⁴⁴

In a case report, a 4-year-old boy with severe behavioral dyscontrol showed complete remission of stammering after 1 day of risperidone, 0.25 mg/d.⁴⁵ The patient’s symptoms reappeared several days after the drug was stopped. In a case series of 2 patients with developmental stuttering, 1 patient reported significant improvement in fluency with olanzapine, 2.5 mg/d, and the other showed marked improvement in fluency with 5 mg/d.⁴⁶

Related Resources

• Sipahimalani A, Masand PS. Use of risperidone in delirium: case reports. Ann Clin Psychiatry. 1997;9(2):105-107.
• Shapiro AK, Shapiro E, Wayne HL. Treatment of Tourette’s syndrome with haloperidol: review of 34 cases. Arch Gen Psychiatry. 1973;28(1):92-96.
• Sipahimalani A, Masand PS. Olanzapine in the treatment of delirium. Psychosomatics. 1998;39(5):422-430.

Drug Brand Names

• Aripiprazole • Abilify
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluphenazine • Permitil, Prolixin
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Pimozide • Orap
• Prochlorperazine • Compazine
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Trifluoperazine • Stelazine
• Ziprasidone • Geodon

Disclosure

Dr. Macaluso has received grant or research support from EnVivo Pharmaceuticals, Janssen, L.P., and Pfizer, Inc.

Dr. Tripathi reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

In this series, I review what I call prescription apps—apps that you might consider recommending to your patient to enhance her medical care. Many patients are already looking at medical apps and want to hear your opinion. Often, the free apps I recommend to patients are downloaded before they leave my office. When recommending apps, their cost (not necessarily a measure of quality or utility) and platform (device that the app has been designed for) should be taken into account. It is helpful to know whether the app you are recommending is supported by your patient’s smartphone.

Chronic pelvic pain: multifactorial

Chronic pelvic pain, like most chronic pain conditions, is multifactorial in nature. It is not surprising then that most women with chronic pelvic pain do best with a multidisciplinary management approach that addresses both physical and emotional well-being, including the mind-body aspect of chronic pain (how mood and emotions affect pain), exercise, pacing of activities, attention to sleep hygiene, and the role of dysfunctional eating patterns. However, a patient’s access to formal mind-body programs or even a pain psychologist can be hard to come by for a variety of reasons.

An app that tracks pain and treatment

WebMD Pain Coach is a mobile mind-body program and pain coach all rolled into one. While specifically designed for nongynecologic pain conditions (fibromyalgia, migraine, back pain), the app works just as well for pelvic pain. Pain conditions, such as pelvic pain, that are not preloaded into the app are easy to add.^1,2

WebMD Pain Coach provides a way for the user to journal as well as track her pain scores, pain triggers, mood, sleep, diet, and response to therapies. It can provide a snapshot, yearly for instance, of tracked pain levels and is preloaded with goals that a user can customize easily. The app also is loaded with excellent pain management tips, videos, and slide shows. There are more than 300 patient-focused articles from the archives of WebMD and other sources that have been reviewed by experts. Progress and notes can be converted into a PDF for use at home or with a health-care provider—a very helpful tool as it can be hard to arrange the many domains of food, rest, exercise, mood, treatments, and pain scores in an organized fashion.^1,2

Pros: With a multidisciplinary approach to managing chronic pain, it can be very helpful for patients to track their daily activity, pain triggers, pain levels, and tried therapies. The app provides an opportunity to learn more about the mind–body connection, which is a core component of effective pain management. This app also has excellent medical information and useful strategies for managing chronic pain. It’s easy to use as a source of information, a journal, and a pocket coach.

Cons: This is a free app for iPhone, iTouch, and the iPad—but currently only available for Apple products.

Verdict: This is a great tool on many levels. It would be useful for someone who just wants to track their pain and triggers, but also helpful for the patient who wants to obtain more control and learn more about managing pain. This app would be complementary for someone already engaged in mind–body work, but also be useful for someone who does not have access to those services.

We want to hear from you! Tell us what you think.

In this series, I review what I call prescription apps—apps that you might consider recommending to your patient to enhance her medical care. Many patients are already looking at medical apps and want to hear your opinion. Often, the free apps I recommend to patients are downloaded before they leave my office. When recommending apps, their cost (not necessarily a measure of quality or utility) and platform (device that the app has been designed for) should be taken into account. It is helpful to know whether the app you are recommending is supported by your patient’s smartphone.

Chronic pelvic pain: multifactorial

Chronic pelvic pain, like most chronic pain conditions, is multifactorial in nature. It is not surprising then that most women with chronic pelvic pain do best with a multidisciplinary management approach that addresses both physical and emotional well-being, including the mind-body aspect of chronic pain (how mood and emotions affect pain), exercise, pacing of activities, attention to sleep hygiene, and the role of dysfunctional eating patterns. However, a patient’s access to formal mind-body programs or even a pain psychologist can be hard to come by for a variety of reasons.

An app that tracks pain and treatment

WebMD Pain Coach is a mobile mind-body program and pain coach all rolled into one. While specifically designed for nongynecologic pain conditions (fibromyalgia, migraine, back pain), the app works just as well for pelvic pain. Pain conditions, such as pelvic pain, that are not preloaded into the app are easy to add.^1,2

WebMD Pain Coach provides a way for the user to journal as well as track her pain scores, pain triggers, mood, sleep, diet, and response to therapies. It can provide a snapshot, yearly for instance, of tracked pain levels and is preloaded with goals that a user can customize easily. The app also is loaded with excellent pain management tips, videos, and slide shows. There are more than 300 patient-focused articles from the archives of WebMD and other sources that have been reviewed by experts. Progress and notes can be converted into a PDF for use at home or with a health-care provider—a very helpful tool as it can be hard to arrange the many domains of food, rest, exercise, mood, treatments, and pain scores in an organized fashion.^1,2

Pros: With a multidisciplinary approach to managing chronic pain, it can be very helpful for patients to track their daily activity, pain triggers, pain levels, and tried therapies. The app provides an opportunity to learn more about the mind–body connection, which is a core component of effective pain management. This app also has excellent medical information and useful strategies for managing chronic pain. It’s easy to use as a source of information, a journal, and a pocket coach.

Cons: This is a free app for iPhone, iTouch, and the iPad—but currently only available for Apple products.

Verdict: This is a great tool on many levels. It would be useful for someone who just wants to track their pain and triggers, but also helpful for the patient who wants to obtain more control and learn more about managing pain. This app would be complementary for someone already engaged in mind–body work, but also be useful for someone who does not have access to those services.

We want to hear from you! Tell us what you think.

In this series, I review what I call prescription apps—apps that you might consider recommending to your patient to enhance her medical care. Many patients are already looking at medical apps and want to hear your opinion. Often, the free apps I recommend to patients are downloaded before they leave my office. When recommending apps, their cost (not necessarily a measure of quality or utility) and platform (device that the app has been designed for) should be taken into account. It is helpful to know whether the app you are recommending is supported by your patient’s smartphone.

Chronic pelvic pain: multifactorial

Chronic pelvic pain, like most chronic pain conditions, is multifactorial in nature. It is not surprising then that most women with chronic pelvic pain do best with a multidisciplinary management approach that addresses both physical and emotional well-being, including the mind-body aspect of chronic pain (how mood and emotions affect pain), exercise, pacing of activities, attention to sleep hygiene, and the role of dysfunctional eating patterns. However, a patient’s access to formal mind-body programs or even a pain psychologist can be hard to come by for a variety of reasons.

An app that tracks pain and treatment

WebMD Pain Coach is a mobile mind-body program and pain coach all rolled into one. While specifically designed for nongynecologic pain conditions (fibromyalgia, migraine, back pain), the app works just as well for pelvic pain. Pain conditions, such as pelvic pain, that are not preloaded into the app are easy to add.^1,2

WebMD Pain Coach provides a way for the user to journal as well as track her pain scores, pain triggers, mood, sleep, diet, and response to therapies. It can provide a snapshot, yearly for instance, of tracked pain levels and is preloaded with goals that a user can customize easily. The app also is loaded with excellent pain management tips, videos, and slide shows. There are more than 300 patient-focused articles from the archives of WebMD and other sources that have been reviewed by experts. Progress and notes can be converted into a PDF for use at home or with a health-care provider—a very helpful tool as it can be hard to arrange the many domains of food, rest, exercise, mood, treatments, and pain scores in an organized fashion.^1,2

Pros: With a multidisciplinary approach to managing chronic pain, it can be very helpful for patients to track their daily activity, pain triggers, pain levels, and tried therapies. The app provides an opportunity to learn more about the mind–body connection, which is a core component of effective pain management. This app also has excellent medical information and useful strategies for managing chronic pain. It’s easy to use as a source of information, a journal, and a pocket coach.

Cons: This is a free app for iPhone, iTouch, and the iPad—but currently only available for Apple products.

Verdict: This is a great tool on many levels. It would be useful for someone who just wants to track their pain and triggers, but also helpful for the patient who wants to obtain more control and learn more about managing pain. This app would be complementary for someone already engaged in mind–body work, but also be useful for someone who does not have access to those services.

We want to hear from you! Tell us what you think.

This morning while attending our department’s weekly Surgical Morbidity and Mortality conference, I was struck by how similar the case sounded to so many others that we have discussed in the past. An elderly patient with multiple comorbidities was found to have evidence of an acute abdomen. Unfortunately, the patient was intubated at the time of the surgical consultation, and it was unclear what his wishes would have been. Here was an apparent surgical problem in a very-high-risk patient.

The patient’s family, the medicine team, and the surgery team had several discussions and all agreed that the patient’s condition was very serious and that he would likely die without surgery. In addition, the surgical team felt that the chances for survival even with an exploratory laparotomy were extremely low. After much discussion, the decision was made to operate on the patient. He survived the operation only to have a gradual decline in his condition such that he developed multisystem organ failure. The resident presenting the case noted that eventually the surgical team was convinced that "further treatments were futile" and "after discussing the patient’s condition with the family, the decision was made to withdraw aggressive treatment." The patient was made comfortable and died a short time later.

As the discussion at the M&M conference showed, there were many surgeons present who felt that the outcome was expected and even a few who questioned whether the patient should even have had surgery. These are important issues, but what struck me most was the use of the term "futility" in reference to this patient’s care.

In recent years, there has been significant analysis within the medical ethics literature of the concept of futility. Futility in this context is difficult to define. Moreover, it appears some doctors determine a treatment to be futile as a means of pulling back control from the patient or surrogate who may be asking for a course of action. In other words, if we accept the importance of respecting patient autonomy and if patients/surrogates want a particular treatment, doctors often have difficulty saying "no" unless they define the treatment as futile. Since it is widely accepted that physicians need not offer futile treatments, defining a treatment as futile may be a way to limit the choices for patients/surrogates to consider or request.

In line with much of this literature, I have previously argued that we should "strike the term ["futility"] from our professional lexicon" (World J. Surg. 2009;33:1338-40). However, despite the chorus of suggestions that futility is a problematic concept when it comes to caring for patients, it continues to be used in discussions of actual patient care. I have concluded that it is impossible to eliminate the term "futility." In contrast, perhaps a better approach would be to realize that calling a certain set of treatments "futile" actually provides very little information to the people with whom we are talking. When we say a treatment would be an exercise in futility, we are really saying that in our best medical judgment the likelihood of success is very low. In addition, calling something futile suggests that a careful weighing of burdens and benefits of a particular treatment has been undertaken, and the doctor believes that the burdens so clearly outweigh the benefits that the treatment should not be offered to the patient. Therefore, rather than removing "futility" from our discussions with patients and each other, we should strive to realize how little the term actually conveys to our patients/surrogates.

When we use the term "futile" to describe a treatment, we are saying it just does not make sense in a specific case. The problem is that what a patient/surrogate considers to be the burdens and benefits might differ from what the medical team sees. For example, if an operation has virtually no chance of curing a patient, it might be considered futile. However, if the patient’s primary goal is palliation of certain symptoms for even a few days, then the operation should perhaps be viewed as "potentially beneficial" relative to a particular goal rather than "futile."

Surgeons should remember that the weighing of burdens and benefits requires more than medical knowledge. As such, every time the concept of "futility" is raised in the context of caring for a specific patient, the medical team should carefully explain to the patient/surrogate the benefits and burdens are that are being considered. Since it seems impossible for us to eliminate "futility" from our clinical discussions, let us instead use the term as a reminder to communicate the details and implications of a course of action. In this manner, a surgeon’s assessment of futility might prove an opportunity for further discussions rather than a statement of a definitive conclusion.

Dr. Peter Angelos is an ACS Fellow, the Linda Kohler Anderson Professor of Surgery and Surgical Ethics, chief of endocrine surgery, and associate director, MacLean Center for Clinical Medical Ethics, University of Chicago.

This morning while attending our department’s weekly Surgical Morbidity and Mortality conference, I was struck by how similar the case sounded to so many others that we have discussed in the past. An elderly patient with multiple comorbidities was found to have evidence of an acute abdomen. Unfortunately, the patient was intubated at the time of the surgical consultation, and it was unclear what his wishes would have been. Here was an apparent surgical problem in a very-high-risk patient.

The patient’s family, the medicine team, and the surgery team had several discussions and all agreed that the patient’s condition was very serious and that he would likely die without surgery. In addition, the surgical team felt that the chances for survival even with an exploratory laparotomy were extremely low. After much discussion, the decision was made to operate on the patient. He survived the operation only to have a gradual decline in his condition such that he developed multisystem organ failure. The resident presenting the case noted that eventually the surgical team was convinced that "further treatments were futile" and "after discussing the patient’s condition with the family, the decision was made to withdraw aggressive treatment." The patient was made comfortable and died a short time later.

As the discussion at the M&M conference showed, there were many surgeons present who felt that the outcome was expected and even a few who questioned whether the patient should even have had surgery. These are important issues, but what struck me most was the use of the term "futility" in reference to this patient’s care.

In recent years, there has been significant analysis within the medical ethics literature of the concept of futility. Futility in this context is difficult to define. Moreover, it appears some doctors determine a treatment to be futile as a means of pulling back control from the patient or surrogate who may be asking for a course of action. In other words, if we accept the importance of respecting patient autonomy and if patients/surrogates want a particular treatment, doctors often have difficulty saying "no" unless they define the treatment as futile. Since it is widely accepted that physicians need not offer futile treatments, defining a treatment as futile may be a way to limit the choices for patients/surrogates to consider or request.

In line with much of this literature, I have previously argued that we should "strike the term ["futility"] from our professional lexicon" (World J. Surg. 2009;33:1338-40). However, despite the chorus of suggestions that futility is a problematic concept when it comes to caring for patients, it continues to be used in discussions of actual patient care. I have concluded that it is impossible to eliminate the term "futility." In contrast, perhaps a better approach would be to realize that calling a certain set of treatments "futile" actually provides very little information to the people with whom we are talking. When we say a treatment would be an exercise in futility, we are really saying that in our best medical judgment the likelihood of success is very low. In addition, calling something futile suggests that a careful weighing of burdens and benefits of a particular treatment has been undertaken, and the doctor believes that the burdens so clearly outweigh the benefits that the treatment should not be offered to the patient. Therefore, rather than removing "futility" from our discussions with patients and each other, we should strive to realize how little the term actually conveys to our patients/surrogates.

When we use the term "futile" to describe a treatment, we are saying it just does not make sense in a specific case. The problem is that what a patient/surrogate considers to be the burdens and benefits might differ from what the medical team sees. For example, if an operation has virtually no chance of curing a patient, it might be considered futile. However, if the patient’s primary goal is palliation of certain symptoms for even a few days, then the operation should perhaps be viewed as "potentially beneficial" relative to a particular goal rather than "futile."

Surgeons should remember that the weighing of burdens and benefits requires more than medical knowledge. As such, every time the concept of "futility" is raised in the context of caring for a specific patient, the medical team should carefully explain to the patient/surrogate the benefits and burdens are that are being considered. Since it seems impossible for us to eliminate "futility" from our clinical discussions, let us instead use the term as a reminder to communicate the details and implications of a course of action. In this manner, a surgeon’s assessment of futility might prove an opportunity for further discussions rather than a statement of a definitive conclusion.

Dr. Peter Angelos is an ACS Fellow, the Linda Kohler Anderson Professor of Surgery and Surgical Ethics, chief of endocrine surgery, and associate director, MacLean Center for Clinical Medical Ethics, University of Chicago.

This morning while attending our department’s weekly Surgical Morbidity and Mortality conference, I was struck by how similar the case sounded to so many others that we have discussed in the past. An elderly patient with multiple comorbidities was found to have evidence of an acute abdomen. Unfortunately, the patient was intubated at the time of the surgical consultation, and it was unclear what his wishes would have been. Here was an apparent surgical problem in a very-high-risk patient.

The patient’s family, the medicine team, and the surgery team had several discussions and all agreed that the patient’s condition was very serious and that he would likely die without surgery. In addition, the surgical team felt that the chances for survival even with an exploratory laparotomy were extremely low. After much discussion, the decision was made to operate on the patient. He survived the operation only to have a gradual decline in his condition such that he developed multisystem organ failure. The resident presenting the case noted that eventually the surgical team was convinced that "further treatments were futile" and "after discussing the patient’s condition with the family, the decision was made to withdraw aggressive treatment." The patient was made comfortable and died a short time later.

As the discussion at the M&M conference showed, there were many surgeons present who felt that the outcome was expected and even a few who questioned whether the patient should even have had surgery. These are important issues, but what struck me most was the use of the term "futility" in reference to this patient’s care.

In recent years, there has been significant analysis within the medical ethics literature of the concept of futility. Futility in this context is difficult to define. Moreover, it appears some doctors determine a treatment to be futile as a means of pulling back control from the patient or surrogate who may be asking for a course of action. In other words, if we accept the importance of respecting patient autonomy and if patients/surrogates want a particular treatment, doctors often have difficulty saying "no" unless they define the treatment as futile. Since it is widely accepted that physicians need not offer futile treatments, defining a treatment as futile may be a way to limit the choices for patients/surrogates to consider or request.

In line with much of this literature, I have previously argued that we should "strike the term ["futility"] from our professional lexicon" (World J. Surg. 2009;33:1338-40). However, despite the chorus of suggestions that futility is a problematic concept when it comes to caring for patients, it continues to be used in discussions of actual patient care. I have concluded that it is impossible to eliminate the term "futility." In contrast, perhaps a better approach would be to realize that calling a certain set of treatments "futile" actually provides very little information to the people with whom we are talking. When we say a treatment would be an exercise in futility, we are really saying that in our best medical judgment the likelihood of success is very low. In addition, calling something futile suggests that a careful weighing of burdens and benefits of a particular treatment has been undertaken, and the doctor believes that the burdens so clearly outweigh the benefits that the treatment should not be offered to the patient. Therefore, rather than removing "futility" from our discussions with patients and each other, we should strive to realize how little the term actually conveys to our patients/surrogates.

When we use the term "futile" to describe a treatment, we are saying it just does not make sense in a specific case. The problem is that what a patient/surrogate considers to be the burdens and benefits might differ from what the medical team sees. For example, if an operation has virtually no chance of curing a patient, it might be considered futile. However, if the patient’s primary goal is palliation of certain symptoms for even a few days, then the operation should perhaps be viewed as "potentially beneficial" relative to a particular goal rather than "futile."

Surgeons should remember that the weighing of burdens and benefits requires more than medical knowledge. As such, every time the concept of "futility" is raised in the context of caring for a specific patient, the medical team should carefully explain to the patient/surrogate the benefits and burdens are that are being considered. Since it seems impossible for us to eliminate "futility" from our clinical discussions, let us instead use the term as a reminder to communicate the details and implications of a course of action. In this manner, a surgeon’s assessment of futility might prove an opportunity for further discussions rather than a statement of a definitive conclusion.

Dr. Peter Angelos is an ACS Fellow, the Linda Kohler Anderson Professor of Surgery and Surgical Ethics, chief of endocrine surgery, and associate director, MacLean Center for Clinical Medical Ethics, University of Chicago.

LAS VEGAS – Knowing and respecting the anatomy of the levator muscle can help clinicians steer clear of complications from blepharoplasty and manage ptosis, according to Dr. Marc S. Cohen.

"It’s very helpful if you have a good understanding of how to find the levator muscle during eyelid surgery," said Dr. Cohen, an ophthalmic plastic surgeon at the Wills Eye Institute, Philadelphia. "In order to do this, you need to understand the relationship between the levator and the other eyelid structures."

The levator muscle elevates the eyelid and helps form the eyelid crease. It also creates the margin contour. As the levator muscle approaches the eyelid, it changes direction from vertically oriented to horizontally oriented. The muscle then advances inferiorly toward the eyelid margin, "and for the final centimeter or so, it becomes a fibrous aponeurosis, which attaches to the tarsus posteriorly," said Dr. Cohen, who also has a private cosmetic surgery practice. Behind the levator muscle are Müller’s muscle and the conjunctiva.

Whether a surgeon performs blepharoplasty with a CO₂ laser, a blade, cautery, or radiofrequency, the first structure encountered posteriorly is the orbicularis oculi muscle, which closes the eyelid. "It’s highly vascular, and is the site where most of the bleeding occurs during blepharoplasty," Dr. Cohen said at the annual meeting of the American Academy of Cosmetic Surgery.

The next layer contains the orbital septum. "It’s important to understand that the septum does not travel all the way to the eyelid margin," he added. "The septum starts at the orbital rim and attaches to the levator muscle. This layer really has two structures: the septum and the levator. Behind the septum are the eyelid fat pads."

In a dissection above and behind in the eyelid, the septum and the fat precede the levator muscle. However, in the inferior eyelid, the levator is just deep to the orbicularis muscle. Beneath the fat, the levator muscle moves posteriorly into the orbit; this causes it to narrow.

"Lateral to the muscle at this point is the lacrimal gland, but medially is just orbital fat," Dr. Cohen said. Upon reaching the orbicularis muscle, the goal is to protect the levator muscle. "The levator muscle is protected by septum fat superiorly, whereas more inferiorly the levator fuses with the orbicularis, so this is a danger zone," Dr. Cohen said. "Laterally is the lacrimal gland and supramedially is the safest point, because there you have the fat, and nothing else to really worry about superficially. So what you do is press on the globe through the eyelid, have the fat prolapse forward, and dissect there."

Reattaching the levator muscle can be tricky in the context of levator resection ptosis surgery, said Dr. Cohen. "Where you make the attachment is going to affect the contour postoperatively," he said. "Grasp the tarsus and pull it upward to see if you have obtained a natural curve. If you grasp it at the wrong point, you’ll have a curve that’s not aesthetically pleasing," he cautioned.

"When you get the right point, that is where you are going to put the sutures to reattach the levator. A double-armed 6-0 suture is passed in a horizontal mattress fashion, partial thickness, through the tarsus. The suture is then passed in a posterior to anterior direction, which shortens the levator muscle."

Placement of the suture determines how much the muscle shortens. "The suture is then temporarily tied, and the patient is asked to open their eyes to assess the height and the contour," Dr. Cohen said. "If you need to adjust height vertically, you can move the suture vertically on the levator muscle. If there’s a problem with the contour, you change the fixation point to the tarsus. Then the suture is permanently tied and the skin is closed."

Dr. Cohen warned about the risk of complications from blepharoplasty in patients with active Graves’ disease, a common autoimmune condition that can cause hyperthyroidism and fibrosis of the extraocular tissues. The severe form of Graves’ disease can cause eyelid retraction, difficulty closing the eyes, double vision, and anterior displacement of the globes. "Many patients present with much more subtle findings," he noted. "For example, fibrosis of the levator with lid retraction is a common presentation in women aged 40-60 – the same demographic that tends to have blepharoplasty. It’s often subtle and underdiagnosed."

Patients with undiagnosed Graves’ disease prior to a blepharoplasty "can develop signs and symptoms which are indistinguishable from the complications of blepharoplasty," Dr. Cohen said. "You need to make the diagnosis before surgery and make sure the disease has stabilized before you do any surgery. That happens on average in about 18 months but is variable."

Dr. Cohen disclosed that he is a member of the advisory board for Allergan and that he is a speaker for Allergan and Medicis.

[email protected]

LAS VEGAS – Knowing and respecting the anatomy of the levator muscle can help clinicians steer clear of complications from blepharoplasty and manage ptosis, according to Dr. Marc S. Cohen.

"It’s very helpful if you have a good understanding of how to find the levator muscle during eyelid surgery," said Dr. Cohen, an ophthalmic plastic surgeon at the Wills Eye Institute, Philadelphia. "In order to do this, you need to understand the relationship between the levator and the other eyelid structures."

The levator muscle elevates the eyelid and helps form the eyelid crease. It also creates the margin contour. As the levator muscle approaches the eyelid, it changes direction from vertically oriented to horizontally oriented. The muscle then advances inferiorly toward the eyelid margin, "and for the final centimeter or so, it becomes a fibrous aponeurosis, which attaches to the tarsus posteriorly," said Dr. Cohen, who also has a private cosmetic surgery practice. Behind the levator muscle are Müller’s muscle and the conjunctiva.

Whether a surgeon performs blepharoplasty with a CO₂ laser, a blade, cautery, or radiofrequency, the first structure encountered posteriorly is the orbicularis oculi muscle, which closes the eyelid. "It’s highly vascular, and is the site where most of the bleeding occurs during blepharoplasty," Dr. Cohen said at the annual meeting of the American Academy of Cosmetic Surgery.

The next layer contains the orbital septum. "It’s important to understand that the septum does not travel all the way to the eyelid margin," he added. "The septum starts at the orbital rim and attaches to the levator muscle. This layer really has two structures: the septum and the levator. Behind the septum are the eyelid fat pads."

In a dissection above and behind in the eyelid, the septum and the fat precede the levator muscle. However, in the inferior eyelid, the levator is just deep to the orbicularis muscle. Beneath the fat, the levator muscle moves posteriorly into the orbit; this causes it to narrow.

"Lateral to the muscle at this point is the lacrimal gland, but medially is just orbital fat," Dr. Cohen said. Upon reaching the orbicularis muscle, the goal is to protect the levator muscle. "The levator muscle is protected by septum fat superiorly, whereas more inferiorly the levator fuses with the orbicularis, so this is a danger zone," Dr. Cohen said. "Laterally is the lacrimal gland and supramedially is the safest point, because there you have the fat, and nothing else to really worry about superficially. So what you do is press on the globe through the eyelid, have the fat prolapse forward, and dissect there."

Reattaching the levator muscle can be tricky in the context of levator resection ptosis surgery, said Dr. Cohen. "Where you make the attachment is going to affect the contour postoperatively," he said. "Grasp the tarsus and pull it upward to see if you have obtained a natural curve. If you grasp it at the wrong point, you’ll have a curve that’s not aesthetically pleasing," he cautioned.

"When you get the right point, that is where you are going to put the sutures to reattach the levator. A double-armed 6-0 suture is passed in a horizontal mattress fashion, partial thickness, through the tarsus. The suture is then passed in a posterior to anterior direction, which shortens the levator muscle."

Placement of the suture determines how much the muscle shortens. "The suture is then temporarily tied, and the patient is asked to open their eyes to assess the height and the contour," Dr. Cohen said. "If you need to adjust height vertically, you can move the suture vertically on the levator muscle. If there’s a problem with the contour, you change the fixation point to the tarsus. Then the suture is permanently tied and the skin is closed."

Dr. Cohen warned about the risk of complications from blepharoplasty in patients with active Graves’ disease, a common autoimmune condition that can cause hyperthyroidism and fibrosis of the extraocular tissues. The severe form of Graves’ disease can cause eyelid retraction, difficulty closing the eyes, double vision, and anterior displacement of the globes. "Many patients present with much more subtle findings," he noted. "For example, fibrosis of the levator with lid retraction is a common presentation in women aged 40-60 – the same demographic that tends to have blepharoplasty. It’s often subtle and underdiagnosed."

Patients with undiagnosed Graves’ disease prior to a blepharoplasty "can develop signs and symptoms which are indistinguishable from the complications of blepharoplasty," Dr. Cohen said. "You need to make the diagnosis before surgery and make sure the disease has stabilized before you do any surgery. That happens on average in about 18 months but is variable."

Dr. Cohen disclosed that he is a member of the advisory board for Allergan and that he is a speaker for Allergan and Medicis.

[email protected]

LAS VEGAS – Knowing and respecting the anatomy of the levator muscle can help clinicians steer clear of complications from blepharoplasty and manage ptosis, according to Dr. Marc S. Cohen.

"It’s very helpful if you have a good understanding of how to find the levator muscle during eyelid surgery," said Dr. Cohen, an ophthalmic plastic surgeon at the Wills Eye Institute, Philadelphia. "In order to do this, you need to understand the relationship between the levator and the other eyelid structures."

The levator muscle elevates the eyelid and helps form the eyelid crease. It also creates the margin contour. As the levator muscle approaches the eyelid, it changes direction from vertically oriented to horizontally oriented. The muscle then advances inferiorly toward the eyelid margin, "and for the final centimeter or so, it becomes a fibrous aponeurosis, which attaches to the tarsus posteriorly," said Dr. Cohen, who also has a private cosmetic surgery practice. Behind the levator muscle are Müller’s muscle and the conjunctiva.

Whether a surgeon performs blepharoplasty with a CO₂ laser, a blade, cautery, or radiofrequency, the first structure encountered posteriorly is the orbicularis oculi muscle, which closes the eyelid. "It’s highly vascular, and is the site where most of the bleeding occurs during blepharoplasty," Dr. Cohen said at the annual meeting of the American Academy of Cosmetic Surgery.

The next layer contains the orbital septum. "It’s important to understand that the septum does not travel all the way to the eyelid margin," he added. "The septum starts at the orbital rim and attaches to the levator muscle. This layer really has two structures: the septum and the levator. Behind the septum are the eyelid fat pads."

In a dissection above and behind in the eyelid, the septum and the fat precede the levator muscle. However, in the inferior eyelid, the levator is just deep to the orbicularis muscle. Beneath the fat, the levator muscle moves posteriorly into the orbit; this causes it to narrow.

"Lateral to the muscle at this point is the lacrimal gland, but medially is just orbital fat," Dr. Cohen said. Upon reaching the orbicularis muscle, the goal is to protect the levator muscle. "The levator muscle is protected by septum fat superiorly, whereas more inferiorly the levator fuses with the orbicularis, so this is a danger zone," Dr. Cohen said. "Laterally is the lacrimal gland and supramedially is the safest point, because there you have the fat, and nothing else to really worry about superficially. So what you do is press on the globe through the eyelid, have the fat prolapse forward, and dissect there."

Reattaching the levator muscle can be tricky in the context of levator resection ptosis surgery, said Dr. Cohen. "Where you make the attachment is going to affect the contour postoperatively," he said. "Grasp the tarsus and pull it upward to see if you have obtained a natural curve. If you grasp it at the wrong point, you’ll have a curve that’s not aesthetically pleasing," he cautioned.

"When you get the right point, that is where you are going to put the sutures to reattach the levator. A double-armed 6-0 suture is passed in a horizontal mattress fashion, partial thickness, through the tarsus. The suture is then passed in a posterior to anterior direction, which shortens the levator muscle."

Placement of the suture determines how much the muscle shortens. "The suture is then temporarily tied, and the patient is asked to open their eyes to assess the height and the contour," Dr. Cohen said. "If you need to adjust height vertically, you can move the suture vertically on the levator muscle. If there’s a problem with the contour, you change the fixation point to the tarsus. Then the suture is permanently tied and the skin is closed."

Dr. Cohen warned about the risk of complications from blepharoplasty in patients with active Graves’ disease, a common autoimmune condition that can cause hyperthyroidism and fibrosis of the extraocular tissues. The severe form of Graves’ disease can cause eyelid retraction, difficulty closing the eyes, double vision, and anterior displacement of the globes. "Many patients present with much more subtle findings," he noted. "For example, fibrosis of the levator with lid retraction is a common presentation in women aged 40-60 – the same demographic that tends to have blepharoplasty. It’s often subtle and underdiagnosed."

Patients with undiagnosed Graves’ disease prior to a blepharoplasty "can develop signs and symptoms which are indistinguishable from the complications of blepharoplasty," Dr. Cohen said. "You need to make the diagnosis before surgery and make sure the disease has stabilized before you do any surgery. That happens on average in about 18 months but is variable."

Dr. Cohen disclosed that he is a member of the advisory board for Allergan and that he is a speaker for Allergan and Medicis.

[email protected]

The short-term compromise congressional leaders reached earlier this month on Draconian cuts to Medicare payments can only be viewed as a good thing for hospital medicine, says the head of SHM's Public Policy Committee. However, the fight is far from over.

"Just like everything else they've been doing, they're kicking the can down the road,” says committee chair Ron Greeno, MD, FCCP, MHM. "At least they kicked it a year this time, so that gives us a little bit of breathing room in terms of our physician practices being able to plan."

The American Taxpayer Relief Act of 2012 averts a 26.5% cut to Medicare payment rates and extends the current Medicare physician fee schedule through the end of this year. The downside is the one-year delay is to be paid for "largely through adjustments to payments for hospitals and non-physician providers, and reductions in Medicaid disproportionate share hospital payments," according to a report from SHM issued earlier this month.

Dr. Greeno agrees that by reducing hospital revenue, the compromise puts additional fiscal pressures on HM groups, but that is the reality of the political logjam in Washington. Still, SHM will continue to lobby for a long-term answer.

The decision has drawn criticism from hospital trade associations. Chip Kahn, president and CEO of the Federation of American Hospitals (FAH), described it as a plan to "rob hospital Peter to pay for fiscal cliff Paul." [PDF]

"This is all just another patch," Dr. Greeno says, "and it doesn't create the solution that everybody is looking for, which is basically repeal of the SGR and replacing it with something that creates the incentives needed to engage physicians in improving the healthcare system."

The compromise also does not address the budget sequester, which was delayed until the end of March. Without action on that front, SHM says providers will lose 2% from their Medicare payments. The sequestration also would reduce funding dedicated to medical research.

Visit our website for more information about efforts to repeal the SGR.

The short-term compromise congressional leaders reached earlier this month on Draconian cuts to Medicare payments can only be viewed as a good thing for hospital medicine, says the head of SHM's Public Policy Committee. However, the fight is far from over.

"Just like everything else they've been doing, they're kicking the can down the road,” says committee chair Ron Greeno, MD, FCCP, MHM. "At least they kicked it a year this time, so that gives us a little bit of breathing room in terms of our physician practices being able to plan."

The American Taxpayer Relief Act of 2012 averts a 26.5% cut to Medicare payment rates and extends the current Medicare physician fee schedule through the end of this year. The downside is the one-year delay is to be paid for "largely through adjustments to payments for hospitals and non-physician providers, and reductions in Medicaid disproportionate share hospital payments," according to a report from SHM issued earlier this month.

Dr. Greeno agrees that by reducing hospital revenue, the compromise puts additional fiscal pressures on HM groups, but that is the reality of the political logjam in Washington. Still, SHM will continue to lobby for a long-term answer.

The decision has drawn criticism from hospital trade associations. Chip Kahn, president and CEO of the Federation of American Hospitals (FAH), described it as a plan to "rob hospital Peter to pay for fiscal cliff Paul." [PDF]

"This is all just another patch," Dr. Greeno says, "and it doesn't create the solution that everybody is looking for, which is basically repeal of the SGR and replacing it with something that creates the incentives needed to engage physicians in improving the healthcare system."

The compromise also does not address the budget sequester, which was delayed until the end of March. Without action on that front, SHM says providers will lose 2% from their Medicare payments. The sequestration also would reduce funding dedicated to medical research.

Visit our website for more information about efforts to repeal the SGR.

The short-term compromise congressional leaders reached earlier this month on Draconian cuts to Medicare payments can only be viewed as a good thing for hospital medicine, says the head of SHM's Public Policy Committee. However, the fight is far from over.

"Just like everything else they've been doing, they're kicking the can down the road,” says committee chair Ron Greeno, MD, FCCP, MHM. "At least they kicked it a year this time, so that gives us a little bit of breathing room in terms of our physician practices being able to plan."

The American Taxpayer Relief Act of 2012 averts a 26.5% cut to Medicare payment rates and extends the current Medicare physician fee schedule through the end of this year. The downside is the one-year delay is to be paid for "largely through adjustments to payments for hospitals and non-physician providers, and reductions in Medicaid disproportionate share hospital payments," according to a report from SHM issued earlier this month.

Dr. Greeno agrees that by reducing hospital revenue, the compromise puts additional fiscal pressures on HM groups, but that is the reality of the political logjam in Washington. Still, SHM will continue to lobby for a long-term answer.

The decision has drawn criticism from hospital trade associations. Chip Kahn, president and CEO of the Federation of American Hospitals (FAH), described it as a plan to "rob hospital Peter to pay for fiscal cliff Paul." [PDF]

"This is all just another patch," Dr. Greeno says, "and it doesn't create the solution that everybody is looking for, which is basically repeal of the SGR and replacing it with something that creates the incentives needed to engage physicians in improving the healthcare system."

The compromise also does not address the budget sequester, which was delayed until the end of March. Without action on that front, SHM says providers will lose 2% from their Medicare payments. The sequestration also would reduce funding dedicated to medical research.

Visit our website for more information about efforts to repeal the SGR.

Clinical question: What are the changes in the updated Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines?

Background: Chronic obstructive pulmonary disease (COPD) remains a leading cause of death in the U.S. and worldwide. The GOLD guidelines are an international consensus report on COPD diagnosis, management, and prevention, first released in 2001. The 2011 revision to the guidelines was recently published and outlines substantial changes based on updated literature and expert opinion.

Study design: Guidelines based on studies with varying designs.

Setting: Expert panel review of multiple studies from different settings.

Synopsis: While the diagnosis of COPD remains based on a post-bronchodilator fixed ratio of FEV1/FVC <0.70, there is more emphasis on global clinical assessment in the new guidelines. The updated approach describes classifying COPD severity based on risk/symptom frequency using established symptom assessment and the frequency of acute exacerbations of COPD. Instead of five “stages” based on FEV1 measures alone, there are now four "grades" of A through D (A: low risk/fewer symptoms; B: low risk/more symptoms; C: high risk/fewer symptoms; D: high risk/more symptoms) to more easily guide treatment options.

Treatment strategies are also updated, focusing not only on reduction of current symptoms, but also risk of future events. Pharmacologic treatment recommendations include using bronchodilator monotherapy in Group A patients, favoring long-acting over short-acting bronchodilators in Group B patients, prescribing inhaled corticosteroids only in combination with long-acting bronchodilators in Groups C and D patients, and considering newer agents such as phosphodiesterase-4 inhibitors in Group D patients.

Non-pharmacologic interventions include ongoing smoking cessation strategies, exercise promotion, treatment of comorbidities, and even public health strategies in pollution control.

Bottom line: The GOLD guidelines have undergone major revisions that provide a more practical approach to classification of COPD based on symptom severity and risk assessment in order to direct providers in evidence-based treatment that addresses both short-term and long-term impact of the disease.

Citation: Global Initiative for Chronic Obstructive Lung Disease. Global strategy for diagnosis, management, and prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease website. Accessed Oct. 29, 2012.

For more physician reviews of recent HM-relevant literature, visit our website.

Clinical question: What are the changes in the updated Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines?

Background: Chronic obstructive pulmonary disease (COPD) remains a leading cause of death in the U.S. and worldwide. The GOLD guidelines are an international consensus report on COPD diagnosis, management, and prevention, first released in 2001. The 2011 revision to the guidelines was recently published and outlines substantial changes based on updated literature and expert opinion.

Study design: Guidelines based on studies with varying designs.

Setting: Expert panel review of multiple studies from different settings.

Synopsis: While the diagnosis of COPD remains based on a post-bronchodilator fixed ratio of FEV1/FVC <0.70, there is more emphasis on global clinical assessment in the new guidelines. The updated approach describes classifying COPD severity based on risk/symptom frequency using established symptom assessment and the frequency of acute exacerbations of COPD. Instead of five “stages” based on FEV1 measures alone, there are now four "grades" of A through D (A: low risk/fewer symptoms; B: low risk/more symptoms; C: high risk/fewer symptoms; D: high risk/more symptoms) to more easily guide treatment options.

Treatment strategies are also updated, focusing not only on reduction of current symptoms, but also risk of future events. Pharmacologic treatment recommendations include using bronchodilator monotherapy in Group A patients, favoring long-acting over short-acting bronchodilators in Group B patients, prescribing inhaled corticosteroids only in combination with long-acting bronchodilators in Groups C and D patients, and considering newer agents such as phosphodiesterase-4 inhibitors in Group D patients.

Non-pharmacologic interventions include ongoing smoking cessation strategies, exercise promotion, treatment of comorbidities, and even public health strategies in pollution control.

Bottom line: The GOLD guidelines have undergone major revisions that provide a more practical approach to classification of COPD based on symptom severity and risk assessment in order to direct providers in evidence-based treatment that addresses both short-term and long-term impact of the disease.

Citation: Global Initiative for Chronic Obstructive Lung Disease. Global strategy for diagnosis, management, and prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease website. Accessed Oct. 29, 2012.

For more physician reviews of recent HM-relevant literature, visit our website.

Clinical question: What are the changes in the updated Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines?

Background: Chronic obstructive pulmonary disease (COPD) remains a leading cause of death in the U.S. and worldwide. The GOLD guidelines are an international consensus report on COPD diagnosis, management, and prevention, first released in 2001. The 2011 revision to the guidelines was recently published and outlines substantial changes based on updated literature and expert opinion.

Study design: Guidelines based on studies with varying designs.

Setting: Expert panel review of multiple studies from different settings.

Synopsis: While the diagnosis of COPD remains based on a post-bronchodilator fixed ratio of FEV1/FVC <0.70, there is more emphasis on global clinical assessment in the new guidelines. The updated approach describes classifying COPD severity based on risk/symptom frequency using established symptom assessment and the frequency of acute exacerbations of COPD. Instead of five “stages” based on FEV1 measures alone, there are now four "grades" of A through D (A: low risk/fewer symptoms; B: low risk/more symptoms; C: high risk/fewer symptoms; D: high risk/more symptoms) to more easily guide treatment options.

Treatment strategies are also updated, focusing not only on reduction of current symptoms, but also risk of future events. Pharmacologic treatment recommendations include using bronchodilator monotherapy in Group A patients, favoring long-acting over short-acting bronchodilators in Group B patients, prescribing inhaled corticosteroids only in combination with long-acting bronchodilators in Groups C and D patients, and considering newer agents such as phosphodiesterase-4 inhibitors in Group D patients.

Non-pharmacologic interventions include ongoing smoking cessation strategies, exercise promotion, treatment of comorbidities, and even public health strategies in pollution control.

Bottom line: The GOLD guidelines have undergone major revisions that provide a more practical approach to classification of COPD based on symptom severity and risk assessment in order to direct providers in evidence-based treatment that addresses both short-term and long-term impact of the disease.

Citation: Global Initiative for Chronic Obstructive Lung Disease. Global strategy for diagnosis, management, and prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease website. Accessed Oct. 29, 2012.

For more physician reviews of recent HM-relevant literature, visit our website.

Using interferon monotherapy to treat hepatitis C in patients who have failed to respond to other treatments did not improve mortality rates and may actually cause harm, according to a Cochrane Collaboration review.

Although interferon does appear to reduce the levels of hepatitis C virus in the blood, this reduced viral load does not translate to increased survival or quality of life.

Dr. Ronald L. Koretz, a gastroenterologist and internal medicine specialist in Granada Hills, Calif., and his associates reported that they could not recommend interferon monotherapy because of the increased risk of all-cause mortality paired with a higher number of adverse events. The report was published online Jan. 30 (Cochrane Database Syst. Rev. 2013 Jan. 30 [doi:10.1002/14651858.CD003617.pub2]).

Interferon is typically used in hepatitis C retreatment when ribavirin or protease inhibitors have not been effective (or are contraindicated or not tolerated). The outcome goal is sustained viral response (SVR), referring to no measurable viral RNA in the blood for 6 months after treatment.

However, using SVR as a surrogate outcome for hepatitis C improvement had not been validated due to the dearth of randomized clinical trials with mortality data.

Dr. Koretz and his colleagues investigated randomized trials in which interferon was compared with a placebo or no treatment at all in chronic hepatitis C patients who had severe fibrosis (grade 3 or 4) and who had not responded to another treatment or had relapsed following interferon treatment. Patients were excluded if they had undergone a liver transplant, had HBV and/or HIV, or had evidence of hepatic decompensation.

Primary outcomes included all-cause and hepatic death, quality of life, and adverse events. Secondary outcomes included liver-related morbidity, SVR, biochemical responses, and histological responses. The researchers identified seven trials with a total of 1,976 patients, but five of these (n = 300) were at high risk of bias due to lack of blinding and, in four, possible selection and reporting bias.

Only three trials included outcomes on mortality and hepatic morbidity: HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) and EPIC 3 (Evaluation of PegIntron in Control of Hepatitis C Cirrhosis), which tracked patients who had severe fibrosis for 3-5 years, and a third trial that was ended before its 48-week endpoint because of the former trials’ results.

When the researchers analyzed only the two larger trials with low bias risk, they found all-cause mortality among the 1,676 patients to be significantly higher in the patients receiving pegylated interferon. The all-cause mortality rate was 9.4% (78/828) among interferon patients, compared with 6.7% (57/848) in patients receiving a placebo or no treatment (RR, 1.41; 95% CI: 1.02-1.96).

The additional deaths among interferon recipients appeared to be unrelated to liver function. Liver-related mortality in the large 5-year trial (low bias risk) showed no significant difference between interferon patients and untreated patients alone or when analyzed along with a trial at high bias risk (RR, 1.07; 95% CI: 0.7-1.63). In the one large trial whose 622 patients began without cirrhosis, interferon recipients were no less likely to develop cirrhosis (RR, 0.93; 95% CI: 0.69-1.25).

Interferon recipients did experience less variceal bleeding: 0.5% (4/843) in interferon recipients, compared with 2.1% (18/867) in untreated patients. No significant differences were seen for fibrosis markers or for encephalopathy, ascites, hepatocellular carcinoma, or liver transplantation. Only one small trial reported quality of life scores with pain scores among interferon patients to be "significantly higher, P < .001," but without numbers provided.

In the two large trials with low bias risk, interferon recipients also experienced significantly more adverse events (RR, 1.18; 95% CI: 0.99-1.41, P = .07), primarily infections, rash, irritability, fatigue, headaches, muscle pain, flu-like symptoms, and hematologic complications such as neutropenia and thrombocytopenia.

Analysis of four trials did show that 3.6% (20/557) of interferon recipients achieved SVR, compared with 0.2% (1/579) of untreated patients (RR, 15.38; 95% CI: 2.93-80.71). Interferon was also linked to reduced inflammation – but not reduced fibrosis – as measured by METAVIR activity scores. Among interferon recipients, 65% (36/55) had improved METAVIR activity scores, compared with 43.5% (20/46) of untreated patients (RR, 1.49; 95% CI: 1.02-2.18).

But these surrogate outcome improvements did not translate to better clinical outcomes. "Two of the commonly employed surrogate markers, sustained viral response and markers of inflammation, failed to be validated since they improved even though the clinical outcomes did not (or may even have become worse)," the researchers wrote.

The review did not receive internal or external funding support. The authors reported no permanent financial contracts with companies producing interferon or other conflicts of interest. Dr. Pilar Barrera Baena receives research funding from Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas (CIBERehd).

Using interferon monotherapy to treat hepatitis C in patients who have failed to respond to other treatments did not improve mortality rates and may actually cause harm, according to a Cochrane Collaboration review.

Although interferon does appear to reduce the levels of hepatitis C virus in the blood, this reduced viral load does not translate to increased survival or quality of life.

Dr. Ronald L. Koretz, a gastroenterologist and internal medicine specialist in Granada Hills, Calif., and his associates reported that they could not recommend interferon monotherapy because of the increased risk of all-cause mortality paired with a higher number of adverse events. The report was published online Jan. 30 (Cochrane Database Syst. Rev. 2013 Jan. 30 [doi:10.1002/14651858.CD003617.pub2]).

Interferon is typically used in hepatitis C retreatment when ribavirin or protease inhibitors have not been effective (or are contraindicated or not tolerated). The outcome goal is sustained viral response (SVR), referring to no measurable viral RNA in the blood for 6 months after treatment.

However, using SVR as a surrogate outcome for hepatitis C improvement had not been validated due to the dearth of randomized clinical trials with mortality data.

Dr. Koretz and his colleagues investigated randomized trials in which interferon was compared with a placebo or no treatment at all in chronic hepatitis C patients who had severe fibrosis (grade 3 or 4) and who had not responded to another treatment or had relapsed following interferon treatment. Patients were excluded if they had undergone a liver transplant, had HBV and/or HIV, or had evidence of hepatic decompensation.

Primary outcomes included all-cause and hepatic death, quality of life, and adverse events. Secondary outcomes included liver-related morbidity, SVR, biochemical responses, and histological responses. The researchers identified seven trials with a total of 1,976 patients, but five of these (n = 300) were at high risk of bias due to lack of blinding and, in four, possible selection and reporting bias.

Only three trials included outcomes on mortality and hepatic morbidity: HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) and EPIC 3 (Evaluation of PegIntron in Control of Hepatitis C Cirrhosis), which tracked patients who had severe fibrosis for 3-5 years, and a third trial that was ended before its 48-week endpoint because of the former trials’ results.

When the researchers analyzed only the two larger trials with low bias risk, they found all-cause mortality among the 1,676 patients to be significantly higher in the patients receiving pegylated interferon. The all-cause mortality rate was 9.4% (78/828) among interferon patients, compared with 6.7% (57/848) in patients receiving a placebo or no treatment (RR, 1.41; 95% CI: 1.02-1.96).

The additional deaths among interferon recipients appeared to be unrelated to liver function. Liver-related mortality in the large 5-year trial (low bias risk) showed no significant difference between interferon patients and untreated patients alone or when analyzed along with a trial at high bias risk (RR, 1.07; 95% CI: 0.7-1.63). In the one large trial whose 622 patients began without cirrhosis, interferon recipients were no less likely to develop cirrhosis (RR, 0.93; 95% CI: 0.69-1.25).

Interferon recipients did experience less variceal bleeding: 0.5% (4/843) in interferon recipients, compared with 2.1% (18/867) in untreated patients. No significant differences were seen for fibrosis markers or for encephalopathy, ascites, hepatocellular carcinoma, or liver transplantation. Only one small trial reported quality of life scores with pain scores among interferon patients to be "significantly higher, P < .001," but without numbers provided.

In the two large trials with low bias risk, interferon recipients also experienced significantly more adverse events (RR, 1.18; 95% CI: 0.99-1.41, P = .07), primarily infections, rash, irritability, fatigue, headaches, muscle pain, flu-like symptoms, and hematologic complications such as neutropenia and thrombocytopenia.

Analysis of four trials did show that 3.6% (20/557) of interferon recipients achieved SVR, compared with 0.2% (1/579) of untreated patients (RR, 15.38; 95% CI: 2.93-80.71). Interferon was also linked to reduced inflammation – but not reduced fibrosis – as measured by METAVIR activity scores. Among interferon recipients, 65% (36/55) had improved METAVIR activity scores, compared with 43.5% (20/46) of untreated patients (RR, 1.49; 95% CI: 1.02-2.18).

But these surrogate outcome improvements did not translate to better clinical outcomes. "Two of the commonly employed surrogate markers, sustained viral response and markers of inflammation, failed to be validated since they improved even though the clinical outcomes did not (or may even have become worse)," the researchers wrote.

The review did not receive internal or external funding support. The authors reported no permanent financial contracts with companies producing interferon or other conflicts of interest. Dr. Pilar Barrera Baena receives research funding from Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas (CIBERehd).

Using interferon monotherapy to treat hepatitis C in patients who have failed to respond to other treatments did not improve mortality rates and may actually cause harm, according to a Cochrane Collaboration review.

Although interferon does appear to reduce the levels of hepatitis C virus in the blood, this reduced viral load does not translate to increased survival or quality of life.

Dr. Ronald L. Koretz, a gastroenterologist and internal medicine specialist in Granada Hills, Calif., and his associates reported that they could not recommend interferon monotherapy because of the increased risk of all-cause mortality paired with a higher number of adverse events. The report was published online Jan. 30 (Cochrane Database Syst. Rev. 2013 Jan. 30 [doi:10.1002/14651858.CD003617.pub2]).

Interferon is typically used in hepatitis C retreatment when ribavirin or protease inhibitors have not been effective (or are contraindicated or not tolerated). The outcome goal is sustained viral response (SVR), referring to no measurable viral RNA in the blood for 6 months after treatment.

However, using SVR as a surrogate outcome for hepatitis C improvement had not been validated due to the dearth of randomized clinical trials with mortality data.

Dr. Koretz and his colleagues investigated randomized trials in which interferon was compared with a placebo or no treatment at all in chronic hepatitis C patients who had severe fibrosis (grade 3 or 4) and who had not responded to another treatment or had relapsed following interferon treatment. Patients were excluded if they had undergone a liver transplant, had HBV and/or HIV, or had evidence of hepatic decompensation.

Primary outcomes included all-cause and hepatic death, quality of life, and adverse events. Secondary outcomes included liver-related morbidity, SVR, biochemical responses, and histological responses. The researchers identified seven trials with a total of 1,976 patients, but five of these (n = 300) were at high risk of bias due to lack of blinding and, in four, possible selection and reporting bias.

Only three trials included outcomes on mortality and hepatic morbidity: HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) and EPIC 3 (Evaluation of PegIntron in Control of Hepatitis C Cirrhosis), which tracked patients who had severe fibrosis for 3-5 years, and a third trial that was ended before its 48-week endpoint because of the former trials’ results.

When the researchers analyzed only the two larger trials with low bias risk, they found all-cause mortality among the 1,676 patients to be significantly higher in the patients receiving pegylated interferon. The all-cause mortality rate was 9.4% (78/828) among interferon patients, compared with 6.7% (57/848) in patients receiving a placebo or no treatment (RR, 1.41; 95% CI: 1.02-1.96).

The additional deaths among interferon recipients appeared to be unrelated to liver function. Liver-related mortality in the large 5-year trial (low bias risk) showed no significant difference between interferon patients and untreated patients alone or when analyzed along with a trial at high bias risk (RR, 1.07; 95% CI: 0.7-1.63). In the one large trial whose 622 patients began without cirrhosis, interferon recipients were no less likely to develop cirrhosis (RR, 0.93; 95% CI: 0.69-1.25).

Interferon recipients did experience less variceal bleeding: 0.5% (4/843) in interferon recipients, compared with 2.1% (18/867) in untreated patients. No significant differences were seen for fibrosis markers or for encephalopathy, ascites, hepatocellular carcinoma, or liver transplantation. Only one small trial reported quality of life scores with pain scores among interferon patients to be "significantly higher, P < .001," but without numbers provided.

In the two large trials with low bias risk, interferon recipients also experienced significantly more adverse events (RR, 1.18; 95% CI: 0.99-1.41, P = .07), primarily infections, rash, irritability, fatigue, headaches, muscle pain, flu-like symptoms, and hematologic complications such as neutropenia and thrombocytopenia.

Analysis of four trials did show that 3.6% (20/557) of interferon recipients achieved SVR, compared with 0.2% (1/579) of untreated patients (RR, 15.38; 95% CI: 2.93-80.71). Interferon was also linked to reduced inflammation – but not reduced fibrosis – as measured by METAVIR activity scores. Among interferon recipients, 65% (36/55) had improved METAVIR activity scores, compared with 43.5% (20/46) of untreated patients (RR, 1.49; 95% CI: 1.02-2.18).

But these surrogate outcome improvements did not translate to better clinical outcomes. "Two of the commonly employed surrogate markers, sustained viral response and markers of inflammation, failed to be validated since they improved even though the clinical outcomes did not (or may even have become worse)," the researchers wrote.

The review did not receive internal or external funding support. The authors reported no permanent financial contracts with companies producing interferon or other conflicts of interest. Dr. Pilar Barrera Baena receives research funding from Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas (CIBERehd).

ATLANTA – The antilymphoma drug vorinostat may help to reduce the incidence of serious acute graft-versus-host disease in patients who have undergone blood and bone marrow transplants, said researchers at the annual meeting of the American Society of Hematology.

In a first-in-humans phase I/II trial, adults with hematologic malignancies who underwent hematopoietic stem-cell transplants (HSCTs) with reduced-intensity conditioning and also received vorinostat (Zolinza) before, during, and after transplant had significantly fewer episodes of graft-versus-host disease (GvHD) than did historical controls who received standard GvHD prophylaxis but not vorinostat, reported Dr. Pavan Reddy of the University of Michigan, Ann Arbor.

"From a biological standpoint, we found that using this drug, just as we did in our experimental mouse models, we were able to reduce inflammation." The results were based on measurement of different cytokines, as well as increased acetylation of certain proteins, said Dr. Reddy at a media briefing.

Vorinostat treatment also increased the population of regulatory T cells, "which really have salutary effects on graft-versus-host disease outcomes," he added.

Vorinostat is a histone deacetylase (HDAC) inhibitor approved as a third-line therapy for the treatment of progressive, persistent, or recurrent cutaneous T-cell lymphoma.

In animal studies, Dr. Reddy and his colleague Dr. Sung W. Choi, as well as other groups, have shown that HDAC inhibitors are effective against experimental GvHD, suppress the production of proinflammatory cytokines, and alter the immune response by modulating antigen-presenting cells and by enhancing the production and function of regulatory T cells.

With investigators at Washington University in St. Louis, the Michigan researchers enrolled adult patients scheduled to undergo allogeneic HSCT from donors matched by at least 7 of 8 HLA factors. The patients could be in either complete or partial remission or have progressive disease.

A total of 47 patients were available for the analysis presented at the meeting. In phase I, 10 patients received 100 mg of vorinostat twice daily, and nine additional patients underwent dose escalation to 200 mg twice daily. The remaining 28 patients were treated in phase II at the 100-mg b.i.d. dose. All patients also received standard GvHD prophylaxis with tacrolimus and mycophenolate mofetil. Patients received vorinostat beginning 10 days before transplant and continuing through day 100, when the incidence of grade 2-4 GvHD, the primary endpoint, was assessed.

Neil Osterweil/IMNG Medical Media

The results were compared with those of 25 historical controls. Both neutrophil and platelet engraftment occurred at a median of 12 days on study, compared with 11 days each for controls.

The cumulative incidence of grade 2-4 GvHD at day 100 was 22% for patients on vorinostat, compared with 48% for controls (P = .03). There was also a nonsignificant trend favoring vorinostat for prevention of grade 3-4 GvHD, Dr. Reddy noted.

There were nine cases of thrombocytopenia among patients on vorinostat, six among patients on the 200-mg b.i.d. dose, and three at the 100-mg b.i.d. dose. Ten patients on the drug had nausea. There were no significant differences in adverse event profiles, infectious complications, or causes of death between patients in the study and historical controls.

A hematologist who was not involved in the study commented that with vorinostat, investigators seemed to have found a balance between preventing serious GvHD, which significantly increases the risk of death, and mild or moderate GvHD, which is helpful for mounting an immune defense against malignant cells.

"We have seen in some biological studies that this kind of drug – and not only this drug but this group of drugs – can increase some cells in the blood of patients that will in fact decrease the probability of acute graft-versus-host disease and at the same time can also fight against the cancer cells," said Dr. Vanderson Rocha from the University of Oxford (England). Dr. Rocha moderated the briefing where Dr. Reddy presented the data.

The study was supported by the National Institutes of Health. Dr. Reddy, Dr. Choi, and Dr. Rocha all declared having no relevant conflicts of interest to disclose.

ATLANTA – The antilymphoma drug vorinostat may help to reduce the incidence of serious acute graft-versus-host disease in patients who have undergone blood and bone marrow transplants, said researchers at the annual meeting of the American Society of Hematology.

In a first-in-humans phase I/II trial, adults with hematologic malignancies who underwent hematopoietic stem-cell transplants (HSCTs) with reduced-intensity conditioning and also received vorinostat (Zolinza) before, during, and after transplant had significantly fewer episodes of graft-versus-host disease (GvHD) than did historical controls who received standard GvHD prophylaxis but not vorinostat, reported Dr. Pavan Reddy of the University of Michigan, Ann Arbor.

"From a biological standpoint, we found that using this drug, just as we did in our experimental mouse models, we were able to reduce inflammation." The results were based on measurement of different cytokines, as well as increased acetylation of certain proteins, said Dr. Reddy at a media briefing.

Vorinostat treatment also increased the population of regulatory T cells, "which really have salutary effects on graft-versus-host disease outcomes," he added.

Vorinostat is a histone deacetylase (HDAC) inhibitor approved as a third-line therapy for the treatment of progressive, persistent, or recurrent cutaneous T-cell lymphoma.

In animal studies, Dr. Reddy and his colleague Dr. Sung W. Choi, as well as other groups, have shown that HDAC inhibitors are effective against experimental GvHD, suppress the production of proinflammatory cytokines, and alter the immune response by modulating antigen-presenting cells and by enhancing the production and function of regulatory T cells.

With investigators at Washington University in St. Louis, the Michigan researchers enrolled adult patients scheduled to undergo allogeneic HSCT from donors matched by at least 7 of 8 HLA factors. The patients could be in either complete or partial remission or have progressive disease.

A total of 47 patients were available for the analysis presented at the meeting. In phase I, 10 patients received 100 mg of vorinostat twice daily, and nine additional patients underwent dose escalation to 200 mg twice daily. The remaining 28 patients were treated in phase II at the 100-mg b.i.d. dose. All patients also received standard GvHD prophylaxis with tacrolimus and mycophenolate mofetil. Patients received vorinostat beginning 10 days before transplant and continuing through day 100, when the incidence of grade 2-4 GvHD, the primary endpoint, was assessed.

Neil Osterweil/IMNG Medical Media

The results were compared with those of 25 historical controls. Both neutrophil and platelet engraftment occurred at a median of 12 days on study, compared with 11 days each for controls.

The cumulative incidence of grade 2-4 GvHD at day 100 was 22% for patients on vorinostat, compared with 48% for controls (P = .03). There was also a nonsignificant trend favoring vorinostat for prevention of grade 3-4 GvHD, Dr. Reddy noted.

There were nine cases of thrombocytopenia among patients on vorinostat, six among patients on the 200-mg b.i.d. dose, and three at the 100-mg b.i.d. dose. Ten patients on the drug had nausea. There were no significant differences in adverse event profiles, infectious complications, or causes of death between patients in the study and historical controls.

A hematologist who was not involved in the study commented that with vorinostat, investigators seemed to have found a balance between preventing serious GvHD, which significantly increases the risk of death, and mild or moderate GvHD, which is helpful for mounting an immune defense against malignant cells.

"We have seen in some biological studies that this kind of drug – and not only this drug but this group of drugs – can increase some cells in the blood of patients that will in fact decrease the probability of acute graft-versus-host disease and at the same time can also fight against the cancer cells," said Dr. Vanderson Rocha from the University of Oxford (England). Dr. Rocha moderated the briefing where Dr. Reddy presented the data.

The study was supported by the National Institutes of Health. Dr. Reddy, Dr. Choi, and Dr. Rocha all declared having no relevant conflicts of interest to disclose.

ATLANTA – The antilymphoma drug vorinostat may help to reduce the incidence of serious acute graft-versus-host disease in patients who have undergone blood and bone marrow transplants, said researchers at the annual meeting of the American Society of Hematology.

In a first-in-humans phase I/II trial, adults with hematologic malignancies who underwent hematopoietic stem-cell transplants (HSCTs) with reduced-intensity conditioning and also received vorinostat (Zolinza) before, during, and after transplant had significantly fewer episodes of graft-versus-host disease (GvHD) than did historical controls who received standard GvHD prophylaxis but not vorinostat, reported Dr. Pavan Reddy of the University of Michigan, Ann Arbor.

"From a biological standpoint, we found that using this drug, just as we did in our experimental mouse models, we were able to reduce inflammation." The results were based on measurement of different cytokines, as well as increased acetylation of certain proteins, said Dr. Reddy at a media briefing.

Vorinostat treatment also increased the population of regulatory T cells, "which really have salutary effects on graft-versus-host disease outcomes," he added.

Vorinostat is a histone deacetylase (HDAC) inhibitor approved as a third-line therapy for the treatment of progressive, persistent, or recurrent cutaneous T-cell lymphoma.

In animal studies, Dr. Reddy and his colleague Dr. Sung W. Choi, as well as other groups, have shown that HDAC inhibitors are effective against experimental GvHD, suppress the production of proinflammatory cytokines, and alter the immune response by modulating antigen-presenting cells and by enhancing the production and function of regulatory T cells.

With investigators at Washington University in St. Louis, the Michigan researchers enrolled adult patients scheduled to undergo allogeneic HSCT from donors matched by at least 7 of 8 HLA factors. The patients could be in either complete or partial remission or have progressive disease.

A total of 47 patients were available for the analysis presented at the meeting. In phase I, 10 patients received 100 mg of vorinostat twice daily, and nine additional patients underwent dose escalation to 200 mg twice daily. The remaining 28 patients were treated in phase II at the 100-mg b.i.d. dose. All patients also received standard GvHD prophylaxis with tacrolimus and mycophenolate mofetil. Patients received vorinostat beginning 10 days before transplant and continuing through day 100, when the incidence of grade 2-4 GvHD, the primary endpoint, was assessed.

Neil Osterweil/IMNG Medical Media

The results were compared with those of 25 historical controls. Both neutrophil and platelet engraftment occurred at a median of 12 days on study, compared with 11 days each for controls.

The cumulative incidence of grade 2-4 GvHD at day 100 was 22% for patients on vorinostat, compared with 48% for controls (P = .03). There was also a nonsignificant trend favoring vorinostat for prevention of grade 3-4 GvHD, Dr. Reddy noted.

There were nine cases of thrombocytopenia among patients on vorinostat, six among patients on the 200-mg b.i.d. dose, and three at the 100-mg b.i.d. dose. Ten patients on the drug had nausea. There were no significant differences in adverse event profiles, infectious complications, or causes of death between patients in the study and historical controls.

A hematologist who was not involved in the study commented that with vorinostat, investigators seemed to have found a balance between preventing serious GvHD, which significantly increases the risk of death, and mild or moderate GvHD, which is helpful for mounting an immune defense against malignant cells.

"We have seen in some biological studies that this kind of drug – and not only this drug but this group of drugs – can increase some cells in the blood of patients that will in fact decrease the probability of acute graft-versus-host disease and at the same time can also fight against the cancer cells," said Dr. Vanderson Rocha from the University of Oxford (England). Dr. Rocha moderated the briefing where Dr. Reddy presented the data.

The study was supported by the National Institutes of Health. Dr. Reddy, Dr. Choi, and Dr. Rocha all declared having no relevant conflicts of interest to disclose.

In 2000, the Institute of Medicine published an oft-cited report, "To Err Is Human: Building a Safer Health System – A Report of The Committee on Quality of Health Care in America." The report estimated that up to 98,000 patients die from preventable medical errors each year.

Many of us can remember the boot camp–like conditions of residency: working incredibly long shifts that made every part of our bodies (and brains) cry out for rest – even a 10-minute nap could bring much-needed relief.

I remember sometimes working 48- to 72-hour shifts, between my regular residency responsibilities and moonlighting in the VA emergency room. That seems like a lifetime ago, a lifetime I would not want to relive.

While we may have been trained to believe we can perform at our peak despite sleep deprivation, in reality many of us made mistakes, whether great or small, as a result of our highly stressed, sleep-deprived state. And if we are honest with ourselves, we would not want to be a patient who is cared for by any doctor whose mental facilities have been impaired due to lack of sleep. Finally, wisdom defeated pride and custom, and residents’ shifts have been limited, which was a true victory for patients and residents alike.

Subsequently, it was acknowledged that nurses also made errors when working in suboptimal conditions. A study in the New England Journal of Medicine found a significant association between low staffing and patient mortality ("Nurse Staffing and Inpatient Hospital Mortality," N. Engl. J. Med. 2011;364:1037-45).

Truth be told, we already knew that nurses and inexperienced resident physicians make mistakes when overwhelmed and overworked, but what about seasoned hospitalists? What about us? Do we honestly believe we are somehow immune to making medical errors because of years of experience?

A piece in the Jan. 28 edition of JAMA – "Impact of Attending Physician Workload on Patient Care: A Survey of Hospitalists" – sheds light on how we really feel. The survey assessed hospitalists’ perceptions of the association between their workload and patient safety and quality-of-care measures during daytime shifts. The respondents’ average age was 38 years, median time in practice was 6 years, and median annual compensation was $180,000 (doi: 10.1001/jamainternmed.2013.1864).

Important study findings include the following:

• Forty percent of respondents reported that at least once per month, their census exceeded safe levels, and 36% of these noted they experienced unsafe levels multiple times per week.

• Fifteen patients per shift was the magic number that would optimize patient safety, regardless of any assistance doctors received, and that was assuming their shift was a purely clinical shift.

• More than 20% of hospitalists believe their average workload likely contributed to patient transfers, patient suffering, or even the death of patients. That was the most sobering finding of the study.

This study has profound implications for patient safety, and less importantly, patient satisfaction. The potential for unnecessary suffering, excessive medical costs, and unnecessary death is staggering. The actual number of physicians who are willing to admit their limitations is likely far lower than the actual number who experience these adverse effects, even if they are oblivious to their understandable limitations.

When the pager is going off incessantly while you are answering another call, and nurses are lined up to ask you questions about their patients, and, of course, you have a patient or two in the ER who need your attention, it is easy to get sidetracked. To err is human.

The bottom line is patients are the bottom line. They depend on us to provide safe, compassionate, high-quality health care. They literally entrust their lives to us, and we must honor that trust by speaking up if we feel like their safety is in jeopardy, and work with hospitalist directors and hospital administrators to create an environment in which patient safety is valued above all.

Dr. Hester is a hospitalist with Baltimore-Washington Medical Center, Glen Burnie, Md., who has a passion for empowering patients to partner in their health care.

In 2000, the Institute of Medicine published an oft-cited report, "To Err Is Human: Building a Safer Health System – A Report of The Committee on Quality of Health Care in America." The report estimated that up to 98,000 patients die from preventable medical errors each year.

Many of us can remember the boot camp–like conditions of residency: working incredibly long shifts that made every part of our bodies (and brains) cry out for rest – even a 10-minute nap could bring much-needed relief.

I remember sometimes working 48- to 72-hour shifts, between my regular residency responsibilities and moonlighting in the VA emergency room. That seems like a lifetime ago, a lifetime I would not want to relive.

While we may have been trained to believe we can perform at our peak despite sleep deprivation, in reality many of us made mistakes, whether great or small, as a result of our highly stressed, sleep-deprived state. And if we are honest with ourselves, we would not want to be a patient who is cared for by any doctor whose mental facilities have been impaired due to lack of sleep. Finally, wisdom defeated pride and custom, and residents’ shifts have been limited, which was a true victory for patients and residents alike.

Subsequently, it was acknowledged that nurses also made errors when working in suboptimal conditions. A study in the New England Journal of Medicine found a significant association between low staffing and patient mortality ("Nurse Staffing and Inpatient Hospital Mortality," N. Engl. J. Med. 2011;364:1037-45).

Truth be told, we already knew that nurses and inexperienced resident physicians make mistakes when overwhelmed and overworked, but what about seasoned hospitalists? What about us? Do we honestly believe we are somehow immune to making medical errors because of years of experience?

A piece in the Jan. 28 edition of JAMA – "Impact of Attending Physician Workload on Patient Care: A Survey of Hospitalists" – sheds light on how we really feel. The survey assessed hospitalists’ perceptions of the association between their workload and patient safety and quality-of-care measures during daytime shifts. The respondents’ average age was 38 years, median time in practice was 6 years, and median annual compensation was $180,000 (doi: 10.1001/jamainternmed.2013.1864).

Important study findings include the following:

• Forty percent of respondents reported that at least once per month, their census exceeded safe levels, and 36% of these noted they experienced unsafe levels multiple times per week.

• Fifteen patients per shift was the magic number that would optimize patient safety, regardless of any assistance doctors received, and that was assuming their shift was a purely clinical shift.

• More than 20% of hospitalists believe their average workload likely contributed to patient transfers, patient suffering, or even the death of patients. That was the most sobering finding of the study.

This study has profound implications for patient safety, and less importantly, patient satisfaction. The potential for unnecessary suffering, excessive medical costs, and unnecessary death is staggering. The actual number of physicians who are willing to admit their limitations is likely far lower than the actual number who experience these adverse effects, even if they are oblivious to their understandable limitations.

When the pager is going off incessantly while you are answering another call, and nurses are lined up to ask you questions about their patients, and, of course, you have a patient or two in the ER who need your attention, it is easy to get sidetracked. To err is human.

The bottom line is patients are the bottom line. They depend on us to provide safe, compassionate, high-quality health care. They literally entrust their lives to us, and we must honor that trust by speaking up if we feel like their safety is in jeopardy, and work with hospitalist directors and hospital administrators to create an environment in which patient safety is valued above all.

Dr. Hester is a hospitalist with Baltimore-Washington Medical Center, Glen Burnie, Md., who has a passion for empowering patients to partner in their health care.

In 2000, the Institute of Medicine published an oft-cited report, "To Err Is Human: Building a Safer Health System – A Report of The Committee on Quality of Health Care in America." The report estimated that up to 98,000 patients die from preventable medical errors each year.

Many of us can remember the boot camp–like conditions of residency: working incredibly long shifts that made every part of our bodies (and brains) cry out for rest – even a 10-minute nap could bring much-needed relief.

I remember sometimes working 48- to 72-hour shifts, between my regular residency responsibilities and moonlighting in the VA emergency room. That seems like a lifetime ago, a lifetime I would not want to relive.

While we may have been trained to believe we can perform at our peak despite sleep deprivation, in reality many of us made mistakes, whether great or small, as a result of our highly stressed, sleep-deprived state. And if we are honest with ourselves, we would not want to be a patient who is cared for by any doctor whose mental facilities have been impaired due to lack of sleep. Finally, wisdom defeated pride and custom, and residents’ shifts have been limited, which was a true victory for patients and residents alike.

Subsequently, it was acknowledged that nurses also made errors when working in suboptimal conditions. A study in the New England Journal of Medicine found a significant association between low staffing and patient mortality ("Nurse Staffing and Inpatient Hospital Mortality," N. Engl. J. Med. 2011;364:1037-45).

Truth be told, we already knew that nurses and inexperienced resident physicians make mistakes when overwhelmed and overworked, but what about seasoned hospitalists? What about us? Do we honestly believe we are somehow immune to making medical errors because of years of experience?

A piece in the Jan. 28 edition of JAMA – "Impact of Attending Physician Workload on Patient Care: A Survey of Hospitalists" – sheds light on how we really feel. The survey assessed hospitalists’ perceptions of the association between their workload and patient safety and quality-of-care measures during daytime shifts. The respondents’ average age was 38 years, median time in practice was 6 years, and median annual compensation was $180,000 (doi: 10.1001/jamainternmed.2013.1864).

Important study findings include the following:

• Forty percent of respondents reported that at least once per month, their census exceeded safe levels, and 36% of these noted they experienced unsafe levels multiple times per week.

• Fifteen patients per shift was the magic number that would optimize patient safety, regardless of any assistance doctors received, and that was assuming their shift was a purely clinical shift.

• More than 20% of hospitalists believe their average workload likely contributed to patient transfers, patient suffering, or even the death of patients. That was the most sobering finding of the study.

This study has profound implications for patient safety, and less importantly, patient satisfaction. The potential for unnecessary suffering, excessive medical costs, and unnecessary death is staggering. The actual number of physicians who are willing to admit their limitations is likely far lower than the actual number who experience these adverse effects, even if they are oblivious to their understandable limitations.

When the pager is going off incessantly while you are answering another call, and nurses are lined up to ask you questions about their patients, and, of course, you have a patient or two in the ER who need your attention, it is easy to get sidetracked. To err is human.

The bottom line is patients are the bottom line. They depend on us to provide safe, compassionate, high-quality health care. They literally entrust their lives to us, and we must honor that trust by speaking up if we feel like their safety is in jeopardy, and work with hospitalist directors and hospital administrators to create an environment in which patient safety is valued above all.

Dr. Hester is a hospitalist with Baltimore-Washington Medical Center, Glen Burnie, Md., who has a passion for empowering patients to partner in their health care.