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Common Symptoms Common Symptoms sudden-onset fever and myalgia, especially during influenza season (between autumn and early spring). For the most current

Common Symptoms Common Symptoms sudden-onset fever and myalgia, especially during influenza season (between autumn and early spring). For the most current Introduction information on SARS-CoV-2, see COVID-19: An ACP Physician’s Guide (https://www.acponline.org/clinical-information/ Symptom concerns are responsible for nearly half of all outpa- clinical-resources-products/coronavirus-disease-2019-covid- tient visits. Although most symptoms resolve within several 19-information-for-internists). Bacterial infections also can weeks, clinicians are challenged to determine symptom sig- cause acute sinusitis or bronchitis, although sinus imaging is nificance and the role of testing in the diagnostic approach. not recommended unless a complication, such as spread of Unnecessary testing accounts for nearly 30% of health care infection into contiguous structures, is suspected. costs, and physicians have a responsibility when evaluating Another important cause of acute cough is therapy with an symptoms to use testing strategies that offer the highest value. ACE inhibitor. Up to 20% of patients taking an ACE inhibitor Fortunately, a thorough history alone generates the highest develop a dry cough, usually within 1 to 2 weeks of therapy diagnostic yield—up to 75% in some studies—with physical initiation, although cough onset may be delayed by months in a examination contributing an additional 10% to 15%. In con- small percentage of patients. Cough usually subsides within trast, testing results in less than 10% of diagnoses. Diagnostic days of discontinuation of the offending agent but can persist testing may provide information that justifies the costs; how- for weeks in some cases. All ACE inhibitors can cause this side ever, physicians should consider the value of testing and the effect. Angiotensin receptor blockers typically do not cause effects of test results on patient management. cough and may be substituted if ACE inhibitor therapy is not This chapter focuses on high-value approaches to the tolerated. diagnosis and treatment of commonly encountered symp- Treatment of acute cough is primarily symptomatic and toms, including cough, dizziness, dyspnea, fatigue, insomnia, dependent on the underlying etiology. The mainstay of treat- lower extremity edema and ulcers, medically unexplained ment of bronchitis is patient education and reassurance that symptoms, and syncope. In-flight emergencies, a common the cough usually resolves in 2 to 3 weeks. Empiric treatment event encountered by physicians, also are reviewed. of acute bronchitis or upper respiratory tract infection with antibiotics is ineffective; increases bacterial antibiotic resis- tance; and may cause multiple adverse effects, including Cough Clostridioides difficile colitis. Antibiotics should not be initi- Cough results in roughly 30 million physician office visits annu- ated without clearly established bacterial infection, and most ally in the United States, costing billions of dollars. An evidence- patients with acute bacterial sinusitis will improve without based and cost-effective approach to the evaluation of cough is antibiotics. A limited number of studies suggest that honey based on cough duration (acute, subacute, or chronic). may decrease cough frequency and severity. Patients sus- pected of having acute bronchitis should be counseled to Acute Cough return if symptoms do not improve; further evaluation and Acute cough (<3 weeks’ duration) most often is caused by viral antibiotic therapy should be considered in patients with infections, including upper respiratory tract infections and worsening or persistent symptoms. Treatment of acute rhi- bronchitis. Other conditions that may present with acute nosinusitis includes intranasal glucocorticoids. Limited cough include allergic rhinosinusitis, pneumonia, medication evidence supports the effectiveness of other treatments, adverse effects, and pulmonary edema. including saline irrigation, antihistamines, and decongestants The initial evaluation of the patient with acute cough (see MKSAP 19 General Internal Medicine 2). focuses on identifying potentially life-threatening illnesses. Concomitant fever, dyspnea, chest pain, and abnormalities on Subacute and Chronic Cough lung or cardiovascular examination suggest a serious respira- Subacute cough (3-8 weeks’ duration) is most often postinfec- tory or cardiovascular disease as the source of cough, and tious after acute respiratory tract infection, particularly viral further evaluation should be completed as appropriate. Chest or Mycoplasma infection. It is usually caused by postnasal radiography is indicated with suspicion of pneumonia; find- drip or airway hyperreactivity. First-generation antihistamines ings that support obtaining a chest radiograph include abnor- may be beneficial in patients with postnasal drip. Asthma mal vital signs (heart rate >100/min, respiration rate >24/min, therapies are usually effective in patients with evidence of temperature >38.0 °C [100.4 °F]), abnormal lung examination airway hyperreactivity, such as wheezing. Patients with findings (rales, egophony, or tactile fremitus), and altered postinfectious cough not attributed to postnasal drip or airway mental status. hyperreactivity may benefit from inhaled ipratropium. Acute cough without evidence of lower respiratory tract Bordetella pertussis infection should be considered in patients infection or cardiovascular disease is most often caused by acute with subacute cough characterized by paroxysms of severe bronchitis or viral rhinosinusitis. Coronaviruses and rhinovi- coughing and posttussive emesis. If infectious causes of sub- ruses are the most common causative pathogens; influenza acute cough are excluded, the evaluation shifts to considera- virus should be highly suspected in patients presenting with tion of the causes of chronic cough.

Introduction information on SARS-CoV-2, see COVID-19: An ACP Physician’s Guide (https://www.acponline.org/clinical-information/ Symptom concerns are responsible for nearly half of all outpa- clinical-resources-products/coronavirus-disease-2019-covid- tient visits. Although most symptoms resolve within several 19-information-for-internists). Bacterial infections also can weeks, clinicians are challenged to determine symptom sig- cause acute sinusitis or bronchitis, although sinus imaging is nificance and the role of testing in the diagnostic approach. not recommended unless a complication, such as spread of Unnecessary testing accounts for nearly 30% of health care infection into contiguous structures, is suspected. costs, and physicians have a responsibility when evaluating Another important cause of acute cough is therapy with an symptoms to use testing strategies that offer the highest value. ACE inhibitor. Up to 20% of patients taking an ACE inhibitor Fortunately, a thorough history alone generates the highest develop a dry cough, usually within 1 to 2 weeks of therapy diagnostic yield—up to 75% in some studies—with physical initiation, although cough onset may be delayed by months in a examination contributing an additional 10% to 15%. In con- small percentage of patients. Cough usually subsides within trast, testing results in less than 10% of diagnoses. Diagnostic days of discontinuation of the offending agent but can persist testing may provide information that justifies the costs; how- for weeks in some cases. All ACE inhibitors can cause this side ever, physicians should consider the value of testing and the effect. Angiotensin receptor blockers typically do not cause effects of test results on patient management. cough and may be substituted if ACE inhibitor therapy is not This chapter focuses on high-value approaches to the tolerated. diagnosis and treatment of commonly encountered symp- Treatment of acute cough is primarily symptomatic and toms, including cough, dizziness, dyspnea, fatigue, insomnia, dependent on the underlying etiology. The mainstay of treat- lower extremity edema and ulcers, medically unexplained ment of bronchitis is patient education and reassurance that symptoms, and syncope. In-flight emergencies, a common the cough usually resolves in 2 to 3 weeks. Empiric treatment event encountered by physicians, also are reviewed. of acute bronchitis or upper respiratory tract infection with antibiotics is ineffective; increases bacterial antibiotic resis- tance; and may cause multiple adverse effects, including Cough Clostridioides difficile colitis. Antibiotics should not be initi- Cough results in roughly 30 million physician office visits annu- ated without clearly established bacterial infection, and most ally in the United States, costing billions of dollars. An evidence- patients with acute bacterial sinusitis will improve without based and cost-effective approach to the evaluation of cough is antibiotics. A limited number of studies suggest that honey based on cough duration (acute, subacute, or chronic). may decrease cough frequency and severity. Patients sus- pected of having acute bronchitis should be counseled to Acute Cough return if symptoms do not improve; further evaluation and Acute cough (<3 weeks’ duration) most often is caused by viral antibiotic therapy should be considered in patients with infections, including upper respiratory tract infections and worsening or persistent symptoms. Treatment of acute rhi- bronchitis. Other conditions that may present with acute nosinusitis includes intranasal glucocorticoids. Limited cough include allergic rhinosinusitis, pneumonia, medication evidence supports the effectiveness of other treatments, adverse effects, and pulmonary edema. including saline irrigation, antihistamines, and decongestants The initial evaluation of the patient with acute cough (see MKSAP 19 General Internal Medicine 2). focuses on identifying potentially life-threatening illnesses. Concomitant fever, dyspnea, chest pain, and abnormalities on Subacute and Chronic Cough lung or cardiovascular examination suggest a serious respira- Subacute cough (3-8 weeks’ duration) is most often postinfec- tory or cardiovascular disease as the source of cough, and tious after acute respiratory tract infection, particularly viral further evaluation should be completed as appropriate. Chest or Mycoplasma infection. It is usually caused by postnasal radiography is indicated with suspicion of pneumonia; find- drip or airway hyperreactivity. First-generation antihistamines ings that support obtaining a chest radiograph include abnor- may be beneficial in patients with postnasal drip. Asthma mal vital signs (heart rate >100/min, respiration rate >24/min, therapies are usually effective in patients with evidence of temperature >38.0 °C [100.4 °F]), abnormal lung examination airway hyperreactivity, such as wheezing. Patients with findings (rales, egophony, or tactile fremitus), and altered postinfectious cough not attributed to postnasal drip or airway mental status. hyperreactivity may benefit from inhaled ipratropium. Acute cough without evidence of lower respiratory tract Bordetella pertussis infection should be considered in patients infection or cardiovascular disease is most often caused by acute with subacute cough characterized by paroxysms of severe bronchitis or viral rhinosinusitis. Coronaviruses and rhinovi- coughing and posttussive emesis. If infectious causes of sub- ruses are the most common causative pathogens; influenza acute cough are excluded, the evaluation shifts to considera- virus should be highly suspected in patients presenting with tion of the causes of chronic cough. 19

Common Symptoms Chronic cough (>8 weeks’ duration) is most often increasingly recognized etiology. Important but less com- caused by upper airway cough syndrome (UACS) (formerly mon causes include chronic bronchitis, lung neoplasm, known as postnasal drip syndrome), gastroesophageal reflux bronchiectasis, and chronic aspiration. disease (GERD), asthma, smoking, and ACE inhibitor use. Evaluation of chronic cough begins with a thorough his- Nonasthmatic eosinophilic bronchitis (NAEB) is another tory, physical examination, and chest radiography (Figure 5). Chronic cough (>8 weeks’ duration) v History, examination, chest radiograph | f Diagnosis suggested | No clear diagnosis Vv: f Y Investigate and treat Nonsmoker, no ACE inhibitor use Smoker or ACE inhibitor use Y Discontinue Upper airway cough syndrome Cough persists Empiric treatment (intranasal glucocorticoids for allergic Cough persists A thinitis-related UACS, antihistamine/decongestant for nonallergic rhinitis-related UACS)

Upper airway cough syndrome Cough persists Empiric treatment (intranasal glucocorticoids for allergic Cough persists A thinitis-related UACS, antihistamine/decongestant for nonallergic rhinitis-related UACS) Cough persists 4 Asthma Ideally evaluate (spirometry, bronchodilator reversibility, bronchial provocation challenge) or provide empiric asthma treatment according to current guidelines Cough persists Nonasthmatic eosinophilic bronchitis Ideally evaluate for sputum eosinophilia (sputum analysis, exhaled nitric oxide testing) or provide empiric treatment Cough persists | Gastroesophageal reflux disease Empiric treatment (proton pump inhibitor, diet/lifestyle)

Nonasthmatic eosinophilic bronchitis Ideally evaluate for sputum eosinophilia (sputum analysis, exhaled nitric oxide testing) or provide empiric treatment Cough persists | Gastroesophageal reflux disease Empiric treatment (proton pump inhibitor, diet/lifestyle) Cough persists | Consider further investigation: ¢ Barium esophagography ¢ Bronchoscopy General considerations: ¢ Echocardiography © Optimize therapy for each ¢ Environmental assessment diagnosis ¢ Endoscopic or videofluoroscopic swallow evaluation ° Check adherence ¢ High-resolution CT © Due to possibility of multiple ¢ 24-Hour esophageal pH monitoring causes, maintain all partially ¢ Sinus imaging effective treatments ¢ Consider other rare causes

Cough persists | Consider further investigation: ¢ Barium esophagography ¢ Bronchoscopy General considerations: ¢ Echocardiography © Optimize therapy for each ¢ Environmental assessment diagnosis ¢ Endoscopic or videofluoroscopic swallow evaluation ° Check adherence ¢ High-resolution CT © Due to possibility of multiple ¢ 24-Hour esophageal pH monitoring causes, maintain all partially ¢ Sinus imaging effective treatments ¢ Consider other rare causes FIGURE 5. Evaluation of chronic cough. UACS = upper airway cough syndrome. Recommendations from Irwin RS, French CL, Chang AB, et al; CHEST Expert Cough Panel. Classification of cough as a symptom in adults and g and expert panel report. Chest. 2018; 153:196-209. er CHEST [PMID: 29080708] doi:10.1016/j.chest.2017.10.016 and Kahrilas PJ, Altman KW, Chang AB, et al; CHEST Expert Cough Panel. Chronic cough due to gastroesophageal refluxin adults: CHEST guideline and expert panel report. Chest. 2016;150:1341-60. [PMID: 27614002] doi:10.1016/j.chest.2016.08.1458 20

Common Symptoms Therapy for specific causes should be initiated on the basis of Pneumocystis jirovecii. Regardless of radiographic findings, the initial evaluation. ACE inhibitor therapy and tobacco use tuberculosis should be considered in the initial evaluation of should be discontinued. If the cause is not determined after patients with HIV infection and subacute or chronic cough who initial evaluation, a stepwise approach is pursued, beginning reside in regions with a high prevalence of tuberculosis. with a 2-week trial of empiric treatment for UACS. Allergic Clinicians should have a low threshold for initiating empiric rhinitis-associated UACS is optimally treated with intranasal antibiotic therapy while diagnostic testing is pursued. glucocorticoids, whereas UACS resulting from nonallergic rhinitis responds best to first-generation antihistamines Hemoptysis (chlorpheniramine, brompheniramine, diphenhydramine) Hemoptysis is expectoration of blood from the lower respira- and decongestants (pseudoephedrine) (see MKSAP 19 General tory tract. Acute bronchitis is a common cause of mild and Internal Medicine 2). self-limited hemoptysis; more serious causes include bronchi- Asthma should be considered in patients with symptoms ectasis, cancer, tuberculosis, pulmonary embolism, and left that do not respond to empiric treatment for UACS. Cough- ventricular failure. Rare causes include anti-glomerular base- variant asthma is diagnosed if spirometry and/or bronchial ment membrane antibody disease (Goodpasture syndrome) hyperresponsiveness testing results are abnormal and symp- and granulomatosis with polyangiitis. Hemoptysis requires toms improve with standard therapy for asthma, including urgent evaluation, beginning with assessment to confirm the inhaled glucocorticoids. lower respiratory tract as the source of bleeding and exclude In patients with normal findings on evaluation and in epistaxis or hematemesis. Chest radiography should be per- whom empiric treatment for UACS and asthma has failed, the formed, but many patients additionally require chest CT and/or most reasonable next step is to exclude NAEB with sputum bronchoscopy to determine the cause. analysis for eosinophils or exhaled nitric oxide testing. If test results are abnormal, therapy with inhaled glucocorticoids should be initiated. e Chest radiography is not indicated in the evaluation of HVC

Therapy for specific causes should be initiated on the basis of Pneumocystis jirovecii. Regardless of radiographic findings, the initial evaluation. ACE inhibitor therapy and tobacco use tuberculosis should be considered in the initial evaluation of should be discontinued. If the cause is not determined after patients with HIV infection and subacute or chronic cough who initial evaluation, a stepwise approach is pursued, beginning reside in regions with a high prevalence of tuberculosis. with a 2-week trial of empiric treatment for UACS. Allergic Clinicians should have a low threshold for initiating empiric rhinitis-associated UACS is optimally treated with intranasal antibiotic therapy while diagnostic testing is pursued. glucocorticoids, whereas UACS resulting from nonallergic rhinitis responds best to first-generation antihistamines Hemoptysis (chlorpheniramine, brompheniramine, diphenhydramine) Hemoptysis is expectoration of blood from the lower respira- and decongestants (pseudoephedrine) (see MKSAP 19 General tory tract. Acute bronchitis is a common cause of mild and Internal Medicine 2). self-limited hemoptysis; more serious causes include bronchi- Asthma should be considered in patients with symptoms ectasis, cancer, tuberculosis, pulmonary embolism, and left that do not respond to empiric treatment for UACS. Cough- ventricular failure. Rare causes include anti-glomerular base- variant asthma is diagnosed if spirometry and/or bronchial ment membrane antibody disease (Goodpasture syndrome) hyperresponsiveness testing results are abnormal and symp- and granulomatosis with polyangiitis. Hemoptysis requires toms improve with standard therapy for asthma, including urgent evaluation, beginning with assessment to confirm the inhaled glucocorticoids. lower respiratory tract as the source of bleeding and exclude In patients with normal findings on evaluation and in epistaxis or hematemesis. Chest radiography should be per- whom empiric treatment for UACS and asthma has failed, the formed, but many patients additionally require chest CT and/or most reasonable next step is to exclude NAEB with sputum bronchoscopy to determine the cause. analysis for eosinophils or exhaled nitric oxide testing. If test results are abnormal, therapy with inhaled glucocorticoids should be initiated. e Chest radiography is not indicated in the evaluation of HVC Cough without a clear etiology that does not appear acute cough in the absence of abnormal vital signs or

Therapy for specific causes should be initiated on the basis of Pneumocystis jirovecii. Regardless of radiographic findings, the initial evaluation. ACE inhibitor therapy and tobacco use tuberculosis should be considered in the initial evaluation of should be discontinued. If the cause is not determined after patients with HIV infection and subacute or chronic cough who initial evaluation, a stepwise approach is pursued, beginning reside in regions with a high prevalence of tuberculosis. with a 2-week trial of empiric treatment for UACS. Allergic Clinicians should have a low threshold for initiating empiric rhinitis-associated UACS is optimally treated with intranasal antibiotic therapy while diagnostic testing is pursued. glucocorticoids, whereas UACS resulting from nonallergic rhinitis responds best to first-generation antihistamines Hemoptysis (chlorpheniramine, brompheniramine, diphenhydramine) Hemoptysis is expectoration of blood from the lower respira- and decongestants (pseudoephedrine) (see MKSAP 19 General tory tract. Acute bronchitis is a common cause of mild and Internal Medicine 2). self-limited hemoptysis; more serious causes include bronchi- Asthma should be considered in patients with symptoms ectasis, cancer, tuberculosis, pulmonary embolism, and left that do not respond to empiric treatment for UACS. Cough- ventricular failure. Rare causes include anti-glomerular base- variant asthma is diagnosed if spirometry and/or bronchial ment membrane antibody disease (Goodpasture syndrome) hyperresponsiveness testing results are abnormal and symp- and granulomatosis with polyangiitis. Hemoptysis requires toms improve with standard therapy for asthma, including urgent evaluation, beginning with assessment to confirm the inhaled glucocorticoids. lower respiratory tract as the source of bleeding and exclude In patients with normal findings on evaluation and in epistaxis or hematemesis. Chest radiography should be per- whom empiric treatment for UACS and asthma has failed, the formed, but many patients additionally require chest CT and/or most reasonable next step is to exclude NAEB with sputum bronchoscopy to determine the cause. analysis for eosinophils or exhaled nitric oxide testing. If test results are abnormal, therapy with inhaled glucocorticoids should be initiated. e Chest radiography is not indicated in the evaluation of HVC Cough without a clear etiology that does not appear acute cough in the absence of abnormal vital signs or secondary to UACS, asthma, or NAEB may be treated with lung examination findings, unless there are other con-

Therapy for specific causes should be initiated on the basis of Pneumocystis jirovecii. Regardless of radiographic findings, the initial evaluation. ACE inhibitor therapy and tobacco use tuberculosis should be considered in the initial evaluation of should be discontinued. If the cause is not determined after patients with HIV infection and subacute or chronic cough who initial evaluation, a stepwise approach is pursued, beginning reside in regions with a high prevalence of tuberculosis. with a 2-week trial of empiric treatment for UACS. Allergic Clinicians should have a low threshold for initiating empiric rhinitis-associated UACS is optimally treated with intranasal antibiotic therapy while diagnostic testing is pursued. glucocorticoids, whereas UACS resulting from nonallergic rhinitis responds best to first-generation antihistamines Hemoptysis (chlorpheniramine, brompheniramine, diphenhydramine) Hemoptysis is expectoration of blood from the lower respira- and decongestants (pseudoephedrine) (see MKSAP 19 General tory tract. Acute bronchitis is a common cause of mild and Internal Medicine 2). self-limited hemoptysis; more serious causes include bronchi- Asthma should be considered in patients with symptoms ectasis, cancer, tuberculosis, pulmonary embolism, and left that do not respond to empiric treatment for UACS. Cough- ventricular failure. Rare causes include anti-glomerular base- variant asthma is diagnosed if spirometry and/or bronchial ment membrane antibody disease (Goodpasture syndrome) hyperresponsiveness testing results are abnormal and symp- and granulomatosis with polyangiitis. Hemoptysis requires toms improve with standard therapy for asthma, including urgent evaluation, beginning with assessment to confirm the inhaled glucocorticoids. lower respiratory tract as the source of bleeding and exclude In patients with normal findings on evaluation and in epistaxis or hematemesis. Chest radiography should be per- whom empiric treatment for UACS and asthma has failed, the formed, but many patients additionally require chest CT and/or most reasonable next step is to exclude NAEB with sputum bronchoscopy to determine the cause. analysis for eosinophils or exhaled nitric oxide testing. If test results are abnormal, therapy with inhaled glucocorticoids should be initiated. e Chest radiography is not indicated in the evaluation of HVC Cough without a clear etiology that does not appear acute cough in the absence of abnormal vital signs or secondary to UACS, asthma, or NAEB may be treated with lung examination findings, unless there are other con- antireflux lifestyle changes to address possible GERD; empiric cerning clinical features (e.g., altered mental status).

Cough without a clear etiology that does not appear acute cough in the absence of abnormal vital signs or secondary to UACS, asthma, or NAEB may be treated with lung examination findings, unless there are other con- antireflux lifestyle changes to address possible GERD; empiric cerning clinical features (e.g., altered mental status). proton pump inhibitor therapy also may be considered. e Treatment of acute cough is primarily symptomatic; HVC Patients with partial responses to treatment for UACS, antibiotics are not recommended in patients with acute asthma, NAEB, and/or GERD should continue those thera- bronchitis or upper respiratory tract infection without a pies. More advanced investigation may be necessary in some clear bacterial cause. patients (see Figure 5). ¢ Common causes of chronic cough include smoking, Persistent cough without an identifiable cause despite ACE inhibitor use, upper airway cough syndrome, gas- comprehensive evaluation is termed unexplained chronic troesophageal reflux disease, asthma, and nonasthmatic cough. Patients with unexplained chronic cough may benefit eosinophilic bronchitis. from other therapies for symptomatic relief. Multimodality e Patients with unexplained chronic cough may benefit speech pathology therapy may provide benefit and should be from multimodality speech pathology therapy, antitus- offered to all patients with chronic cough of undetermined sives, and/or gabapentin. cause. Antitussives, including dextromethorphan and topical

proton pump inhibitor therapy also may be considered. e Treatment of acute cough is primarily symptomatic; HVC Patients with partial responses to treatment for UACS, antibiotics are not recommended in patients with acute asthma, NAEB, and/or GERD should continue those thera- bronchitis or upper respiratory tract infection without a pies. More advanced investigation may be necessary in some clear bacterial cause. patients (see Figure 5). ¢ Common causes of chronic cough include smoking, Persistent cough without an identifiable cause despite ACE inhibitor use, upper airway cough syndrome, gas- comprehensive evaluation is termed unexplained chronic troesophageal reflux disease, asthma, and nonasthmatic cough. Patients with unexplained chronic cough may benefit eosinophilic bronchitis. from other therapies for symptomatic relief. Multimodality e Patients with unexplained chronic cough may benefit speech pathology therapy may provide benefit and should be from multimodality speech pathology therapy, antitus- offered to all patients with chronic cough of undetermined sives, and/or gabapentin. cause. Antitussives, including dextromethorphan and topical anesthetics (benzonatate), have been shown to reduce cough and improve quality of life. Gabapentin may be effective for unexplained chronic cough and should be considered if the Dizziness risk for adverse effects is acceptable. Protussives, such as Approach to the Patient With Dizziness guaifenesin, can improve mucus clearance and cough inten- Dizziness is a common, nonspecific symptom seen in inpa- sity in selected patients with excessive sputum production. tient and outpatient settings. Patients often interchangeably Opioids, such as codeine, may be effective but should be used use such terms as “dizzy,” “lightheaded,” “woozy,” “cloudy,” with caution and only if other measures fail. “faint,” or “off-balance” to describe the perception of dizzi- ness. Owing to its subjective nature, variability in symptom Cough in the Immunocompromised Patient description, and broad differential diagnosis (which includes The evaluation of cough in ambulatory immunocompromised posterior circulation stroke and other life-threatening disor- patients should follow the same protocol as for immunocompe- ders), dizziness is a challenging symptom to assess and treat. tent patients; however, immunocompromised patients require A relevant history and physical examination should be heightened suspicion for infections, particularly if immunosup- performed to classify dizziness into one of four focused group- pression is severe and common causes of cough have been ings: vertigo, presyncope, disequilibrium, and nonspecific excluded. Aside from common pathogens, other causes to con- dizziness. This classification facilitates establishing a formal sider include fungi, cytomegalovirus, varicella, herpesvirus, and diagnosis and treatment strategy.

anesthetics (benzonatate), have been shown to reduce cough and improve quality of life. Gabapentin may be effective for unexplained chronic cough and should be considered if the Dizziness risk for adverse effects is acceptable. Protussives, such as Approach to the Patient With Dizziness guaifenesin, can improve mucus clearance and cough inten- Dizziness is a common, nonspecific symptom seen in inpa- sity in selected patients with excessive sputum production. tient and outpatient settings. Patients often interchangeably Opioids, such as codeine, may be effective but should be used use such terms as “dizzy,” “lightheaded,” “woozy,” “cloudy,” with caution and only if other measures fail. “faint,” or “off-balance” to describe the perception of dizzi- ness. Owing to its subjective nature, variability in symptom Cough in the Immunocompromised Patient description, and broad differential diagnosis (which includes The evaluation of cough in ambulatory immunocompromised posterior circulation stroke and other life-threatening disor- patients should follow the same protocol as for immunocompe- ders), dizziness is a challenging symptom to assess and treat. tent patients; however, immunocompromised patients require A relevant history and physical examination should be heightened suspicion for infections, particularly if immunosup- performed to classify dizziness into one of four focused group- pression is severe and common causes of cough have been ings: vertigo, presyncope, disequilibrium, and nonspecific excluded. Aside from common pathogens, other causes to con- dizziness. This classification facilitates establishing a formal sider include fungi, cytomegalovirus, varicella, herpesvirus, and diagnosis and treatment strategy. 21

Common Symptoms TABLE 13. Differential Diagnosis of Acute Vertigo Cause Onset and Course Nystagmus Auditory Other Features Symptoms | | BPPV Recurrent, transient, positional; Positional, with mixed vertical None Recent inciting event fil Kl | TV , Wl over or getting in and out of Wn nystagmus In Ml) involving posterior canal and (e.g., recumbent position at dentist's office or hair salon, bed horizontal nystagmus in BPPV prolonged bed rest, head trauma); involving horizontal canal history of similar episodes

Kl | TV , Wl over or getting in and out of Wn nystagmus In Ml) involving posterior canal and (e.g., recumbent position at dentist's office or hair salon, bed horizontal nystagmus in BPPV prolonged bed rest, head trauma); involving horizontal canal history of similar episodes | Stroke Spontaneous, usually Spontaneous, with beating in Occasional Neurologic symptoms or signs sustained; may be worsened various or changing directions often occur, but stroke may by positional change present as isolated vertigo; results | of head impulse test are typically normal? Vestibular | Spontaneous, sustained; may Spontaneous, predominantly None May be preceded by viral illness; neuronitis be worsened by positional horizontal results of head impulse test are change abnormal?

Vestibular | Spontaneous, sustained; may Spontaneous, predominantly None May be preceded by viral illness; neuronitis be worsened by positional horizontal results of head impulse test are change abnormal? Vestibular Recurrent, spontaneous; Rare, but when present usually — Occasional Migrainous headaches, motion migraine duration for minutes to hours; positional sickness, family history may be positional Meniere Recurrent, spontaneous; Spontaneous, horizontal Fluctuating Ear pain, sensation of fullness in | disease typical duration for hours hearingloss, ear tinnitus BPPV = benign paroxysmal positional vertigo. | #In the head impulse test, the presence of catch-up saccades is a positive result for peripheral vertigo. Absence of catch-up saccades in a patient with acute vertigo is concerning for stroke. Reproduced with permission from Kim JS, Zee DS. Clinical practice. Benign paroxysmal positional vertigo. N Eng! J Med. 2014;370:1140. [PMID: 24645946] doi:10.1056/ | NEJMcp1309481. © 2014, Massachusetts Medical Society. Vertigo vertigo are presented in Table 13. Examination should include Vertigo is patient perception of false personal or environmen- an in-depth neurologic assessment and, in the case of acute

Vertigo vertigo are presented in Table 13. Examination should include Vertigo is patient perception of false personal or environmen- an in-depth neurologic assessment and, in the case of acute tal movement. Patients describe a spinning or whirling sensa- persistent vertigo, the HINTS (Head Impulse, Nystagmus, and tion, which is often accompanied by concomitant nausea, Test of Skew) oculomotor assessment (Table 14). Demonstration vomiting, and sudden-onset fatigue. Symptoms are typically of the HINTS assessment in a normal patient can be viewed at episodic and brief and are often triggered by positional changes https://collections.lib.utah.edu/details?id=1209722&q=HINTS. of the head. Vertigo is classified as peripheral or central, depending on the specific etiology. Peripheral Vertigo A thorough history and examination are crucial for dif- Common causes of peripheral vertigo include benign paroxys- ferentiating between central and peripheral causes, especially mal positional vertigo (BPPV), vestibular neuronitis, labyrin- in patients with acute vertigo concerning for vertebrobasilar thitis, Meniere disease, medication effects (toxicity from ischemia and other central etiologies. Major causes of acute aminoglycoside or diuretic use), Ramsay Hunt syndrome TABLE 14. HINTS (Head Impulse, Nystagmus, and Test of Skew) Examination and Interpretation Maneuver Method Reassuring Results? Concerning Results’

of the head. Vertigo is classified as peripheral or central, depending on the specific etiology. Peripheral Vertigo A thorough history and examination are crucial for dif- Common causes of peripheral vertigo include benign paroxys- ferentiating between central and peripheral causes, especially mal positional vertigo (BPPV), vestibular neuronitis, labyrin- in patients with acute vertigo concerning for vertebrobasilar thitis, Meniere disease, medication effects (toxicity from ischemia and other central etiologies. Major causes of acute aminoglycoside or diuretic use), Ramsay Hunt syndrome TABLE 14. HINTS (Head Impulse, Nystagmus, and Test of Skew) Examination and Interpretation Maneuver Method Reassuring Results? Concerning Results’ Head impulse test With the patient focusing on the examiner, the Presence of catch-up saccades Absence of catch-up examiner slowly moves the patient's head in (consistent with peripheral saccades (consistent with either direction about 20 degrees and then cause of vertigo) central cause of vertigo) rapidly rotates back to midline, while assessing for catch-up saccades Nystagmus Examiner observes for the presence and Unidirectional nystagmus (fast- Bidirectional nystagmus assessment directionality of nystagmus on lateral gaze phase nystagmus contralaterally) (fast-phase nystagmus alternating)

Nystagmus Examiner observes for the presence and Unidirectional nystagmus (fast- Bidirectional nystagmus assessment directionality of nystagmus on lateral gaze phase nystagmus contralaterally) (fast-phase nystagmus alternating) Test of skew Examiner alternates covering and uncovering Absence of vertical skew Presence of vertical skew deviation® each of the patient's eyes and assesses for vertical adjustment or refixation ?All present is suggestive of vestibular neuronitis. | ’Any present in the correct clinical scenario is concerning for stroke. } | ‘Vertical deviation of one eye compared with the other. = 7 22

Common Symptoms (herpes zoster involving cranial nerve VII), and vestibular status. Positive answers to the following three questions have schwannoma (acoustic neuroma). been found to be helpful in the diagnosis of BPPV: (1) Do you BPPV is the most common form of vertigo, with a lifetime have spinning or a whirling sensation of the surroundings or prevalence of 2.4%. It is more common in women (female-to- yourself? (2) Do you feel dizzy mostly when your head is male ratio of 2:1 to 3:1). BPPV is caused by displacement and moved? (3) Does the dizziness last less than 3 minutes? The migration of otoconia (calcium carbonate crystals) within the sensitivity, specificity, and precision of these questions is semicircular canals. Up to 90% of cases of BPPV involve the 87.0%, 89.8%, and 80.0%, respectively. These questions may be posterior semicircular canal because it is the most gravity- helpful for in-office visits as well in the telephone triage of dependent semicircular canal. patients with acute-onset dizziness. BPPV is characterized by sudden-onset, recurrent, and The diagnostic test of choice for BPPV is the Dix-Hallpike brief (usually <1 minute) vertiginous symptoms that are pro- maneuver (Figure 6), which also can help differentiate voked and worsened with positional changes of the head. between peripheral and central causes of vertigo (Table 15). In Patients report dizziness, imbalance, nausea, and vomiting; the setting of BPPV, a positive finding includes the presence of however, no focal neurologic findings are present. Symptoms a mixed upbeat-torsional nystagmus toward the affected side. lead to increased risk for falls and a decline in functional Brain imaging is unnecessary for diagnosis of BPPV. First-line

(herpes zoster involving cranial nerve VII), and vestibular status. Positive answers to the following three questions have schwannoma (acoustic neuroma). been found to be helpful in the diagnosis of BPPV: (1) Do you BPPV is the most common form of vertigo, with a lifetime have spinning or a whirling sensation of the surroundings or prevalence of 2.4%. It is more common in women (female-to- yourself? (2) Do you feel dizzy mostly when your head is male ratio of 2:1 to 3:1). BPPV is caused by displacement and moved? (3) Does the dizziness last less than 3 minutes? The migration of otoconia (calcium carbonate crystals) within the sensitivity, specificity, and precision of these questions is semicircular canals. Up to 90% of cases of BPPV involve the 87.0%, 89.8%, and 80.0%, respectively. These questions may be posterior semicircular canal because it is the most gravity- helpful for in-office visits as well in the telephone triage of dependent semicircular canal. patients with acute-onset dizziness. BPPV is characterized by sudden-onset, recurrent, and The diagnostic test of choice for BPPV is the Dix-Hallpike brief (usually <1 minute) vertiginous symptoms that are pro- maneuver (Figure 6), which also can help differentiate voked and worsened with positional changes of the head. between peripheral and central causes of vertigo (Table 15). In Patients report dizziness, imbalance, nausea, and vomiting; the setting of BPPV, a positive finding includes the presence of however, no focal neurologic findings are present. Symptoms a mixed upbeat-torsional nystagmus toward the affected side. lead to increased risk for falls and a decline in functional Brain imaging is unnecessary for diagnosis of BPPV. First-line FIGURE 6. Use of the Dix-Hallpike maneuver to induce nystagmus in benign paroxysmal positional vertigo involving the right posterior semicircular canal. With the patient sitting upright (A), the head is turned 45 degrees to the patient's right (B). The patient is then moved from the sitting position to the supine position with the head hanging below the top end of the examination table at an angle of 20 degrees (C). The resulting nystagmus would be upbeat and torsional, with the top poles of the eyes beating toward the lower (right) ear (D). Reproduced with permission from Kim JS, Zee DS. Clinical practice. Benign paroxysmal positional vertigo. N EnglJ Med. 2014;370:1142. [PMID: 24645946] doi:10.1056/NEJMcp 1309481 ©2014, Massachusetts Medical Society.

FIGURE 6. Use of the Dix-Hallpike maneuver to induce nystagmus in benign paroxysmal positional vertigo involving the right posterior semicircular canal. With the patient sitting upright (A), the head is turned 45 degrees to the patient's right (B). The patient is then moved from the sitting position to the supine position with the head hanging below the top end of the examination table at an angle of 20 degrees (C). The resulting nystagmus would be upbeat and torsional, with the top poles of the eyes beating toward the lower (right) ear (D). Reproduced with permission from Kim JS, Zee DS. Clinical practice. Benign paroxysmal positional vertigo. N EnglJ Med. 2014;370:1142. [PMID: 24645946] doi:10.1056/NEJMcp 1309481 ©2014, Massachusetts Medical Society. 23

Common Symptoms TABLE 15. Interpretation of the Dix-Hallpike Maneuver stroke (posterior circulation ischemic or hemorrhagic events), migraine, central nervous system infection, trauma (concus- Findings Peripheral Disease Central Disease sion, traumatic brain injury), demyelinating disease (multiple Latency of Delayed No delay sclerosis), or chronic alcoholism. Risk factors for posterior nystagmus?

TABLE 15. Interpretation of the Dix-Hallpike Maneuver stroke (posterior circulation ischemic or hemorrhagic events), migraine, central nervous system infection, trauma (concus- Findings Peripheral Disease Central Disease sion, traumatic brain injury), demyelinating disease (multiple Latency of Delayed No delay sclerosis), or chronic alcoholism. Risk factors for posterior nystagmus? | Nal | nystagmus ; min >1 min | ICON NC I IC A, | OT diabetes mellitus, peripheral vascular disease, hypertension, and hyperlipidemia. Fatigability of Fatigable Not fatigable nystagmus? Patients with central vertigo secondary to vertebrobasi- lar stroke frequently display neurologic findings, such as Direction of Unidirectional or Variable (vertical nystagmus mixed upbeat- or horizontal) nystagmus, dysphagia, dysarthria, diplopia, ataxia, postural torsional instability, hemiparesis, and mental status changes. On Severity of More severe Less severe HINTS assessment, the presence of a normal head impulse symptoms test, direction-changing nystagmus, or skew deviation @Time to onset of nystagmus after positioning the patient. additionally suggest a central cause. Approximately 20% of

| Nal | nystagmus ; min >1 min | ICON NC I IC A, | OT diabetes mellitus, peripheral vascular disease, hypertension, and hyperlipidemia. Fatigability of Fatigable Not fatigable nystagmus? Patients with central vertigo secondary to vertebrobasi- lar stroke frequently display neurologic findings, such as Direction of Unidirectional or Variable (vertical nystagmus mixed upbeat- or horizontal) nystagmus, dysphagia, dysarthria, diplopia, ataxia, postural torsional instability, hemiparesis, and mental status changes. On Severity of More severe Less severe HINTS assessment, the presence of a normal head impulse symptoms test, direction-changing nystagmus, or skew deviation @Time to onset of nystagmus after positioning the patient. additionally suggest a central cause. Approximately 20% of Decrease in the intensity and duration of nystagmus with repeated maneuvers. patients with vertebrobasilar stroke present with isolated vertigo, and studies have shown that up to one third of these cases are misclassified as peripheral vertigo. To a lesser therapy is canalith repositioning with the Epley maneuver, extent, neurologic findings may be present in patients with which is effective in up to 85% of patients (Figure 7). other central processes, but they are not present in peripher- Vestibular neuronitis is most often preceded by a viral ally mediated forms of vertigo. infection affecting the vestibular portion of cranial nerve VIII. Imaging should be performed in patients with central Symptoms are generally more severe and of longer duration vertigo. MRI is more sensitive than CT in detecting ischemic than in BPPV and may take longer to resolve. Labyrinthitis has stroke and can detect infarction in the posterior fossa, often a presentation similar to that of vestibular neuronitis with the within minutes of symptom onset. CT provides an effective additional symptom of hearing loss. Meniere disease presents and expedited evaluation of hemorrhagic stroke, although with vertigo lasting less than 24 hours accompanied by tinni- hemorrhagic vertebrobasilar stroke accounts for a very small tus, hearing loss, or fullness in the affected ear; symptoms are percentage of cases of centrally mediated vertigo. episodic and recurrent and may be severe. Diuretics and the vasodilator betahistine (not available in Presyncope the United States) may reduce symptoms of Meniere disease, Presyncope is a temporary reduction in global cerebral per- but pharmacologic therapy has not otherwise been shown to fusion, causing symptoms of lightheadedness, dizziness, be significantly effective for peripheral vertigo. Rather, ves- visual changes (tunnel vision), auditory changes, a sense of tibular suppressants (antihistamines, benzodiazepines, and impending doom, warmth, nausea, and near loss of con- antiemetics) can be used in conjunction with other forms of sciousness. Patients often report the sensation of “almost therapy for temporary symptomatic relief. If vestibular sup- blacking out.” Postural tone is retained. In contrast, syncope pressants are selected, treatment duration must be limited is transient reduction in global cerebral perfusion, leading to because these agents impede vestibular functioning, vestibu- a true loss of consciousness and loss of postural tone. lar recovery, and the central compensatory mechanism. Notably, patients with presyncope do not have vertigo. The Vestibular and balance rehabilitation therapy (VBRT) is differential diagnosis for presyncope is similar to that for effective in the treatment of various forms of dizziness (ver- syncope (see Syncope). tigo, disequilibrium, and nonspecific dizziness), although the Epley maneuver is the treatment of choice for BPPV. VBRT Disequilibrium focuses on balance training, core stabilization, and desensiti- Disequilibrium refers to a sensation of imbalance or unsteadi- zation exercises. Therapy is often performed by physical and ness that is primarily experienced during positional changes, occupational therapists. Internet-based therapy may be an standing, or walking and is relieved with sitting or lying down. attractive option for patients (https://balance.lifeguidehealth. Disequilibrium predominantly affects older adults, and its org/player/play/balance). Clinical trials have demonstrated prevalence increases with age. Falls are four times more likely that both standalone internet-based vestibular rehabilitation in patients with disequilibrium and are in turn associated and combined internet-based rehabilitation and face-to-face with significant morbidity, functional decline, and fear of physiotherapy support are clinically effective and safe inter- future falls. ventions to treat adults with a chronic vestibular syndrome. The etiology of disequilibrium is thought to be multi- factorial and can involve visual and auditory impairment; Central Vertigo muscle weakness or atrophy; physical deconditioning; pain; Central vertigo is a frequently missed and potentially life- and/or impairment in proprioception, balance, and gait. threatening diagnosis. It may be caused by vertebrobasilar Disequilibrium must be differentiated from specific causes

Decrease in the intensity and duration of nystagmus with repeated maneuvers. patients with vertebrobasilar stroke present with isolated vertigo, and studies have shown that up to one third of these cases are misclassified as peripheral vertigo. To a lesser therapy is canalith repositioning with the Epley maneuver, extent, neurologic findings may be present in patients with which is effective in up to 85% of patients (Figure 7). other central processes, but they are not present in peripher- Vestibular neuronitis is most often preceded by a viral ally mediated forms of vertigo. infection affecting the vestibular portion of cranial nerve VIII. Imaging should be performed in patients with central Symptoms are generally more severe and of longer duration vertigo. MRI is more sensitive than CT in detecting ischemic than in BPPV and may take longer to resolve. Labyrinthitis has stroke and can detect infarction in the posterior fossa, often a presentation similar to that of vestibular neuronitis with the within minutes of symptom onset. CT provides an effective additional symptom of hearing loss. Meniere disease presents and expedited evaluation of hemorrhagic stroke, although with vertigo lasting less than 24 hours accompanied by tinni- hemorrhagic vertebrobasilar stroke accounts for a very small tus, hearing loss, or fullness in the affected ear; symptoms are percentage of cases of centrally mediated vertigo. episodic and recurrent and may be severe. Diuretics and the vasodilator betahistine (not available in Presyncope the United States) may reduce symptoms of Meniere disease, Presyncope is a temporary reduction in global cerebral per- but pharmacologic therapy has not otherwise been shown to fusion, causing symptoms of lightheadedness, dizziness, be significantly effective for peripheral vertigo. Rather, ves- visual changes (tunnel vision), auditory changes, a sense of tibular suppressants (antihistamines, benzodiazepines, and impending doom, warmth, nausea, and near loss of con- antiemetics) can be used in conjunction with other forms of sciousness. Patients often report the sensation of “almost therapy for temporary symptomatic relief. If vestibular sup- blacking out.” Postural tone is retained. In contrast, syncope pressants are selected, treatment duration must be limited is transient reduction in global cerebral perfusion, leading to because these agents impede vestibular functioning, vestibu- a true loss of consciousness and loss of postural tone. lar recovery, and the central compensatory mechanism. Notably, patients with presyncope do not have vertigo. The Vestibular and balance rehabilitation therapy (VBRT) is differential diagnosis for presyncope is similar to that for effective in the treatment of various forms of dizziness (ver- syncope (see Syncope). tigo, disequilibrium, and nonspecific dizziness), although the Epley maneuver is the treatment of choice for BPPV. VBRT Disequilibrium focuses on balance training, core stabilization, and desensiti- Disequilibrium refers to a sensation of imbalance or unsteadi- zation exercises. Therapy is often performed by physical and ness that is primarily experienced during positional changes, occupational therapists. Internet-based therapy may be an standing, or walking and is relieved with sitting or lying down. attractive option for patients (https://balance.lifeguidehealth. Disequilibrium predominantly affects older adults, and its org/player/play/balance). Clinical trials have demonstrated prevalence increases with age. Falls are four times more likely that both standalone internet-based vestibular rehabilitation in patients with disequilibrium and are in turn associated and combined internet-based rehabilitation and face-to-face with significant morbidity, functional decline, and fear of physiotherapy support are clinically effective and safe inter- future falls. ventions to treat adults with a chronic vestibular syndrome. The etiology of disequilibrium is thought to be multi- factorial and can involve visual and auditory impairment; Central Vertigo muscle weakness or atrophy; physical deconditioning; pain; Central vertigo is a frequently missed and potentially life- and/or impairment in proprioception, balance, and gait. threatening diagnosis. It may be caused by vertebrobasilar Disequilibrium must be differentiated from specific causes 24

Common Symptoms FIGURE 7. Epley canalith-repositioning maneuver for the treatment of benign paroxysmal positional vertigo involving the right posterior semicircular canal. After resolution of the induced nystagmus with the use of the right-sided Dix-Hallpike maneuver (A, B, and C), the head is turned 90 degrees toward the unaffected left side (D), causing the otolithic debris to move closer to the common crus. The induced nystagmus, if present, would be in the same direction as that evoked during the Dix-Hallpike maneuver. The head is then turned another 90 degrees, to a face-down position, and the trunk is turned 90 degrees in the same direction, so that the patient is lying on the unaffected side (E); the otolithic debris migrates in the same direction. The patient is then moved to the sitting position (F), and the otolithic debris falls into the vestibule, through the common crus. Each position should be maintained until the induced nystagmus and vertigo resolve but always for a minimum of 30 seconds. Reproduced with permission from Kim JS, Zee DS. Clinical practice. Benign paroxysmal positional vertigo. N EnglJMed. 2014;370:1144. [PMID: 24645946] doi:10.1056/NEJMcp1309481 ©2014, Massachusetts Medical Society. 25

Common Symptoms of gait abnormalities and ataxia, such as movement disor- Dyspnea ders (Parkinson disease), peripheral neuropathy, and cere- Dyspnea is a common symptom with a diverse pathophysio- bellar disease (mass lesions) (see MKSAP 19 Neurology). logic basis and substantial variation in patient experience. The Brain MRI in patients with disequilibrium has shown sig- prevalence of dyspnea increases with age; more than one third nificantly more subcortical white-matter lesions and frontal of persons older than 65 years report dyspnea in an ambula- atrophy than in patients without disequilibrium, although tory setting. Dyspnea affects up to half of hospitalized patients the significance of these findings is unclear. and is acommon reason for patients to seek care in urgent and Given the multifactorial nature of disequilibrium, treat- emergent care settings. ment should be multifaceted. Treatment options include visual Dyspnea is caused by multiple underlying neurophysio- and auditory corrective measures (eyeglasses, hearing aids), logic mechanisms, including greater work of breathing, air medication review (to mitigate side effects), mobility aids, phys- hunger, and airway irritation or damage. These mechanisms ical therapy (balance and gait training), weight-bearing and may be triggered by poor functional status, organ-specific resistance exercises, and fall prevention counseling. pathology, medication effects, or physiologic stimuli (includ- ing hypoxia and hypercapnia). Persistent Postural-Perceptual Dizziness Dizziness that remains nonspecific despite a thorough history, Evaluation examination, and evaluation is referred to as persistent The history and physical examination are the most important postural-perceptual dizziness (PPPD) (formerly known as components of the evaluation of dyspnea. An essential aspect chronic subjective dizziness). PPPD is described as persistent, of the history is the patient’s qualitative description of dysp- nonvertiginous dizziness or imbalance that worsens with per- nea, which may aid in the diagnosis. Chest tightness may be sonal motion, upright positioning, and movement of objects in relatively specific for bronchoconstriction, whereas smother- the surrounding environment. Symptoms must be present on ing or suffocating at rest may suggest heart failure. Air hunger most days for at least 3 months. PPPD is often preceded by and “inability to get a deep breath” are commonly associated another vestibular process (BPPV, vestibular neuronitis, ves- with hyperinflation (such as that caused by COPD) or restric- tibular migraine, or stroke), trauma (concussion or traumatic tive conditions (such as pulmonary fibrosis). brain injury), infection, or certain psychiatric conditions (anx- The onset, duration, and progression of dyspnea may sug- iety, panic disorder, or major depression). Approximately 75% gest an etiology (Table 16). Although exercise-induced dyspnea of patients with PPPD have concomitant anxiety or depressive occurs with most causes of dyspnea, its absence may suggest a symptoms. Diagnosis is typically made on the basis of chronic functional cause. Seasonal or diurnal dyspnea may occur with symptoms without an alternative cause after an appropriate evaluation. TABLE 16. Causes of Dyspnea Based on Symptom Onset Treatment options for PPPD include pharmacologic ther- and Progression

of gait abnormalities and ataxia, such as movement disor- Dyspnea ders (Parkinson disease), peripheral neuropathy, and cere- Dyspnea is a common symptom with a diverse pathophysio- bellar disease (mass lesions) (see MKSAP 19 Neurology). logic basis and substantial variation in patient experience. The Brain MRI in patients with disequilibrium has shown sig- prevalence of dyspnea increases with age; more than one third nificantly more subcortical white-matter lesions and frontal of persons older than 65 years report dyspnea in an ambula- atrophy than in patients without disequilibrium, although tory setting. Dyspnea affects up to half of hospitalized patients the significance of these findings is unclear. and is acommon reason for patients to seek care in urgent and Given the multifactorial nature of disequilibrium, treat- emergent care settings. ment should be multifaceted. Treatment options include visual Dyspnea is caused by multiple underlying neurophysio- and auditory corrective measures (eyeglasses, hearing aids), logic mechanisms, including greater work of breathing, air medication review (to mitigate side effects), mobility aids, phys- hunger, and airway irritation or damage. These mechanisms ical therapy (balance and gait training), weight-bearing and may be triggered by poor functional status, organ-specific resistance exercises, and fall prevention counseling. pathology, medication effects, or physiologic stimuli (includ- ing hypoxia and hypercapnia). Persistent Postural-Perceptual Dizziness Dizziness that remains nonspecific despite a thorough history, Evaluation examination, and evaluation is referred to as persistent The history and physical examination are the most important postural-perceptual dizziness (PPPD) (formerly known as components of the evaluation of dyspnea. An essential aspect chronic subjective dizziness). PPPD is described as persistent, of the history is the patient’s qualitative description of dysp- nonvertiginous dizziness or imbalance that worsens with per- nea, which may aid in the diagnosis. Chest tightness may be sonal motion, upright positioning, and movement of objects in relatively specific for bronchoconstriction, whereas smother- the surrounding environment. Symptoms must be present on ing or suffocating at rest may suggest heart failure. Air hunger most days for at least 3 months. PPPD is often preceded by and “inability to get a deep breath” are commonly associated another vestibular process (BPPV, vestibular neuronitis, ves- with hyperinflation (such as that caused by COPD) or restric- tibular migraine, or stroke), trauma (concussion or traumatic tive conditions (such as pulmonary fibrosis). brain injury), infection, or certain psychiatric conditions (anx- The onset, duration, and progression of dyspnea may sug- iety, panic disorder, or major depression). Approximately 75% gest an etiology (Table 16). Although exercise-induced dyspnea of patients with PPPD have concomitant anxiety or depressive occurs with most causes of dyspnea, its absence may suggest a symptoms. Diagnosis is typically made on the basis of chronic functional cause. Seasonal or diurnal dyspnea may occur with symptoms without an alternative cause after an appropriate evaluation. TABLE 16. Causes of Dyspnea Based on Symptom Onset Treatment options for PPPD include pharmacologic ther- and Progression apies (selective serotonin reuptake inhibitors and serotonin- Symptom Onset Cause norepinephrine reuptake inhibitors) and ongoing VBRT. | and Progression |

of gait abnormalities and ataxia, such as movement disor- Dyspnea ders (Parkinson disease), peripheral neuropathy, and cere- Dyspnea is a common symptom with a diverse pathophysio- bellar disease (mass lesions) (see MKSAP 19 Neurology). logic basis and substantial variation in patient experience. The Brain MRI in patients with disequilibrium has shown sig- prevalence of dyspnea increases with age; more than one third nificantly more subcortical white-matter lesions and frontal of persons older than 65 years report dyspnea in an ambula- atrophy than in patients without disequilibrium, although tory setting. Dyspnea affects up to half of hospitalized patients the significance of these findings is unclear. and is acommon reason for patients to seek care in urgent and Given the multifactorial nature of disequilibrium, treat- emergent care settings. ment should be multifaceted. Treatment options include visual Dyspnea is caused by multiple underlying neurophysio- and auditory corrective measures (eyeglasses, hearing aids), logic mechanisms, including greater work of breathing, air medication review (to mitigate side effects), mobility aids, phys- hunger, and airway irritation or damage. These mechanisms ical therapy (balance and gait training), weight-bearing and may be triggered by poor functional status, organ-specific resistance exercises, and fall prevention counseling. pathology, medication effects, or physiologic stimuli (includ- ing hypoxia and hypercapnia). Persistent Postural-Perceptual Dizziness Dizziness that remains nonspecific despite a thorough history, Evaluation examination, and evaluation is referred to as persistent The history and physical examination are the most important postural-perceptual dizziness (PPPD) (formerly known as components of the evaluation of dyspnea. An essential aspect chronic subjective dizziness). PPPD is described as persistent, of the history is the patient’s qualitative description of dysp- nonvertiginous dizziness or imbalance that worsens with per- nea, which may aid in the diagnosis. Chest tightness may be sonal motion, upright positioning, and movement of objects in relatively specific for bronchoconstriction, whereas smother- the surrounding environment. Symptoms must be present on ing or suffocating at rest may suggest heart failure. Air hunger most days for at least 3 months. PPPD is often preceded by and “inability to get a deep breath” are commonly associated another vestibular process (BPPV, vestibular neuronitis, ves- with hyperinflation (such as that caused by COPD) or restric- tibular migraine, or stroke), trauma (concussion or traumatic tive conditions (such as pulmonary fibrosis). brain injury), infection, or certain psychiatric conditions (anx- The onset, duration, and progression of dyspnea may sug- iety, panic disorder, or major depression). Approximately 75% gest an etiology (Table 16). Although exercise-induced dyspnea of patients with PPPD have concomitant anxiety or depressive occurs with most causes of dyspnea, its absence may suggest a symptoms. Diagnosis is typically made on the basis of chronic functional cause. Seasonal or diurnal dyspnea may occur with symptoms without an alternative cause after an appropriate evaluation. TABLE 16. Causes of Dyspnea Based on Symptom Onset Treatment options for PPPD include pharmacologic ther- and Progression apies (selective serotonin reuptake inhibitors and serotonin- Symptom Onset Cause norepinephrine reuptake inhibitors) and ongoing VBRT. | and Progression | | Sudden onset Acute coronary syndrome

of gait abnormalities and ataxia, such as movement disor- Dyspnea ders (Parkinson disease), peripheral neuropathy, and cere- Dyspnea is a common symptom with a diverse pathophysio- bellar disease (mass lesions) (see MKSAP 19 Neurology). logic basis and substantial variation in patient experience. The Brain MRI in patients with disequilibrium has shown sig- prevalence of dyspnea increases with age; more than one third nificantly more subcortical white-matter lesions and frontal of persons older than 65 years report dyspnea in an ambula- atrophy than in patients without disequilibrium, although tory setting. Dyspnea affects up to half of hospitalized patients the significance of these findings is unclear. and is acommon reason for patients to seek care in urgent and Given the multifactorial nature of disequilibrium, treat- emergent care settings. ment should be multifaceted. Treatment options include visual Dyspnea is caused by multiple underlying neurophysio- and auditory corrective measures (eyeglasses, hearing aids), logic mechanisms, including greater work of breathing, air medication review (to mitigate side effects), mobility aids, phys- hunger, and airway irritation or damage. These mechanisms ical therapy (balance and gait training), weight-bearing and may be triggered by poor functional status, organ-specific resistance exercises, and fall prevention counseling. pathology, medication effects, or physiologic stimuli (includ- ing hypoxia and hypercapnia). Persistent Postural-Perceptual Dizziness Dizziness that remains nonspecific despite a thorough history, Evaluation examination, and evaluation is referred to as persistent The history and physical examination are the most important postural-perceptual dizziness (PPPD) (formerly known as components of the evaluation of dyspnea. An essential aspect chronic subjective dizziness). PPPD is described as persistent, of the history is the patient’s qualitative description of dysp- nonvertiginous dizziness or imbalance that worsens with per- nea, which may aid in the diagnosis. Chest tightness may be sonal motion, upright positioning, and movement of objects in relatively specific for bronchoconstriction, whereas smother- the surrounding environment. Symptoms must be present on ing or suffocating at rest may suggest heart failure. Air hunger most days for at least 3 months. PPPD is often preceded by and “inability to get a deep breath” are commonly associated another vestibular process (BPPV, vestibular neuronitis, ves- with hyperinflation (such as that caused by COPD) or restric- tibular migraine, or stroke), trauma (concussion or traumatic tive conditions (such as pulmonary fibrosis). brain injury), infection, or certain psychiatric conditions (anx- The onset, duration, and progression of dyspnea may sug- iety, panic disorder, or major depression). Approximately 75% gest an etiology (Table 16). Although exercise-induced dyspnea of patients with PPPD have concomitant anxiety or depressive occurs with most causes of dyspnea, its absence may suggest a symptoms. Diagnosis is typically made on the basis of chronic functional cause. Seasonal or diurnal dyspnea may occur with symptoms without an alternative cause after an appropriate evaluation. TABLE 16. Causes of Dyspnea Based on Symptom Onset Treatment options for PPPD include pharmacologic ther- and Progression apies (selective serotonin reuptake inhibitors and serotonin- Symptom Onset Cause norepinephrine reuptake inhibitors) and ongoing VBRT. | and Progression | | Sudden onset Acute coronary syndrome Acute pulmonary embolism HVC e The diagnostic test of choice for benign paroxysmal Spontaneous pneumothorax positional vertigo is the Dix-Hallpike maneuver; routine imaging is not recommended. Gradual onset Interstitial lung disease

Acute pulmonary embolism HVC e The diagnostic test of choice for benign paroxysmal Spontaneous pneumothorax positional vertigo is the Dix-Hallpike maneuver; routine imaging is not recommended. Gradual onset Interstitial lung disease HVC e First-line therapy for benign paroxysmal positional ver- Pulmonary hypertension tigo is canalith repositioning with the Epley maneuver. Neuromuscular disease e Patients with central vertigo often display focal neu- COPD rologic findings, but approximately 20% of patients Intermittent onset Aspiration with vertebrobasilar stroke present with isolated Asthma vertigo. Gastroesophageal reflux disease e Evaluation of patients with vertigo includes an in-depth Heart failure neurologic assessment and, in the case of acute persis- Progressive symptoms Anemia tent vertigo, the HINTS (Head Impulse, Nystagmus, and COPD Test of Skew) oculomotor assessment. Heart failure e Treatment options for disequilibrium include visual and auditory corrective measures, medication changes, Interstitial lung disease mobility aids, physical therapy, weight-bearing and Cancer resistance exercises, and fall prevention counseling. | Pneumonia 26

Common Symptoms asthma, and worsening during the winter months is often devices that enhance airflow are the least invasive and easiest associated with COPD. to administer. Pulmonary rehabilitation provides significant Worsening of dyspnea with positional changes can pro- benefit for patients with chronic lung disease and improves vide useful clues. Orthopnea suggests heart failure, whereas dyspnea in patients with COPD; exercise is the component breathlessness relieved by lying down (platypnea-orthode- primarily responsible for symptom relief. oxia) suggests hepatopulmonary syndrome or a large patent Oxygen therapy improves survival and quality of life in foramen ovale. Dyspnea when lying on one side (trepopnea) patients with hypoxemia and COPD. However, the role of sup- has been associated with decompensated heart failure, dia- plemental oxygen in patients without hypoxemia is less clear. phragmatic paralysis, and severe tricuspid regurgitation. Opioids are an effective therapy for patients with dysp- Nocturnal dyspnea may suggest asthma, heart failure, or nea refractory to nonpharmacologic therapies and maximal GERD. The onset of dyspnea when leaning forward (bendo- medical management of the underlying disease. Opioids pnea), such as when tying shoelaces, is a newly described appear to exert an antidyspneic effect through modulation of symptom of heart failure. sensory input in the central nervous system, similar to how A thorough evaluation for associated symptoms may fur- they modulate pain signaling. Although opioids affect respira- ther narrow the differential diagnosis. For example, a produc- tory mechanics and may blunt respiratory drive, appropri- tive cough may characterize COPD and pneumonia, and a dry ately dosed opioids do not cause respiratory depression if cough can be associated with interstitial lung diseases and treatment is symptom directed. Patient selection and subse- cough-variant asthma. A nocturnal cough may suggest GERD quent opioid selection should be based on symptom burden, or asthma. Chest tightness or pressure may signal acute coro- underlying disease, comorbid organ dysfunction, and overall nary syndrome or pulmonary embolism. Unilateral or pleu- risk for respiratory depression. Although systemic opioids ritic chest pain suggests pulmonary embolism, pneumonia, or have shown clear benefit in treating refractory dyspnea, other pleural-based conditions (e.g., pneumothorax). inhaled opioids have not shown efficacy in several placebo- In the absence of an obvious etiology, the initial evalua- controlled trials. Other therapies found to be ineffective or tion may include measurement of oxygen saturation and lacking in sufficient data to recommend their use include hemoglobin, ECG, and chest radiography. In the correct clini- anxiolytics, antidepressants, phenothiazines, indomethacin, cal scenario, B-type natriuretic peptide or N-terminal pro-B- nitrous oxide, and sodium bicarbonate. type natriuretic peptide levels are useful for ruling out heart Management of dyspnea in patients with serious illness is failure. In patients with predicted low or intermediate risk for discussed in Palliative Medicine. pulmonary embolism, an age-adjusted D-dimer cutoff is use- ful for ruling out this condition. Echocardiography is indicated e In patients with dyspnea, point-of-care lung ultra- for the evaluation of dyspnea of suspected cardiac origin. sonography is an accurate means of rapidly detecting Point-of-care lung ultrasonography is an accurate means of pleural effusion, interstitial syndromes (e.g., pulmonary rapidly detecting pleural effusion, interstitial syndrome (e.g., edema, acute respiratory distress syndrome), alveolar pulmonary edema, acute respiratory distress syndrome), alve- consolidation, and pneumothorax, and it is safer and olar consolidation, and pneumothorax. Advanced imaging of less expensive than radiography and CT. the cardiac or pulmonary systems should be pursued only when the initial evaluation reveals a reasonable likelihood of ¢ Cardiopulmonary exercise testing can be helpful in the

asthma, and worsening during the winter months is often devices that enhance airflow are the least invasive and easiest associated with COPD. to administer. Pulmonary rehabilitation provides significant Worsening of dyspnea with positional changes can pro- benefit for patients with chronic lung disease and improves vide useful clues. Orthopnea suggests heart failure, whereas dyspnea in patients with COPD; exercise is the component breathlessness relieved by lying down (platypnea-orthode- primarily responsible for symptom relief. oxia) suggests hepatopulmonary syndrome or a large patent Oxygen therapy improves survival and quality of life in foramen ovale. Dyspnea when lying on one side (trepopnea) patients with hypoxemia and COPD. However, the role of sup- has been associated with decompensated heart failure, dia- plemental oxygen in patients without hypoxemia is less clear. phragmatic paralysis, and severe tricuspid regurgitation. Opioids are an effective therapy for patients with dysp- Nocturnal dyspnea may suggest asthma, heart failure, or nea refractory to nonpharmacologic therapies and maximal GERD. The onset of dyspnea when leaning forward (bendo- medical management of the underlying disease. Opioids pnea), such as when tying shoelaces, is a newly described appear to exert an antidyspneic effect through modulation of symptom of heart failure. sensory input in the central nervous system, similar to how A thorough evaluation for associated symptoms may fur- they modulate pain signaling. Although opioids affect respira- ther narrow the differential diagnosis. For example, a produc- tory mechanics and may blunt respiratory drive, appropri- tive cough may characterize COPD and pneumonia, and a dry ately dosed opioids do not cause respiratory depression if cough can be associated with interstitial lung diseases and treatment is symptom directed. Patient selection and subse- cough-variant asthma. A nocturnal cough may suggest GERD quent opioid selection should be based on symptom burden, or asthma. Chest tightness or pressure may signal acute coro- underlying disease, comorbid organ dysfunction, and overall nary syndrome or pulmonary embolism. Unilateral or pleu- risk for respiratory depression. Although systemic opioids ritic chest pain suggests pulmonary embolism, pneumonia, or have shown clear benefit in treating refractory dyspnea, other pleural-based conditions (e.g., pneumothorax). inhaled opioids have not shown efficacy in several placebo- In the absence of an obvious etiology, the initial evalua- controlled trials. Other therapies found to be ineffective or tion may include measurement of oxygen saturation and lacking in sufficient data to recommend their use include hemoglobin, ECG, and chest radiography. In the correct clini- anxiolytics, antidepressants, phenothiazines, indomethacin, cal scenario, B-type natriuretic peptide or N-terminal pro-B- nitrous oxide, and sodium bicarbonate. type natriuretic peptide levels are useful for ruling out heart Management of dyspnea in patients with serious illness is failure. In patients with predicted low or intermediate risk for discussed in Palliative Medicine. pulmonary embolism, an age-adjusted D-dimer cutoff is use- ful for ruling out this condition. Echocardiography is indicated e In patients with dyspnea, point-of-care lung ultra- for the evaluation of dyspnea of suspected cardiac origin. sonography is an accurate means of rapidly detecting Point-of-care lung ultrasonography is an accurate means of pleural effusion, interstitial syndromes (e.g., pulmonary rapidly detecting pleural effusion, interstitial syndrome (e.g., edema, acute respiratory distress syndrome), alveolar pulmonary edema, acute respiratory distress syndrome), alve- consolidation, and pneumothorax, and it is safer and olar consolidation, and pneumothorax. Advanced imaging of less expensive than radiography and CT. the cardiac or pulmonary systems should be pursued only when the initial evaluation reveals a reasonable likelihood of ¢ Cardiopulmonary exercise testing can be helpful in the disease. Cardiopulmonary exercise testing can be helpful ifthe evaluation of dyspnea if the initial evaluation is unre- initial evaluation is unrevealing, deconditioning is a possibil- vealing, deconditioning is a possibility, or multiple ity, or multiple problems may be contributing to dyspnea. problems may be contributing to dyspnea. Referral to a cardiologist or pulmonologist may be appropriate when the diagnosis remains elusive or when conditions Fatigue and Systemic Exertion require subspecialized input. Intolerance Disease Management Fatigue is a truly subjective symptom, with little to no corrobo- Initial management strategies are aimed at treating or modify- rating objective measures. It can be described as tiredness, ing the patient’s dyspnea generator and underlying disease exhaustion, reduction in endurance, or lack of physical or men- state. In patients with chronic conditions, the first step in tal energy. Fatigue may be categorized as acute (<1 month’s dura- reducing dyspnea is to maximize standard therapies, with tion), subacute (1-6 months’ duration), or chronic (>6 months’ regular assessment of symptom response. duration). In patients with persistent debilitating symptoms despite Fatigue occurs in one quarter to one third of patients in maximal medical therapy, there are nonpharmacologic and the primary care setting. Despite its high prevalence, the cause pharmacologic strategies to reduce dyspnea severity, each is often elusive, leading to prolonged delays in diagnosis, with varying levels of evidence. Of these therapies, pursed substantial functional decline, and high direct and indirect lip breathing, diaphragmatic breathing, handheld fans, and societal costs.

disease. Cardiopulmonary exercise testing can be helpful ifthe evaluation of dyspnea if the initial evaluation is unre- initial evaluation is unrevealing, deconditioning is a possibil- vealing, deconditioning is a possibility, or multiple ity, or multiple problems may be contributing to dyspnea. problems may be contributing to dyspnea. Referral to a cardiologist or pulmonologist may be appropriate when the diagnosis remains elusive or when conditions Fatigue and Systemic Exertion require subspecialized input. Intolerance Disease Management Fatigue is a truly subjective symptom, with little to no corrobo- Initial management strategies are aimed at treating or modify- rating objective measures. It can be described as tiredness, ing the patient’s dyspnea generator and underlying disease exhaustion, reduction in endurance, or lack of physical or men- state. In patients with chronic conditions, the first step in tal energy. Fatigue may be categorized as acute (<1 month’s dura- reducing dyspnea is to maximize standard therapies, with tion), subacute (1-6 months’ duration), or chronic (>6 months’ regular assessment of symptom response. duration). In patients with persistent debilitating symptoms despite Fatigue occurs in one quarter to one third of patients in maximal medical therapy, there are nonpharmacologic and the primary care setting. Despite its high prevalence, the cause pharmacologic strategies to reduce dyspnea severity, each is often elusive, leading to prolonged delays in diagnosis, with varying levels of evidence. Of these therapies, pursed substantial functional decline, and high direct and indirect lip breathing, diaphragmatic breathing, handheld fans, and societal costs. 27

Common Symptoms Evaluation lymphadenopathy, muscle atrophy, and synovitis). Patients Fatigue is most often secondary to a specific underlying cause should be assessed for an underlying sleep disorder as well. (Table 17) or multiple factors (termed chronic multifactorial Diagnostic testing choices should be driven by the history fatigue). It can occur as a primary condition, such as in sys- and physical examination findings. In patients with fatigue temic exertion intolerance disease, although this is a diagnosis without a clear cause, it is reasonable to obtain a complete of exclusion. The diagnostic evaluation of fatigue begins with blood count, electrolyte panel, thyroid-stimulating hormone a careful history and physical examination. Clinicians should level, fasting glucose level, and kidney and liver chemistry note the duration, preceding factors, concomitant symptoms, tests. Laboratory, imaging, and invasive studies without a clear prolonged deleterious lifestyle factors, medication use, and the indication should be avoided because most patients will have presence of “red flag” signs or symptoms that suggest a serious unrevealing or contradictory findings that provide little reas- underlying etiology (fever, involuntary weight loss, persistent surance to the patient or clinician. Some patients experience progressive, debilitating fatigue with no identifiable cause despite an appropriate evaluation. In TABLE 17. Common Causes of Fatigue the past, this condition was termed chronic fatigue syndrome, | Lifestyle myalgic encephalitis, or neurasthenia. Each of these diagnoses

underlying etiology (fever, involuntary weight loss, persistent surance to the patient or clinician. Some patients experience progressive, debilitating fatigue with no identifiable cause despite an appropriate evaluation. In TABLE 17. Common Causes of Fatigue the past, this condition was termed chronic fatigue syndrome, | Lifestyle myalgic encephalitis, or neurasthenia. Each of these diagnoses | Alcohol had different criteria, creating inconsistencies in diagnosis and treatment. In 2015, the Institute of Medicine issued an exten- Chemical dependency (overuse and withdrawal) | sive guideline establishing evidence-based, consensus-based Extremes of activity clinical diagnostic criteria under the consolidated term of sys- Frequent travel (jet lag) temic exertion intolerance disease (SEID). Diagnosis of SEID | Night shift work requires the presence of all of the following three symptoms: Work/life imbalance | e A substantial reduction or impairment in the ability to Medical engage in pre-illness levels of occupational, educational,

Night shift work requires the presence of all of the following three symptoms: Work/life imbalance | e A substantial reduction or impairment in the ability to Medical engage in pre-illness levels of occupational, educational, social, or personal activities that persists for more than Anemia 6 months and is accompanied by fatigue, which is often Cancer profound, is of new or definite onset (not lifelong), is not Chronic kidney disease the result of ongoing excessive exertion, and is not sub- Chronic liver disease stantially alleviated by rest Chronic lung disease, hypoxemia e Postexertional malaise Heart failure e Unrefreshing sleep HIV/AIDS In addition, the patient must have at least one of the fol- Hyperglycemia, uncontrolled diabetes mellitus lowing two manifestations: | Medication side effects ¢ Cognitive impairment Antidepressants ¢ Orthostatic intolerance (symptoms such as lightheaded- | Antihistamines ness, dizziness, and headache that worsen with upright | Antipsychotics posture and improve with recumbency)

social, or personal activities that persists for more than Anemia 6 months and is accompanied by fatigue, which is often Cancer profound, is of new or definite onset (not lifelong), is not Chronic kidney disease the result of ongoing excessive exertion, and is not sub- Chronic liver disease stantially alleviated by rest Chronic lung disease, hypoxemia e Postexertional malaise Heart failure e Unrefreshing sleep HIV/AIDS In addition, the patient must have at least one of the fol- Hyperglycemia, uncontrolled diabetes mellitus lowing two manifestations: | Medication side effects ¢ Cognitive impairment Antidepressants ¢ Orthostatic intolerance (symptoms such as lightheaded- | Antihistamines ness, dizziness, and headache that worsen with upright | Antipsychotics posture and improve with recumbency) | Benzodiazepines Although the pathophysiology of SEID remains unclear, | B-Blockers central sensitization is thought to contribute to SEID, which

social, or personal activities that persists for more than Anemia 6 months and is accompanied by fatigue, which is often Cancer profound, is of new or definite onset (not lifelong), is not Chronic kidney disease the result of ongoing excessive exertion, and is not sub- Chronic liver disease stantially alleviated by rest Chronic lung disease, hypoxemia e Postexertional malaise Heart failure e Unrefreshing sleep HIV/AIDS In addition, the patient must have at least one of the fol- Hyperglycemia, uncontrolled diabetes mellitus lowing two manifestations: | Medication side effects ¢ Cognitive impairment Antidepressants ¢ Orthostatic intolerance (symptoms such as lightheaded- | Antihistamines ness, dizziness, and headache that worsen with upright | Antipsychotics posture and improve with recumbency) | Benzodiazepines Although the pathophysiology of SEID remains unclear, | B-Blockers central sensitization is thought to contribute to SEID, which | Opioids may explain the high prevalence of comorbid conditions, such as fibromyalgia, mood disturbances, irritable bowel syndrome, | Obesity and interstitial cystitis (see Medically Unexplained Symptoms | Thyroid disorder (hyper- and hypothyroidism) for further discussion of central sensitization). Studies have Psychological demonstrated alterations in the function of immune cells, Anxiety particularly natural killer cells, in patients with SEID; how-

| Opioids may explain the high prevalence of comorbid conditions, such as fibromyalgia, mood disturbances, irritable bowel syndrome, | Obesity and interstitial cystitis (see Medically Unexplained Symptoms | Thyroid disorder (hyper- and hypothyroidism) for further discussion of central sensitization). Studies have Psychological demonstrated alterations in the function of immune cells, Anxiety particularly natural killer cells, in patients with SEID; how- Depression ever, these changes are thought to be a biomarker of the dis- ease rather than the cause. There is no convincing evidence | Stress that indolent chronic infection plays a role. | Sleep Mood disorders often occur concomitantly in patients with | Poor sleep habits SEID (approximately 70% of patients), and all patients with Restless legs syndrome SEID should be screened for depression and anxiety. In addi- Sleep apnea tion, clinicians should ensure that all age-appropriate screening has been performed. Sleep disorders can coexist with SEID and Sleep deprivation do not invalidate a diagnosis of SEID if identified. 28

Common Symptoms Management Insomnia Treatment of fatigue should focus on correcting any underlying Insomnia is a complex health problem manifesting as poor causes. In patients with SEID, the goals of treatment shift to sleep quality, frustration with sleep quantity, difficulty initiat- functional rehabilitation and restoration. Patients benefit most ing sleep, or inability to return to sleep after awakening. The from a structured multimodal approach that includes regularly prevalence of insomnia increases with age, and women tend to scheduled office visits, patient education, and longitudinal reas- be affected more than are men. Medical disorders, including sessment. Cognitive behavioral therapy (CBT) and graded exer- cardiopulmonary diseases, neurodegenerative disorders, and cise therapy may decrease fatigue and improve function, and psychiatric disorders, are often implicated in sleep disruption. these therapies should be offered to all patients. Pacing Medications and other substances, such as caffeine, alcohol, strategies, in which specific limits are placed on the degree of glucocorticoids, diuretics, and antidepressants, also com- exertion, may help patients avoid “push-and-crash” cycles monly contribute to symptoms of insomnia. (overexertion resulting in worsening of symptoms, known as Chronic insomnia is diagnosed by the presence of symp- postexertional malaise). All patients should also receive instruc- toms that (1) cause substantial functional distress or impair- tion on effective sleep hygiene. Other modalities that may be of ment; (2) occur at least 3 nights per week for at least 3 months; benefit include physical therapy, occupational therapy, biofeed- and (3) are not associated with other sleep, medical, or mental back therapy, massage therapy, acupuncture, yoga, tai chi, and disorders. Although 1 in 10 adults meet the diagnostic criteria stress management activities. In patients with mood disorders, for chronic insomnia, some studies have shown that up to 50% referral to a psychiatrist or psychologist is reasonable. of adults report experiencing sleep problems. There are no FDA-approved medications for the treat- ment of SEID, and no medications have shown consistent, Evaluation reproducible benefit. Medical therapy is typically limited to All patients should be asked about problems of sleep disrup- the treatment of comorbid conditions (e.g., depression). tion, given the wide range of affected patients and the sub- Despite evidence of cytokine activation and altered immune stantial impact insufficient sleep can have on function. In system function, randomized trials targeting these pathways patients with symptoms of insomnia, a thorough history and with immunomodulators, such as anakinra or rituximab, have physical examination may point to potentially reversible failed to demonstrate benefit in patients with SEID. There is no causes, such as sleep apnea or restless legs syndrome. consistent evidence that stimulants (including ampheta- Eliciting an accurate medication history, including use of mines), opioids, glucocorticoids, pharmacologic sleep aids, over-the-counter medications, herbal supplements, caf- prolonged antibiotics or antiviral agents, or immunotherapies feine, alcohol, tobacco, and illicit drugs, is also an important improve symptoms or disease course. part of the diagnostic approach. Physicians should obtain The prognosis for SEID varies and is often a source of information on sleep pattern, including sleep difficulties frustration for patients and physicians alike. It depends on (sleep initiation, sleep maintenance, sleep quality) and envi- many factors, including patient age, formal education level, ronmental factors (work schedule). Use of electronics should severity and duration of symptoms, decline in functional sta- be assessed, because there is increasing evidence that screen tus relative to premorbid level of functioning, presence of time, such as smartphone and tablet use, before bed can other somatic (or medically unexplained) symptoms, comor- alter circadian patterns and increase insomnia symptoms. A bid mood disorders, availability of resources, and adherence to sleep diary can facilitate collection of an accurate sleep his- the treatment recommendations. tory, and obtaining a collateral history from the patient’s sleep partner may shed light on specific sleep-related disor- ¢ In patients with fatigue without a clear cause, it is rea- ders. Use of the Insomnia Severity Index or the Athens

Management Insomnia Treatment of fatigue should focus on correcting any underlying Insomnia is a complex health problem manifesting as poor causes. In patients with SEID, the goals of treatment shift to sleep quality, frustration with sleep quantity, difficulty initiat- functional rehabilitation and restoration. Patients benefit most ing sleep, or inability to return to sleep after awakening. The from a structured multimodal approach that includes regularly prevalence of insomnia increases with age, and women tend to scheduled office visits, patient education, and longitudinal reas- be affected more than are men. Medical disorders, including sessment. Cognitive behavioral therapy (CBT) and graded exer- cardiopulmonary diseases, neurodegenerative disorders, and cise therapy may decrease fatigue and improve function, and psychiatric disorders, are often implicated in sleep disruption. these therapies should be offered to all patients. Pacing Medications and other substances, such as caffeine, alcohol, strategies, in which specific limits are placed on the degree of glucocorticoids, diuretics, and antidepressants, also com- exertion, may help patients avoid “push-and-crash” cycles monly contribute to symptoms of insomnia. (overexertion resulting in worsening of symptoms, known as Chronic insomnia is diagnosed by the presence of symp- postexertional malaise). All patients should also receive instruc- toms that (1) cause substantial functional distress or impair- tion on effective sleep hygiene. Other modalities that may be of ment; (2) occur at least 3 nights per week for at least 3 months; benefit include physical therapy, occupational therapy, biofeed- and (3) are not associated with other sleep, medical, or mental back therapy, massage therapy, acupuncture, yoga, tai chi, and disorders. Although 1 in 10 adults meet the diagnostic criteria stress management activities. In patients with mood disorders, for chronic insomnia, some studies have shown that up to 50% referral to a psychiatrist or psychologist is reasonable. of adults report experiencing sleep problems. There are no FDA-approved medications for the treat- ment of SEID, and no medications have shown consistent, Evaluation reproducible benefit. Medical therapy is typically limited to All patients should be asked about problems of sleep disrup- the treatment of comorbid conditions (e.g., depression). tion, given the wide range of affected patients and the sub- Despite evidence of cytokine activation and altered immune stantial impact insufficient sleep can have on function. In system function, randomized trials targeting these pathways patients with symptoms of insomnia, a thorough history and with immunomodulators, such as anakinra or rituximab, have physical examination may point to potentially reversible failed to demonstrate benefit in patients with SEID. There is no causes, such as sleep apnea or restless legs syndrome. consistent evidence that stimulants (including ampheta- Eliciting an accurate medication history, including use of mines), opioids, glucocorticoids, pharmacologic sleep aids, over-the-counter medications, herbal supplements, caf- prolonged antibiotics or antiviral agents, or immunotherapies feine, alcohol, tobacco, and illicit drugs, is also an important improve symptoms or disease course. part of the diagnostic approach. Physicians should obtain The prognosis for SEID varies and is often a source of information on sleep pattern, including sleep difficulties frustration for patients and physicians alike. It depends on (sleep initiation, sleep maintenance, sleep quality) and envi- many factors, including patient age, formal education level, ronmental factors (work schedule). Use of electronics should severity and duration of symptoms, decline in functional sta- be assessed, because there is increasing evidence that screen tus relative to premorbid level of functioning, presence of time, such as smartphone and tablet use, before bed can other somatic (or medically unexplained) symptoms, comor- alter circadian patterns and increase insomnia symptoms. A bid mood disorders, availability of resources, and adherence to sleep diary can facilitate collection of an accurate sleep his- the treatment recommendations. tory, and obtaining a collateral history from the patient’s sleep partner may shed light on specific sleep-related disor- ¢ In patients with fatigue without a clear cause, it is rea- ders. Use of the Insomnia Severity Index or the Athens sonable to obtain a complete blood count, electrolyte Insomnia Scale can be helpful as part of a comprehensive

Management Insomnia Treatment of fatigue should focus on correcting any underlying Insomnia is a complex health problem manifesting as poor causes. In patients with SEID, the goals of treatment shift to sleep quality, frustration with sleep quantity, difficulty initiat- functional rehabilitation and restoration. Patients benefit most ing sleep, or inability to return to sleep after awakening. The from a structured multimodal approach that includes regularly prevalence of insomnia increases with age, and women tend to scheduled office visits, patient education, and longitudinal reas- be affected more than are men. Medical disorders, including sessment. Cognitive behavioral therapy (CBT) and graded exer- cardiopulmonary diseases, neurodegenerative disorders, and cise therapy may decrease fatigue and improve function, and psychiatric disorders, are often implicated in sleep disruption. these therapies should be offered to all patients. Pacing Medications and other substances, such as caffeine, alcohol, strategies, in which specific limits are placed on the degree of glucocorticoids, diuretics, and antidepressants, also com- exertion, may help patients avoid “push-and-crash” cycles monly contribute to symptoms of insomnia. (overexertion resulting in worsening of symptoms, known as Chronic insomnia is diagnosed by the presence of symp- postexertional malaise). All patients should also receive instruc- toms that (1) cause substantial functional distress or impair- tion on effective sleep hygiene. Other modalities that may be of ment; (2) occur at least 3 nights per week for at least 3 months; benefit include physical therapy, occupational therapy, biofeed- and (3) are not associated with other sleep, medical, or mental back therapy, massage therapy, acupuncture, yoga, tai chi, and disorders. Although 1 in 10 adults meet the diagnostic criteria stress management activities. In patients with mood disorders, for chronic insomnia, some studies have shown that up to 50% referral to a psychiatrist or psychologist is reasonable. of adults report experiencing sleep problems. There are no FDA-approved medications for the treat- ment of SEID, and no medications have shown consistent, Evaluation reproducible benefit. Medical therapy is typically limited to All patients should be asked about problems of sleep disrup- the treatment of comorbid conditions (e.g., depression). tion, given the wide range of affected patients and the sub- Despite evidence of cytokine activation and altered immune stantial impact insufficient sleep can have on function. In system function, randomized trials targeting these pathways patients with symptoms of insomnia, a thorough history and with immunomodulators, such as anakinra or rituximab, have physical examination may point to potentially reversible failed to demonstrate benefit in patients with SEID. There is no causes, such as sleep apnea or restless legs syndrome. consistent evidence that stimulants (including ampheta- Eliciting an accurate medication history, including use of mines), opioids, glucocorticoids, pharmacologic sleep aids, over-the-counter medications, herbal supplements, caf- prolonged antibiotics or antiviral agents, or immunotherapies feine, alcohol, tobacco, and illicit drugs, is also an important improve symptoms or disease course. part of the diagnostic approach. Physicians should obtain The prognosis for SEID varies and is often a source of information on sleep pattern, including sleep difficulties frustration for patients and physicians alike. It depends on (sleep initiation, sleep maintenance, sleep quality) and envi- many factors, including patient age, formal education level, ronmental factors (work schedule). Use of electronics should severity and duration of symptoms, decline in functional sta- be assessed, because there is increasing evidence that screen tus relative to premorbid level of functioning, presence of time, such as smartphone and tablet use, before bed can other somatic (or medically unexplained) symptoms, comor- alter circadian patterns and increase insomnia symptoms. A bid mood disorders, availability of resources, and adherence to sleep diary can facilitate collection of an accurate sleep his- the treatment recommendations. tory, and obtaining a collateral history from the patient’s sleep partner may shed light on specific sleep-related disor- ¢ In patients with fatigue without a clear cause, it is rea- ders. Use of the Insomnia Severity Index or the Athens sonable to obtain a complete blood count, electrolyte Insomnia Scale can be helpful as part of a comprehensive panel, thyroid-stimulating hormone level, fasting glu- sleep assessment. cose level, and kidney and liver chemistry tests. Diagnostic testing, such as polysomnography, is not a

sonable to obtain a complete blood count, electrolyte Insomnia Scale can be helpful as part of a comprehensive panel, thyroid-stimulating hormone level, fasting glu- sleep assessment. cose level, and kidney and liver chemistry tests. Diagnostic testing, such as polysomnography, is not a first-line approach and is useful only when the clinical presen- HVC e Patients with systemic exertion intolerance disease ben- tation is suggestive of a sleep disorder, such as sleep apnea, efit most from a structured, multimodal approach that narcolepsy, or sleep movement disorder (see Sleep Medicine in includes regularly scheduled office visits; cognitive MKSAP 19 Pulmonary and Critical Care Medicine). behavioral therapy and graded exercise therapy may decrease fatigue and improve function and should be offered to all patients. Treatment The goals of treatment are to improve overall sleep and quality e There are no FDA-approved medications for the treat- of life. Effective treatment programs are multimodal in their ment of systemic exertion intolerance disease, and approach and include CBT for insomnia (CBT-I); sleep hygiene medical therapy is limited to the management of techniques; environmental changes; and, in poorly controlled comorbid conditions. cases, pharmacologic therapy. 29

Common Symptoms Nonpharmacologic Therapy sleep time (Table 19), but few studies have examined their overall CBT-I is recommended as first-line therapy for insomnia. This effect on functioning and quality of life. Pharmacologic therapy is

Common Symptoms Nonpharmacologic Therapy sleep time (Table 19), but few studies have examined their overall CBT-I is recommended as first-line therapy for insomnia. This effect on functioning and quality of life. Pharmacologic therapy is multicomponent treatment includes cognitive therapy (to also associated with harms, including daytime drowsiness, address maladaptive beliefs and expectations about sleep), increased risk for falls and hip fracture, and medication-related educational interventions (such as sleep hygiene), and behav- hallucinations. Factors that should be considered before initiating ioral interventions (such as sleep restriction therapy, stimulus- pharmacologic therapy for insomnia are included in Table 20. control therapy, and relaxation techniques). CBT-I may be Ideally, medications should be taken in short-term trials (no more delivered in various formats, such as individual or group ther- than 4-5 weeks) and should be selected to target the most prob- apy, web-based modules, or written materials. CBT-I provides lematic phase of sleep (onset versus maintenance). significant value over pharmacologic-driven approaches and Benzodiazepines induce sedation by activating inhibitory carries little risk for adverse effects. y-aminobutyric acid (GABA) receptors. These drugs decrease Brief behavioral therapy for insomnia is an abbreviated sleep latency and have a sleep-promoting effect. The associ- version of CBT-I, focusing on the behavioral components of ated risk for rebound insomnia, addiction potential, and seda- sleep restriction, stimulus control, and sleep hygiene only. It is tion make benzodiazepines poor candidates for treatment of more convenient for many patients and of greater value than insomnia, particularly in combination with other sedating pharmacologic therapy. agents (including opioids) and in geriatric populations. Sleep hygiene strategies focus on optimizing environmen- Nonbenzodiazepine GABA-receptor agonists are typically tal factors and reducing stimuli (Table 18). Blue-light-filtering more selective in their activity at the GABA receptor. These glasses or software programs are frequently used by the gen- agents (zolpidem, eszopiclone, and zaleplon) have a rapid eral public, but their effectiveness has not been established. onset of action and short half-life, making them better choices Sleep hygiene education has not been shown to be effective as for patients with difficulty initiating sleep. Long-acting for- a standalone therapy for chronic insomnia. Sleep restriction mulations and formulations meant for use with middle-of- therapy, which entails limiting the amount of time in bed to the-night awakenings also are available. There is potential for increase sleep efficiency, also may be used. prolonged impaired driving skills, somnolence, and amnesia with use of zolpidem, eszopiclone, and zaleplon, and reports Pharmacologic Therapy of serious or fatal injuries associated with complex sleep Physicians should engage in a thorough shared decision-making behaviors prompted the FDA to issue a boxed warning for process to decide whether to add pharmacologic therapy to CBT-I these agents. Few data on long-term safety or efficacy are in patients with refractory insomnia. Several pharmacologic available, and long-term therapy should be avoided. There are agents have been demonstrated to improve sleep latency and total few choices for long-term pharmacologic treatment of chronic insomnia, although very-low-dose doxepin may be effective. TABLE 18. Techniques for Good Sleep Hygiene The melatonin receptor agonist ramelteon can decrease sleep latency and increase total sleep time, although the effect During the Day is modest and can be measured in minutes. Side effects are less | Ensure adequate exposure to natural light common with ramelteon than with GABA-receptor agonists. | Avoid napping Patients frequently use over-the-counter medications for | Avoid the following close to bedtime: insomnia, including anticholinergic and antihistamine medica- | Substances that may fragment sleep (caffeine, nicotine, tions and melatonin. Evidence supporting over-the-counter sleep | alcohol, pseudoephedrine) aid use is limited, and the American Academy of Sleep Medicine Vigorous exercise found insufficient evidence to recommend any over-the-counter | | Large meals medication because of associated anticholinergic side effects and carry-over daytime sleepiness. In addition, there is a growing Emotionally upsetting activities or conversations body of evidence linking long-term anticholinergic use to an | At Bedtime increased risk for dementia. Antihistamines should be avoided in Establish a regular relaxing bedtime routine (30 minutes) older adults, in whom the risk for side effects is magnified. Over- | | Associate the bed and the bedroom with sleep the-counter melatonin may be effective for circadian rhythm

multicomponent treatment includes cognitive therapy (to also associated with harms, including daytime drowsiness, address maladaptive beliefs and expectations about sleep), increased risk for falls and hip fracture, and medication-related educational interventions (such as sleep hygiene), and behav- hallucinations. Factors that should be considered before initiating ioral interventions (such as sleep restriction therapy, stimulus- pharmacologic therapy for insomnia are included in Table 20. control therapy, and relaxation techniques). CBT-I may be Ideally, medications should be taken in short-term trials (no more delivered in various formats, such as individual or group ther- than 4-5 weeks) and should be selected to target the most prob- apy, web-based modules, or written materials. CBT-I provides lematic phase of sleep (onset versus maintenance). significant value over pharmacologic-driven approaches and Benzodiazepines induce sedation by activating inhibitory carries little risk for adverse effects. y-aminobutyric acid (GABA) receptors. These drugs decrease Brief behavioral therapy for insomnia is an abbreviated sleep latency and have a sleep-promoting effect. The associ- version of CBT-I, focusing on the behavioral components of ated risk for rebound insomnia, addiction potential, and seda- sleep restriction, stimulus control, and sleep hygiene only. It is tion make benzodiazepines poor candidates for treatment of more convenient for many patients and of greater value than insomnia, particularly in combination with other sedating pharmacologic therapy. agents (including opioids) and in geriatric populations. Sleep hygiene strategies focus on optimizing environmen- Nonbenzodiazepine GABA-receptor agonists are typically tal factors and reducing stimuli (Table 18). Blue-light-filtering more selective in their activity at the GABA receptor. These glasses or software programs are frequently used by the gen- agents (zolpidem, eszopiclone, and zaleplon) have a rapid eral public, but their effectiveness has not been established. onset of action and short half-life, making them better choices Sleep hygiene education has not been shown to be effective as for patients with difficulty initiating sleep. Long-acting for- a standalone therapy for chronic insomnia. Sleep restriction mulations and formulations meant for use with middle-of- therapy, which entails limiting the amount of time in bed to the-night awakenings also are available. There is potential for increase sleep efficiency, also may be used. prolonged impaired driving skills, somnolence, and amnesia with use of zolpidem, eszopiclone, and zaleplon, and reports Pharmacologic Therapy of serious or fatal injuries associated with complex sleep Physicians should engage in a thorough shared decision-making behaviors prompted the FDA to issue a boxed warning for process to decide whether to add pharmacologic therapy to CBT-I these agents. Few data on long-term safety or efficacy are in patients with refractory insomnia. Several pharmacologic available, and long-term therapy should be avoided. There are agents have been demonstrated to improve sleep latency and total few choices for long-term pharmacologic treatment of chronic insomnia, although very-low-dose doxepin may be effective. TABLE 18. Techniques for Good Sleep Hygiene The melatonin receptor agonist ramelteon can decrease sleep latency and increase total sleep time, although the effect During the Day is modest and can be measured in minutes. Side effects are less | Ensure adequate exposure to natural light common with ramelteon than with GABA-receptor agonists. | Avoid napping Patients frequently use over-the-counter medications for | Avoid the following close to bedtime: insomnia, including anticholinergic and antihistamine medica- | Substances that may fragment sleep (caffeine, nicotine, tions and melatonin. Evidence supporting over-the-counter sleep | alcohol, pseudoephedrine) aid use is limited, and the American Academy of Sleep Medicine Vigorous exercise found insufficient evidence to recommend any over-the-counter | | Large meals medication because of associated anticholinergic side effects and carry-over daytime sleepiness. In addition, there is a growing Emotionally upsetting activities or conversations body of evidence linking long-term anticholinergic use to an | At Bedtime increased risk for dementia. Antihistamines should be avoided in Establish a regular relaxing bedtime routine (30 minutes) older adults, in whom the risk for side effects is magnified. Over- | | Associate the bed and the bedroom with sleep the-counter melatonin may be effective for circadian rhythm Keep the bedroom quiet and dark disruptions and has a more favorable side effect profile than antihistamines, but data supporting its efficacy are poor. Keep stable bedtime and arising time | | Spend no more than 20 minutes awake in bed

Keep the bedroom quiet and dark disruptions and has a more favorable side effect profile than antihistamines, but data supporting its efficacy are poor. Keep stable bedtime and arising time | | Spend no more than 20 minutes awake in bed Spend no more than 8 hours in bed ¢ Diagnostic testing, such as polysomnography, is usually HVC Avoid screen time (use oftelevision, computer/tablet, or phone) | unnecessary in the evaluation of insomnia unless the | Information from Masters PA. In the clinic. Insomnia. Ann Intern Med. clinical presentation is suggestive of a sleep disorder. | 2014;161:ITC1-15; quiz ITC16. [PMID: 25285559] doi:10.7326/0003-4819-161-7- {| 201 410070-0100 (Continued on page 32) 30

Common Symptoms TABLE 19. FDA-Approved Prescription Drug Treatment for Insomnia Agent? UsualDose Onsetof Durationof Phase of Sleep Notes Action® — Action‘ Targeted | Recommended? Nonbenzodiazepines Eszopiclone (generic) 1-3mg Rapid Intermediate Sleep The recommended initial dosage was maintenance reduced to 1 mg because of prolonged impaired driving skills, memory, and coordination at the previously | recommended 3-mg dosage | Zaleplon (generic) 5-20 mg Rapid Short Sleep onset 5-mg dose recommended for debilitated or low-body-weight patients Zolpidem Sleep onsetand/ Doses 210 mg are not recommended or maintenance for women owing to prolonged sedation Oral tablet (generic) 5-10 mg Rapid Short Extended-release oral 6.25-12.5mg Rapid Intermediate tablet (generic) Sublingual

Zolpidem Sleep onsetand/ Doses 210 mg are not recommended or maintenance for women owing to prolonged sedation Oral tablet (generic) 5-10 mg Rapid Short Extended-release oral 6.25-12.5mg Rapid Intermediate tablet (generic) Sublingual Intermezzo 1.75-3.5 mg Rapid Ultra-short Indicated for as-needed use for treatment of middle-of-the-night insomnia with =4 h of sleep time remaining Edluar 5-10 mg Rapid Short Oral spray (Zolpimist) 5-10 mg Rapid Short Antidepressant Doxepin (Silenor) 3-6 mg Rapid Intermediate Sleep Best choice for chronic maintenance pharmacologic therapy, if necessary? Insufficient Evidence to Recommend for or Against@ Orexin-Receptor Antagonists Lemborexant (Dayvigo) 5-10 mg Rapid Intermediate | Sleeponsetand/ _Next-day driving impairment possible or maintenance after 10-mg dose

Orexin-Receptor Antagonists Lemborexant (Dayvigo) 5-10 mg Rapid Intermediate | Sleeponsetand/ _Next-day driving impairment possible or maintenance after 10-mg dose Suvorexant (Belsomra) 5-20 mg Slow Long Sleep The recommended initial dosage is maintenance 10 mg; the daily dosage should not | exceed 20 mg | Melatonin Agonist | Ramelteon (Rozerem) 8mg Rapid Short Sleep onset Not Recommended? Benzodiazepines (oral) Estazolam (generic) 1-2mg Slow Intermediate Not established Flurazepam (generic) 15-30 mg Rapid Long Not established Quazepam (generic) 7.5-15 mg Slow Long Not established Temazepam (generic) 7.5-30 mg Slow Intermediate Sleep onset and/ or maintenance Triazolam (generic) 0.125-0.5mg Rapid Short Sleep onset Short-acting benzodiazepines have been associated with an increased risk for anterograde amnesia *All agents are classified as schedule IV by the Drug Enforcement Agency except doxepin and ramelteon, which are not scheduled. ®Onset of action: rapid = 15-30 minutes; slow = 30-60 minutes.

Triazolam (generic) 0.125-0.5mg Rapid Short Sleep onset Short-acting benzodiazepines have been associated with an increased risk for anterograde amnesia *All agents are classified as schedule IV by the Drug Enforcement Agency except doxepin and ramelteon, which are not scheduled. ®Onset of action: rapid = 15-30 minutes; slow = 30-60 minutes. “Based on elimination half-life and preparation: short= 1-5 hours; intermediate = 5-12 hours; long = >12 hours. ¢Recommendations from Mysliwiec V, Martin JL, Ulmer CS, et al. The management of chronic insomnia disorder and obstructive sleep apnea: synopsis of the 2019 U.S. Department of Veterans Affairs and U.S. Department of Defense clinical practice guidelines. Ann Intern Med. 2020;172:325-36. [PMID: 32066145] doi:10.7326/M19-3575 Adapted with permission from Masters PA. In the clinic. Insomnia. Ann Intern Med. 2014;161:ITC9. [PMID: 25285559] doi:10.7326/0003-4819-161-7-201410070-0100. © 2014, American College of Physicians. 31

Common Symptoms TABLE 20. Factors to Consider When Prescribing Drugs to measurement of kidney and liver function, urinalysis (for Treat Insomnia detection of protein), and albumin measurement. The decision to pursue further testing (e.g., echocardiography) should be Use the minimal effective dosage guided by the findings on the initial evaluation. Avoid long-half-life medications, including long-half-life metabolites Chronic Venous Insufficiency Be aware of potential interactions between drugs, including over-the-counter drugs Chronic venous insufficiency is a common condition in which the veins or valves in the lower extremities are incompetent, Caution patients who are receiving these medications about | interaction with alcohol | resulting in pooling of blood in the legs. The most common cause is venous hypertension, which is usually induced by Review potential side effects: daytime sleepiness, complex sleep behaviors, serious injury, or death acquired risk factors but can be congenital (Klippel-Trenaunay Confer with the patient to determine an appropriate period of syndrome). Symptoms include aching, itching, restlessness, use heaviness, swelling, and pain in the legs. Use a y-aminobutyric acid agonist before other sedative- A thorough history and physical examination should be hypnotics for treatment of acute or short-term insomnia performed. The examination may reveal edema, dilated veins | Look for rebound insomnia after discontinuation (both varicosities and superficial telangiectasias), thin or Consider consulting a sleep specialist before starting long-term hyperpigmented skin, and ulceration. Physical findings are therapy with hypnotic medication best observed in the gravity-dependent upright position. Consider intermittent or long-term use of hypnotic medications, Chronic venous insufficiency is a clinical diagnosis, but venous depending on the clinical situation duplex Doppler ultrasonography can be used if the diagnosis Ann Intern Med. Adapted with permission from Masters PA. In the clinic. Insomnia. | is in doubt and in those considering intervention. 2014;161:ITC8. [PMID: 25285559] doi:10.7326/0003-4819-161-7-201410070-01004. | Conservative measures, including exercise, leg elevation, © 2014, American College of Physicians. | lifestyle changes (weight loss), and compression therapy (20- 50 mm Hg depending on the stage of disease), are first-line treatments. Exercise has not been shown to improve leg edema but can contribute to other outcomes, such as weight loss. The e First-line therapy for insomnia is cognitive behavioral presence of skin changes or ulceration should prompt at least therapy, which includes cognitive therapy, education on 30 mm Hg of compression (see Foot and Leg Ulcers). Skin care sleep hygiene, and behavioral interventions. is another important part of management, and daily use of e Pharmacologic therapies for insomnia are associated topical moisturizers may reduce skin breakdown and prevent with adverse effects and should be initiated only in infection. Stasis dermatitis may require sparing use of a topical patients with insomnia refractory to nonpharmacologic steroid. Wound care, including use of hydrocolloids and foam interventions. dressings, is essential to control drainage from ulcers and to prevent maceration of the surrounding skin. Many drugs, including horse chestnut extracts and other nonprescription Lower Extremity Edema and Ulcers agents, have been studied for chronic venous insufficiency Lower extremity edema is a common symptom in inpatient and without ulceration; however, no medications are FDA approved outpatient settings. It results from accumulation of interstitial for this condition, and only low-quality studies of their use fluid in the most dependent part of the body and may be secon- have been published. Patients with bothersome spider veins dary to several different pathophysiologic mechanisms. The most and small varicose veins can undergo sclerotherapy, thermo- common causes include venous obstruction or insufficiency, coagulation, or laser therapy. Patients with confirmed reflux heart failure (including right-sided heart failure secondary to and persistent symptoms despite conservative therapy may be pulmonary disease), cirrhosis, nephrotic syndrome and hypoal- treated with venous ablation; stripping; excision; or, in the buminemia of other etiologies, and use of certain medications case of stenosis and obstruction, stenting. Surgical options can (Table 21). If lower extremity edema is unilateral, it is usually the be considered for those with symptoms that are refractory to result of a mechanical obstruction to venous or lymphatic flow, medical and endovenous therapies. such as deep venous thrombosis or cancer. Obstruction of the lymphatic system is a less common mechanism of edema. Foot and Leg Ulcers A detailed history and physical examination will suggest Venous stasis ulcers, arterial insufficiency ulcers, and neuro- the cause of lower extremity edema in most patients. For uni- pathic ulcers are the most common ulcerations of the feet and lateral leg edema, the clinical probability of deep venous lower extremities (Table 22). The proper diagnosis is important thrombosis needs to be determined. D-dimer and/or Doppler because treatments are directed at the underlying cause. ultrasonography of the lower extremities may be necessary. Arterial insufficiency ulcers are discussed in MKSAP 19 Cellulitis can be considered on the basis of findings. For bilat- Cardiovascular Medicine, and neuropathic ulcers are dis- eral leg edema, reasonable initial laboratory testing includes cussed in MKSAP 19 Endocrinology and Metabolism.

TABLE 20. Factors to Consider When Prescribing Drugs to measurement of kidney and liver function, urinalysis (for Treat Insomnia detection of protein), and albumin measurement. The decision to pursue further testing (e.g., echocardiography) should be Use the minimal effective dosage guided by the findings on the initial evaluation. Avoid long-half-life medications, including long-half-life metabolites Chronic Venous Insufficiency Be aware of potential interactions between drugs, including over-the-counter drugs Chronic venous insufficiency is a common condition in which the veins or valves in the lower extremities are incompetent, Caution patients who are receiving these medications about | interaction with alcohol | resulting in pooling of blood in the legs. The most common cause is venous hypertension, which is usually induced by Review potential side effects: daytime sleepiness, complex sleep behaviors, serious injury, or death acquired risk factors but can be congenital (Klippel-Trenaunay Confer with the patient to determine an appropriate period of syndrome). Symptoms include aching, itching, restlessness, use heaviness, swelling, and pain in the legs. Use a y-aminobutyric acid agonist before other sedative- A thorough history and physical examination should be hypnotics for treatment of acute or short-term insomnia performed. The examination may reveal edema, dilated veins | Look for rebound insomnia after discontinuation (both varicosities and superficial telangiectasias), thin or Consider consulting a sleep specialist before starting long-term hyperpigmented skin, and ulceration. Physical findings are therapy with hypnotic medication best observed in the gravity-dependent upright position. Consider intermittent or long-term use of hypnotic medications, Chronic venous insufficiency is a clinical diagnosis, but venous depending on the clinical situation duplex Doppler ultrasonography can be used if the diagnosis Ann Intern Med. Adapted with permission from Masters PA. In the clinic. Insomnia. | is in doubt and in those considering intervention. 2014;161:ITC8. [PMID: 25285559] doi:10.7326/0003-4819-161-7-201410070-01004. | Conservative measures, including exercise, leg elevation, © 2014, American College of Physicians. | lifestyle changes (weight loss), and compression therapy (20- 50 mm Hg depending on the stage of disease), are first-line treatments. Exercise has not been shown to improve leg edema but can contribute to other outcomes, such as weight loss. The e First-line therapy for insomnia is cognitive behavioral presence of skin changes or ulceration should prompt at least therapy, which includes cognitive therapy, education on 30 mm Hg of compression (see Foot and Leg Ulcers). Skin care sleep hygiene, and behavioral interventions. is another important part of management, and daily use of e Pharmacologic therapies for insomnia are associated topical moisturizers may reduce skin breakdown and prevent with adverse effects and should be initiated only in infection. Stasis dermatitis may require sparing use of a topical patients with insomnia refractory to nonpharmacologic steroid. Wound care, including use of hydrocolloids and foam interventions. dressings, is essential to control drainage from ulcers and to prevent maceration of the surrounding skin. Many drugs, including horse chestnut extracts and other nonprescription Lower Extremity Edema and Ulcers agents, have been studied for chronic venous insufficiency Lower extremity edema is a common symptom in inpatient and without ulceration; however, no medications are FDA approved outpatient settings. It results from accumulation of interstitial for this condition, and only low-quality studies of their use fluid in the most dependent part of the body and may be secon- have been published. Patients with bothersome spider veins dary to several different pathophysiologic mechanisms. The most and small varicose veins can undergo sclerotherapy, thermo- common causes include venous obstruction or insufficiency, coagulation, or laser therapy. Patients with confirmed reflux heart failure (including right-sided heart failure secondary to and persistent symptoms despite conservative therapy may be pulmonary disease), cirrhosis, nephrotic syndrome and hypoal- treated with venous ablation; stripping; excision; or, in the buminemia of other etiologies, and use of certain medications case of stenosis and obstruction, stenting. Surgical options can (Table 21). If lower extremity edema is unilateral, it is usually the be considered for those with symptoms that are refractory to result of a mechanical obstruction to venous or lymphatic flow, medical and endovenous therapies. such as deep venous thrombosis or cancer. Obstruction of the lymphatic system is a less common mechanism of edema. Foot and Leg Ulcers A detailed history and physical examination will suggest Venous stasis ulcers, arterial insufficiency ulcers, and neuro- the cause of lower extremity edema in most patients. For uni- pathic ulcers are the most common ulcerations of the feet and lateral leg edema, the clinical probability of deep venous lower extremities (Table 22). The proper diagnosis is important thrombosis needs to be determined. D-dimer and/or Doppler because treatments are directed at the underlying cause. ultrasonography of the lower extremities may be necessary. Arterial insufficiency ulcers are discussed in MKSAP 19 Cellulitis can be considered on the basis of findings. For bilat- Cardiovascular Medicine, and neuropathic ulcers are dis- eral leg edema, reasonable initial laboratory testing includes cussed in MKSAP 19 Endocrinology and Metabolism. 32

Common Symptoms TABLE 21. Differential Diagnosis of Lower Extremity Edema | Condition or Cause Clinical Presentation Diagnostic Testing | Chronic venous insufficiency Gradual-onset leg aching/heaviness that is more likely Duplex ultrasonography if considering to improve with elevation/recumbency and walking intervention (decreased venous pressure) Edema (most commonly bilateral but can be unilateral) that usually spares forefoot Hyperpigmentation (hemosiderin deposits); telangiectasias, reticular veins, varicose veins; eczematous dermatitis and lipodermatosclerosis leading to ulceration, especially over the medial malleolus Heart failure Dyspnea, orthopnea, paroxysmal nocturnal dyspnea, Echocardiography elevated jugular venous pressure, lung crackles, ventricular gallop, symmetric pitting edema | Kidney disease Symmetric pitting edema Urinalysis, random urine albumin- creatinine ratio, serum creatinine level Liver disease Symmetric pitting edema, ascites, spider angiomas, Liver chemistry tests, albumin level, palmar erythema, jaundice/icterus INR Hypothyroidism Symptoms of hypothyroidism, nonpitting bilateral Thyroid-stimulating hormone level, edema serum thyroxine level

Liver disease Symmetric pitting edema, ascites, spider angiomas, Liver chemistry tests, albumin level, palmar erythema, jaundice/icterus INR Hypothyroidism Symptoms of hypothyroidism, nonpitting bilateral Thyroid-stimulating hormone level, edema serum thyroxine level Lymphedema (bilateral) Brawny induration; pitting edema present initially; Can consider CT of the abdomen/ nonpitting present late in process; involves feet pelvis, lymphoscintigraphy (square toes) Kaposi-Stemmer sign (inability to pinch a fold ofskin on the dorsal surface of the base of the second toe) Lipedema Fatty tissue accumulation, nonpitting edema that spares the feet Pregnancy Symmetric pitting edema Obstructive sleep apnea Daytime sleepiness, snoring, witnessed apnea, neck Polysomnography circumference >43 cm (17 in), symmetric pitting edema Pulmonary hypertension Exertional dyspnea, elevated jugular venous pressure, Echocardiography prominent jugular venous a wave, widened split S» Deep venous thrombosis Unilateral, painful edema (most commonly) that may be D-dimer and/or lower extremity tender on examination; typically pitting edema ultrasonography depending on

Deep venous thrombosis Unilateral, painful edema (most commonly) that may be D-dimer and/or lower extremity tender on examination; typically pitting edema ultrasonography depending on | Should be strongly suspected with acute edema <72 h Bieeet pie eability Drugs (vasodilators, NSAIDs, Gradual-onset, bilateral pitting edema that usually No diagnostic testing; symptoms | gabapentinoids, hormones, improves with recumbency; one side may be largerthan _ resolve within days of discontinuing antiestrogens, thiazolidinediones, the other, particularly if there is more pronounced the offending agent dihydropyridine calcium channel venous disease blockers) TABLE 22. Common Types of Foot and Leg Ulcers Ulcer Type Location Clinical Presentation Associated Findings Risk Factors Venous stasis ulcers Mid-calf to ankle, often Pain variably present; Edema, venous Chronic venous over medial malleolus irregularly shaped, varicosities, eczematous insufficiency shallow, weeping serous changes, hyperpigmenta- fluid; normal arterial tion, lipodermatosclerosis pulses Arterial insufficiency Distal toes, anterior Painful; sharply Evidence of Advanced age, smoking, ulcers lower leg demarcated borders; dry, atherosclerosis, poor obesity, diabetes pale gray or yellow pulses, hair loss, shiny mellitus, hyperlipidemia, wound base skin hypertension

Arterial insufficiency Distal toes, anterior Painful; sharply Evidence of Advanced age, smoking, ulcers lower leg demarcated borders; dry, atherosclerosis, poor obesity, diabetes pale gray or yellow pulses, hair loss, shiny mellitus, hyperlipidemia, wound base skin hypertension Neuropathic ulcers Plantar aspect of feet Painless, occur over Decreased sensation, Diabetes, peripheral pressure points callus formation, neuropathy neuropathic (Charcot) arthropathy 33

Common Symptoms Venous stasis ulcers account for up to 70% of all leg ulcers. Antibiotics should be reserved for patients with signs of infec- They occur on the lower extremities in the area from the mid- tion, including erythema and tenderness at the site of the calf to the ankle, most commonly near the medial malleolus, ulcer, lymphangitis, rapidly increasing ulcer size, and fever. and are associated with signs of chronic venous insufficiency. Venous stasis ulcers can be single or multiple and are typically ¢ The most common causes of lower extremity edema irregularly shaped, shallow, and often weep serous fluid include venous obstruction or insufficiency, heart fail- (Figure 8). The presence of fibrinous tissue is common, and ure, cirrhosis, nephrotic syndrome, and medication use. ulcers are rarely necrotic. Pain may or may not be present. Physical findings suggestive of a venous stasis ulcer e Conservative measures, including exercise, leg elevation, include concomitant edema, varicosities, eezematous changes, lifestyle changes, and compression stockings, are first-line brown pigmentation from hemosiderin deposition, lipoder- therapies for chronic venous insufficiency. matosclerosis (fibrosis of subcutaneous tissue), atrophie e The mainstay of venous ulcer treatment is compression blanche (pale plaques of scar tissue), and evidence of healed therapy, which improves venous flow, reduces edema, ulcers. Like chronic venous insufficiency, diagnosis is usually and promotes fibrinolysis. made clinically, although duplex ultrasonography can be help- ¢ Routine use of systemic antibiotics is not recommended for ful in evaluating venous reflux and obstruction, or if the diag- the treatment of venous stasis ulcers, except for patients nosis is unclear. The ankle-brachial index should be measured with suspected infection. to rule out concurrent arterial disease. Treatment consists of compression therapy (=30 mm Hg), which improves venous flow, reduces edema, and promotes Medically Unexplained Symptoms fibrinolysis. Compression therapy is best administered by using high-compression, multicomponent bandaging; other Medically unexplained symptoms (MUS) are symptoms that

Venous stasis ulcers account for up to 70% of all leg ulcers. Antibiotics should be reserved for patients with signs of infec- They occur on the lower extremities in the area from the mid- tion, including erythema and tenderness at the site of the calf to the ankle, most commonly near the medial malleolus, ulcer, lymphangitis, rapidly increasing ulcer size, and fever. and are associated with signs of chronic venous insufficiency. Venous stasis ulcers can be single or multiple and are typically ¢ The most common causes of lower extremity edema irregularly shaped, shallow, and often weep serous fluid include venous obstruction or insufficiency, heart fail- (Figure 8). The presence of fibrinous tissue is common, and ure, cirrhosis, nephrotic syndrome, and medication use. ulcers are rarely necrotic. Pain may or may not be present. Physical findings suggestive of a venous stasis ulcer e Conservative measures, including exercise, leg elevation, include concomitant edema, varicosities, eezematous changes, lifestyle changes, and compression stockings, are first-line brown pigmentation from hemosiderin deposition, lipoder- therapies for chronic venous insufficiency. matosclerosis (fibrosis of subcutaneous tissue), atrophie e The mainstay of venous ulcer treatment is compression blanche (pale plaques of scar tissue), and evidence of healed therapy, which improves venous flow, reduces edema, ulcers. Like chronic venous insufficiency, diagnosis is usually and promotes fibrinolysis. made clinically, although duplex ultrasonography can be help- ¢ Routine use of systemic antibiotics is not recommended for ful in evaluating venous reflux and obstruction, or if the diag- the treatment of venous stasis ulcers, except for patients nosis is unclear. The ankle-brachial index should be measured with suspected infection. to rule out concurrent arterial disease. Treatment consists of compression therapy (=30 mm Hg), which improves venous flow, reduces edema, and promotes Medically Unexplained Symptoms fibrinolysis. Compression therapy is best administered by using high-compression, multicomponent bandaging; other Medically unexplained symptoms (MUS) are symptoms that options include elastic or inelastic compression bandages cannot be attributed to a specific medical cause after a thor-

Venous stasis ulcers account for up to 70% of all leg ulcers. Antibiotics should be reserved for patients with signs of infec- They occur on the lower extremities in the area from the mid- tion, including erythema and tenderness at the site of the calf to the ankle, most commonly near the medial malleolus, ulcer, lymphangitis, rapidly increasing ulcer size, and fever. and are associated with signs of chronic venous insufficiency. Venous stasis ulcers can be single or multiple and are typically ¢ The most common causes of lower extremity edema irregularly shaped, shallow, and often weep serous fluid include venous obstruction or insufficiency, heart fail- (Figure 8). The presence of fibrinous tissue is common, and ure, cirrhosis, nephrotic syndrome, and medication use. ulcers are rarely necrotic. Pain may or may not be present. Physical findings suggestive of a venous stasis ulcer e Conservative measures, including exercise, leg elevation, include concomitant edema, varicosities, eezematous changes, lifestyle changes, and compression stockings, are first-line brown pigmentation from hemosiderin deposition, lipoder- therapies for chronic venous insufficiency. matosclerosis (fibrosis of subcutaneous tissue), atrophie e The mainstay of venous ulcer treatment is compression blanche (pale plaques of scar tissue), and evidence of healed therapy, which improves venous flow, reduces edema, ulcers. Like chronic venous insufficiency, diagnosis is usually and promotes fibrinolysis. made clinically, although duplex ultrasonography can be help- ¢ Routine use of systemic antibiotics is not recommended for ful in evaluating venous reflux and obstruction, or if the diag- the treatment of venous stasis ulcers, except for patients nosis is unclear. The ankle-brachial index should be measured with suspected infection. to rule out concurrent arterial disease. Treatment consists of compression therapy (=30 mm Hg), which improves venous flow, reduces edema, and promotes Medically Unexplained Symptoms fibrinolysis. Compression therapy is best administered by using high-compression, multicomponent bandaging; other Medically unexplained symptoms (MUS) are symptoms that options include elastic or inelastic compression bandages cannot be attributed to a specific medical cause after a thor- (Unna boots, compression stockings) or intermittent pneu- ough medical evaluation. The prevalence of patients with at

Venous stasis ulcers account for up to 70% of all leg ulcers. Antibiotics should be reserved for patients with signs of infec- They occur on the lower extremities in the area from the mid- tion, including erythema and tenderness at the site of the calf to the ankle, most commonly near the medial malleolus, ulcer, lymphangitis, rapidly increasing ulcer size, and fever. and are associated with signs of chronic venous insufficiency. Venous stasis ulcers can be single or multiple and are typically ¢ The most common causes of lower extremity edema irregularly shaped, shallow, and often weep serous fluid include venous obstruction or insufficiency, heart fail- (Figure 8). The presence of fibrinous tissue is common, and ure, cirrhosis, nephrotic syndrome, and medication use. ulcers are rarely necrotic. Pain may or may not be present. Physical findings suggestive of a venous stasis ulcer e Conservative measures, including exercise, leg elevation, include concomitant edema, varicosities, eezematous changes, lifestyle changes, and compression stockings, are first-line brown pigmentation from hemosiderin deposition, lipoder- therapies for chronic venous insufficiency. matosclerosis (fibrosis of subcutaneous tissue), atrophie e The mainstay of venous ulcer treatment is compression blanche (pale plaques of scar tissue), and evidence of healed therapy, which improves venous flow, reduces edema, ulcers. Like chronic venous insufficiency, diagnosis is usually and promotes fibrinolysis. made clinically, although duplex ultrasonography can be help- ¢ Routine use of systemic antibiotics is not recommended for ful in evaluating venous reflux and obstruction, or if the diag- the treatment of venous stasis ulcers, except for patients nosis is unclear. The ankle-brachial index should be measured with suspected infection. to rule out concurrent arterial disease. Treatment consists of compression therapy (=30 mm Hg), which improves venous flow, reduces edema, and promotes Medically Unexplained Symptoms fibrinolysis. Compression therapy is best administered by using high-compression, multicomponent bandaging; other Medically unexplained symptoms (MUS) are symptoms that options include elastic or inelastic compression bandages cannot be attributed to a specific medical cause after a thor- (Unna boots, compression stockings) or intermittent pneu- ough medical evaluation. The prevalence of patients with at monic compression devices. An absolute contraindication to least one unexplained symptom ranges from 40% to 49%.

options include elastic or inelastic compression bandages cannot be attributed to a specific medical cause after a thor- (Unna boots, compression stockings) or intermittent pneu- ough medical evaluation. The prevalence of patients with at monic compression devices. An absolute contraindication to least one unexplained symptom ranges from 40% to 49%. compression therapy is an ankle-brachial index of 0.5 or less, Patients with MUS are frequently seen in both primary and although cautious use is advised for any patient with an ankle- subspecialty clinics, resulting in significantly increased health brachial index less than 0.9. For patients who cannot be care utilization. The costs associated with MUS are estimated treated with compression therapy, referral to a vascular spe- at more than $250 billion annually. cialist should be considered. Central sensitization has a potential role in the formation Local wound care includes debridement of devitalized of MUS as well as in some common chronic pain syndromes, tissue. Simple nonadherent dressings appear to be as effective such as fibromyalgia and irritable bowel syndrome (Table 23). as other more expensive dressings, and the addition of topical Central sensitization occurs when central nervous system cadexomer iodine may improve healing. When added to stan- hyperexcitability and reduced inhibitory responses lead to dard care, pentoxifylline, simvastatin, and aspirin have each pain, often in the absence of nociceptive stimuli; sensory dis- individually been shown to increase ulcer healing, although turbances, such as allodynia and hyperalgesia; and alterations the relative effectiveness of combination therapy is unknown. in autonomic, motor, and cognitive function. It is often precipi-

dard care, pentoxifylline, simvastatin, and aspirin have each pain, often in the absence of nociceptive stimuli; sensory dis- individually been shown to increase ulcer healing, although turbances, such as allodynia and hyperalgesia; and alterations the relative effectiveness of combination therapy is unknown. in autonomic, motor, and cognitive function. It is often precipi- tated by a prodromal event, such as infection, physical or emo- tional trauma, surgery, medical illness, or prolonged stress. Although patients with central sensitization demonstrate changes to the peripheral immune system, hypothalamic- pituitary-adrenal axis, and nerve fiber density, these changes are consequences of the disease process rather than primary pathophysiologic mechanisms. The National Institutes of Health has coined the term chronic overlapping pain condi- tions to describe the interrelatedness of many of these condi- tions, including those listed in Table 23.

tated by a prodromal event, such as infection, physical or emo- tional trauma, surgery, medical illness, or prolonged stress. Although patients with central sensitization demonstrate changes to the peripheral immune system, hypothalamic- pituitary-adrenal axis, and nerve fiber density, these changes are consequences of the disease process rather than primary pathophysiologic mechanisms. The National Institutes of Health has coined the term chronic overlapping pain condi- tions to describe the interrelatedness of many of these condi- tions, including those listed in Table 23. Clinical Presentation and Evaluation Common symptoms in patients with MUS include fatigue, headache, abdominal pain, musculoskeletal pain (back pain, myalgia, arthralgia), dizziness, paresthesia, generalized weak- ness, transient edema, insomnia, dyspnea, chest pain, chronic FIGURE 8. An irregularly shaped, shallow, exudative ulcer with some areas of tissue granulation in association with hyperpigmentation and evidence of previous facial pain, chronic pelvic pain, and chemical sensitivities. healed ulcers. MUS appear more frequently in women, persons with lower 34

Common Symptoms TABLE 23. Conditions Associated with Central Sensitization being mindful to acknowledge the patient’s concerns and frus- | Burning mouth syndrome | trations. Frequently, patients will request, or even demand, additional testing and consultations that may not be clinically Chronic daily headache indicated. Although doing so may be challenging, clinicians Chronic prostatitis should limit additional evaluations to those deemed medically Complex regional pain syndrome necessary because unrevealing studies provide negligible reas- Dry eye disease surance, pose iatrogenic risks, and increase patient anxiety. Endometriosis Fibromyalgia Management The foundation of MUS management is an effective therapeu- | Functional gait disorder tic relationship. Patients should be treated respectfully and Generalized sensory hyperresponsiveness cared for in a nonjudgmental manner. It is important not only Interstitial cystitis/bladder pain syndrome to expect but also to accept the patient’s feelings of frustration: Irritable bowel syndrome acknowledging these feelings early in the patient’s manage- Joint hypermobility syndrome ment course can help to build and strengthen the therapeutic

Fibromyalgia Management The foundation of MUS management is an effective therapeu- | Functional gait disorder tic relationship. Patients should be treated respectfully and Generalized sensory hyperresponsiveness cared for in a nonjudgmental manner. It is important not only Interstitial cystitis/bladder pain syndrome to expect but also to accept the patient’s feelings of frustration: Irritable bowel syndrome acknowledging these feelings early in the patient’s manage- Joint hypermobility syndrome ment course can help to build and strengthen the therapeutic Migraine alliance. Patients often fear that they will be perceived as pro- ducing factitious symptoms or malingering, and it is crucial to Nonepileptic seizure address these concerns directly if raised. Nonulcer dyspepsia Management of MUS requires a patient-focused, holistic, Ocular migraine and multimodal approach. The goals of management are Pelvic floor dysfunction restoration of function, decreased symptom focus, and Persistent postsurgical pain acquisition of coping mechanisms rather than abatement of

Migraine alliance. Patients often fear that they will be perceived as pro- ducing factitious symptoms or malingering, and it is crucial to Nonepileptic seizure address these concerns directly if raised. Nonulcer dyspepsia Management of MUS requires a patient-focused, holistic, Ocular migraine and multimodal approach. The goals of management are Pelvic floor dysfunction restoration of function, decreased symptom focus, and Persistent postsurgical pain acquisition of coping mechanisms rather than abatement of Persistent postural-perceptual dizziness symptoms. It should be made clear to patients that the treat- ment of MUS will probably not be curative and that symp- Postural orthostatic tachycardia syndrome toms may persist. Patients should be encouraged to develop Rumination syndrome short-term and long-term goals with the recognition that Systemic exertional intolerance disease (formerly chronic many goals will change from a physical symptom focus to a fatigue syndrome/myalgic encephalomyelitis) psychosocial focus. If additional symptoms arise, clinicians Temporomandibular dysfunction should respond empathically and perform an appropriately | Thoracic outlet syndrome thorough investigation. Vulvodynia (vulvar pain of unknown cause) Interventions that may benefit patients with MUS include CBT, physical therapy, occupational therapy, individual or group psychotherapy, social support, biofeedback therapy, levels of education, and those with lower socioeconomic graded exercise therapy, stress management activities, and status. training in coping mechanisms. Patients with comorbid mood There is no formal approach to the diagnostic evaluation disorders should be considered for a trial of antidepressant of MUS; however, the initial evaluation should involve a thor- therapy and referral to a psychiatrist or psychologist. Given the ough history and physical examination related to each symp- wide-ranging effects of MUS, treatment should be focused on tom. Clinicians must address symptoms in a focused manner both physical and psychosocial aspects (Table 24). and diligently review any previous diagnostic evaluations. Laboratory and radiographic studies should be guided by the findings on the history and physical examination, and subspe- * Central sensitization plays a role in many medically cialty referrals should be used judiciously. Given the high unexplained symptoms as well as in some common comorbidity of mood disturbances in patients with MUS, chronic pain syndromes, such as fibromyalgia and irri- patients with features concerning for an underlying mood table bowel syndrome. disorder should be evaluated accordingly. ¢ In patients with medically unexplained symptoms, cli- HVC Patients with MUS must be distinguished from those with nicians should limit diagnostic testing to those tests somatic symptom disorders, which are psychiatric conditions deemed medically necessary because unrevealing stud- with specific diagnostic criteria (see Mental and Behavioral ies provide negligible reassurance, pose iatrogenic risks, Health). Although many somatic symptom disorders involve and result in additional patient anxiety. MUS, most patients with MUS do not meet the diagnostic cri- ¢ The goals of management in patients with medically HVC teria for these disorders. unexplained symptoms are restoration of function, If an underlying medical cause cannot be identified after decreased symptom focus, and acquisition of coping an appropriately thorough evaluation, it is imperative that cli- mechanisms rather than abatement of symptoms. nicians have an open and honest discussion with the patient,

Persistent postural-perceptual dizziness symptoms. It should be made clear to patients that the treat- ment of MUS will probably not be curative and that symp- Postural orthostatic tachycardia syndrome toms may persist. Patients should be encouraged to develop Rumination syndrome short-term and long-term goals with the recognition that Systemic exertional intolerance disease (formerly chronic many goals will change from a physical symptom focus to a fatigue syndrome/myalgic encephalomyelitis) psychosocial focus. If additional symptoms arise, clinicians Temporomandibular dysfunction should respond empathically and perform an appropriately | Thoracic outlet syndrome thorough investigation. Vulvodynia (vulvar pain of unknown cause) Interventions that may benefit patients with MUS include CBT, physical therapy, occupational therapy, individual or group psychotherapy, social support, biofeedback therapy, levels of education, and those with lower socioeconomic graded exercise therapy, stress management activities, and status. training in coping mechanisms. Patients with comorbid mood There is no formal approach to the diagnostic evaluation disorders should be considered for a trial of antidepressant of MUS; however, the initial evaluation should involve a thor- therapy and referral to a psychiatrist or psychologist. Given the ough history and physical examination related to each symp- wide-ranging effects of MUS, treatment should be focused on tom. Clinicians must address symptoms in a focused manner both physical and psychosocial aspects (Table 24). and diligently review any previous diagnostic evaluations. Laboratory and radiographic studies should be guided by the findings on the history and physical examination, and subspe- * Central sensitization plays a role in many medically cialty referrals should be used judiciously. Given the high unexplained symptoms as well as in some common comorbidity of mood disturbances in patients with MUS, chronic pain syndromes, such as fibromyalgia and irri- patients with features concerning for an underlying mood table bowel syndrome. disorder should be evaluated accordingly. ¢ In patients with medically unexplained symptoms, cli- HVC Patients with MUS must be distinguished from those with nicians should limit diagnostic testing to those tests somatic symptom disorders, which are psychiatric conditions deemed medically necessary because unrevealing stud- with specific diagnostic criteria (see Mental and Behavioral ies provide negligible reassurance, pose iatrogenic risks, Health). Although many somatic symptom disorders involve and result in additional patient anxiety. MUS, most patients with MUS do not meet the diagnostic cri- ¢ The goals of management in patients with medically HVC teria for these disorders. unexplained symptoms are restoration of function, If an underlying medical cause cannot be identified after decreased symptom focus, and acquisition of coping an appropriately thorough evaluation, it is imperative that cli- mechanisms rather than abatement of symptoms. nicians have an open and honest discussion with the patient, 35

Common Symptoms TABLE 24. Follow-up Management of the Patient with Medically Unexplained Symptoms | Category Issue How? -How Notes Often? | Nonpharmacologic Maintaining an Elicit and address the patient's Each visit Monitor the provider-patient therapy effective emotional concerns; use a relationship regularly as you would, relationship with negotiated rather than a for example, monitor blood the patient prescriptive approach; tailor care pressure in a patient with to patient's personality; address hypertension. Ask, “So, how is this your own negative reactions to the going? How are you and | working patient together?” Examples of indicators of an effective relationship are adherence to the treatment plan, friendliness, improved eye contact, positive statements about the provider and the treatment

| Category Issue How? -How Notes Often? | Nonpharmacologic Maintaining an Elicit and address the patient's Each visit Monitor the provider-patient therapy effective emotional concerns; use a relationship regularly as you would, relationship with negotiated rather than a for example, monitor blood the patient prescriptive approach; tailor care pressure in a patient with to patient's personality; address hypertension. Ask, “So, how is this your own negative reactions to the going? How are you and | working patient together?” Examples of indicators of an effective relationship are adherence to the treatment plan, friendliness, improved eye contact, positive statements about the provider and the treatment Dissociating Schedule regular, consistent, time- Each visit Titrate number of scheduled visits treatment regimen contingent visits rather than ad hoc and amount of treatment to from symptoms (as-needed) visits; give all patient's needs and progress medications on a scheduled rather than on an as-needed basis

Dissociating Schedule regular, consistent, time- Each visit Titrate number of scheduled visits treatment regimen contingent visits rather than ad hoc and amount of treatment to from symptoms (as-needed) visits; give all patient's needs and progress medications on a scheduled rather than on an as-needed basis Pharmacologic Medically Consider the lowest effective Each visit Minimize or avoid use of opioids therapy unexplained dosage of antidepressant and and tranquilizers symptoms nonopioid analgesics Comorbid Treat depression as indicated As needed depression and anxiety Patient education Overall Review patient's diary and facilitate | Ongoing management understanding of how his or her thoughts, emotions, and behaviors are related to symptoms Education and Educate the patient so that the Each visit treatment plan patient understands the plan of care and its purpose

Patient education Overall Review patient's diary and facilitate | Ongoing management understanding of how his or her thoughts, emotions, and behaviors are related to symptoms Education and Educate the patient so that the Each visit treatment plan patient understands the plan of care and its purpose Reinforcing patient | Give appropriate praise for Each visit commitment to commitment behavior, such as treatment completing homework; address noncommittal behavior, such as not keeping appointments or visiting an acute care facility without prior discussion Reviewing and Reinforce previous short-term Each visit Help patient to identify solutions to revising patient goals or negotiate new ones to roadblocks goals operationalize patient’s long-term goals | Negotiating new Negotiate plans to adjust physical Each visit Continuously encourage the patient plans activity; recommend relaxation to add new healthy behaviors and techniques; refer for physical to progress in what he or she is therapy already doing

| Negotiating new Negotiate plans to adjust physical Each visit Continuously encourage the patient plans activity; recommend relaxation to add new healthy behaviors and techniques; refer for physical to progress in what he or she is therapy already doing Adapted from Dwamena FC, Fortin AH, Smith RC. Medically unexplained symptoms. In ACP Smart Medicine (online database). Philadelphia: American College of Physicians; 2015. Accessed June 25, 2015.

Adapted from Dwamena FC, Fortin AH, Smith RC. Medically unexplained symptoms. In ACP Smart Medicine (online database). Philadelphia: American College of Physicians; 2015. Accessed June 25, 2015. Syncope episode before age 30 years. Although the Framingham Heart Study found that 44% of patients who experienced a syncopal Syncope is complete, transient loss of consciousness and pos- event did not seek medical care, a 2014 financial analysis showed tural tone due to global cerebral hypoperfusion resulting from a that the diagnostic and therapeutic costs associated with syn- decrease in cardiac output or systemic vascular resistance. The cope exceed $4.1 billion annually in the United States. onset of syncope is sudden and abrupt, and recovery is rapid, with a complete return to the baseline level of functioning. Syncope has a reported cumulative incidence of 3% to 6% over a Classification 10-year period and accounts for 1% to 2% of all emergency Syncope can be classified according to the specific etiology of department visits. Approximately 40% of adults have experi- the event as neurally mediated (reflex), cardiovascular, ortho- enced a syncopal event, and 80% of these patients had a first static, neurologic, psychogenic, or idiopathic. These etiologies 36

Common Symptoms can be further subdivided according to the specific pathophysi- TABLE 25. Historical Characteristics Associated with ologic mechanism. Approximately 40% of syncopal events are Increased Probability of Cardiac and Noncardiac Causes unexplained (idiopathic). of Syncope

can be further subdivided according to the specific pathophysi- TABLE 25. Historical Characteristics Associated with ologic mechanism. Approximately 40% of syncopal events are Increased Probability of Cardiac and Noncardiac Causes unexplained (idiopathic). of Syncope Neurally mediated syncope, or reflex syncope, is the most | More Often Associated with Cardiac Causes of Syncope common form and is seen primarily in younger adults. The Older age (>60 y) underlying syncopal mechanism, termed the neurocardiogenic Male sex or vasodepressor reflex, is a response of vasodilation, bradycar- Presence of known ischemic heart disease, structural heart dia, and systemic hypotension, which leads to transient hypo- disease, previous arrhythmias, or reduced ventricular function perfusion of the brain. Neurally mediated syncope includes | Brief prodrome, such as palpitations, or sudden loss of vasovagal syncope, which is provoked by noxious stimuli, fear, consciousness without prodrome stress, or heat overexposure; situational syncope, which is trig- Syncope during exertion gered by cough, micturition, defecation, or deglutition; and Syncope in the supine position carotid sinus hypersensitivity, which is sometimes experienced Low number of syncope episodes (one or two) during head rotation, shaving, or use of a tight-fitting neck col- Abnormal cardiac examination lar. Prodromal symptoms, including nausea and diaphoresis, are classically present before the syncopal event, and fatigue Family history of inheritable conditions or premature sudden cardiac death (<50 y of age) and generalized weakness are typically present afterward. Cardiovascular syncope is the second most common form Presence of known congenital heart disease

Neurally mediated syncope, or reflex syncope, is the most | More Often Associated with Cardiac Causes of Syncope common form and is seen primarily in younger adults. The Older age (>60 y) underlying syncopal mechanism, termed the neurocardiogenic Male sex or vasodepressor reflex, is a response of vasodilation, bradycar- Presence of known ischemic heart disease, structural heart dia, and systemic hypotension, which leads to transient hypo- disease, previous arrhythmias, or reduced ventricular function perfusion of the brain. Neurally mediated syncope includes | Brief prodrome, such as palpitations, or sudden loss of vasovagal syncope, which is provoked by noxious stimuli, fear, consciousness without prodrome stress, or heat overexposure; situational syncope, which is trig- Syncope during exertion gered by cough, micturition, defecation, or deglutition; and Syncope in the supine position carotid sinus hypersensitivity, which is sometimes experienced Low number of syncope episodes (one or two) during head rotation, shaving, or use of a tight-fitting neck col- Abnormal cardiac examination lar. Prodromal symptoms, including nausea and diaphoresis, are classically present before the syncopal event, and fatigue Family history of inheritable conditions or premature sudden cardiac death (<50 y of age) and generalized weakness are typically present afterward. Cardiovascular syncope is the second most common form Presence of known congenital heart disease of syncope and is associated with increased morbidity, mortal- | More Often Associated with Noncardiac Causes of Syncope ity (including sudden death), and direct traumatic injury. Younger age Historical characteristics that are associated with increased No known cardiac disease probability of cardiac versus noncardiac causes are listed in Syncope only in the standing position Table 25. Cardiovascular syncopal events often occur suddenly and usually without a significant prodrome, although chest | Positional change from supine or sitting to standing

of syncope and is associated with increased morbidity, mortal- | More Often Associated with Noncardiac Causes of Syncope ity (including sudden death), and direct traumatic injury. Younger age Historical characteristics that are associated with increased No known cardiac disease probability of cardiac versus noncardiac causes are listed in Syncope only in the standing position Table 25. Cardiovascular syncopal events often occur suddenly and usually without a significant prodrome, although chest | Positional change from supine or sitting to standing pain and palpitations may be present briefly. Causes of cardio- | Presence of prodrome: nausea, vomiting, feeling of warmth i vascular syncope include arrhythmia; coronary artery disease; Presence of specific triggers: dehydration, pain, distressful and structural and obstructive disease, including aortic and stimulus, medical environment pulmonary valve stenosis, obstructive hypertrophic cardiomy- Situational triggers: cough, laugh, micturition, defecation, deglutition opathy, aortic dissection, and cardiac tamponade. Pulmonary | |

pulmonary valve stenosis, obstructive hypertrophic cardiomy- Situational triggers: cough, laugh, micturition, defecation, deglutition opathy, aortic dissection, and cardiac tamponade. Pulmonary | | embolism is increasingly appreciated as a cause of syncope, | Frequent recurrence and prolonged history of syncope with | similar characteristics with a prevalence as high as 17% in some studies. Orthostatic syncope is the third most common form of | Reproduced with permission from Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/ERS guideline for the evaluation and management of patients with syncope and predominantly affects older adults. It classically syncope: executive summary: a report of the American College of Cardiology/ | American Heart Association Task Force on Clinical Practice Guidelines and the occurs after changes in position and is typically associated with | Heart Rhythm Society. Circulation. 2017;136:e32. [PMID: 28280232] doi:10.1161/ | CIR.0000000000000498. © 2017, American Heart Association, Inc. prodromal symptoms, such as lightheadedness. Orthostatic syncope is most commonly caused by hypovolemia, medica- tions, or alcohol intoxication. Less commonly, primary auto- abnormal posturing, involuntary head turning, and tongue nomic failure (Parkinson disease, multiple system atrophy, laceration. Auras, incontinence, and prolonged postepisode multiple sclerosis) or secondary autonomic failure (diabetes, confusion also favor a seizure. amyloidosis, connective tissue disease, spinal cord injury) can Psychogenic syncope, which has been referred to as pseu- lead to neurogenic orthostatic syncope. dosyncope, generally occurs in younger patients with underly- Neurologic conditions are a rare cause of syncope. ing anxiety, panic disorder, or depression. Cerebrovascular events (transient ischemic attack, ischemic or hemorrhagic stroke), seizures, and direct head trauma may Evaluation lead to transient loss of consciousness but should be distin- The American Heart Association (AHA), American College of guished from true syncope. Cerebrovascular events that lead to Cardiology (ACC), and Heart Rhythm Society (HRS) jointly true syncope primarily involve the posterior (vertebrobasilar) conclude that the history and physical examination are the circulation and usually present with concomitant symptoms most important diagnostic tools in determining the underly- of dizziness, vertigo, gait changes, and focal neurologic find- ing cause of a syncopal event. The history should focus on ings. Anterior circulation involvement rarely leads to syncope. eliciting information on prodromal or postepisode symptoms, Seizures can be confused with syncopal events, and bystander comorbid medical or psychiatric conditions, the psychosocial information can help distinguish between the two. A prospec- context of the event, and bystander information. A thorough tive study demonstrated that the features most suggestive of a review of the patient’s prescription and over-the-counter seizure in patients with loss of consciousness were witnessed medications should be completed.

embolism is increasingly appreciated as a cause of syncope, | Frequent recurrence and prolonged history of syncope with | similar characteristics with a prevalence as high as 17% in some studies. Orthostatic syncope is the third most common form of | Reproduced with permission from Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/ERS guideline for the evaluation and management of patients with syncope and predominantly affects older adults. It classically syncope: executive summary: a report of the American College of Cardiology/ | American Heart Association Task Force on Clinical Practice Guidelines and the occurs after changes in position and is typically associated with | Heart Rhythm Society. Circulation. 2017;136:e32. [PMID: 28280232] doi:10.1161/ | CIR.0000000000000498. © 2017, American Heart Association, Inc. prodromal symptoms, such as lightheadedness. Orthostatic syncope is most commonly caused by hypovolemia, medica- tions, or alcohol intoxication. Less commonly, primary auto- abnormal posturing, involuntary head turning, and tongue nomic failure (Parkinson disease, multiple system atrophy, laceration. Auras, incontinence, and prolonged postepisode multiple sclerosis) or secondary autonomic failure (diabetes, confusion also favor a seizure. amyloidosis, connective tissue disease, spinal cord injury) can Psychogenic syncope, which has been referred to as pseu- lead to neurogenic orthostatic syncope. dosyncope, generally occurs in younger patients with underly- Neurologic conditions are a rare cause of syncope. ing anxiety, panic disorder, or depression. Cerebrovascular events (transient ischemic attack, ischemic or hemorrhagic stroke), seizures, and direct head trauma may Evaluation lead to transient loss of consciousness but should be distin- The American Heart Association (AHA), American College of guished from true syncope. Cerebrovascular events that lead to Cardiology (ACC), and Heart Rhythm Society (HRS) jointly true syncope primarily involve the posterior (vertebrobasilar) conclude that the history and physical examination are the circulation and usually present with concomitant symptoms most important diagnostic tools in determining the underly- of dizziness, vertigo, gait changes, and focal neurologic find- ing cause of a syncopal event. The history should focus on ings. Anterior circulation involvement rarely leads to syncope. eliciting information on prodromal or postepisode symptoms, Seizures can be confused with syncopal events, and bystander comorbid medical or psychiatric conditions, the psychosocial information can help distinguish between the two. A prospec- context of the event, and bystander information. A thorough tive study demonstrated that the features most suggestive of a review of the patient’s prescription and over-the-counter seizure in patients with loss of consciousness were witnessed medications should be completed. 37

Common Symptoms — The physical examination should include an in-depth exercise-related syncope. ECG monitoring (in the emergency cardiovascular evaluation, including orthostatic (postural) department with an ambulatory monitor, event monitor, or blood pressure measurements, as well as a basic neurologic implantable loop recorder) should be considered in selected examination to evaluate for focal defects. Carotid hypersensi- patients with a probable arrhythmic cause; the choice of test is tivity can be assessed by using carotid sinus massage in indi- based on the frequency and nature of the syncopal event (see viduals older than 40 years with syncope of unknown cause; MKSAP 19 Cardiovascular Medicine). Targeted laboratory however, this technique is contraindicated in patients with studies are guided by findings in the history and physical known carotid disease or transient ischemic attack/stroke examination. Tilt-table testing is most commonly useful in within the past 3 months. patients suspected of having recurrent vasovagal syncope or The AHA/ACC/HRS syncope guideline recommends that when the initial evaluation of delayed orthostatic hypotension an ECG be obtained in all patients with syncope to identify is not diagnostic. Cardiac imaging with CT or MRI is most use- underlying arrhythmia, myocardial ischemia, or QT prolonga- ful when structural or infiltrative heart disease is suspected tion. In general, additional studies have a low diagnostic yield; but initial diagnostic tests are inconclusive. CT angiography is however, when there is a moderate to high pretest probability indicated for patients with a significant pretest probability of of a specific condition, these studies can help to identify or pulmonary embolism. Electrophysiology studies are reserved confirm a diagnosis (Figure 9). Echocardiography is indicated for patients suspected of having an arrhythmic cause of syn- to detect suspected valvular heart disease, hypertrophic car- cope, and the decision to perform electroencephalography diomyopathy, and reduced left ventricular function. An exer- should be based on the specific clinical scenario. The American cise stress test is most likely to be helpful in patients with College of Physicians recommends against routinely obtaining

The physical examination should include an in-depth exercise-related syncope. ECG monitoring (in the emergency cardiovascular evaluation, including orthostatic (postural) department with an ambulatory monitor, event monitor, or blood pressure measurements, as well as a basic neurologic implantable loop recorder) should be considered in selected examination to evaluate for focal defects. Carotid hypersensi- patients with a probable arrhythmic cause; the choice of test is tivity can be assessed by using carotid sinus massage in indi- based on the frequency and nature of the syncopal event (see viduals older than 40 years with syncope of unknown cause; MKSAP 19 Cardiovascular Medicine). Targeted laboratory however, this technique is contraindicated in patients with studies are guided by findings in the history and physical known carotid disease or transient ischemic attack/stroke examination. Tilt-table testing is most commonly useful in within the past 3 months. patients suspected of having recurrent vasovagal syncope or The AHA/ACC/HRS syncope guideline recommends that when the initial evaluation of delayed orthostatic hypotension an ECG be obtained in all patients with syncope to identify is not diagnostic. Cardiac imaging with CT or MRI is most use- underlying arrhythmia, myocardial ischemia, or QT prolonga- ful when structural or infiltrative heart disease is suspected tion. In general, additional studies have a low diagnostic yield; but initial diagnostic tests are inconclusive. CT angiography is however, when there is a moderate to high pretest probability indicated for patients with a significant pretest probability of of a specific condition, these studies can help to identify or pulmonary embolism. Electrophysiology studies are reserved confirm a diagnosis (Figure 9). Echocardiography is indicated for patients suspected of having an arrhythmic cause of syn- to detect suspected valvular heart disease, hypertrophic car- cope, and the decision to perform electroencephalography diomyopathy, and reduced left ventricular function. An exer- should be based on the specific clinical scenario. The American cise stress test is most likely to be helpful in patients with College of Physicians recommends against routinely obtaining Syncope additional evaluation and diagnosis

The physical examination should include an in-depth exercise-related syncope. ECG monitoring (in the emergency cardiovascular evaluation, including orthostatic (postural) department with an ambulatory monitor, event monitor, or blood pressure measurements, as well as a basic neurologic implantable loop recorder) should be considered in selected examination to evaluate for focal defects. Carotid hypersensi- patients with a probable arrhythmic cause; the choice of test is tivity can be assessed by using carotid sinus massage in indi- based on the frequency and nature of the syncopal event (see viduals older than 40 years with syncope of unknown cause; MKSAP 19 Cardiovascular Medicine). Targeted laboratory however, this technique is contraindicated in patients with studies are guided by findings in the history and physical known carotid disease or transient ischemic attack/stroke examination. Tilt-table testing is most commonly useful in within the past 3 months. patients suspected of having recurrent vasovagal syncope or The AHA/ACC/HRS syncope guideline recommends that when the initial evaluation of delayed orthostatic hypotension an ECG be obtained in all patients with syncope to identify is not diagnostic. Cardiac imaging with CT or MRI is most use- underlying arrhythmia, myocardial ischemia, or QT prolonga- ful when structural or infiltrative heart disease is suspected tion. In general, additional studies have a low diagnostic yield; but initial diagnostic tests are inconclusive. CT angiography is however, when there is a moderate to high pretest probability indicated for patients with a significant pretest probability of of a specific condition, these studies can help to identify or pulmonary embolism. Electrophysiology studies are reserved confirm a diagnosis (Figure 9). Echocardiography is indicated for patients suspected of having an arrhythmic cause of syn- to detect suspected valvular heart disease, hypertrophic car- cope, and the decision to perform electroencephalography diomyopathy, and reduced left ventricular function. An exer- should be based on the specific clinical scenario. The American cise stress test is most likely to be helpful in patients with College of Physicians recommends against routinely obtaining Syncope additional evaluation and diagnosis \

The physical examination should include an in-depth exercise-related syncope. ECG monitoring (in the emergency cardiovascular evaluation, including orthostatic (postural) department with an ambulatory monitor, event monitor, or blood pressure measurements, as well as a basic neurologic implantable loop recorder) should be considered in selected examination to evaluate for focal defects. Carotid hypersensi- patients with a probable arrhythmic cause; the choice of test is tivity can be assessed by using carotid sinus massage in indi- based on the frequency and nature of the syncopal event (see viduals older than 40 years with syncope of unknown cause; MKSAP 19 Cardiovascular Medicine). Targeted laboratory however, this technique is contraindicated in patients with studies are guided by findings in the history and physical known carotid disease or transient ischemic attack/stroke examination. Tilt-table testing is most commonly useful in within the past 3 months. patients suspected of having recurrent vasovagal syncope or The AHA/ACC/HRS syncope guideline recommends that when the initial evaluation of delayed orthostatic hypotension an ECG be obtained in all patients with syncope to identify is not diagnostic. Cardiac imaging with CT or MRI is most use- underlying arrhythmia, myocardial ischemia, or QT prolonga- ful when structural or infiltrative heart disease is suspected tion. In general, additional studies have a low diagnostic yield; but initial diagnostic tests are inconclusive. CT angiography is however, when there is a moderate to high pretest probability indicated for patients with a significant pretest probability of of a specific condition, these studies can help to identify or pulmonary embolism. Electrophysiology studies are reserved confirm a diagnosis (Figure 9). Echocardiography is indicated for patients suspected of having an arrhythmic cause of syn- to detect suspected valvular heart disease, hypertrophic car- cope, and the decision to perform electroencephalography diomyopathy, and reduced left ventricular function. An exer- should be based on the specific clinical scenario. The American cise stress test is most likely to be helpful in patients with College of Physicians recommends against routinely obtaining Syncope additional evaluation and diagnosis \ y Initial evaluation suggests Initial evaluation suggests clear etiology unclear etiology

The physical examination should include an in-depth exercise-related syncope. ECG monitoring (in the emergency cardiovascular evaluation, including orthostatic (postural) department with an ambulatory monitor, event monitor, or blood pressure measurements, as well as a basic neurologic implantable loop recorder) should be considered in selected examination to evaluate for focal defects. Carotid hypersensi- patients with a probable arrhythmic cause; the choice of test is tivity can be assessed by using carotid sinus massage in indi- based on the frequency and nature of the syncopal event (see viduals older than 40 years with syncope of unknown cause; MKSAP 19 Cardiovascular Medicine). Targeted laboratory however, this technique is contraindicated in patients with studies are guided by findings in the history and physical known carotid disease or transient ischemic attack/stroke examination. Tilt-table testing is most commonly useful in within the past 3 months. patients suspected of having recurrent vasovagal syncope or The AHA/ACC/HRS syncope guideline recommends that when the initial evaluation of delayed orthostatic hypotension an ECG be obtained in all patients with syncope to identify is not diagnostic. Cardiac imaging with CT or MRI is most use- underlying arrhythmia, myocardial ischemia, or QT prolonga- ful when structural or infiltrative heart disease is suspected tion. In general, additional studies have a low diagnostic yield; but initial diagnostic tests are inconclusive. CT angiography is however, when there is a moderate to high pretest probability indicated for patients with a significant pretest probability of of a specific condition, these studies can help to identify or pulmonary embolism. Electrophysiology studies are reserved confirm a diagnosis (Figure 9). Echocardiography is indicated for patients suspected of having an arrhythmic cause of syn- to detect suspected valvular heart disease, hypertrophic car- cope, and the decision to perform electroencephalography diomyopathy, and reduced left ventricular function. An exer- should be based on the specific clinical scenario. The American cise stress test is most likely to be helpful in patients with College of Physicians recommends against routinely obtaining Syncope additional evaluation and diagnosis \ y Initial evaluation suggests Initial evaluation suggests clear etiology unclear etiology |! a ‘ ) | Seria? | No additional Initial Initial evaluation Initial evaluation evaluation evaluation suggests reflex suggests CV — needed? suggests syncope abnormalities = OH

|! a ‘ ) | Seria? | No additional Initial Initial evaluation Initial evaluation evaluation evaluation suggests reflex suggests CV — needed? suggests syncope abnormalities = OH ee Options FIGURE 9. Additional evaluation and diagnosis of syncope. Colors correspond to class (strength) of recommendation, with green corresponding to a class | (strong) recommendation, yellow corresponding to a class Ila (moderate) recommendation, and orange corresponding to a class Ilb (weak) recommendation. CV = cardiovascular; ECG = electrocardiography; EPS = electrophysiology study; OH = orthostatic hypotension; TTE = transthoracic echocardiography. Applies to patients after a normal initial evaluation without significant injury or cardiovascular morbidities; patients should be followed up by a primary care physician as needed. *In selected patients. Reproduced with permission from Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: executive summary: a report of the American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2017;136:e36. [PMID: 28280232] doi:10.1161/CIR.0000000000000498 ©2017, American Heart Association, Inc. 38

Common Symptoms brain imaging (CT or MRI) in cases of syncope that do not contributing medications, compression stockings, and educa- involve objective focal neurologic findings. Carotid duplex tion on postural changes. Initiation of additional vasoactive ultrasonography plays no role in the evaluation of syncope. agents, such as fludrocortisone or midodrine, can be consid- ered; however, available evidence on their efficacy is limited Risk Stratification and Decision and conflicting. Referral to a mental health specialist is appro- for Hospital Admission priate for patients with psychogenic syncope. The AHA/ACC/HRS syncope guideline recommends evalua- tion to determine the cause of syncope and assessment of the Prognosis patient’s short- and long-term morbidity and mortality risk. The underlying cause of the syncopal event determines the Short-term adverse events and deaths are primarily deter- prognosis. Patients with a syncopal episode are at increased mined by the underlying etiology and the effectiveness of the risk for all-cause mortality (hazard ratio [HR], 1.3; 95% Cl, treatment. Risk scores have been developed to assist in risk 1.1-1.5) and cardiovascular events (HR, 1.3; 95% CI, 1.0-1.6). stratification and to guide patient disposition; however, they The risk for death is even greater in cases of cardiac syncope generally do not outperform unstructured clinical judgment. (HR, 2.0; 95% CI, 1.5-2.7). Neurally mediated and orthostatic The presence of high-risk clinical characteristics should syncope do not portend increased cardiovascular mortality. prompt consideration of hospitalization (Table 26). Patients Syncope of any cause, especially if recurrent, can severely with likely reflex-mediated syncope who do not have serious affect quality of life, functional independence, and self- underlying medical conditions can be managed in the outpa- confidence. Clinicians should assess for any ensuing mood tient setting. changes, the need for skilled assistance, and the need for pos- sible driving restrictions (which vary per state law). Management Neurally mediated syncope can be managed with reassurance e The history and physical examination, including ortho- HVC and education on avoiding provoking measures. Physical coun- static (postural) blood pressure measurement, are the terpressure techniques, such as leg crossing, squatting, or most important diagnostic tools in determining the handgrip maneuvers, can be beneficial for neurally mediated underlying cause of syncope. syncope with a prolonged prodrome. Cardiovascular syncope management should target the specific underlying cardiac con- e An ECG should be obtained in all patients with syncope to HVC dition. Orthostatic syncope may be treated with volume expan- identify underlying arrhythmia, ischemia, or QT prolon-

brain imaging (CT or MRI) in cases of syncope that do not contributing medications, compression stockings, and educa- involve objective focal neurologic findings. Carotid duplex tion on postural changes. Initiation of additional vasoactive ultrasonography plays no role in the evaluation of syncope. agents, such as fludrocortisone or midodrine, can be consid- ered; however, available evidence on their efficacy is limited Risk Stratification and Decision and conflicting. Referral to a mental health specialist is appro- for Hospital Admission priate for patients with psychogenic syncope. The AHA/ACC/HRS syncope guideline recommends evalua- tion to determine the cause of syncope and assessment of the Prognosis patient’s short- and long-term morbidity and mortality risk. The underlying cause of the syncopal event determines the Short-term adverse events and deaths are primarily deter- prognosis. Patients with a syncopal episode are at increased mined by the underlying etiology and the effectiveness of the risk for all-cause mortality (hazard ratio [HR], 1.3; 95% Cl, treatment. Risk scores have been developed to assist in risk 1.1-1.5) and cardiovascular events (HR, 1.3; 95% CI, 1.0-1.6). stratification and to guide patient disposition; however, they The risk for death is even greater in cases of cardiac syncope generally do not outperform unstructured clinical judgment. (HR, 2.0; 95% CI, 1.5-2.7). Neurally mediated and orthostatic The presence of high-risk clinical characteristics should syncope do not portend increased cardiovascular mortality. prompt consideration of hospitalization (Table 26). Patients Syncope of any cause, especially if recurrent, can severely with likely reflex-mediated syncope who do not have serious affect quality of life, functional independence, and self- underlying medical conditions can be managed in the outpa- confidence. Clinicians should assess for any ensuing mood tient setting. changes, the need for skilled assistance, and the need for pos- sible driving restrictions (which vary per state law). Management Neurally mediated syncope can be managed with reassurance e The history and physical examination, including ortho- HVC and education on avoiding provoking measures. Physical coun- static (postural) blood pressure measurement, are the terpressure techniques, such as leg crossing, squatting, or most important diagnostic tools in determining the handgrip maneuvers, can be beneficial for neurally mediated underlying cause of syncope. syncope with a prolonged prodrome. Cardiovascular syncope management should target the specific underlying cardiac con- e An ECG should be obtained in all patients with syncope to HVC dition. Orthostatic syncope may be treated with volume expan- identify underlying arrhythmia, ischemia, or QT prolon- sion (with salt liberalization, if appropriate), reconsideration of gation; other tests have low diagnostic yield and should be performed only when there is a moderate to high pre- test probability of a specific underlying condition. TABLE 26. High-Risk Clinical Characteristics in the Patient with Syncope? e The American College of Physicians recommends HVC Syncope during exertion against routinely performing brain imaging in cases of syncope that do not involve objective focal neurologic Syncope in supine position findings. Symptoms of chest discomfort or palpitations before syncope e Neurally mediated syncope is treated with reassurance HVC Family history of sudden death and avoidance of provoking measures; physical coun- History of structural heart abnormalities, ischemic heart disease, terpressure techniques can be useful in patients with a known arrhythmia, or heart failure prolonged prodrome. New or previously unknown left bundle branch block, bifascicular block, Brugada pattern, findings consistent with ¢ Orthostatic syncope may be treated with volume acute ischemia, nonsinus rhythm, prolonged QTc (>450 ms) expansion (with salt liberalization, if appropriate), Hemoglobin <9 g/dL (90 g/L) reconsideration of contributing medications, compres- Systolic blood pressure <0 mm Hg or >180 mm Hg sion stockings, and education on postural changes.

sion (with salt liberalization, if appropriate), reconsideration of gation; other tests have low diagnostic yield and should be performed only when there is a moderate to high pre- test probability of a specific underlying condition. TABLE 26. High-Risk Clinical Characteristics in the Patient with Syncope? e The American College of Physicians recommends HVC Syncope during exertion against routinely performing brain imaging in cases of syncope that do not involve objective focal neurologic Syncope in supine position findings. Symptoms of chest discomfort or palpitations before syncope e Neurally mediated syncope is treated with reassurance HVC Family history of sudden death and avoidance of provoking measures; physical coun- History of structural heart abnormalities, ischemic heart disease, terpressure techniques can be useful in patients with a known arrhythmia, or heart failure prolonged prodrome. New or previously unknown left bundle branch block, bifascicular block, Brugada pattern, findings consistent with ¢ Orthostatic syncope may be treated with volume acute ischemia, nonsinus rhythm, prolonged QTc (>450 ms) expansion (with salt liberalization, if appropriate), Hemoglobin <9 g/dL (90 g/L) reconsideration of contributing medications, compres- Systolic blood pressure <0 mm Hg or >180 mm Hg sion stockings, and education on postural changes. Sinus bradycardia (<40/min)

sion (with salt liberalization, if appropriate), reconsideration of gation; other tests have low diagnostic yield and should be performed only when there is a moderate to high pre- test probability of a specific underlying condition. TABLE 26. High-Risk Clinical Characteristics in the Patient with Syncope? e The American College of Physicians recommends HVC Syncope during exertion against routinely performing brain imaging in cases of syncope that do not involve objective focal neurologic Syncope in supine position findings. Symptoms of chest discomfort or palpitations before syncope e Neurally mediated syncope is treated with reassurance HVC Family history of sudden death and avoidance of provoking measures; physical coun- History of structural heart abnormalities, ischemic heart disease, terpressure techniques can be useful in patients with a known arrhythmia, or heart failure prolonged prodrome. New or previously unknown left bundle branch block, bifascicular block, Brugada pattern, findings consistent with ¢ Orthostatic syncope may be treated with volume acute ischemia, nonsinus rhythm, prolonged QTc (>450 ms) expansion (with salt liberalization, if appropriate), Hemoglobin <9 g/dL (90 g/L) reconsideration of contributing medications, compres- Systolic blood pressure <0 mm Hg or >180 mm Hg sion stockings, and education on postural changes. Sinus bradycardia (<40/min) Infrequent syncopal episodes Common In-Flight Emergencies Male sex In-flight medical emergencies are relatively common during Age >60 y air travel, occurring in an estimated 1 in 600 flights. The most | QTc =corrected QT interval. common in-flight emergencies are presyncope or syncope °A patient is considered at high cardiac risk if any of the above risk factors are (typically vasovagal), which account for up to one third of present. in-flight emergencies. The frequency of these events is Information from Costantino G, Sun BC, Barbic F, et al. Syncope clinical management in the emergency department: a consensus from the first international workshop on explained by the physiologic conditions in flight, including syncope risk stratification in the emergency department. Eur Heart J. 2016;37:1493- low humidity and high altitudes. Other common in-flight 8. [PMID: 26242712] doi:10.1093/eurheartj/ehv378 emergencies include gastrointestinal disorders (diarrhea and

Infrequent syncopal episodes Common In-Flight Emergencies Male sex In-flight medical emergencies are relatively common during Age >60 y air travel, occurring in an estimated 1 in 600 flights. The most | QTc =corrected QT interval. common in-flight emergencies are presyncope or syncope °A patient is considered at high cardiac risk if any of the above risk factors are (typically vasovagal), which account for up to one third of present. in-flight emergencies. The frequency of these events is Information from Costantino G, Sun BC, Barbic F, et al. Syncope clinical management in the emergency department: a consensus from the first international workshop on explained by the physiologic conditions in flight, including syncope risk stratification in the emergency department. Eur Heart J. 2016;37:1493- low humidity and high altitudes. Other common in-flight 8. [PMID: 26242712] doi:10.1093/eurheartj/ehv378 emergencies include gastrointestinal disorders (diarrhea and 39

vomiting), cardiovascular symptoms (chest pain), and res- piratory symptoms (dyspnea and hyperventilation). Most air- e The physician’s role in in-flight emergencies involves craft cabins are pressurized to 6000 to 8000 feet, and the assessing the patient, establishing a diagnosis when lower partial pressure of oxygen may cause dyspnea in those possible, administering basic medical treatments, pro- with significant underlying cardiopulmonary disease. viding reassurance as appropriate, and recommending In-flight cardiac arrest is rare (approximately 0.2% of in-flight flight diversion if necessary. emergencies); however, it is responsible for the majority of e In the United States, physicians are not legally mandated in-flight deaths. In the event of suspected acute myocardial to assist in the event of an in-flight emergency; however, infarction or stroke, immediate flight diversion should be physicians have an ethical obligation to provide assistance recommended to the crew. Other frequently encountered as able. issues include trauma caused by objects falling from over- head bins, hypoglycemia, psychiatric problems (most com- monly anxiety or phobias), allergic reactions, seizures, headaches, and obstetric or gynecologic events. Physicians who respond to in-flight emergencies have Pain access to medical resources and support. Airlines based in Classification the United States are mandated by the Federal Aviation Acute pain (<6 weeks’ duration) is the most common reason Administration to carry at least one automated external that patients seek emergent care and frequently occurs in hos- defibrillator; supplemental oxygen; and a medical kit that pitalized patients. Chronic pain (>3 months’ duration or last- contains a stethoscope, sphygmomanometer, gloves, airway ing longer than is typically associated with tissue healing) supplies, intravenous access supplies (needles, syringes, affects more than 10% of the U.S. population and has substan- saline), and some basic medications (epinephrine, lidocaine, tial negative effects on patient quality of life and physical, atropine, aspirin, nitroglycerin, antihistamines, bronchodila- social, financial, and functional status. tors, and dextrose). Many U.S. airlines augment their kits with Identification of pain as either nociceptive or neuropathic additional supplies. The contents of international kits may can be helpful in tailoring approaches for some pain syn- vary. In addition, patients experiencing an in-flight emergency dromes, particularly in the acute setting. Many patients with may have their own prescription medications with them. chronic noncancer pain syndromes, however, experience both The physician’s role in in-flight medical emergencies nociceptive and neuropathic pain from multiple sources. involves assessing the patient, establishing a diagnosis when pos- Nociceptive pain is caused by involvement of either vis- sible, administering basic medical treatments, providing reassur- ceral or somatic nociceptors. Visceral pain classically results ance as appropriate, and recommending flight diversion if from injury to or abnormal firing of visceral pain fibers, and necessary. Most airlines contract with 24-hour call centers staffed patients typically report poorly localized cramping or aching with emergency medicine physicians with special training on the pain. Somatic pain is more commonly associated with injury in-flight environment. Such support is accessed through the to somatic pain fibers that convey signals from muscles, bones, pilot, and direct communication between the physician provid- and joints. Types of somatic pain include musculoskeletal pain ing assistance and the ground-based support physician may not (see Common Musculoskeletal Problems) and inflammatory be possible. Flight crews are required to receive cardiopulmonary pain. Often described by patients as sharp and stabbing pain, resuscitation training, including training on the use of automated somatic nociception may be easier to localize than visceral external defibrillators, and to be familiar with first-aid equip- pain. ment. If the patient’s condition is critical, the physician can rec- Neuropathic pain results from injury to peripheral nerve ommend diversion of the flight to the nearest airport, although structures or the central nervous system. Peripheral nerve the ultimate decision rests with the aircraft captain. syndromes, such as postherpetic neuralgia, are common and In the United States, physicians are not legally mandated can be diagnosed by identifying sensory symptoms within the to assist in the event of an in-flight emergency, although some distribution of the affected peripheral nerves. Central neuro- countries do impose such obligations. The laws of the country pathic pain syndromes, such as those caused by cerebrovascu- in which the aircraft is registered usually prevail. Ethically, lar accidents or spinal cord injuries, often have widely varying physicians should provide assistance as able. The Aviation presentations and can evade diagnosis. Pain may be vaguely Medical Assistance Act of 1998 includes a Good Samaritan localized and associated with hyperalgesia (oversensitivity to a provision that protects individuals who are medically qualified painful stimulus) or allodynia (pain from a normally nonpain- “from liability for rendering assistance unless that person is ful stimulus). engaged in gross negligence or willful misconduct,” such as Pain induced by chronic opioid therapy is being increas- providing care while intoxicated. Providers should practice ingly recognized. Opioid-induced hyperalgesia is thought to within their scope of training, be mindful of patient privacy, result from repeated exposure to systemic opioids. Patients and document the patient encounter. with this pain syndrome may experience a change in the

vomiting), cardiovascular symptoms (chest pain), and res- piratory symptoms (dyspnea and hyperventilation). Most air- e The physician’s role in in-flight emergencies involves craft cabins are pressurized to 6000 to 8000 feet, and the assessing the patient, establishing a diagnosis when lower partial pressure of oxygen may cause dyspnea in those possible, administering basic medical treatments, pro- with significant underlying cardiopulmonary disease. viding reassurance as appropriate, and recommending In-flight cardiac arrest is rare (approximately 0.2% of in-flight flight diversion if necessary. emergencies); however, it is responsible for the majority of e In the United States, physicians are not legally mandated in-flight deaths. In the event of suspected acute myocardial to assist in the event of an in-flight emergency; however, infarction or stroke, immediate flight diversion should be physicians have an ethical obligation to provide assistance recommended to the crew. Other frequently encountered as able. issues include trauma caused by objects falling from over- head bins, hypoglycemia, psychiatric problems (most com- monly anxiety or phobias), allergic reactions, seizures, headaches, and obstetric or gynecologic events. Physicians who respond to in-flight emergencies have Pain access to medical resources and support. Airlines based in Classification the United States are mandated by the Federal Aviation Acute pain (<6 weeks’ duration) is the most common reason Administration to carry at least one automated external that patients seek emergent care and frequently occurs in hos- defibrillator; supplemental oxygen; and a medical kit that pitalized patients. Chronic pain (>3 months’ duration or last- contains a stethoscope, sphygmomanometer, gloves, airway ing longer than is typically associated with tissue healing) supplies, intravenous access supplies (needles, syringes, affects more than 10% of the U.S. population and has substan- saline), and some basic medications (epinephrine, lidocaine, tial negative effects on patient quality of life and physical, atropine, aspirin, nitroglycerin, antihistamines, bronchodila- social, financial, and functional status. tors, and dextrose). Many U.S. airlines augment their kits with Identification of pain as either nociceptive or neuropathic additional supplies. The contents of international kits may can be helpful in tailoring approaches for some pain syn- vary. In addition, patients experiencing an in-flight emergency dromes, particularly in the acute setting. Many patients with may have their own prescription medications with them. chronic noncancer pain syndromes, however, experience both The physician’s role in in-flight medical emergencies nociceptive and neuropathic pain from multiple sources. involves assessing the patient, establishing a diagnosis when pos- Nociceptive pain is caused by involvement of either vis- sible, administering basic medical treatments, providing reassur- ceral or somatic nociceptors. Visceral pain classically results ance as appropriate, and recommending flight diversion if from injury to or abnormal firing of visceral pain fibers, and necessary. Most airlines contract with 24-hour call centers staffed patients typically report poorly localized cramping or aching with emergency medicine physicians with special training on the pain. Somatic pain is more commonly associated with injury in-flight environment. Such support is accessed through the to somatic pain fibers that convey signals from muscles, bones, pilot, and direct communication between the physician provid- and joints. Types of somatic pain include musculoskeletal pain ing assistance and the ground-based support physician may not (see Common Musculoskeletal Problems) and inflammatory be possible. Flight crews are required to receive cardiopulmonary pain. Often described by patients as sharp and stabbing pain, resuscitation training, including training on the use of automated somatic nociception may be easier to localize than visceral external defibrillators, and to be familiar with first-aid equip- pain. ment. If the patient’s condition is critical, the physician can rec- Neuropathic pain results from injury to peripheral nerve ommend diversion of the flight to the nearest airport, although structures or the central nervous system. Peripheral nerve the ultimate decision rests with the aircraft captain. syndromes, such as postherpetic neuralgia, are common and In the United States, physicians are not legally mandated can be diagnosed by identifying sensory symptoms within the to assist in the event of an in-flight emergency, although some distribution of the affected peripheral nerves. Central neuro- countries do impose such obligations. The laws of the country pathic pain syndromes, such as those caused by cerebrovascu- in which the aircraft is registered usually prevail. Ethically, lar accidents or spinal cord injuries, often have widely varying physicians should provide assistance as able. The Aviation presentations and can evade diagnosis. Pain may be vaguely Medical Assistance Act of 1998 includes a Good Samaritan localized and associated with hyperalgesia (oversensitivity to a provision that protects individuals who are medically qualified painful stimulus) or allodynia (pain from a normally nonpain- “from liability for rendering assistance unless that person is ful stimulus). engaged in gross negligence or willful misconduct,” such as Pain induced by chronic opioid therapy is being increas- providing care while intoxicated. Providers should practice ingly recognized. Opioid-induced hyperalgesia is thought to within their scope of training, be mindful of patient privacy, result from repeated exposure to systemic opioids. Patients and document the patient encounter. with this pain syndrome may experience a change in the 40

character of their pain during the course of opioid therapy, Management worsening pain with increasing opioid dosages, and pain The goal of pain management is to improve function and qual- reduction when opioid dosages are decreased. ity of life. Management should be directed to the cause of the patient’s pain; acuity of presentation; pain severity (as it affects Assessment functional status); medical and psychosocial comorbid condi- The first step in the assessment of any pain syndrome, regard- tions; and barriers to treatment, such as health care access and less of time course, is a thorough history and physical examina- concomitant mental health disorders. tion. Determination of pain location, character, duration, sever- Nonpharmacologic strategies are the cornerstone of pain ity, temporal nature, and responsiveness to treatment is crucial management. In patients with chronic pain syndromes, devel- to identifying the pain generator and tailoring the diagnostic oping a therapeutic relationship in which patients feel their and therapeutic approaches. Numeric pain scales are a common pain is taken seriously and in which patients, family members, measurement technique for identifying pain intensity; however, and social supports are active participants is important for the numbers may not directly correlate with patient perceived success over time. Physical activity, engagement in work activ- severity, tolerability, or functional impairment. ities, and behavioral interventions should be encouraged The physical examination should include a careful inspec- regardless of pain score.

tion. Determination of pain location, character, duration, sever- Nonpharmacologic strategies are the cornerstone of pain ity, temporal nature, and responsiveness to treatment is crucial management. In patients with chronic pain syndromes, devel- to identifying the pain generator and tailoring the diagnostic oping a therapeutic relationship in which patients feel their and therapeutic approaches. Numeric pain scales are a common pain is taken seriously and in which patients, family members, measurement technique for identifying pain intensity; however, and social supports are active participants is important for the numbers may not directly correlate with patient perceived success over time. Physical activity, engagement in work activ- severity, tolerability, or functional impairment. ities, and behavioral interventions should be encouraged The physical examination should include a careful inspec- regardless of pain score. tion of the painful region and a comprehensive neurologic evalu- A multimodal approach plays an important role in the ation. In patients with acute pain, additional testing and imaging management of all pain subtypes, including acute and chronic may be warranted, although such measures are unlikely to pro- noncancer-related pain, cancer-related pain, and pain at the duce further diagnostic yield in those with chronic pain. end of life (see Pain Management in Patients With Serious In patients with a history of cancer and chronic cancer- Illness). Pharmacologic therapy, including nonopioid and opi- related or cancer treatment-related pain, including those in oid therapies (when appropriate), should be viewed as adjunc- survivorship, new or worsening pain should prompt a more tive to nonpharmacologic therapy. Frequent monitoring of detailed diagnostic assessment. The evaluation should include pain severity, associated effect on functional status, response determination of significant changes in pain experience, new to interventions, and quality of life should be documented.

related or cancer treatment-related pain, including those in oid therapies (when appropriate), should be viewed as adjunc- survivorship, new or worsening pain should prompt a more tive to nonpharmacologic therapy. Frequent monitoring of detailed diagnostic assessment. The evaluation should include pain severity, associated effect on functional status, response determination of significant changes in pain experience, new to interventions, and quality of life should be documented. acute pain syndromes superimposed on chronic pain, and development of “red flag” symptoms. Red flags include pain Nonpharmacologic Therapy occurring with constitutional symptoms (e.g., fever, involun- In patients with acute pain, distraction techniques and music tary weight loss), change in bowel or bladder function, and therapy have shown benefit for patients in both emergency weakness or sensory deficits. These signs and symptoms raise department and postoperative settings. suspicion for infection or recurrent cancer and should trigger Patients with chronic pain should be referred to a struc- further investigation. tured physical therapy program for evaluation and treatment A key component of chronic pain assessment is a thor- aimed at improving functional status. High-quality evidence ough review of the patient’s functional status, including physi- suggests that physical therapy programs improve both pain cal functioning, ability to perform basic activities of daily and function in patients with debilitation due to pain. living, and psycho-social-spiritual functioning. Psychological Continuation of physical therapy beyond 12 weeks should be comorbidities influence and are influenced by experiences of based on iterative clinical assessments and documented chronic pain, and they affect response and adherence to a gains. Like physical therapy, exercise programs improve pain multimodal treatment strategy. Patients should be screened for and function in patients with chronic pain, although no mental health disorders, especially depression and anxiety specific regimen has proved superior. Cognitive behavioral (see Mental and Behavioral Health), because patients with techniques, including cognitive behavioral therapy (CBT), chronic pain are up to four times more likely to have concomi- mindfulness practices, and biofeedback, have been associ- tant depression. ated with reduced pain and improved overall function and Substance use screening is another essential part of the mood. Referral to practices or specialized pain centers that assessment of patients with chronic pain (see Mental and provide these therapies should be explored when available. Behavioral Health). Substance use disorders are more com- Low- to moderate-quality evidence supports the use of com- mon in patients with chronic pain syndromes and increase the plementary and integrative therapies, such as massage, spinal risk for opioid misuse. manipulation, and acupuncture, in chronic pain manage- ment, and these interventions may be helpful adjuncts in some patients. ¢ In patients with pain, determination of pain location, Interventional approaches may be appropriate for acute duration, character, severity, temporal nature, and or chronic pain symptoms that can be anatomically targeted responsiveness to treatment is crucial in identifying the with injection-based therapy, such as nerve blocks and trigger pain generator and tailoring the diagnostic and thera- point injections. Advanced therapies, such as high-frequency peutic approaches. neurostimulation, hold promise for appropriately selected

acute pain syndromes superimposed on chronic pain, and development of “red flag” symptoms. Red flags include pain Nonpharmacologic Therapy occurring with constitutional symptoms (e.g., fever, involun- In patients with acute pain, distraction techniques and music tary weight loss), change in bowel or bladder function, and therapy have shown benefit for patients in both emergency weakness or sensory deficits. These signs and symptoms raise department and postoperative settings. suspicion for infection or recurrent cancer and should trigger Patients with chronic pain should be referred to a struc- further investigation. tured physical therapy program for evaluation and treatment A key component of chronic pain assessment is a thor- aimed at improving functional status. High-quality evidence ough review of the patient’s functional status, including physi- suggests that physical therapy programs improve both pain cal functioning, ability to perform basic activities of daily and function in patients with debilitation due to pain. living, and psycho-social-spiritual functioning. Psychological Continuation of physical therapy beyond 12 weeks should be comorbidities influence and are influenced by experiences of based on iterative clinical assessments and documented chronic pain, and they affect response and adherence to a gains. Like physical therapy, exercise programs improve pain multimodal treatment strategy. Patients should be screened for and function in patients with chronic pain, although no mental health disorders, especially depression and anxiety specific regimen has proved superior. Cognitive behavioral (see Mental and Behavioral Health), because patients with techniques, including cognitive behavioral therapy (CBT), chronic pain are up to four times more likely to have concomi- mindfulness practices, and biofeedback, have been associ- tant depression. ated with reduced pain and improved overall function and Substance use screening is another essential part of the mood. Referral to practices or specialized pain centers that assessment of patients with chronic pain (see Mental and provide these therapies should be explored when available. Behavioral Health). Substance use disorders are more com- Low- to moderate-quality evidence supports the use of com- mon in patients with chronic pain syndromes and increase the plementary and integrative therapies, such as massage, spinal risk for opioid misuse. manipulation, and acupuncture, in chronic pain manage- ment, and these interventions may be helpful adjuncts in some patients. ¢ In patients with pain, determination of pain location, Interventional approaches may be appropriate for acute duration, character, severity, temporal nature, and or chronic pain symptoms that can be anatomically targeted responsiveness to treatment is crucial in identifying the with injection-based therapy, such as nerve blocks and trigger pain generator and tailoring the diagnostic and thera- point injections. Advanced therapies, such as high-frequency peutic approaches. neurostimulation, hold promise for appropriately selected 41

Pain patients with chronic pain. Patients may be referred to a pain In patients with chronic pain, pharmacologic therapy may specialist for consideration of these therapies. be used as adjunctive treatment when nonpharmacologic ther- The incidence of depression increases as pain symptoms apies have not achieved their desired effect. Clinicians should intensify, and depression itself may manifest as pain. emphasize that pharmacologic therapies have limited efficacy Aggressive treatment of depression with CBT and pharmaco- in the long-term management of pain and are intended to logic therapy can lead to substantial improvement in both improve function and quality of life, not pain scores. Patients chronic pain and depressive symptoms. Iterative evaluation of should be informed that drugs may take weeks to be effective depressive symptoms during chronic pain treatment is critical and that a combination of medications with differing mecha- to ensuring that patients can sustain improvements. nisms may be necessary to provide optimal benefit (e.g., rational polypharmacy). When selecting pharmacologic ther- apy to add to a multimodal treatment regimen, attention to e Physical therapy improves both pain and function in comorbid illnesses (particularly organ dysfunction) and poten- patients with debilitation due to chronic pain. tial drug-drug interactions is necessary to limit side effects. e Treatment of depression and cognitive behavioral tech- Chronic musculoskeletal or inflammatory nociceptive niques, including cognitive behavioral therapy, mindful- pain may be treated initially with trials of acetaminophen or ness practices, and biofeedback, have been associated NSAIDs. These drugs are most appropriately used for periodic with reduced pain and improved overall function and pain flares or potentially while opioid therapy is being titrated mood in patients with chronic pain. down, but they should be avoided as long-term therapy, owing to the potential for gastrointestinal, renal, and cardiovascular adverse effects. Pharmacologic Therapy Gabapentin, pregabalin, and duloxetine are first-line Nonopioid Pharmacologic Therapy therapy for chronic neuropathic pain. Other pharmacologic Nonopioid pharmacologic therapy is frequently effective for options for neuropathic pain include capsaicin and topical mild or moderate acute pain. Acetaminophen and NSAIDs are lidocaine if pain generators are focal and topically located. The first-line therapy, although efficacy of these agents varies by role of antiseizure medications in the treatment of chronic the specific indication. Regularly scheduled and combination neuropathic pain is unclear, although carbamazepine appears therapies are often required to achieve a reasonable level of to be effective in the treatment of trigeminal neuralgia. pain control, and specific regimens should be tailored to the Tricyclic antidepressants, such as nortriptyline and desipra- severity of pain, its expected duration, and the presence of mine, are also effective for neuropathic pain syndromes, comorbidities. Topical NSAIDs, such as diclofenac, have few although titration to effective dosages is often limited by side systemic side effects, are generally well tolerated, and may be effects and drug-drug interactions. effective for treatment of musculoskeletal nociceptive condi- Medical cannabis is increasingly available to patients with tions. Short courses of muscle relaxants may be beneficial in chronic pain. Many states have passed laws legalizing the use some patients with acute pain; however, long-term use should of cannabis or allowing its use for medical conditions, although be avoided because of the potential for side effects and drug- it is still classified by the U.S. Drug Enforcement Administration drug interactions. as a schedule | agent. Current data on the effectiveness of Nonopioid adjuvants historically associated with neuro- medical cannabis for chronic pain are characterized by signifi- pathic pain syndromes, including the gabapentinoids (gabapen- cant heterogeneity in both patient populations and cannabis tin and pregabalin) and serotonin-norepinephrine reuptake preparations, although recent systematic reviews have demon- inhibitors (duloxetine), are frequently used off-label to treat strated that cannabis has some efficacy in the treatment of acute pain in hospitalized or postoperative patients (as an chronic noncancer pain. The most robust data originate from opioid-sparing strategy); cancer-associated pain; and various studies of compounds available outside the United States (such chronic pain syndromes. This practice is supported by only as nabiximols), which contain higher ratios of cannabidiol to modest-quality data, which are often extrapolated from studies tetrahydrocannabinol (THC) than the existing FDA-approved of other pain syndromes. Side effects of gabapentinoids include synthetic THC (dronabinol). Little is known about the com- dizziness, disequilibrium, somnolence, weight gain, peripheral parative efficacy of cannabis preparations. edema, and cognitive difficulties. In 2019, the FDA issued a warning that gabapentinoids may cause serious breathing dif- ficulties in patients with respiratory risk factors, including opi- e¢ Musculoskeletal or inflammatory nociceptive pain may HVC oid use and COPD. Clinicians should be aware of the limited be treated initially with trials of acetaminophen or evidence and potential adverse effects when prescribing neuro- NSAIDs. pathic pain agents in these settings; however, if pharmacologic e Gabapentinoids and serotonin-norepinephrine reuptake options are limited or harm reduction strategies are necessary, inhibitors are first-line therapy for chronic neuropathic these drugs can be helpful when combined with patient- pain syndromes. centered functional goals and shared decision making.

patients with chronic pain. Patients may be referred to a pain In patients with chronic pain, pharmacologic therapy may specialist for consideration of these therapies. be used as adjunctive treatment when nonpharmacologic ther- The incidence of depression increases as pain symptoms apies have not achieved their desired effect. Clinicians should intensify, and depression itself may manifest as pain. emphasize that pharmacologic therapies have limited efficacy Aggressive treatment of depression with CBT and pharmaco- in the long-term management of pain and are intended to logic therapy can lead to substantial improvement in both improve function and quality of life, not pain scores. Patients chronic pain and depressive symptoms. Iterative evaluation of should be informed that drugs may take weeks to be effective depressive symptoms during chronic pain treatment is critical and that a combination of medications with differing mecha- to ensuring that patients can sustain improvements. nisms may be necessary to provide optimal benefit (e.g., rational polypharmacy). When selecting pharmacologic ther- apy to add to a multimodal treatment regimen, attention to e Physical therapy improves both pain and function in comorbid illnesses (particularly organ dysfunction) and poten- patients with debilitation due to chronic pain. tial drug-drug interactions is necessary to limit side effects. e Treatment of depression and cognitive behavioral tech- Chronic musculoskeletal or inflammatory nociceptive niques, including cognitive behavioral therapy, mindful- pain may be treated initially with trials of acetaminophen or ness practices, and biofeedback, have been associated NSAIDs. These drugs are most appropriately used for periodic with reduced pain and improved overall function and pain flares or potentially while opioid therapy is being titrated mood in patients with chronic pain. down, but they should be avoided as long-term therapy, owing to the potential for gastrointestinal, renal, and cardiovascular adverse effects. Pharmacologic Therapy Gabapentin, pregabalin, and duloxetine are first-line Nonopioid Pharmacologic Therapy therapy for chronic neuropathic pain. Other pharmacologic Nonopioid pharmacologic therapy is frequently effective for options for neuropathic pain include capsaicin and topical mild or moderate acute pain. Acetaminophen and NSAIDs are lidocaine if pain generators are focal and topically located. The first-line therapy, although efficacy of these agents varies by role of antiseizure medications in the treatment of chronic the specific indication. Regularly scheduled and combination neuropathic pain is unclear, although carbamazepine appears therapies are often required to achieve a reasonable level of to be effective in the treatment of trigeminal neuralgia. pain control, and specific regimens should be tailored to the Tricyclic antidepressants, such as nortriptyline and desipra- severity of pain, its expected duration, and the presence of mine, are also effective for neuropathic pain syndromes, comorbidities. Topical NSAIDs, such as diclofenac, have few although titration to effective dosages is often limited by side systemic side effects, are generally well tolerated, and may be effects and drug-drug interactions. effective for treatment of musculoskeletal nociceptive condi- Medical cannabis is increasingly available to patients with tions. Short courses of muscle relaxants may be beneficial in chronic pain. Many states have passed laws legalizing the use some patients with acute pain; however, long-term use should of cannabis or allowing its use for medical conditions, although be avoided because of the potential for side effects and drug- it is still classified by the U.S. Drug Enforcement Administration drug interactions. as a schedule | agent. Current data on the effectiveness of Nonopioid adjuvants historically associated with neuro- medical cannabis for chronic pain are characterized by signifi- pathic pain syndromes, including the gabapentinoids (gabapen- cant heterogeneity in both patient populations and cannabis tin and pregabalin) and serotonin-norepinephrine reuptake preparations, although recent systematic reviews have demon- inhibitors (duloxetine), are frequently used off-label to treat strated that cannabis has some efficacy in the treatment of acute pain in hospitalized or postoperative patients (as an chronic noncancer pain. The most robust data originate from opioid-sparing strategy); cancer-associated pain; and various studies of compounds available outside the United States (such chronic pain syndromes. This practice is supported by only as nabiximols), which contain higher ratios of cannabidiol to modest-quality data, which are often extrapolated from studies tetrahydrocannabinol (THC) than the existing FDA-approved of other pain syndromes. Side effects of gabapentinoids include synthetic THC (dronabinol). Little is known about the com- dizziness, disequilibrium, somnolence, weight gain, peripheral parative efficacy of cannabis preparations. edema, and cognitive difficulties. In 2019, the FDA issued a warning that gabapentinoids may cause serious breathing dif- ficulties in patients with respiratory risk factors, including opi- e¢ Musculoskeletal or inflammatory nociceptive pain may HVC oid use and COPD. Clinicians should be aware of the limited be treated initially with trials of acetaminophen or evidence and potential adverse effects when prescribing neuro- NSAIDs. pathic pain agents in these settings; however, if pharmacologic e Gabapentinoids and serotonin-norepinephrine reuptake options are limited or harm reduction strategies are necessary, inhibitors are first-line therapy for chronic neuropathic these drugs can be helpful when combined with patient- pain syndromes. centered functional goals and shared decision making. 42

Pain Opioid Therapy chronic opioids also have been misconstrued, and care must be Opioid therapy may be used to treat moderate to severe acute taken to ensure proper application of the guideline. pain. The Society of Hospital Medicine has published consen- Opioid Initiation and Risk Assessment sus guidelines on safe opioid prescribing in the hospital for When initiating or continuing opioid therapy, clear treatment noncancer-associated pain. These practice guidelines rein- goals based on functional improvement and quality-of-life force the need to limit opioid therapy to patients with moder- considerations should be established to manage patient expec- ate to severe pain; use the lowest effective dose for the shortest tations and provide a means for measuring the success or period of time; limit coadministration with other central ner- failure of treatment. These goals can be incorporated into a vous system depressants; limit parenteral opioids formulations patient-physician prescribing agreement (a contract), which to patients who are unable to use oral medications or in whom also can be used to communicate expectations for follow-up, parenteral forms are needed for rapid analgesia; avoid the use monitoring, risk mitigation, and discontinuation or tapering. of extended-release or transdermal opioids for acute pain; and Sample patient agreement forms are available from the use both nonpharmacologic and nonopioid pharmacologic National Institute on Drug Abuse (www.drugabuse.gov/sites/ agents in a multimodal strategy to improve pain and function. default/files/files/SamplePatientAgreementForms.pdf). Finally, a bowel regimen to prevent opioid-induced constipa- Clinicians should evaluate for risk factors associated with tion should be employed. Opioid delivery via patient- opioid-related harms, such as substance use, the presence of controlled analgesia pumps can be an effective means of con- kidney or liver disease (which may affect drug metabolism), trolling acute pain; however, the patient must have a clear sleep-disordered breathing, and pregnancy. A commonly used mental status, and care should be taken not to prescribe a basal risk assessment instrument, the Opioid Risk Tool, is available at dose to opioid-naive patients. Current approaches additionally www.drugabuse.gov/sites/default/files/files/OpioidRiskTool. eschew the use of opioid-acetaminophen combination prod- pdf. ucts because of the risk for acetaminophen overdose with The risk for opioid-related overdose is dose dependent, titration of the opioid component, particularly when used with significantly increased risk for overdose in patients concurrently with other acetaminophen-containing drugs. receiving dosages higher than 90 morphine milligram equiva- Patients with chronic pain are frequently provided with lents (MME)/d. The lowest possible dosage should be used to prescriptions for opioids. Despite high prescribing rates, how- achieve the functional and quality-of-life goals established by ever, no evidence supports the use of long-term opioid therapy the patient and prescriber. Given the risks and limited efficacy in patients with chronic noncancer pain, and opioids should of opioid therapy in treating chronic noncancer pain, these not be considered first-line therapy in any patient with a dosages should not typically exceed more than 50 MME/d. chronic noncancer pain syndrome. Evidence demonstrates Follow-up evaluation should occur at frequent intervals after that long-term opioid use is associated with poorer overall therapy initiation or dosage changes and at least every functional status, worse quality of life, and worse pain (possi- 3 months. Dosages exceeding 50 MME/d should prompt re- bly mediated through opioid tolerance and hyperalgesic evaluation and closer follow-up intervals. Dosages higher than mechanisms). In addition, these prescribing patterns lead to 90 MME/d are considered high risk and should be prescribed substantial morbidity and mortality. From 1999 to 2017, almost only in consultation with pain specialists. Very long-acting 400,000 Americans died of an overdose related to opioids, opioid formulations, such as transdermal fentanyl and metha- with over half of these deaths resulting from the use of pre- done, are associated with a higher risk for overdose, and dos- scription opioids. In 2017, there were nearly 50,000 deaths ages should not be increased more frequently than weekly. secondary to opioid use, an increase of 12% over 2016. Co-prescription of opioids and benzodiazepines is associated Opioids may be appropriate in selected patients with with an increased risk for death from overdose and should be chronic pain in whom multimodal analgesic therapy has not avoided. improved function and quality of life. In 2016, the CDC released For patients who previously received opioid prescriptions a comprehensive guideline for prescribing opioids in patients for chronic pain and present to a physician as a new patient, a with chronic pain, not including patients with active cancer, discussion on opioid prescribing best practices should be patients receiving palliative care, and patients at the end of life. framed by the CDC guideline recommendations (see Table 27). Central to these guidelines are a thorough assessment and robust Discussions on tapering opioid therapy, incorporating a non- discussion of risks and benefits, close monitoring, and use of opioid multimodal pain strategy, and setting appropriate goals risk-mitigation strategies (Table 27 and Table 28). The CDC are fundamental to these prescribing relationships. If tapering provides a checklist to assist clinicians in opioid prescribing, is intended, an individualized plan should include clear dis- available at https://stacks.cde.gov/view/cde/38025. Although cussions with the patient, assessment for opioid use disorder, valuable in establishing practices for opioid use in chronic pain, a reasonable rate of taper (usually 5%-20% dose reduction per the CDC guideline has been misapplied to other patient groups, month), close observation for symptoms of opioid withdrawal, such as those with postsurgical pain or cancer-related pain. and involvement of behavioral health specialists when signifi- Recommendations regarding maximal dosing and tapering of cant mental illness or risk for suicide is present.

Opioid Therapy chronic opioids also have been misconstrued, and care must be Opioid therapy may be used to treat moderate to severe acute taken to ensure proper application of the guideline. pain. The Society of Hospital Medicine has published consen- Opioid Initiation and Risk Assessment sus guidelines on safe opioid prescribing in the hospital for When initiating or continuing opioid therapy, clear treatment noncancer-associated pain. These practice guidelines rein- goals based on functional improvement and quality-of-life force the need to limit opioid therapy to patients with moder- considerations should be established to manage patient expec- ate to severe pain; use the lowest effective dose for the shortest tations and provide a means for measuring the success or period of time; limit coadministration with other central ner- failure of treatment. These goals can be incorporated into a vous system depressants; limit parenteral opioids formulations patient-physician prescribing agreement (a contract), which to patients who are unable to use oral medications or in whom also can be used to communicate expectations for follow-up, parenteral forms are needed for rapid analgesia; avoid the use monitoring, risk mitigation, and discontinuation or tapering. of extended-release or transdermal opioids for acute pain; and Sample patient agreement forms are available from the use both nonpharmacologic and nonopioid pharmacologic National Institute on Drug Abuse (www.drugabuse.gov/sites/ agents in a multimodal strategy to improve pain and function. default/files/files/SamplePatientAgreementForms.pdf). Finally, a bowel regimen to prevent opioid-induced constipa- Clinicians should evaluate for risk factors associated with tion should be employed. Opioid delivery via patient- opioid-related harms, such as substance use, the presence of controlled analgesia pumps can be an effective means of con- kidney or liver disease (which may affect drug metabolism), trolling acute pain; however, the patient must have a clear sleep-disordered breathing, and pregnancy. A commonly used mental status, and care should be taken not to prescribe a basal risk assessment instrument, the Opioid Risk Tool, is available at dose to opioid-naive patients. Current approaches additionally www.drugabuse.gov/sites/default/files/files/OpioidRiskTool. eschew the use of opioid-acetaminophen combination prod- pdf. ucts because of the risk for acetaminophen overdose with The risk for opioid-related overdose is dose dependent, titration of the opioid component, particularly when used with significantly increased risk for overdose in patients concurrently with other acetaminophen-containing drugs. receiving dosages higher than 90 morphine milligram equiva- Patients with chronic pain are frequently provided with lents (MME)/d. The lowest possible dosage should be used to prescriptions for opioids. Despite high prescribing rates, how- achieve the functional and quality-of-life goals established by ever, no evidence supports the use of long-term opioid therapy the patient and prescriber. Given the risks and limited efficacy in patients with chronic noncancer pain, and opioids should of opioid therapy in treating chronic noncancer pain, these not be considered first-line therapy in any patient with a dosages should not typically exceed more than 50 MME/d. chronic noncancer pain syndrome. Evidence demonstrates Follow-up evaluation should occur at frequent intervals after that long-term opioid use is associated with poorer overall therapy initiation or dosage changes and at least every functional status, worse quality of life, and worse pain (possi- 3 months. Dosages exceeding 50 MME/d should prompt re- bly mediated through opioid tolerance and hyperalgesic evaluation and closer follow-up intervals. Dosages higher than mechanisms). In addition, these prescribing patterns lead to 90 MME/d are considered high risk and should be prescribed substantial morbidity and mortality. From 1999 to 2017, almost only in consultation with pain specialists. Very long-acting 400,000 Americans died of an overdose related to opioids, opioid formulations, such as transdermal fentanyl and metha- with over half of these deaths resulting from the use of pre- done, are associated with a higher risk for overdose, and dos- scription opioids. In 2017, there were nearly 50,000 deaths ages should not be increased more frequently than weekly. secondary to opioid use, an increase of 12% over 2016. Co-prescription of opioids and benzodiazepines is associated Opioids may be appropriate in selected patients with with an increased risk for death from overdose and should be chronic pain in whom multimodal analgesic therapy has not avoided. improved function and quality of life. In 2016, the CDC released For patients who previously received opioid prescriptions a comprehensive guideline for prescribing opioids in patients for chronic pain and present to a physician as a new patient, a with chronic pain, not including patients with active cancer, discussion on opioid prescribing best practices should be patients receiving palliative care, and patients at the end of life. framed by the CDC guideline recommendations (see Table 27). Central to these guidelines are a thorough assessment and robust Discussions on tapering opioid therapy, incorporating a non- discussion of risks and benefits, close monitoring, and use of opioid multimodal pain strategy, and setting appropriate goals risk-mitigation strategies (Table 27 and Table 28). The CDC are fundamental to these prescribing relationships. If tapering provides a checklist to assist clinicians in opioid prescribing, is intended, an individualized plan should include clear dis- available at https://stacks.cde.gov/view/cde/38025. Although cussions with the patient, assessment for opioid use disorder, valuable in establishing practices for opioid use in chronic pain, a reasonable rate of taper (usually 5%-20% dose reduction per the CDC guideline has been misapplied to other patient groups, month), close observation for symptoms of opioid withdrawal, such as those with postsurgical pain or cancer-related pain. and involvement of behavioral health specialists when signifi- Recommendations regarding maximal dosing and tapering of cant mental illness or risk for suicide is present. 43

TABLE 27. Centers for Disease Control and Prevention Recommendations for Prescribing Opioids for Chronic Pain Outside of Active Cancer, Palliative, and End-of-Life Care? Determining When to Initiate or Continue Opioids for Chronic Pain 1. Nonpharmacologic therapy and nonopioid pharmacologic therapy are preferred for chronic pain. Clinicians should consider opioid therapy only if expected benefits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, they | should be combined with nonpharmacologic therapy and nonopioid pharmacologic therapy, as appropriate. 2. Before starting opioid therapy for chronic pain, clinicians should establish treatment goals with all patients, including realistic goals for pain and function, and should consider how therapy will be discontinued if benefits do not outweigh risks. Clinicians should continue opioid therapy only if there is clinically meaningful improvement in pain and function that outweighs risks to patient safety. 3. Before starting and periodically during opioid therapy, clinicians should discuss with patients known risks and realistic benefits of opioid therapy and patient and clinician responsibilities for managing therapy. Opioid Selection, Dosage, Duration, Follow-up, and Discontinuation 4. When starting opioid therapy for chronic pain, clinicians should prescribe immediate-release opioids instead of extended-release/ long-acting (ER/LA) opioids. 5. When opioids are started, clinicians should prescribe the lowest effective dosage. Clinicians should use caution when prescribing | | opioids at any dosage, should carefully reassess evidence of individual benefits and risks when increasing dosage to >50 morphine milligram equivalents (MME)/day, and should avoid increasing dosage to 290 MME/day or carefully justify a decision to titrate dosage to 290 MME/day.

5. When opioids are started, clinicians should prescribe the lowest effective dosage. Clinicians should use caution when prescribing | | opioids at any dosage, should carefully reassess evidence of individual benefits and risks when increasing dosage to >50 morphine milligram equivalents (MME)/day, and should avoid increasing dosage to 290 MME/day or carefully justify a decision to titrate dosage to 290 MME/day. 6. Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dosage of immediate-release opioids and should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids. Three days or less will often be sufficient; more than 7 days will rarely be needed. 7. Clinicians should evaluate benefits and harms with patients within 1 to 4 weeks of starting opioid therapy for chronic pain or of dose escalation. Clinicians should evaluate benefits and harms of continued therapy with patients every 3 months or more frequently. If benefits do not outweigh harms of continued opioid therapy, clinicians should optimize other therapies and work with patients to taper opioids to lower dosages or to taper and discontinue opioids. Assessing Risk and Addressing Harms of Opioid Use 8. Before starting and periodically during continuation of opioid therapy, clinicians should evaluate risk factors for opioid-related harms. Clinicians should incorporate into the management plan strategies to mitigate risk, including considering offering naloxone when factors that increase risk for opioid overdose, such as history of overdose, history of substance use disorder, higher opioid dosages (250 MME/day), or concurrent benzodiazepine use, are present.

8. Before starting and periodically during continuation of opioid therapy, clinicians should evaluate risk factors for opioid-related harms. Clinicians should incorporate into the management plan strategies to mitigate risk, including considering offering naloxone when factors that increase risk for opioid overdose, such as history of overdose, history of substance use disorder, higher opioid dosages (250 MME/day), or concurrent benzodiazepine use, are present. 9. Clinicians should review the patient's history of controlled substance prescriptions using state prescription drug monitoring | program (PDMP) data to determine whether the patient is receiving opioid dosages or dangerous combinations that put him or her at high risk for overdose. Clinicians should review PDMP data when starting opioid therapy for chronic pain and periodically during opioid therapy for chronic pain, ranging from every prescription to every 3 months. 10. When prescribing opioids for chronic pain, clinicians should use urine drug testing before starting opioid therapy and consider urine drug testing at least annually to assess for prescribed medications as well as other controlled prescription drugs and illicit | drugs. 11. Clinicians should avoid prescribing opioid pain medication and benzodiazepines concurrently whenever possible. 12. Clinicians should offer or arrange evidence-based treatment (usually medication-assisted treatment with buprenorphine or methadone in combination with behavioral therapies) for patients with opioid use disorder. *All recommendations are category A (apply to all patients outside of active cancer treatment, palliative care, and end-of-life care) except recommendation 10 (designated category B, with individual decision making required); see full guideline at www.cdc.gov/mmwr/volumes/65/rr/rr6501e1.htm for evidence ratings. | Reproduced from Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. MMWR Recomm Rep. 2016;65:16. [PMID: | 26987082] doi:10.15585/mmwr.rr6501e1 |

| Reproduced from Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. MMWR Recomm Rep. 2016;65:16. [PMID: | 26987082] doi:10.15585/mmwr.rr6501e1 | Risk Mitigation TABLE 28. Risks of Long-Term Opioid Therapy Urine drug screening and surveillance of state prescription | Endocrinopathies (e.g.,osteoporosis, hypogonadism) drug monitoring programs (PDMPs) are important risk- | hyperalgesia Increasing pain through mechanisms of opioid-induced | ting of chronic pain. Although the optimal screening fre- mitigation strategies for patients receiving opioids in the set- | Opioid tolerance resulting from adaptive central nervous quency is unclear, patients taking long-term opioid therapy | system mechanisms should undergo urine drug screening at least yearly to assess | Opioid addiction for adherence to the prescribed agent and for the presence of | Overdose and death | substances that could increase the risk for opioid overdose. ; ; F : . | More frequent screening may be recommended on the basis of Risk for family members or children using opioids meeites : — aE | individual patient characteristics. Concurrent use of illicit 44

Pain drugs is a reason to consider discontinuation of opioid pre- Repeated opioid use can result in tolerance, physical scriptions. State PDMPs should also be reviewed on a regular dependence, and potential abuse. Opioid use disorder is char- basis to assess for adherence to the terms of the prescribing acterized by use of opioids in increasing amounts or longer agreement and to identify opioid prescription by multiple cli- than intended, continued use of opioids despite social func- nicians. The regulations for checking PDMPs before prescrib- tional decline, repeated episodes of withdrawal, abandonment ing an opioid vary by state, and physicians should be familiar of important events or activities, and physical and psychologi- with the regulations in the states in which they practice. cal problems. For a discussion on the diagnosis and treatment Evidence shows that naloxone, an opioid antagonist that of opioid use disorder, see Mental and Behavioral Health. reverses life-threatening respiratory depression, is effective in preventing opioid-related overdose death at the community level through community-based distribution. Clinicians should ¢ Long-term opioid use is associated with poorer overall HVC strongly consider offering overdose prevention education and functional status, worse quality of life, and worse pain.

drugs is a reason to consider discontinuation of opioid pre- Repeated opioid use can result in tolerance, physical scriptions. State PDMPs should also be reviewed on a regular dependence, and potential abuse. Opioid use disorder is char- basis to assess for adherence to the terms of the prescribing acterized by use of opioids in increasing amounts or longer agreement and to identify opioid prescription by multiple cli- than intended, continued use of opioids despite social func- nicians. The regulations for checking PDMPs before prescrib- tional decline, repeated episodes of withdrawal, abandonment ing an opioid vary by state, and physicians should be familiar of important events or activities, and physical and psychologi- with the regulations in the states in which they practice. cal problems. For a discussion on the diagnosis and treatment Evidence shows that naloxone, an opioid antagonist that of opioid use disorder, see Mental and Behavioral Health. reverses life-threatening respiratory depression, is effective in preventing opioid-related overdose death at the community level through community-based distribution. Clinicians should ¢ Long-term opioid use is associated with poorer overall HVC strongly consider offering overdose prevention education and functional status, worse quality of life, and worse pain. naloxone kits to patients receiving 50 MME/d or more. e The decision to initiate opioid therapy in patients with Regardless of opioid dosage, naloxone kits also should be chronic pain should involve assessment and robust strongly considered for patients with concurrent benzodiaze- discussion of risks and benefits; close monitoring for pine use; a nonopioid substance use disorder; a mental health benefits and harms; avoidance of long-acting opioid disorder; or respiratory conditions, such as COPD or obstruc- formulations; and use of risk-mitigation strategies, tive sleep apnea. Similar interventions are indicated for including regular follow-up. patients not prescribed opioids but who are otherwise at high ¢ Clinicians should strongly consider offering overdose risk for overdose, such as those illicitly using opioids or drugs prevention education and naloxone kits to patients at that may be contaminated with opioids (methamphetamine increased risk for overdose, such as those receiving dos- and cocaine), those with a history of opioid misuse who have ages of 50 morphine milligram equivalents/d or more, been recently released from incarceration, or those receiving those concurrently taking a benzodiazepine, or those treatment for opioid use disorder. Naloxone kits and overdose with a history of substance use disorder. prevention education should be extended to friends, family e All patients taking scheduled opioids should receive a members, or caregivers of patients at high risk. stimulant laxative, such as senna or bisacodyl.

naloxone kits to patients receiving 50 MME/d or more. e The decision to initiate opioid therapy in patients with Regardless of opioid dosage, naloxone kits also should be chronic pain should involve assessment and robust strongly considered for patients with concurrent benzodiaze- discussion of risks and benefits; close monitoring for pine use; a nonopioid substance use disorder; a mental health benefits and harms; avoidance of long-acting opioid disorder; or respiratory conditions, such as COPD or obstruc- formulations; and use of risk-mitigation strategies, tive sleep apnea. Similar interventions are indicated for including regular follow-up. patients not prescribed opioids but who are otherwise at high ¢ Clinicians should strongly consider offering overdose risk for overdose, such as those illicitly using opioids or drugs prevention education and naloxone kits to patients at that may be contaminated with opioids (methamphetamine increased risk for overdose, such as those receiving dos- and cocaine), those with a history of opioid misuse who have ages of 50 morphine milligram equivalents/d or more, been recently released from incarceration, or those receiving those concurrently taking a benzodiazepine, or those treatment for opioid use disorder. Naloxone kits and overdose with a history of substance use disorder. prevention education should be extended to friends, family e All patients taking scheduled opioids should receive a members, or caregivers of patients at high risk. stimulant laxative, such as senna or bisacodyl. Adverse Effects In patients receiving opioid therapy, constipation is nearly Pain Management in Patients with Serious Illness universal, and tolerance to constipation does not develop over Pain is common in patients with serious illness, and recogni- time. A bowel regimen should be started concurrently with tion and constant evaluation of pain are integral to effective opioid initiation rather than after symptoms of constipation management. Up to 90% of patients with advanced cancer develop. Pharmacologic therapy for all patients taking sched- have pain. Unfortunately, cancer pain remains undertreated, uled opioids should include a stimulant laxative, such as senna with about one third of patients with cancer receiving inade- or bisacodyl. There is little evidence supporting the use of stool quate analgesia. The incidence of pain in patients with other softeners, such as docusate. If constipation develops despite serious illnesses is also underappreciated. prophylactic therapy, intensifying treatment with stimulant In addition to physical pain, many patients with serious laxatives or adding an osmotic laxative (e.g., polyethylene gly- illness face complex psychosocial and spiritual issues related to col) is appropriate. If maximal medical therapy has failed to their illness and may experience total pain, defined as physical, achieve laxation, peripheral opioid antagonists (e.g., nalde- social, psychological, and spiritual suffering. Engaging interdis- medine, naloxegol, or methylnaltrexone) should be consid- ciplinary team members, such as nurses, psychologists, chap- ered. These medications do not cross the blood-brain barrier lains, and social workers, is important in addressing the and therefore do not affect analgesia; however, they are con- nonphysical components of pain. traindicated in patients at risk for bowel obstruction. Patients Nonpharmacologic interventions that benefit patients taking opioids should not receive supplemental fiber, owing with cancer pain include CBT to enhance coping techniques, to concerns about worsening constipation in the setting of physical therapy to improve function in the setting of pain opioid-reduced gastrointestinal motility. from metastatic lesions, or radiation therapy directed to the Nausea related to opioid use is common. No one opioid is underlying lesions. Pharmacologic pain management often known to be less emetogenic than another. Opioid-induced requires a multimodal strategy that uses both opioids and nausea is usually transient, and tolerance generally develops nonopioid analgesics, such as acetaminophen, NSAIDs, gluco- over 2 to 7 days; therefore, opioids should not be switched too corticoids, topical therapies, neuropathic agents, antidepres- quickly. Antidopaminergic agents, such as metoclopramide or sants with analgesic properties, and possibly cannabis. In prochlorperazine, are the preferred agents to treat opioid- cancer-associated pain and particularly in patients with induced nausea. Serotonin receptor antagonists, such as ondan- advanced disease, the severity of the underlying pain necessi- setron, may be used but can cause or worsen constipation. tates the use of opioids.

Adverse Effects In patients receiving opioid therapy, constipation is nearly Pain Management in Patients with Serious Illness universal, and tolerance to constipation does not develop over Pain is common in patients with serious illness, and recogni- time. A bowel regimen should be started concurrently with tion and constant evaluation of pain are integral to effective opioid initiation rather than after symptoms of constipation management. Up to 90% of patients with advanced cancer develop. Pharmacologic therapy for all patients taking sched- have pain. Unfortunately, cancer pain remains undertreated, uled opioids should include a stimulant laxative, such as senna with about one third of patients with cancer receiving inade- or bisacodyl. There is little evidence supporting the use of stool quate analgesia. The incidence of pain in patients with other softeners, such as docusate. If constipation develops despite serious illnesses is also underappreciated. prophylactic therapy, intensifying treatment with stimulant In addition to physical pain, many patients with serious laxatives or adding an osmotic laxative (e.g., polyethylene gly- illness face complex psychosocial and spiritual issues related to col) is appropriate. If maximal medical therapy has failed to their illness and may experience total pain, defined as physical, achieve laxation, peripheral opioid antagonists (e.g., nalde- social, psychological, and spiritual suffering. Engaging interdis- medine, naloxegol, or methylnaltrexone) should be consid- ciplinary team members, such as nurses, psychologists, chap- ered. These medications do not cross the blood-brain barrier lains, and social workers, is important in addressing the and therefore do not affect analgesia; however, they are con- nonphysical components of pain. traindicated in patients at risk for bowel obstruction. Patients Nonpharmacologic interventions that benefit patients taking opioids should not receive supplemental fiber, owing with cancer pain include CBT to enhance coping techniques, to concerns about worsening constipation in the setting of physical therapy to improve function in the setting of pain opioid-reduced gastrointestinal motility. from metastatic lesions, or radiation therapy directed to the Nausea related to opioid use is common. No one opioid is underlying lesions. Pharmacologic pain management often known to be less emetogenic than another. Opioid-induced requires a multimodal strategy that uses both opioids and nausea is usually transient, and tolerance generally develops nonopioid analgesics, such as acetaminophen, NSAIDs, gluco- over 2 to 7 days; therefore, opioids should not be switched too corticoids, topical therapies, neuropathic agents, antidepres- quickly. Antidopaminergic agents, such as metoclopramide or sants with analgesic properties, and possibly cannabis. In prochlorperazine, are the preferred agents to treat opioid- cancer-associated pain and particularly in patients with induced nausea. Serotonin receptor antagonists, such as ondan- advanced disease, the severity of the underlying pain necessi- setron, may be used but can cause or worsen constipation. tates the use of opioids. 45

Pain Opioids may be appropriate in patients in whom nonopi- and offer immediate onset for patients who are not achieving oid treatment is ineffective or not tolerated, with careful atten- adequate analgesia with high-dose morphine. Management of tion to dosing, frequency, and side effect profile. Safe prescribing these medications is challenging because the dosing regimen, practices, such as PDMP review, opioid risk assessment, and escalation, and frequency differ among brands. In addition, close monitoring, should be used. Table 29 outlines the most clinicians require specialized education and certification (TIRF commonly used opioids in the treatment of pain resulting Risk Evaluation and Mitigation Strategy program) to initiate from a serious illness, as well as specific patient population these medications. Methadone is another long-acting agent concerns. Weaker opioids, such as codeine and tramadol, are used to treat pain from a serious illness; however, its complex not first-line options in patients with serious illness because of dosing and variable half-life restrict its general use. TIRF for- marginal effectiveness, significant drug-drug interactions, and mulations and methadone also are associated with a higher wide variations in hepatic metabolism. risk for overdose. Owing to their complicated management, Short-acting opioids should be titrated to achieve symp- they should be prescribed in collaboration with an expert in tom relief. In patients using short-acting opioids who require pain management or a palliative medicine specialist with longer-lasting relief, long-acting agents are appropriate; how- experience in their use. ever, long-acting opioids should not be the initial opioid pre- scribed in opioid-naive patients. Selection of a long-acting e Pharmacologic management of pain in patients with opioid should be based on underlying organ function and serious illness requires a multimodal strategy, which previous response to the equivalent short-acting formulation may incorporate opioids, acetaminophen, NSAIDs, (for example, oxycodone immediate-release and controlled- release forms). glucocorticoids, topical therapies, neuropathic agents, antidepressants with analgesic properties, and possibly Orally administered transmucosal immediate-release cannabis. fentanyl (TIRF) products are approved for the treatment of (Continued) cancer-related pain. TIRF formulations are rapidly absorbed

Opioids may be appropriate in patients in whom nonopi- and offer immediate onset for patients who are not achieving oid treatment is ineffective or not tolerated, with careful atten- adequate analgesia with high-dose morphine. Management of tion to dosing, frequency, and side effect profile. Safe prescribing these medications is challenging because the dosing regimen, practices, such as PDMP review, opioid risk assessment, and escalation, and frequency differ among brands. In addition, close monitoring, should be used. Table 29 outlines the most clinicians require specialized education and certification (TIRF commonly used opioids in the treatment of pain resulting Risk Evaluation and Mitigation Strategy program) to initiate from a serious illness, as well as specific patient population these medications. Methadone is another long-acting agent concerns. Weaker opioids, such as codeine and tramadol, are used to treat pain from a serious illness; however, its complex not first-line options in patients with serious illness because of dosing and variable half-life restrict its general use. TIRF for- marginal effectiveness, significant drug-drug interactions, and mulations and methadone also are associated with a higher wide variations in hepatic metabolism. risk for overdose. Owing to their complicated management, Short-acting opioids should be titrated to achieve symp- they should be prescribed in collaboration with an expert in tom relief. In patients using short-acting opioids who require pain management or a palliative medicine specialist with longer-lasting relief, long-acting agents are appropriate; how- experience in their use. ever, long-acting opioids should not be the initial opioid pre- scribed in opioid-naive patients. Selection of a long-acting e Pharmacologic management of pain in patients with opioid should be based on underlying organ function and serious illness requires a multimodal strategy, which previous response to the equivalent short-acting formulation may incorporate opioids, acetaminophen, NSAIDs, (for example, oxycodone immediate-release and controlled- release forms). glucocorticoids, topical therapies, neuropathic agents, antidepressants with analgesic properties, and possibly Orally administered transmucosal immediate-release cannabis. fentanyl (TIRF) products are approved for the treatment of (Continued) cancer-related pain. TIRF formulations are rapidly absorbed TABLE 29. Opioids Commonly Used in Palliative Care

Opioids may be appropriate in patients in whom nonopi- and offer immediate onset for patients who are not achieving oid treatment is ineffective or not tolerated, with careful atten- adequate analgesia with high-dose morphine. Management of tion to dosing, frequency, and side effect profile. Safe prescribing these medications is challenging because the dosing regimen, practices, such as PDMP review, opioid risk assessment, and escalation, and frequency differ among brands. In addition, close monitoring, should be used. Table 29 outlines the most clinicians require specialized education and certification (TIRF commonly used opioids in the treatment of pain resulting Risk Evaluation and Mitigation Strategy program) to initiate from a serious illness, as well as specific patient population these medications. Methadone is another long-acting agent concerns. Weaker opioids, such as codeine and tramadol, are used to treat pain from a serious illness; however, its complex not first-line options in patients with serious illness because of dosing and variable half-life restrict its general use. TIRF for- marginal effectiveness, significant drug-drug interactions, and mulations and methadone also are associated with a higher wide variations in hepatic metabolism. risk for overdose. Owing to their complicated management, Short-acting opioids should be titrated to achieve symp- they should be prescribed in collaboration with an expert in tom relief. In patients using short-acting opioids who require pain management or a palliative medicine specialist with longer-lasting relief, long-acting agents are appropriate; how- experience in their use. ever, long-acting opioids should not be the initial opioid pre- scribed in opioid-naive patients. Selection of a long-acting e Pharmacologic management of pain in patients with opioid should be based on underlying organ function and serious illness requires a multimodal strategy, which previous response to the equivalent short-acting formulation may incorporate opioids, acetaminophen, NSAIDs, (for example, oxycodone immediate-release and controlled- release forms). glucocorticoids, topical therapies, neuropathic agents, antidepressants with analgesic properties, and possibly Orally administered transmucosal immediate-release cannabis. fentanyl (TIRF) products are approved for the treatment of (Continued) cancer-related pain. TIRF formulations are rapidly absorbed TABLE 29. Opioids Commonly Used in Palliative Care i Opioid Protein Binding Metabolism Comments | | Hydrocodone Low Liver enzyme Not recommended

Opioids may be appropriate in patients in whom nonopi- and offer immediate onset for patients who are not achieving oid treatment is ineffective or not tolerated, with careful atten- adequate analgesia with high-dose morphine. Management of tion to dosing, frequency, and side effect profile. Safe prescribing these medications is challenging because the dosing regimen, practices, such as PDMP review, opioid risk assessment, and escalation, and frequency differ among brands. In addition, close monitoring, should be used. Table 29 outlines the most clinicians require specialized education and certification (TIRF commonly used opioids in the treatment of pain resulting Risk Evaluation and Mitigation Strategy program) to initiate from a serious illness, as well as specific patient population these medications. Methadone is another long-acting agent concerns. Weaker opioids, such as codeine and tramadol, are used to treat pain from a serious illness; however, its complex not first-line options in patients with serious illness because of dosing and variable half-life restrict its general use. TIRF for- marginal effectiveness, significant drug-drug interactions, and mulations and methadone also are associated with a higher wide variations in hepatic metabolism. risk for overdose. Owing to their complicated management, Short-acting opioids should be titrated to achieve symp- they should be prescribed in collaboration with an expert in tom relief. In patients using short-acting opioids who require pain management or a palliative medicine specialist with longer-lasting relief, long-acting agents are appropriate; how- experience in their use. ever, long-acting opioids should not be the initial opioid pre- scribed in opioid-naive patients. Selection of a long-acting e Pharmacologic management of pain in patients with opioid should be based on underlying organ function and serious illness requires a multimodal strategy, which previous response to the equivalent short-acting formulation may incorporate opioids, acetaminophen, NSAIDs, (for example, oxycodone immediate-release and controlled- release forms). glucocorticoids, topical therapies, neuropathic agents, antidepressants with analgesic properties, and possibly Orally administered transmucosal immediate-release cannabis. fentanyl (TIRF) products are approved for the treatment of (Continued) cancer-related pain. TIRF formulations are rapidly absorbed TABLE 29. Opioids Commonly Used in Palliative Care i Opioid Protein Binding Metabolism Comments | | Hydrocodone Low Liver enzyme Not recommended ees Variable efficacy; combination with acetaminophen limits use | | Increased time to analgesic onset in liver failure Tramadol Low/moderate Liver enzymes Not recommended | ere Variable time to onset and unpredictable analgesic efficacy in liver failure | | Interactions with other serotonergic medications, potentially leading to | | serotonin syndrome (agitation, clonus, muscle rigidity, hyperreflexia) |

ees Variable efficacy; combination with acetaminophen limits use | | Increased time to analgesic onset in liver failure Tramadol Low/moderate Liver enzymes Not recommended | ere Variable time to onset and unpredictable analgesic efficacy in liver failure | | Interactions with other serotonergic medications, potentially leading to | | serotonin syndrome (agitation, clonus, muscle rigidity, hyperreflexia) | | Hydromorphone — Low Liver ae Better choice if kidney disease is present | (giacunsnicasen) Reduce dose and frequency in liverfailure/cirrhosis | | Oxycodone Moderate/high Liver enzymes Increased half-life and variable onset in liver failure; if used, reduce dose | CYP2D6/CYP3A4 __ and frequency | | Morphine Moderate/high Liver Avoid in liverfailure/cirrhosis and kidney failure | | toluearenicetion Increased bioavailability with liver failure | | Increased toxic metabolites with kidney failure | Fentany| High Liver enzyme Safer long-acting drug in kidney and liver failure

| (giacunsnicasen) Reduce dose and frequency in liverfailure/cirrhosis | | Oxycodone Moderate/high Liver enzymes Increased half-life and variable onset in liver failure; if used, reduce dose | CYP2D6/CYP3A4 __ and frequency | | Morphine Moderate/high Liver Avoid in liverfailure/cirrhosis and kidney failure | | toluearenicetion Increased bioavailability with liver failure | | Increased toxic metabolites with kidney failure | Fentany| High Liver enzyme Safer long-acting drug in kidney and liver failure Stren Increased bioavailability with liver failure; start lower-dose patch in liver | | failure | | Efficacy may be impaired in very thin individuals | Higher risk for overdose | Methadone High Liver enzymes Opioid receptor agonist and NMDA receptor antagonist; complex CYP2D6, CYP2B6, biphasic metabolism and long half-life CYP3A4 Should only be managed by clinicians with experience in dose conversion and titration Higher risk for overdose | CYP2Bé6 = cytochrome P-450 2B6; CYP2D6 = cytochrome P-450 2D6; CYP3A4 = cytochrome P-450 3A4; NMDA = N-methyl-D-aspartate. 46

Palliative Medicine specialist; rather, the team acts as an extra layer of support, integrating key information from the referring physician into e For patients with advanced illness in whom nonopioid goal-concordant care plans and attending to symptoms that analgesic agents are ineffective or not tolerated, opioids affect quality of life. It remains the responsibility of the pri- may be appropriate, with careful attention to dosing, mary physician to explore psychosocial distress, provide antic- frequency, and side effect profile. ipatory guidance, and perform basic symptom management before or concurrent with referral to palliative medicine specialists.

specialist; rather, the team acts as an extra layer of support, integrating key information from the referring physician into e For patients with advanced illness in whom nonopioid goal-concordant care plans and attending to symptoms that analgesic agents are ineffective or not tolerated, opioids affect quality of life. It remains the responsibility of the pri- may be appropriate, with careful attention to dosing, mary physician to explore psychosocial distress, provide antic- frequency, and side effect profile. ipatory guidance, and perform basic symptom management before or concurrent with referral to palliative medicine specialists. Palliative Medicine Although referral to palliative care historically occurred at the end of life, an emerging consensus of research indicates Introduction that early initiation during a serious illness is associated with substantial advantages. Evidence on the benefits of subspe- Palliative medicine is a medical specialty that seeks to relieve suffering and maximize quality of life for patients with a cialty palliative care has mostly involved patients with incur- able cancer. However, numerous guidelines highlight the need serious illness. It utilizes an interdisciplinary team care for early palliative care in patients with advanced cardiac, model, with a focus on reducing pain and other physical, pulmonary, or kidney disease; advanced dementia; critical ill- emotional, psychological, and spiritual symptoms associated with advanced disease. ness; or cancers with potentially curative interventions.

Palliative Medicine Although referral to palliative care historically occurred at the end of life, an emerging consensus of research indicates Introduction that early initiation during a serious illness is associated with substantial advantages. Evidence on the benefits of subspe- Palliative medicine is a medical specialty that seeks to relieve suffering and maximize quality of life for patients with a cialty palliative care has mostly involved patients with incur- able cancer. However, numerous guidelines highlight the need serious illness. It utilizes an interdisciplinary team care for early palliative care in patients with advanced cardiac, model, with a focus on reducing pain and other physical, pulmonary, or kidney disease; advanced dementia; critical ill- emotional, psychological, and spiritual symptoms associated with advanced disease. ness; or cancers with potentially curative interventions. All physicians practice some degree of palliative medicine and should learn and use basic palliative medicine skills in e Specialty palliative medicine improves overall quality of patient care (Table 30). Specialty palliative medicine teams life, physical symptom burden, mood, and caregiver coordinate with referring physicians to align care with the satisfaction with patient care in the setting of serious patient’s goals, preferences, and values and address multidi- illness. mensional care needs. Evidence shows that specialty palliative medicine improves overall quality of life, physical symptom burden, mood, and caregiver satisfaction with patient care in Communicating With Patients the setting of serious illness. Notably, a palliative medicine With Serious Illness team does not replace the primary physician, hospitalist, or For patients with serious illness, there are considerable dis- parities between the care they report they want and the care TABLE 30. Representative Skill Sets for Primary and Specialty Palliative Care they receive. Patients report a strong desire to have conversa- tions focused on illness progression and prognosis, expected | Primary Palliative Care symptoms and symptom course, and end-of-life issues, and | Basic management of pain and symptoms they wish to have these conversations with the clinician whom | Basic management of depression and anxiety they view as their primary physician contact. Timely and Basic discussions about: skillful communication with patients, family members, and Prognosis caregivers is essential to align care with patients’ wishes.

All physicians practice some degree of palliative medicine and should learn and use basic palliative medicine skills in e Specialty palliative medicine improves overall quality of patient care (Table 30). Specialty palliative medicine teams life, physical symptom burden, mood, and caregiver coordinate with referring physicians to align care with the satisfaction with patient care in the setting of serious patient’s goals, preferences, and values and address multidi- illness. mensional care needs. Evidence shows that specialty palliative medicine improves overall quality of life, physical symptom burden, mood, and caregiver satisfaction with patient care in Communicating With Patients the setting of serious illness. Notably, a palliative medicine With Serious Illness team does not replace the primary physician, hospitalist, or For patients with serious illness, there are considerable dis- parities between the care they report they want and the care TABLE 30. Representative Skill Sets for Primary and Specialty Palliative Care they receive. Patients report a strong desire to have conversa- tions focused on illness progression and prognosis, expected | Primary Palliative Care symptoms and symptom course, and end-of-life issues, and | Basic management of pain and symptoms they wish to have these conversations with the clinician whom | Basic management of depression and anxiety they view as their primary physician contact. Timely and Basic discussions about: skillful communication with patients, family members, and Prognosis caregivers is essential to align care with patients’ wishes. However, many physicians report that they do not have the Goals of treatment training for conversations about end-of-life care, and many Suffering conversations occur too late, are of poor quality, and happen Code status outside of the primary physician-patient relationship. Even Specialty Palliative Care among clinicians caring for populations for which consistent

However, many physicians report that they do not have the Goals of treatment training for conversations about end-of-life care, and many Suffering conversations occur too late, are of poor quality, and happen Code status outside of the primary physician-patient relationship. Even Specialty Palliative Care among clinicians caring for populations for which consistent Management of refractory pain or other symptoms advance care and end-of-life planning are considered usual care, it may be unclear when end-of-life discussions should Management of more complex depression, anxiety, grief, and existential distress take place and who should facilitate them. Assistance with conflict resolution regarding goals or methods Structured conversations are associated with improved of treatment goal-concordant care and reduced patient anxiety. One model

Management of refractory pain or other symptoms advance care and end-of-life planning are considered usual care, it may be unclear when end-of-life discussions should Management of more complex depression, anxiety, grief, and existential distress take place and who should facilitate them. Assistance with conflict resolution regarding goals or methods Structured conversations are associated with improved of treatment goal-concordant care and reduced patient anxiety. One model Within families for skilled communication with patients facing a serious illness is outlined in Table 31. The Serious IIIness Conversation Guide Between staff and families provides sample phrases that are designed to elicit a patient’s Among treatment teams goals, preferences, and values after the patient’s illness under- Assistance in addressing cases of medically inappropriate standing is assessed. In contrast to discussion techniques in interventions at the end of life which information is shared and subsequently patients are Reproduced with permission from Quill TE, Abernethy AP. Generalist plus specialist palliative care—creating a more sustainable model. N Engl J Med. asked to choose froma list of medical interventions, the Serious 2013;368:1174. [PMID: 23465068] doi:10.1056/NEJMp1215620. © 2013, Illness Conversation Guide encourages shared decision making Massachusetts Medical Society. and enables physicians to help patients understand the illness 47

Palliative Medicine TABLE 31. Serious Illness Conversation Guide | Conversation Flow Patient-Tested Language | 1. Set upthe conversation: Introduce the idea and benefits “I'm hoping we can talk about where things are with your illness and where they might be going. Is this okay?” Ask permission 2. Assess illness understanding and “What is your understanding now of where you are with your illness?” information preferences “How much information about what is likely to be ahead with your illness would you like from me?” 3. Share prognosis Tailor information to patient Prognosis: “I’m worried that time may be short.” or "This may be as strong as you feel.” preference Allow silence; explore emotion 4. Explore key topics Goals “What are your most important goals if your health situation worsens?” Fears and worries “What are your biggest fears and worries about the future with your health?” Sources of strength “What gives you strength as you think about the future with your illness?” Critical abilities “What abilities are so critical to your life that you can’t imagine living without them?” Tradeoffs “If you become sicker, how much are you willing to go through for the possibility of gaining | more time?” Family “How much does your family know about your priorities and wishes?” 5. Close the conversation Summarize what you've heard “It sounds like is very important to you.” Make a recommendation “Given your goals and priorities and what we know about your illness at this stage, | recommend....” Affirm your commitment to the “We're in this together.” patient 6. Document your conversation

Summarize what you've heard “It sounds like is very important to you.” Make a recommendation “Given your goals and priorities and what we know about your illness at this stage, | recommend....” Affirm your commitment to the “We're in this together.” patient 6. Document your conversation Licensed under the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-nc-sa/4.0/). Ariadne Labs licenses the original content as-is and as-available, and makes no representations or warranties of any kind concerning the original content or concerning this material, which Ariadne Labs has not reviewed or endorsed. © 2015, Ariadne Labs: A Joint Center for Health Systems Innovation (www.ariadnelabs.org) and Dana-Farber Cancer Institute.

Licensed under the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-nc-sa/4.0/). Ariadne Labs licenses the original content as-is and as-available, and makes no representations or warranties of any kind concerning the original content or concerning this material, which Ariadne Labs has not reviewed or endorsed. © 2015, Ariadne Labs: A Joint Center for Health Systems Innovation (www.ariadnelabs.org) and Dana-Farber Cancer Institute. and prognosis, elicit important goals, and make reeommenda- Symptom Management tions for care. The output of these conversations should be Effective, proactive symptom management is critical to the communicated to the patient’s family, surrogate decision success of both basic and specialty palliative care interven- maker, and other appropriate members of the health care team. tions. Management of debilitating and distressing symptoms Institutional advance directives, commercial advance directive can markedly improve a patient’s functioning, sense of hope, forms or electronic applications, physician orders for life- and overall quality of life. For a discussion of pain manage- sustaining treatment (POLST) paradigm forms, and medical ment at the end of life, see Pain. orders for life-sustaining treatment (MOLST) forms should be viewed as mechanisms to record the outcomes of these discus- Dyspnea sions rather than as conversation guides. For further discussion Dyspnea is a prominent and distressing symptom in patients of advance care planning and advance directives, see Medical with advanced illness. The initial goal of treatment is to address Ethics and Professionalism. the underlying cause (e.g., pleural effusion, infection, anemia, COPD, heart failure) and treat hypoxemia, if present, with

and prognosis, elicit important goals, and make reeommenda- Symptom Management tions for care. The output of these conversations should be Effective, proactive symptom management is critical to the communicated to the patient’s family, surrogate decision success of both basic and specialty palliative care interven- maker, and other appropriate members of the health care team. tions. Management of debilitating and distressing symptoms Institutional advance directives, commercial advance directive can markedly improve a patient’s functioning, sense of hope, forms or electronic applications, physician orders for life- and overall quality of life. For a discussion of pain manage- sustaining treatment (POLST) paradigm forms, and medical ment at the end of life, see Pain. orders for life-sustaining treatment (MOLST) forms should be viewed as mechanisms to record the outcomes of these discus- Dyspnea sions rather than as conversation guides. For further discussion Dyspnea is a prominent and distressing symptom in patients of advance care planning and advance directives, see Medical with advanced illness. The initial goal of treatment is to address Ethics and Professionalism. the underlying cause (e.g., pleural effusion, infection, anemia, COPD, heart failure) and treat hypoxemia, if present, with e Patients report a strong desire to have conversations supplemental oxygen. Many patients with advanced illness

and prognosis, elicit important goals, and make reeommenda- Symptom Management tions for care. The output of these conversations should be Effective, proactive symptom management is critical to the communicated to the patient’s family, surrogate decision success of both basic and specialty palliative care interven- maker, and other appropriate members of the health care team. tions. Management of debilitating and distressing symptoms Institutional advance directives, commercial advance directive can markedly improve a patient’s functioning, sense of hope, forms or electronic applications, physician orders for life- and overall quality of life. For a discussion of pain manage- sustaining treatment (POLST) paradigm forms, and medical ment at the end of life, see Pain. orders for life-sustaining treatment (MOLST) forms should be viewed as mechanisms to record the outcomes of these discus- Dyspnea sions rather than as conversation guides. For further discussion Dyspnea is a prominent and distressing symptom in patients of advance care planning and advance directives, see Medical with advanced illness. The initial goal of treatment is to address Ethics and Professionalism. the underlying cause (e.g., pleural effusion, infection, anemia, COPD, heart failure) and treat hypoxemia, if present, with e Patients report a strong desire to have conversations supplemental oxygen. Many patients with advanced illness focused on illness progression and prognosis, expected have persistent dyspnea despite maximal medical manage-

and prognosis, elicit important goals, and make reeommenda- Symptom Management tions for care. The output of these conversations should be Effective, proactive symptom management is critical to the communicated to the patient’s family, surrogate decision success of both basic and specialty palliative care interven- maker, and other appropriate members of the health care team. tions. Management of debilitating and distressing symptoms Institutional advance directives, commercial advance directive can markedly improve a patient’s functioning, sense of hope, forms or electronic applications, physician orders for life- and overall quality of life. For a discussion of pain manage- sustaining treatment (POLST) paradigm forms, and medical ment at the end of life, see Pain. orders for life-sustaining treatment (MOLST) forms should be viewed as mechanisms to record the outcomes of these discus- Dyspnea sions rather than as conversation guides. For further discussion Dyspnea is a prominent and distressing symptom in patients of advance care planning and advance directives, see Medical with advanced illness. The initial goal of treatment is to address Ethics and Professionalism. the underlying cause (e.g., pleural effusion, infection, anemia, COPD, heart failure) and treat hypoxemia, if present, with e Patients report a strong desire to have conversations supplemental oxygen. Many patients with advanced illness focused on illness progression and prognosis, expected have persistent dyspnea despite maximal medical manage- symptoms and symptom course, and end-of-life issues, ment, and opioids, most commonly morphine, are the treat-

e Patients report a strong desire to have conversations supplemental oxygen. Many patients with advanced illness focused on illness progression and prognosis, expected have persistent dyspnea despite maximal medical manage- symptoms and symptom course, and end-of-life issues, ment, and opioids, most commonly morphine, are the treat- and they wish to have these conversations with the clini- ment of choice in these patients. Opioids reduce the sensation cian whom they view as their primary physician contact. of dyspnea and do not cause respiratory depression or hasten death when appropriately selected and dosed. There is mixed HVC e Structured conversations about serious illness are asso- evidence regarding the benefit of nonpharmacologic interven- ciated with improved goal-concordant care and reduced tions in relieving dyspnea. Mindfulness practices, relaxation, patient anxiety. acupuncture, or chest wall vibration may be reasonable in 48

selected patients. See Common Symptoms for further discus- Constipation sion of dyspnea. Constipation is common in patients with serious illness and can result in extreme discomfort, restlessness, and delirium. Causes Oropharyngeal Secretions include opioids, dehydration, immobility, metabolic distur- Audible oropharyngeal secretions at the end of life (“death rat- bances, and numerous nonopioid medications. Prophylaxis tle”) are often distressing for families and clinicians alike and should be considered when constipation is likely to occur, such may occur in up to 50% of dying patients. These secretions as with opioid initiation or when prolonged immobility is antic- rarely affect respiratory status or cause patient discomfort, and ipated. Patients with constipation should be educated on educating family members on the dying process can ease con- increasing fluid intake and physical activity as much as possible. cerns. Treatment is often initiated in anticipation of or Pharmacologic therapy includes osmotic laxatives, such as poly- response to family distress but is generally ineffective. The ethylene glycol, often in combination with a stimulant laxative, current literature does not support routine use of antimus- such as senna or bisacodyl. Docusate, alone or in combination, carinic drugs to decrease oropharyngeal secretions. There is no is no more effective than placebo for constipation in patients evidence that scopolamine, glycopyrronium, hyoscine butyl- with serious illness. Third-line therapy consists of rectal bromide, atropine, or octreotide is superior to no treatment. In suppositories and/or enema preparations. Phosphate- or addition, the use of anticholinergic agents in patients who are magnesium-containing enema preparations are contraindicated awake can lead to undesirable symptoms, such as dry mouth in patients with serious illness, owing to the potential for dan- and urinary retention. Deep suctioning by catheter should be gerous electrolyte shifts. Treatment strategies for opioid-induced avoided unless secretions are causing obvious respiratory dis- constipation are covered in Pain. tress. Nonpharmacologic interventions, such as raising the head of the bed or positioning the patient on his or her side, Anorexia and Weight Loss may be helpful. Anorexia and weight loss frequently occur as part of the natu- ral progression of life-limiting illness. Management involves Nausea addressing any reversible contributors to anorexia to ease Nausea and vomiting are common and debilitating symptoms patient and family distress. Although some medications are in patients with serious illness, with many patients rating marketed for patients with anorexia and weight loss, they are nausea as more distressing than unrelieved pain. Management marginally effective in a minority of terminally ill patients and of nausea should be tailored to address the underlying mecha- often have unacceptable side effects. Enteral or parenteral arti- nism and associated neurotransmitter pathway (Table 32). ficial nutritional support at the end of life does not improve More than one agent is frequently required for symptom relief. survival; is invasive; and can cause side effects, including In hospitalized patients, parenteral agents should be adminis- increased respiratory secretions and uncomfortable edema. tered on a scheduled basis to achieve symptom control and Discussing common end-of-life symptoms, including ano- reduce the number of emesis events. Nausea prophylaxis in rexia and weight loss, and the lack of clearly effective treat- patients receiving chemotherapy is discussed in more detail in ments for these expected changes can prepare patients and MKSAP 19 Oncology. their family members and set realistic expectations.

selected patients. See Common Symptoms for further discus- Constipation sion of dyspnea. Constipation is common in patients with serious illness and can result in extreme discomfort, restlessness, and delirium. Causes Oropharyngeal Secretions include opioids, dehydration, immobility, metabolic distur- Audible oropharyngeal secretions at the end of life (“death rat- bances, and numerous nonopioid medications. Prophylaxis tle”) are often distressing for families and clinicians alike and should be considered when constipation is likely to occur, such may occur in up to 50% of dying patients. These secretions as with opioid initiation or when prolonged immobility is antic- rarely affect respiratory status or cause patient discomfort, and ipated. Patients with constipation should be educated on educating family members on the dying process can ease con- increasing fluid intake and physical activity as much as possible. cerns. Treatment is often initiated in anticipation of or Pharmacologic therapy includes osmotic laxatives, such as poly- response to family distress but is generally ineffective. The ethylene glycol, often in combination with a stimulant laxative, current literature does not support routine use of antimus- such as senna or bisacodyl. Docusate, alone or in combination, carinic drugs to decrease oropharyngeal secretions. There is no is no more effective than placebo for constipation in patients evidence that scopolamine, glycopyrronium, hyoscine butyl- with serious illness. Third-line therapy consists of rectal bromide, atropine, or octreotide is superior to no treatment. In suppositories and/or enema preparations. Phosphate- or addition, the use of anticholinergic agents in patients who are magnesium-containing enema preparations are contraindicated awake can lead to undesirable symptoms, such as dry mouth in patients with serious illness, owing to the potential for dan- and urinary retention. Deep suctioning by catheter should be gerous electrolyte shifts. Treatment strategies for opioid-induced avoided unless secretions are causing obvious respiratory dis- constipation are covered in Pain. tress. Nonpharmacologic interventions, such as raising the head of the bed or positioning the patient on his or her side, Anorexia and Weight Loss may be helpful. Anorexia and weight loss frequently occur as part of the natu- ral progression of life-limiting illness. Management involves Nausea addressing any reversible contributors to anorexia to ease Nausea and vomiting are common and debilitating symptoms patient and family distress. Although some medications are in patients with serious illness, with many patients rating marketed for patients with anorexia and weight loss, they are nausea as more distressing than unrelieved pain. Management marginally effective in a minority of terminally ill patients and of nausea should be tailored to address the underlying mecha- often have unacceptable side effects. Enteral or parenteral arti- nism and associated neurotransmitter pathway (Table 32). ficial nutritional support at the end of life does not improve More than one agent is frequently required for symptom relief. survival; is invasive; and can cause side effects, including In hospitalized patients, parenteral agents should be adminis- increased respiratory secretions and uncomfortable edema. tered on a scheduled basis to achieve symptom control and Discussing common end-of-life symptoms, including ano- reduce the number of emesis events. Nausea prophylaxis in rexia and weight loss, and the lack of clearly effective treat- patients receiving chemotherapy is discussed in more detail in ments for these expected changes can prepare patients and MKSAP 19 Oncology. their family members and set realistic expectations. TABLE 32. Treatment of Nausea in the Palliative Care Patient

selected patients. See Common Symptoms for further discus- Constipation sion of dyspnea. Constipation is common in patients with serious illness and can result in extreme discomfort, restlessness, and delirium. Causes Oropharyngeal Secretions include opioids, dehydration, immobility, metabolic distur- Audible oropharyngeal secretions at the end of life (“death rat- bances, and numerous nonopioid medications. Prophylaxis tle”) are often distressing for families and clinicians alike and should be considered when constipation is likely to occur, such may occur in up to 50% of dying patients. These secretions as with opioid initiation or when prolonged immobility is antic- rarely affect respiratory status or cause patient discomfort, and ipated. Patients with constipation should be educated on educating family members on the dying process can ease con- increasing fluid intake and physical activity as much as possible. cerns. Treatment is often initiated in anticipation of or Pharmacologic therapy includes osmotic laxatives, such as poly- response to family distress but is generally ineffective. The ethylene glycol, often in combination with a stimulant laxative, current literature does not support routine use of antimus- such as senna or bisacodyl. Docusate, alone or in combination, carinic drugs to decrease oropharyngeal secretions. There is no is no more effective than placebo for constipation in patients evidence that scopolamine, glycopyrronium, hyoscine butyl- with serious illness. Third-line therapy consists of rectal bromide, atropine, or octreotide is superior to no treatment. In suppositories and/or enema preparations. Phosphate- or addition, the use of anticholinergic agents in patients who are magnesium-containing enema preparations are contraindicated awake can lead to undesirable symptoms, such as dry mouth in patients with serious illness, owing to the potential for dan- and urinary retention. Deep suctioning by catheter should be gerous electrolyte shifts. Treatment strategies for opioid-induced avoided unless secretions are causing obvious respiratory dis- constipation are covered in Pain. tress. Nonpharmacologic interventions, such as raising the head of the bed or positioning the patient on his or her side, Anorexia and Weight Loss may be helpful. Anorexia and weight loss frequently occur as part of the natu- ral progression of life-limiting illness. Management involves Nausea addressing any reversible contributors to anorexia to ease Nausea and vomiting are common and debilitating symptoms patient and family distress. Although some medications are in patients with serious illness, with many patients rating marketed for patients with anorexia and weight loss, they are nausea as more distressing than unrelieved pain. Management marginally effective in a minority of terminally ill patients and of nausea should be tailored to address the underlying mecha- often have unacceptable side effects. Enteral or parenteral arti- nism and associated neurotransmitter pathway (Table 32). ficial nutritional support at the end of life does not improve More than one agent is frequently required for symptom relief. survival; is invasive; and can cause side effects, including In hospitalized patients, parenteral agents should be adminis- increased respiratory secretions and uncomfortable edema. tered on a scheduled basis to achieve symptom control and Discussing common end-of-life symptoms, including ano- reduce the number of emesis events. Nausea prophylaxis in rexia and weight loss, and the lack of clearly effective treat- patients receiving chemotherapy is discussed in more detail in ments for these expected changes can prepare patients and MKSAP 19 Oncology. their family members and set realistic expectations. TABLE 32. Treatment of Nausea in the Palliative Care Patient Cause of Nausea Mediating Receptor Pathway Treatment |

selected patients. See Common Symptoms for further discus- Constipation sion of dyspnea. Constipation is common in patients with serious illness and can result in extreme discomfort, restlessness, and delirium. Causes Oropharyngeal Secretions include opioids, dehydration, immobility, metabolic distur- Audible oropharyngeal secretions at the end of life (“death rat- bances, and numerous nonopioid medications. Prophylaxis tle”) are often distressing for families and clinicians alike and should be considered when constipation is likely to occur, such may occur in up to 50% of dying patients. These secretions as with opioid initiation or when prolonged immobility is antic- rarely affect respiratory status or cause patient discomfort, and ipated. Patients with constipation should be educated on educating family members on the dying process can ease con- increasing fluid intake and physical activity as much as possible. cerns. Treatment is often initiated in anticipation of or Pharmacologic therapy includes osmotic laxatives, such as poly- response to family distress but is generally ineffective. The ethylene glycol, often in combination with a stimulant laxative, current literature does not support routine use of antimus- such as senna or bisacodyl. Docusate, alone or in combination, carinic drugs to decrease oropharyngeal secretions. There is no is no more effective than placebo for constipation in patients evidence that scopolamine, glycopyrronium, hyoscine butyl- with serious illness. Third-line therapy consists of rectal bromide, atropine, or octreotide is superior to no treatment. In suppositories and/or enema preparations. Phosphate- or addition, the use of anticholinergic agents in patients who are magnesium-containing enema preparations are contraindicated awake can lead to undesirable symptoms, such as dry mouth in patients with serious illness, owing to the potential for dan- and urinary retention. Deep suctioning by catheter should be gerous electrolyte shifts. Treatment strategies for opioid-induced avoided unless secretions are causing obvious respiratory dis- constipation are covered in Pain. tress. Nonpharmacologic interventions, such as raising the head of the bed or positioning the patient on his or her side, Anorexia and Weight Loss may be helpful. Anorexia and weight loss frequently occur as part of the natu- ral progression of life-limiting illness. Management involves Nausea addressing any reversible contributors to anorexia to ease Nausea and vomiting are common and debilitating symptoms patient and family distress. Although some medications are in patients with serious illness, with many patients rating marketed for patients with anorexia and weight loss, they are nausea as more distressing than unrelieved pain. Management marginally effective in a minority of terminally ill patients and of nausea should be tailored to address the underlying mecha- often have unacceptable side effects. Enteral or parenteral arti- nism and associated neurotransmitter pathway (Table 32). ficial nutritional support at the end of life does not improve More than one agent is frequently required for symptom relief. survival; is invasive; and can cause side effects, including In hospitalized patients, parenteral agents should be adminis- increased respiratory secretions and uncomfortable edema. tered on a scheduled basis to achieve symptom control and Discussing common end-of-life symptoms, including ano- reduce the number of emesis events. Nausea prophylaxis in rexia and weight loss, and the lack of clearly effective treat- patients receiving chemotherapy is discussed in more detail in ments for these expected changes can prepare patients and MKSAP 19 Oncology. their family members and set realistic expectations. TABLE 32. Treatment of Nausea in the Palliative Care Patient Cause of Nausea Mediating Receptor Pathway Treatment | Gut wall stretching or dilatation Dopamine type 2 (D2) receptors in the Antidopaminergic antiemetics (constipation, bowel obstruction, ileus) gastrointestinal tract (metoclopramide, prochlorperazine, haloperidol, olanzapine)

Gut wall stretching or dilatation Dopamine type 2 (D2) receptors in the Antidopaminergic antiemetics (constipation, bowel obstruction, ileus) gastrointestinal tract (metoclopramide, prochlorperazine, haloperidol, olanzapine) Gut mucosal injury (radiation, Serotonin (5-hydroxytryptamine 3[5-HT3]) Serotonin antagonists (ondansetron, chemotherapy, infection, inflammation, receptors in the gastrointestinal tract granisetron) direct tumor invasion) Drugs, metabolic byproducts, bacterial D> receptors, 5-HT3 receptors, and Antidopaminergic antiemetics, toxins neurokinin type 1 receptors in the glucocorticoids, serotonin antagonists, chemoreceptor trigger zone and neurokinin-1 receptor blockers (aprepitant, netupitant) | Motion sickness, labyrinthine disorders Histamine type 1 (H,) receptors and Anticholinergic antiemetics (scopolamine, muscarinic acetylcholine receptors in the diphenhydramine, promethazine) vestibular system Anticipatory nausea Unknown, presumed cerebral cortex Behavioral therapy, benzodiazepines, olanzapine Increased intracranial pressure Unknown Glucocorticoids | 49