Applied Evidence

Palpitations, the sensory perception of one’s heartbeat, are reported in 16% of primary care patients, from causes that are both cardiac (ie, arrhythmias) and noncardiac.¹ Palpitations are usually benign; overall mortality is approximately 1% annually. In fact, a retrospective study found no difference in mortality and morbidity between patients with palpitations and control patients without palpitations.² However, palpitations can reflect a life-threatening cardiac condition, as we discuss in this article, making careful assessment and targeted, sometimes urgent, intervention important.³

Here, we review the clinical work-up of palpitations, recommended diagnostic testing, and the range of interventions for cardiac arrhythmias—ectopic beats, ventricular tachycardia (VT), and atrial fibrillation (AF).

Cardiac and noncardiac causes of palpitations

In a prospective cohort study of 190 consecutive patients presenting with palpitations, the cause was cardiac in 43%, psychiatric in 31%, and of a miscellaneous nature (including medication, thyrotoxicosis, caffeine, cocaine, anemia, amphetamine, and mastocytosis) in 10%; in 16%, the cause was undetermined.² In this study, 77% of patients experienced a recurrence of palpitations after their first episode.²

Cardiac arrhythmias, a common cause of palpitations, are differentiated by site of origin—supraventricular and ventricular. Noncardiac causes of palpitations, which we do not discuss here, include metabolic and psychiatric conditions, medications, and substance use. (For a summary of the causes of palpitations, see TABLE 1.^2-4)

Common complaint: ectopic beats. Premature atrial contractions (PACs; also known as premature atrial beats, atrial premature complexes, and atrial premature beats) and premature ventricular contractions (PVCs; also known as ventricular premature complexes and ventricular premature beats, and also of a variety of possible causes) result in a feeling of a skipped heartbeat or a flipping sensation in the chest.

Palpitations are usually benign. But they can reflect a life-threatening cardiac condition, making careful assessment and targeted, sometimes urgent, intervention important.

The burden of PACs is independently associated with mortality, cardiovascular hospitalization, new-onset AF, and pacemaker implantation. In a multivariate analysis, a PAC burden > 76 beats/d was an independent predictor of mortality (hazard ratio [HR] = 1.4; 95% CI, 1.2-16); cardiovascular hospitalization (HR = 1.3; 95% CI, 1.1-1.5); new-onset AF (HR = 1.8; 95% CI, 1.4-2.2); and pacemaker implantation (HR = 2.8; 95% CI, 1.9-4.2). Frequent PACs can lead to cardiac remodeling, so more intense follow-up of patients with a high PAC burden might allow for early detection of AF or subclinical cardiac disease.^5,6

A burden of PVCs > 24% is associated with an increased risk of PVC-induced cardiomyopathy and heart failure. Polymorphic PVCs are more concerning than monomorphic PVCs because the former suggests the presence of more diffuse, rather than localized, myocardial injury. The presence of frequent (> 1000 beats/d) PVCs warrants evaluation and treatment for underlying structural heart disease and ischemic heart disease. Therapy directed toward underlying heart disease can reduce the frequency of PVCs.^7-9

Continue to: The diagnostic work-up

The most important goal of the evaluation of palpitations is to determine the presence, or risk, of structural heart or coronary artery disease (CAD) by means of the history, physical examination, and electrocardiography (EKG). Patients who have an increased risk of structural heart disease need further evaluation with echocardiography; those at increased risk of CAD should have stress testing.

Hemodynamically unstable patients need admission; patients who have a history of syncope with palpitations usually should be admitted for cardiac monitoring. Patients who have had a single episode of palpitations and have normal baseline results of laboratory testing and a normal EKG, and no risk factors for structural heart disease or known CAD, can usually be observed.^3,4,10 Patients with an abnormal baseline EKG, recurrent palpitations (especially tachyarrhythmia), or significant symptoms during palpitations (syncope, presyncope, dyspnea) need further evaluation with ambulatory monitoring^3,4,10 (Figure).

Take a thorough history; ask these questions

Have the patient describe the palpitations. The history should include the patient’s detailed characterization of the palpitations (sudden or gradual onset, rhythm, duration, frequency). Certain descriptions provide possible diagnostic clues:

• Palpitations lasting < 5 minutes are less likely to be of cardiac origin (likelihood ratio [LR] = 0.38; 95% CI, 0.2-0.6).⁴
• A patient who has a regular, rapid-pounding sensation in the neck has an increased probability of atrioventricular (AV) nodal reentrant tachycardia (AVNRT) (LR = 177; 95% CI, 25-1251); absence of this sensation decreases the likelihood of AVNRT (LR = 0.07; 95% CI, 0.03-0.2).⁴
• PACs and PVCs cause a sensation of a skipped heartbeat or a flipping sensation in the chest; they are not reported as a sustained rapid heartbeat.
• Patients with a supraventricular arrhythmia often report sudden onset and cessation of palpitations.
• Patients with palpitations since childhood are more likely to have supraventricular tachycardia (SVT).⁴

Elicit apparent precipitating and alleviating factors. The history should include notation of situations that appear to the patient to lead to palpitations (eg, context, positional variation). Palpitations that affect sleep (LR = 2.3; 95% CI, 1.3-3.9) and palpitations that occur at work (LR = 2.2; 95% CI, 1.3-5) increase the likelihood of a cardiac cause.⁴ Palpitations associated with sudden change in position, such as bending forward or squatting, are more likely due to AVNRT.¹¹

Patients with an abnormal baseline EKG, recurrent palpitations, or significant symptoms during palpitations need evaluation with ambulatory monitoring.

Ask about aggravating factors (eg, exercise) and relieving factors (eg, rest, performing a Valsalva maneuver). Patients with SVT are often able to have palpitations terminated with a Valsalva maneuver, such as carotid sinus massage. Palpitations and syncope during exertion can be associated with hypertrophic cardiomyopathy, congenital coronary anomalies, and ion channelopathies, and can cause sudden cardiac death in athletes (estimated incidence, 1-3/100,000 person–years¹²).

Endeavor to identify underlying cardiac disease. A comprehensive history should also evaluate for risk factors and symptoms (chest pain, dyspnea, diaphoresis, lightheadedness, syncope) of cardiac disease, such as CAD, valvular disease, cardiomyopathy, and congenital heart disease, which increase the likelihood that the presenting complaint is a cardiac arrhythmia (LR = 2; 95% CI, 1.3-3.1).⁴ A history of syncope in a patient with palpitations should prompt evaluation for structural heart disease, such as aortic stenosis or hypertrophic cardiomyopathy, in which outflow-tract obstruction impairs cardiac output and, subsequently, cerebral blood flow.

Obtain additional key information. Determine the following in taking the history:

• Is there a family history of inherited cardiac disorders or sudden cardiac death?
• What prescription and over-the-counter medications is the patient taking? How does the patient characterize his or her use/intake of recreational drugs, nicotine, caffeine, and alcohol?
• Does the patient have a history of panic disorder, which lessens concern about a cardiac cause (LR = 0.2; 95% CI, 0.07-1.01)?⁴ (Of note: A nonpsychiatric cause can coexist in such patients, and should be considered.)

Continue to: Physical examination clues, and the utility of vagal maneuvers

Physical examination clues, and the utility of vagal maneuvers

Although most patients in whom palpitations are the presenting complaint are, in fact, asymptomatic during clinical assessment, cardiovascular examination can assist in diagnosing the arrhythmia or structural heart disease:

• Resting bradycardia increases the likelihood of a clinically significant arrhythmia (LR = 3; 95% CI, 1.27-7.0).¹¹
• A murmur, such as a midsystolic click or holosystolic murmur, detected during the cardiac exam can indicate mitral valve prolapse; a holosystolic murmur, exacerbated upon performing a Valsalva maneuver, suggests hypertrophic cardiomyopathy.
• Visible neck pulsations detected during assessment of the jugular venous pressure, known as cannon atrial (cannon A) waves, reflect abnormal contraction of the right atrium against a closed tricuspid valve during AV dissociation. Cannon A waves have an LR of 2.68 (95% CI, 1.25-5.78) for predicting AVNRT.⁴

Vagal nerve stimulation. In the rare circumstance that a patient complaining of palpitations is symptomatic during assessment, several tachycardias can be detected with the use of vagal maneuvers. Interruption of the tachycardia during carotid massage suggests a tachycardia involving the AV junction (AVNRT), whereas only a temporary pause or reduction in frequency is more common in atrial flutter, AF, and atrial tachycardias. Carotid massage has no effect on the presentation of ventricular arrhythmias.¹⁰

Diagnostic testing and the role of ambulatory monitoring

Electrocardiography. All patients with palpitations should have a 12-lead EKG, which may provide diagnostic clues (TABLE 2¹⁰).

Ambulatory monitoring. When the EKG is nondiagnostic, ambulatory cardiac monitoring has an established role in the diagnosis of recurrent palpitations. In a small study of patients presenting with palpitations to a general practitioner, the deduction of those practitioners was wrong more than half the time when they predicted a ≤ 20% chance of an arrhythmia based on the history, physical exam, and EKG alone¹³—emphasizing the importance of ambulatory monitoring in patients with recurrent palpitations.

A comprehensive history should also evaluate for risk factors and symptoms of cardiac disease (chest pain, dyspnea, diaphoresis, lightheadedness, syncope).

Which monitoring system is most suitable depends on symptom frequency, availability, cost, and patient competence. Twenty-four- to 48-hour Holter monitoring can be used in cases of frequent (eg, daily) palpitations. An automatic external loop recorder can be used for less frequent (eg, every 30 days) symptoms. Most ambulatory EKG is now automatic, and therefore does not require patient activation; older manual systems require patient activation during symptoms.

Two weeks of ambulatory EKG have proved sufficient for determining that there is a cardiac basis to palpitations. The diagnostic yield of ambulatory EKG is highest during Week 1 (1.04 diagnoses per patient), compared to Week 3 (0.17 diagnoses per patient).¹⁴

Implantable loop recorders are placed subcutaneously to provide EKG monitoring for approximately 3 years. They are better suited for diagnosing infrequent palpitations. The diagnostic yield of an implantable loop recorder over the course of 1 year for the detection of an arrhythmia is 73%, compared to 21% for a 24-hour Holter monitor, electrophysiology studies, and 4 weeks of an external loop recorder.¹⁵ Implantable loop recorders are often reserved for patients with palpitations associated with unexplained recurrent syncope.¹⁵

Continue to: Lab work

Lab work. A comprehensive metabolic panel, complete blood count, lipid panel, and thyroid panel should be ordered for all patients with palpitations. Possible additional tests include a urine drug screen (when recreational drug use is suspected); cardiac enzymes; N-terminal-pro hormone B-type natriuretic peptide (when there is evidence of CAD or heart failure); and urinary catecholamines (when pheochromocytoma is suspected).

Other investigations. Echocardiography is indicated when structural heart disease is suspected (TABLE 1^2-4). Patients who have multiple risk factors for CAD or exertional symptoms might warrant a stress test.

Management

PACs and PVCs

Typically, patients are counseled to minimize potential adrenergic precipitants, such as smoking, alcohol, stress, and caffeine. However, limited studies have demonstrated no significant arrhythmogenic potential of a modest dose of caffeine (200 mg), even in patients with known life-threatening ventricular arrhythmias.¹⁶ Beta-blockers and nondihydropyridine calcium channel blockers (CCBs) can reduce the severity of symptoms related to premature ectopic beats and might reduce their frequency, although response is inconsistent. Use of these medications for PACs is largely based on expert opinion and extrapolated from use in other supraventricular and ventricular arrhythmias.

Implantable cardioverter defibrillator therapy is indicated in patients with nonsustained VT due to prior myocardial infarction, left ventricular ejection fraction ≤ 40%, and inducible ventricular fibrillation or sustained VT on electrophysiological study.⁷

Patients with a high burden of ectopy who do not respond to treatment with AV nodal-blocking agents should be referred to Cardiology for other antiarrhythmic agents or catheter ablation. Last, asymptomatic ectopy does not need to be treated; there is no clear evidence that suppression with pharmacotherapy improves overall survival.^15,17

Supraventricular tachycardia

The priority when evaluating any tachycardia is to assess the patient’s stability. Unstable patients should be treated immediately, usually with cardioversion, before an extensive diagnostic evaluation.¹⁸ Patients with wide-complex tachycardia (QRS > 120 ms) are generally more unstable and require more urgent therapy and cardiac consultation or referral. Hemodynamically stable patients with narrow-complex SVT (QRS < 120 ms) can be treated with IV adenosine, which has an 89.7% success rate.^18,19 If adenosine is unsuccessful, cardioversion is indicated.

Stable patients with minimal symptoms and short episodes do not need treatment.

Continue to: Vagal maneuvers

Vagal maneuvers (eg, Valsalva maneuver; unilateral carotid massage after exclusion of a carotid bruit, with head tilted to the side opposite the massage, and not for longer than 10 seconds; or applying an ice-cold wet towel to the face) have a success rate of about 25% and are most effective when performed shortly after onset of arrhythmia. Vagal maneuvers can be used in all patients while preparing to administer medications.²⁰

Patients who need treatment can take the “pill-in-the-pocket” approach with single-dose oral flecainide (3 mg/kg) or combined diltiazem and propranolol. Flecainide has a 94% success rate; diltiazem–propranolol has a lower success rate (61%) but a shorter time to conversion to sinus rhythm.²¹ Patients with sustained or recurrent episodes of SVT should be referred to a cardiologist for chronic prophylactic drug therapy or radiofrequency ablation.

Atrial fibrillation

Hemodynamically unstable patients with AF or atrial flutter, defined by the presence of angina, decompensated heart failure, hypotension, pulmonary edema, or evidence of organ hypoperfusion, should be electrically cardioverted using synchronized direct current.

Hemodynamically stable patients with a rapid ventricular rate should be treated with an IV or oral beta-blocker, CCB, or amiodarone, or electrically cardioverted. IV medications are typically preferred in the acute setting for ease and rapidity of administration; however, there is no evidence that IV formulations of beta-blockers and CCBs are superior to oral formulations. Once the ventricular rate is controlled, patients can be transitioned to an oral short-acting preparation of the selected agent, then converted to an appropriate dosage of an extended-­release preparation.²²

Cardioversion can be performed in patients with AF < 48 hours. In patients with AF > 48 hours, either 4 weeks of anticoagulation can be given, followed by cardioversion, or transesophageal echocardiography should be performed to evaluate for atrial thrombus; if atrial thrombus is absent, cardioversion can be performed.²² Transesophageal echocardiography might be unnecessary in patients known to have been on sustained anticoagulation.

Rate control is noninferior to rhythm control and does not decrease survival, functional capacity, or quality of life. Rate-control medications include beta-blockers, nondihydropyridine CCBs, amiodarone, and digoxin.

When a patient reporting a history of palpitations is symptomatic during assessment, several tachycardias can be detected with the use of vagal maneuvers.

In the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) trial of 4060 patients, mortality was the same with rhythm control (21.3%) and rate control (23.8%) (HR = 1.15; 95% CI, 0.99-1.34), with no difference in the incidence of cardiac death, arrhythmic death, or death due to stroke.²³ In the RACE (RAte Control versus Electrical cardioversion for persistent atrial fibrillation) trial of 522 patients with persistent AF, rate control was noninferior to rhythm control (by cardioversion and drugs) for reducing morbidity and preventing cardiovascular death.²⁴ One possible reason why the rhythm control strategy in the RACE trial did not show superiority is the low number of patients who achieved sustained sinus rhythm.²⁵

Continue to: The recommended ventricular rate...

The recommended ventricular rate has traditionally been 60 to 80 beats/min at rest and < 110 beats/min during daily activities. However, a recent trial found fewer adverse outcomes and no change in symptoms or the outcome of hospitalization in patients randomized to more lenient control (target resting heart rate, < 110 beats/min), although the mean of the actual lenient rate achieved was 86 beats/minute.²⁴

Rhythm control. Antiarrhythmic agents or procedural interventions can be used in patients who fail or remain symptomatic despite rate control.²⁶ Surgical measures include AV node ablation with placement of a pacemaker; atrial pacing with an implantable atrial defibrillator; the Maze procedure (open-heart surgery) to interrupt reentrant circuits in the left atrium; and percutaneous radiofrequency or cryotherapy ablation of arrhythmogenic foci in and around the junction of the pulmonary veins and left atrium.²⁷

There is no significant benefit to immediate catheter ablation over standard medical therapy in adults with symptomatic AF in reducing the composite outcome of death, stroke, serious bleeding, and cardiac arrest. Catheter ablation is associated with a lower AF recurrence rate (50%) than drug therapy (69%) at 3 years.²⁸

Anticoagulation. Patients at high risk of embolic stroke based on their score on the CHA2DS2-VASc^a risk stratification tool (ie, a score ≥ 2) should be anticoagulated.^29,30 Options include a novel oral anticoagulant (dabigatran, rivaroxaban, apixaban, or edoxaban), the preferred class of agents for nonvalvular AF, and warfarin, with a target International Normalized Ratio of 2 to 3. Novel oral anticoagulants have been compared to warfarin for prevention of stroke in AF and were found more effective than warfarin, although at the expense of an increased risk of gastrointestinal bleeding.³¹ Percutaneous left atrial appendage closure, using a device such as the Watchman implant, is a noninferior surgical method to prevent embolic stroke in patients who are intolerant of, or have a contraindication to, anticoagulation.³²

CORRESPONDENCE
Anne Mounsey, MD, Department of Family Medicine, University of North Carolina, 590 Manning Drive, Chapel Hill, NC 27599; [email protected].

Palpitations, the sensory perception of one’s heartbeat, are reported in 16% of primary care patients, from causes that are both cardiac (ie, arrhythmias) and noncardiac.¹ Palpitations are usually benign; overall mortality is approximately 1% annually. In fact, a retrospective study found no difference in mortality and morbidity between patients with palpitations and control patients without palpitations.² However, palpitations can reflect a life-threatening cardiac condition, as we discuss in this article, making careful assessment and targeted, sometimes urgent, intervention important.³

Here, we review the clinical work-up of palpitations, recommended diagnostic testing, and the range of interventions for cardiac arrhythmias—ectopic beats, ventricular tachycardia (VT), and atrial fibrillation (AF).

Cardiac and noncardiac causes of palpitations

In a prospective cohort study of 190 consecutive patients presenting with palpitations, the cause was cardiac in 43%, psychiatric in 31%, and of a miscellaneous nature (including medication, thyrotoxicosis, caffeine, cocaine, anemia, amphetamine, and mastocytosis) in 10%; in 16%, the cause was undetermined.² In this study, 77% of patients experienced a recurrence of palpitations after their first episode.²

Cardiac arrhythmias, a common cause of palpitations, are differentiated by site of origin—supraventricular and ventricular. Noncardiac causes of palpitations, which we do not discuss here, include metabolic and psychiatric conditions, medications, and substance use. (For a summary of the causes of palpitations, see TABLE 1.^2-4)

Common complaint: ectopic beats. Premature atrial contractions (PACs; also known as premature atrial beats, atrial premature complexes, and atrial premature beats) and premature ventricular contractions (PVCs; also known as ventricular premature complexes and ventricular premature beats, and also of a variety of possible causes) result in a feeling of a skipped heartbeat or a flipping sensation in the chest.

Palpitations are usually benign. But they can reflect a life-threatening cardiac condition, making careful assessment and targeted, sometimes urgent, intervention important.

The burden of PACs is independently associated with mortality, cardiovascular hospitalization, new-onset AF, and pacemaker implantation. In a multivariate analysis, a PAC burden > 76 beats/d was an independent predictor of mortality (hazard ratio [HR] = 1.4; 95% CI, 1.2-16); cardiovascular hospitalization (HR = 1.3; 95% CI, 1.1-1.5); new-onset AF (HR = 1.8; 95% CI, 1.4-2.2); and pacemaker implantation (HR = 2.8; 95% CI, 1.9-4.2). Frequent PACs can lead to cardiac remodeling, so more intense follow-up of patients with a high PAC burden might allow for early detection of AF or subclinical cardiac disease.^5,6

A burden of PVCs > 24% is associated with an increased risk of PVC-induced cardiomyopathy and heart failure. Polymorphic PVCs are more concerning than monomorphic PVCs because the former suggests the presence of more diffuse, rather than localized, myocardial injury. The presence of frequent (> 1000 beats/d) PVCs warrants evaluation and treatment for underlying structural heart disease and ischemic heart disease. Therapy directed toward underlying heart disease can reduce the frequency of PVCs.^7-9

Continue to: The diagnostic work-up

The most important goal of the evaluation of palpitations is to determine the presence, or risk, of structural heart or coronary artery disease (CAD) by means of the history, physical examination, and electrocardiography (EKG). Patients who have an increased risk of structural heart disease need further evaluation with echocardiography; those at increased risk of CAD should have stress testing.

Hemodynamically unstable patients need admission; patients who have a history of syncope with palpitations usually should be admitted for cardiac monitoring. Patients who have had a single episode of palpitations and have normal baseline results of laboratory testing and a normal EKG, and no risk factors for structural heart disease or known CAD, can usually be observed.^3,4,10 Patients with an abnormal baseline EKG, recurrent palpitations (especially tachyarrhythmia), or significant symptoms during palpitations (syncope, presyncope, dyspnea) need further evaluation with ambulatory monitoring^3,4,10 (Figure).

Take a thorough history; ask these questions

Have the patient describe the palpitations. The history should include the patient’s detailed characterization of the palpitations (sudden or gradual onset, rhythm, duration, frequency). Certain descriptions provide possible diagnostic clues:

• Palpitations lasting < 5 minutes are less likely to be of cardiac origin (likelihood ratio [LR] = 0.38; 95% CI, 0.2-0.6).⁴
• A patient who has a regular, rapid-pounding sensation in the neck has an increased probability of atrioventricular (AV) nodal reentrant tachycardia (AVNRT) (LR = 177; 95% CI, 25-1251); absence of this sensation decreases the likelihood of AVNRT (LR = 0.07; 95% CI, 0.03-0.2).⁴
• PACs and PVCs cause a sensation of a skipped heartbeat or a flipping sensation in the chest; they are not reported as a sustained rapid heartbeat.
• Patients with a supraventricular arrhythmia often report sudden onset and cessation of palpitations.
• Patients with palpitations since childhood are more likely to have supraventricular tachycardia (SVT).⁴

Elicit apparent precipitating and alleviating factors. The history should include notation of situations that appear to the patient to lead to palpitations (eg, context, positional variation). Palpitations that affect sleep (LR = 2.3; 95% CI, 1.3-3.9) and palpitations that occur at work (LR = 2.2; 95% CI, 1.3-5) increase the likelihood of a cardiac cause.⁴ Palpitations associated with sudden change in position, such as bending forward or squatting, are more likely due to AVNRT.¹¹

Patients with an abnormal baseline EKG, recurrent palpitations, or significant symptoms during palpitations need evaluation with ambulatory monitoring.

Ask about aggravating factors (eg, exercise) and relieving factors (eg, rest, performing a Valsalva maneuver). Patients with SVT are often able to have palpitations terminated with a Valsalva maneuver, such as carotid sinus massage. Palpitations and syncope during exertion can be associated with hypertrophic cardiomyopathy, congenital coronary anomalies, and ion channelopathies, and can cause sudden cardiac death in athletes (estimated incidence, 1-3/100,000 person–years¹²).

Endeavor to identify underlying cardiac disease. A comprehensive history should also evaluate for risk factors and symptoms (chest pain, dyspnea, diaphoresis, lightheadedness, syncope) of cardiac disease, such as CAD, valvular disease, cardiomyopathy, and congenital heart disease, which increase the likelihood that the presenting complaint is a cardiac arrhythmia (LR = 2; 95% CI, 1.3-3.1).⁴ A history of syncope in a patient with palpitations should prompt evaluation for structural heart disease, such as aortic stenosis or hypertrophic cardiomyopathy, in which outflow-tract obstruction impairs cardiac output and, subsequently, cerebral blood flow.

Obtain additional key information. Determine the following in taking the history:

• Is there a family history of inherited cardiac disorders or sudden cardiac death?
• What prescription and over-the-counter medications is the patient taking? How does the patient characterize his or her use/intake of recreational drugs, nicotine, caffeine, and alcohol?
• Does the patient have a history of panic disorder, which lessens concern about a cardiac cause (LR = 0.2; 95% CI, 0.07-1.01)?⁴ (Of note: A nonpsychiatric cause can coexist in such patients, and should be considered.)

Continue to: Physical examination clues, and the utility of vagal maneuvers

Physical examination clues, and the utility of vagal maneuvers

Although most patients in whom palpitations are the presenting complaint are, in fact, asymptomatic during clinical assessment, cardiovascular examination can assist in diagnosing the arrhythmia or structural heart disease:

• Resting bradycardia increases the likelihood of a clinically significant arrhythmia (LR = 3; 95% CI, 1.27-7.0).¹¹
• A murmur, such as a midsystolic click or holosystolic murmur, detected during the cardiac exam can indicate mitral valve prolapse; a holosystolic murmur, exacerbated upon performing a Valsalva maneuver, suggests hypertrophic cardiomyopathy.
• Visible neck pulsations detected during assessment of the jugular venous pressure, known as cannon atrial (cannon A) waves, reflect abnormal contraction of the right atrium against a closed tricuspid valve during AV dissociation. Cannon A waves have an LR of 2.68 (95% CI, 1.25-5.78) for predicting AVNRT.⁴

Vagal nerve stimulation. In the rare circumstance that a patient complaining of palpitations is symptomatic during assessment, several tachycardias can be detected with the use of vagal maneuvers. Interruption of the tachycardia during carotid massage suggests a tachycardia involving the AV junction (AVNRT), whereas only a temporary pause or reduction in frequency is more common in atrial flutter, AF, and atrial tachycardias. Carotid massage has no effect on the presentation of ventricular arrhythmias.¹⁰

Diagnostic testing and the role of ambulatory monitoring

Electrocardiography. All patients with palpitations should have a 12-lead EKG, which may provide diagnostic clues (TABLE 2¹⁰).

Ambulatory monitoring. When the EKG is nondiagnostic, ambulatory cardiac monitoring has an established role in the diagnosis of recurrent palpitations. In a small study of patients presenting with palpitations to a general practitioner, the deduction of those practitioners was wrong more than half the time when they predicted a ≤ 20% chance of an arrhythmia based on the history, physical exam, and EKG alone¹³—emphasizing the importance of ambulatory monitoring in patients with recurrent palpitations.

A comprehensive history should also evaluate for risk factors and symptoms of cardiac disease (chest pain, dyspnea, diaphoresis, lightheadedness, syncope).

Which monitoring system is most suitable depends on symptom frequency, availability, cost, and patient competence. Twenty-four- to 48-hour Holter monitoring can be used in cases of frequent (eg, daily) palpitations. An automatic external loop recorder can be used for less frequent (eg, every 30 days) symptoms. Most ambulatory EKG is now automatic, and therefore does not require patient activation; older manual systems require patient activation during symptoms.

Two weeks of ambulatory EKG have proved sufficient for determining that there is a cardiac basis to palpitations. The diagnostic yield of ambulatory EKG is highest during Week 1 (1.04 diagnoses per patient), compared to Week 3 (0.17 diagnoses per patient).¹⁴

Implantable loop recorders are placed subcutaneously to provide EKG monitoring for approximately 3 years. They are better suited for diagnosing infrequent palpitations. The diagnostic yield of an implantable loop recorder over the course of 1 year for the detection of an arrhythmia is 73%, compared to 21% for a 24-hour Holter monitor, electrophysiology studies, and 4 weeks of an external loop recorder.¹⁵ Implantable loop recorders are often reserved for patients with palpitations associated with unexplained recurrent syncope.¹⁵

Continue to: Lab work

Lab work. A comprehensive metabolic panel, complete blood count, lipid panel, and thyroid panel should be ordered for all patients with palpitations. Possible additional tests include a urine drug screen (when recreational drug use is suspected); cardiac enzymes; N-terminal-pro hormone B-type natriuretic peptide (when there is evidence of CAD or heart failure); and urinary catecholamines (when pheochromocytoma is suspected).

Other investigations. Echocardiography is indicated when structural heart disease is suspected (TABLE 1^2-4). Patients who have multiple risk factors for CAD or exertional symptoms might warrant a stress test.

Management

PACs and PVCs

Typically, patients are counseled to minimize potential adrenergic precipitants, such as smoking, alcohol, stress, and caffeine. However, limited studies have demonstrated no significant arrhythmogenic potential of a modest dose of caffeine (200 mg), even in patients with known life-threatening ventricular arrhythmias.¹⁶ Beta-blockers and nondihydropyridine calcium channel blockers (CCBs) can reduce the severity of symptoms related to premature ectopic beats and might reduce their frequency, although response is inconsistent. Use of these medications for PACs is largely based on expert opinion and extrapolated from use in other supraventricular and ventricular arrhythmias.

Implantable cardioverter defibrillator therapy is indicated in patients with nonsustained VT due to prior myocardial infarction, left ventricular ejection fraction ≤ 40%, and inducible ventricular fibrillation or sustained VT on electrophysiological study.⁷

Patients with a high burden of ectopy who do not respond to treatment with AV nodal-blocking agents should be referred to Cardiology for other antiarrhythmic agents or catheter ablation. Last, asymptomatic ectopy does not need to be treated; there is no clear evidence that suppression with pharmacotherapy improves overall survival.^15,17

Supraventricular tachycardia

The priority when evaluating any tachycardia is to assess the patient’s stability. Unstable patients should be treated immediately, usually with cardioversion, before an extensive diagnostic evaluation.¹⁸ Patients with wide-complex tachycardia (QRS > 120 ms) are generally more unstable and require more urgent therapy and cardiac consultation or referral. Hemodynamically stable patients with narrow-complex SVT (QRS < 120 ms) can be treated with IV adenosine, which has an 89.7% success rate.^18,19 If adenosine is unsuccessful, cardioversion is indicated.

Stable patients with minimal symptoms and short episodes do not need treatment.

Continue to: Vagal maneuvers

Vagal maneuvers (eg, Valsalva maneuver; unilateral carotid massage after exclusion of a carotid bruit, with head tilted to the side opposite the massage, and not for longer than 10 seconds; or applying an ice-cold wet towel to the face) have a success rate of about 25% and are most effective when performed shortly after onset of arrhythmia. Vagal maneuvers can be used in all patients while preparing to administer medications.²⁰

Patients who need treatment can take the “pill-in-the-pocket” approach with single-dose oral flecainide (3 mg/kg) or combined diltiazem and propranolol. Flecainide has a 94% success rate; diltiazem–propranolol has a lower success rate (61%) but a shorter time to conversion to sinus rhythm.²¹ Patients with sustained or recurrent episodes of SVT should be referred to a cardiologist for chronic prophylactic drug therapy or radiofrequency ablation.

Atrial fibrillation

Hemodynamically unstable patients with AF or atrial flutter, defined by the presence of angina, decompensated heart failure, hypotension, pulmonary edema, or evidence of organ hypoperfusion, should be electrically cardioverted using synchronized direct current.

Hemodynamically stable patients with a rapid ventricular rate should be treated with an IV or oral beta-blocker, CCB, or amiodarone, or electrically cardioverted. IV medications are typically preferred in the acute setting for ease and rapidity of administration; however, there is no evidence that IV formulations of beta-blockers and CCBs are superior to oral formulations. Once the ventricular rate is controlled, patients can be transitioned to an oral short-acting preparation of the selected agent, then converted to an appropriate dosage of an extended-­release preparation.²²

Cardioversion can be performed in patients with AF < 48 hours. In patients with AF > 48 hours, either 4 weeks of anticoagulation can be given, followed by cardioversion, or transesophageal echocardiography should be performed to evaluate for atrial thrombus; if atrial thrombus is absent, cardioversion can be performed.²² Transesophageal echocardiography might be unnecessary in patients known to have been on sustained anticoagulation.

Rate control is noninferior to rhythm control and does not decrease survival, functional capacity, or quality of life. Rate-control medications include beta-blockers, nondihydropyridine CCBs, amiodarone, and digoxin.

When a patient reporting a history of palpitations is symptomatic during assessment, several tachycardias can be detected with the use of vagal maneuvers.

In the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) trial of 4060 patients, mortality was the same with rhythm control (21.3%) and rate control (23.8%) (HR = 1.15; 95% CI, 0.99-1.34), with no difference in the incidence of cardiac death, arrhythmic death, or death due to stroke.²³ In the RACE (RAte Control versus Electrical cardioversion for persistent atrial fibrillation) trial of 522 patients with persistent AF, rate control was noninferior to rhythm control (by cardioversion and drugs) for reducing morbidity and preventing cardiovascular death.²⁴ One possible reason why the rhythm control strategy in the RACE trial did not show superiority is the low number of patients who achieved sustained sinus rhythm.²⁵

Continue to: The recommended ventricular rate...

The recommended ventricular rate has traditionally been 60 to 80 beats/min at rest and < 110 beats/min during daily activities. However, a recent trial found fewer adverse outcomes and no change in symptoms or the outcome of hospitalization in patients randomized to more lenient control (target resting heart rate, < 110 beats/min), although the mean of the actual lenient rate achieved was 86 beats/minute.²⁴

Rhythm control. Antiarrhythmic agents or procedural interventions can be used in patients who fail or remain symptomatic despite rate control.²⁶ Surgical measures include AV node ablation with placement of a pacemaker; atrial pacing with an implantable atrial defibrillator; the Maze procedure (open-heart surgery) to interrupt reentrant circuits in the left atrium; and percutaneous radiofrequency or cryotherapy ablation of arrhythmogenic foci in and around the junction of the pulmonary veins and left atrium.²⁷

There is no significant benefit to immediate catheter ablation over standard medical therapy in adults with symptomatic AF in reducing the composite outcome of death, stroke, serious bleeding, and cardiac arrest. Catheter ablation is associated with a lower AF recurrence rate (50%) than drug therapy (69%) at 3 years.²⁸

Anticoagulation. Patients at high risk of embolic stroke based on their score on the CHA2DS2-VASc^a risk stratification tool (ie, a score ≥ 2) should be anticoagulated.^29,30 Options include a novel oral anticoagulant (dabigatran, rivaroxaban, apixaban, or edoxaban), the preferred class of agents for nonvalvular AF, and warfarin, with a target International Normalized Ratio of 2 to 3. Novel oral anticoagulants have been compared to warfarin for prevention of stroke in AF and were found more effective than warfarin, although at the expense of an increased risk of gastrointestinal bleeding.³¹ Percutaneous left atrial appendage closure, using a device such as the Watchman implant, is a noninferior surgical method to prevent embolic stroke in patients who are intolerant of, or have a contraindication to, anticoagulation.³²

CORRESPONDENCE
Anne Mounsey, MD, Department of Family Medicine, University of North Carolina, 590 Manning Drive, Chapel Hill, NC 27599; [email protected].

Palpitations, the sensory perception of one’s heartbeat, are reported in 16% of primary care patients, from causes that are both cardiac (ie, arrhythmias) and noncardiac.¹ Palpitations are usually benign; overall mortality is approximately 1% annually. In fact, a retrospective study found no difference in mortality and morbidity between patients with palpitations and control patients without palpitations.² However, palpitations can reflect a life-threatening cardiac condition, as we discuss in this article, making careful assessment and targeted, sometimes urgent, intervention important.³

Here, we review the clinical work-up of palpitations, recommended diagnostic testing, and the range of interventions for cardiac arrhythmias—ectopic beats, ventricular tachycardia (VT), and atrial fibrillation (AF).

Cardiac and noncardiac causes of palpitations

In a prospective cohort study of 190 consecutive patients presenting with palpitations, the cause was cardiac in 43%, psychiatric in 31%, and of a miscellaneous nature (including medication, thyrotoxicosis, caffeine, cocaine, anemia, amphetamine, and mastocytosis) in 10%; in 16%, the cause was undetermined.² In this study, 77% of patients experienced a recurrence of palpitations after their first episode.²

Cardiac arrhythmias, a common cause of palpitations, are differentiated by site of origin—supraventricular and ventricular. Noncardiac causes of palpitations, which we do not discuss here, include metabolic and psychiatric conditions, medications, and substance use. (For a summary of the causes of palpitations, see TABLE 1.^2-4)

Common complaint: ectopic beats. Premature atrial contractions (PACs; also known as premature atrial beats, atrial premature complexes, and atrial premature beats) and premature ventricular contractions (PVCs; also known as ventricular premature complexes and ventricular premature beats, and also of a variety of possible causes) result in a feeling of a skipped heartbeat or a flipping sensation in the chest.

Palpitations are usually benign. But they can reflect a life-threatening cardiac condition, making careful assessment and targeted, sometimes urgent, intervention important.

The burden of PACs is independently associated with mortality, cardiovascular hospitalization, new-onset AF, and pacemaker implantation. In a multivariate analysis, a PAC burden > 76 beats/d was an independent predictor of mortality (hazard ratio [HR] = 1.4; 95% CI, 1.2-16); cardiovascular hospitalization (HR = 1.3; 95% CI, 1.1-1.5); new-onset AF (HR = 1.8; 95% CI, 1.4-2.2); and pacemaker implantation (HR = 2.8; 95% CI, 1.9-4.2). Frequent PACs can lead to cardiac remodeling, so more intense follow-up of patients with a high PAC burden might allow for early detection of AF or subclinical cardiac disease.^5,6

A burden of PVCs > 24% is associated with an increased risk of PVC-induced cardiomyopathy and heart failure. Polymorphic PVCs are more concerning than monomorphic PVCs because the former suggests the presence of more diffuse, rather than localized, myocardial injury. The presence of frequent (> 1000 beats/d) PVCs warrants evaluation and treatment for underlying structural heart disease and ischemic heart disease. Therapy directed toward underlying heart disease can reduce the frequency of PVCs.^7-9

Continue to: The diagnostic work-up

The most important goal of the evaluation of palpitations is to determine the presence, or risk, of structural heart or coronary artery disease (CAD) by means of the history, physical examination, and electrocardiography (EKG). Patients who have an increased risk of structural heart disease need further evaluation with echocardiography; those at increased risk of CAD should have stress testing.

Hemodynamically unstable patients need admission; patients who have a history of syncope with palpitations usually should be admitted for cardiac monitoring. Patients who have had a single episode of palpitations and have normal baseline results of laboratory testing and a normal EKG, and no risk factors for structural heart disease or known CAD, can usually be observed.^3,4,10 Patients with an abnormal baseline EKG, recurrent palpitations (especially tachyarrhythmia), or significant symptoms during palpitations (syncope, presyncope, dyspnea) need further evaluation with ambulatory monitoring^3,4,10 (Figure).

Take a thorough history; ask these questions

Have the patient describe the palpitations. The history should include the patient’s detailed characterization of the palpitations (sudden or gradual onset, rhythm, duration, frequency). Certain descriptions provide possible diagnostic clues:

• Palpitations lasting < 5 minutes are less likely to be of cardiac origin (likelihood ratio [LR] = 0.38; 95% CI, 0.2-0.6).⁴
• A patient who has a regular, rapid-pounding sensation in the neck has an increased probability of atrioventricular (AV) nodal reentrant tachycardia (AVNRT) (LR = 177; 95% CI, 25-1251); absence of this sensation decreases the likelihood of AVNRT (LR = 0.07; 95% CI, 0.03-0.2).⁴
• PACs and PVCs cause a sensation of a skipped heartbeat or a flipping sensation in the chest; they are not reported as a sustained rapid heartbeat.
• Patients with a supraventricular arrhythmia often report sudden onset and cessation of palpitations.
• Patients with palpitations since childhood are more likely to have supraventricular tachycardia (SVT).⁴

Elicit apparent precipitating and alleviating factors. The history should include notation of situations that appear to the patient to lead to palpitations (eg, context, positional variation). Palpitations that affect sleep (LR = 2.3; 95% CI, 1.3-3.9) and palpitations that occur at work (LR = 2.2; 95% CI, 1.3-5) increase the likelihood of a cardiac cause.⁴ Palpitations associated with sudden change in position, such as bending forward or squatting, are more likely due to AVNRT.¹¹

Patients with an abnormal baseline EKG, recurrent palpitations, or significant symptoms during palpitations need evaluation with ambulatory monitoring.

Ask about aggravating factors (eg, exercise) and relieving factors (eg, rest, performing a Valsalva maneuver). Patients with SVT are often able to have palpitations terminated with a Valsalva maneuver, such as carotid sinus massage. Palpitations and syncope during exertion can be associated with hypertrophic cardiomyopathy, congenital coronary anomalies, and ion channelopathies, and can cause sudden cardiac death in athletes (estimated incidence, 1-3/100,000 person–years¹²).

Endeavor to identify underlying cardiac disease. A comprehensive history should also evaluate for risk factors and symptoms (chest pain, dyspnea, diaphoresis, lightheadedness, syncope) of cardiac disease, such as CAD, valvular disease, cardiomyopathy, and congenital heart disease, which increase the likelihood that the presenting complaint is a cardiac arrhythmia (LR = 2; 95% CI, 1.3-3.1).⁴ A history of syncope in a patient with palpitations should prompt evaluation for structural heart disease, such as aortic stenosis or hypertrophic cardiomyopathy, in which outflow-tract obstruction impairs cardiac output and, subsequently, cerebral blood flow.

Obtain additional key information. Determine the following in taking the history:

• Is there a family history of inherited cardiac disorders or sudden cardiac death?
• What prescription and over-the-counter medications is the patient taking? How does the patient characterize his or her use/intake of recreational drugs, nicotine, caffeine, and alcohol?
• Does the patient have a history of panic disorder, which lessens concern about a cardiac cause (LR = 0.2; 95% CI, 0.07-1.01)?⁴ (Of note: A nonpsychiatric cause can coexist in such patients, and should be considered.)

Continue to: Physical examination clues, and the utility of vagal maneuvers

Physical examination clues, and the utility of vagal maneuvers

Although most patients in whom palpitations are the presenting complaint are, in fact, asymptomatic during clinical assessment, cardiovascular examination can assist in diagnosing the arrhythmia or structural heart disease:

• Resting bradycardia increases the likelihood of a clinically significant arrhythmia (LR = 3; 95% CI, 1.27-7.0).¹¹
• A murmur, such as a midsystolic click or holosystolic murmur, detected during the cardiac exam can indicate mitral valve prolapse; a holosystolic murmur, exacerbated upon performing a Valsalva maneuver, suggests hypertrophic cardiomyopathy.
• Visible neck pulsations detected during assessment of the jugular venous pressure, known as cannon atrial (cannon A) waves, reflect abnormal contraction of the right atrium against a closed tricuspid valve during AV dissociation. Cannon A waves have an LR of 2.68 (95% CI, 1.25-5.78) for predicting AVNRT.⁴

Vagal nerve stimulation. In the rare circumstance that a patient complaining of palpitations is symptomatic during assessment, several tachycardias can be detected with the use of vagal maneuvers. Interruption of the tachycardia during carotid massage suggests a tachycardia involving the AV junction (AVNRT), whereas only a temporary pause or reduction in frequency is more common in atrial flutter, AF, and atrial tachycardias. Carotid massage has no effect on the presentation of ventricular arrhythmias.¹⁰

Diagnostic testing and the role of ambulatory monitoring

Electrocardiography. All patients with palpitations should have a 12-lead EKG, which may provide diagnostic clues (TABLE 2¹⁰).

Ambulatory monitoring. When the EKG is nondiagnostic, ambulatory cardiac monitoring has an established role in the diagnosis of recurrent palpitations. In a small study of patients presenting with palpitations to a general practitioner, the deduction of those practitioners was wrong more than half the time when they predicted a ≤ 20% chance of an arrhythmia based on the history, physical exam, and EKG alone¹³—emphasizing the importance of ambulatory monitoring in patients with recurrent palpitations.

A comprehensive history should also evaluate for risk factors and symptoms of cardiac disease (chest pain, dyspnea, diaphoresis, lightheadedness, syncope).

Which monitoring system is most suitable depends on symptom frequency, availability, cost, and patient competence. Twenty-four- to 48-hour Holter monitoring can be used in cases of frequent (eg, daily) palpitations. An automatic external loop recorder can be used for less frequent (eg, every 30 days) symptoms. Most ambulatory EKG is now automatic, and therefore does not require patient activation; older manual systems require patient activation during symptoms.

Two weeks of ambulatory EKG have proved sufficient for determining that there is a cardiac basis to palpitations. The diagnostic yield of ambulatory EKG is highest during Week 1 (1.04 diagnoses per patient), compared to Week 3 (0.17 diagnoses per patient).¹⁴

Implantable loop recorders are placed subcutaneously to provide EKG monitoring for approximately 3 years. They are better suited for diagnosing infrequent palpitations. The diagnostic yield of an implantable loop recorder over the course of 1 year for the detection of an arrhythmia is 73%, compared to 21% for a 24-hour Holter monitor, electrophysiology studies, and 4 weeks of an external loop recorder.¹⁵ Implantable loop recorders are often reserved for patients with palpitations associated with unexplained recurrent syncope.¹⁵

Continue to: Lab work

Lab work. A comprehensive metabolic panel, complete blood count, lipid panel, and thyroid panel should be ordered for all patients with palpitations. Possible additional tests include a urine drug screen (when recreational drug use is suspected); cardiac enzymes; N-terminal-pro hormone B-type natriuretic peptide (when there is evidence of CAD or heart failure); and urinary catecholamines (when pheochromocytoma is suspected).

Other investigations. Echocardiography is indicated when structural heart disease is suspected (TABLE 1^2-4). Patients who have multiple risk factors for CAD or exertional symptoms might warrant a stress test.

Management

PACs and PVCs

Typically, patients are counseled to minimize potential adrenergic precipitants, such as smoking, alcohol, stress, and caffeine. However, limited studies have demonstrated no significant arrhythmogenic potential of a modest dose of caffeine (200 mg), even in patients with known life-threatening ventricular arrhythmias.¹⁶ Beta-blockers and nondihydropyridine calcium channel blockers (CCBs) can reduce the severity of symptoms related to premature ectopic beats and might reduce their frequency, although response is inconsistent. Use of these medications for PACs is largely based on expert opinion and extrapolated from use in other supraventricular and ventricular arrhythmias.

Implantable cardioverter defibrillator therapy is indicated in patients with nonsustained VT due to prior myocardial infarction, left ventricular ejection fraction ≤ 40%, and inducible ventricular fibrillation or sustained VT on electrophysiological study.⁷

Patients with a high burden of ectopy who do not respond to treatment with AV nodal-blocking agents should be referred to Cardiology for other antiarrhythmic agents or catheter ablation. Last, asymptomatic ectopy does not need to be treated; there is no clear evidence that suppression with pharmacotherapy improves overall survival.^15,17

Supraventricular tachycardia

The priority when evaluating any tachycardia is to assess the patient’s stability. Unstable patients should be treated immediately, usually with cardioversion, before an extensive diagnostic evaluation.¹⁸ Patients with wide-complex tachycardia (QRS > 120 ms) are generally more unstable and require more urgent therapy and cardiac consultation or referral. Hemodynamically stable patients with narrow-complex SVT (QRS < 120 ms) can be treated with IV adenosine, which has an 89.7% success rate.^18,19 If adenosine is unsuccessful, cardioversion is indicated.

Stable patients with minimal symptoms and short episodes do not need treatment.

Continue to: Vagal maneuvers

Vagal maneuvers (eg, Valsalva maneuver; unilateral carotid massage after exclusion of a carotid bruit, with head tilted to the side opposite the massage, and not for longer than 10 seconds; or applying an ice-cold wet towel to the face) have a success rate of about 25% and are most effective when performed shortly after onset of arrhythmia. Vagal maneuvers can be used in all patients while preparing to administer medications.²⁰

Patients who need treatment can take the “pill-in-the-pocket” approach with single-dose oral flecainide (3 mg/kg) or combined diltiazem and propranolol. Flecainide has a 94% success rate; diltiazem–propranolol has a lower success rate (61%) but a shorter time to conversion to sinus rhythm.²¹ Patients with sustained or recurrent episodes of SVT should be referred to a cardiologist for chronic prophylactic drug therapy or radiofrequency ablation.

Atrial fibrillation

Hemodynamically unstable patients with AF or atrial flutter, defined by the presence of angina, decompensated heart failure, hypotension, pulmonary edema, or evidence of organ hypoperfusion, should be electrically cardioverted using synchronized direct current.

Hemodynamically stable patients with a rapid ventricular rate should be treated with an IV or oral beta-blocker, CCB, or amiodarone, or electrically cardioverted. IV medications are typically preferred in the acute setting for ease and rapidity of administration; however, there is no evidence that IV formulations of beta-blockers and CCBs are superior to oral formulations. Once the ventricular rate is controlled, patients can be transitioned to an oral short-acting preparation of the selected agent, then converted to an appropriate dosage of an extended-­release preparation.²²

Cardioversion can be performed in patients with AF < 48 hours. In patients with AF > 48 hours, either 4 weeks of anticoagulation can be given, followed by cardioversion, or transesophageal echocardiography should be performed to evaluate for atrial thrombus; if atrial thrombus is absent, cardioversion can be performed.²² Transesophageal echocardiography might be unnecessary in patients known to have been on sustained anticoagulation.

Rate control is noninferior to rhythm control and does not decrease survival, functional capacity, or quality of life. Rate-control medications include beta-blockers, nondihydropyridine CCBs, amiodarone, and digoxin.

When a patient reporting a history of palpitations is symptomatic during assessment, several tachycardias can be detected with the use of vagal maneuvers.

In the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) trial of 4060 patients, mortality was the same with rhythm control (21.3%) and rate control (23.8%) (HR = 1.15; 95% CI, 0.99-1.34), with no difference in the incidence of cardiac death, arrhythmic death, or death due to stroke.²³ In the RACE (RAte Control versus Electrical cardioversion for persistent atrial fibrillation) trial of 522 patients with persistent AF, rate control was noninferior to rhythm control (by cardioversion and drugs) for reducing morbidity and preventing cardiovascular death.²⁴ One possible reason why the rhythm control strategy in the RACE trial did not show superiority is the low number of patients who achieved sustained sinus rhythm.²⁵

Continue to: The recommended ventricular rate...

The recommended ventricular rate has traditionally been 60 to 80 beats/min at rest and < 110 beats/min during daily activities. However, a recent trial found fewer adverse outcomes and no change in symptoms or the outcome of hospitalization in patients randomized to more lenient control (target resting heart rate, < 110 beats/min), although the mean of the actual lenient rate achieved was 86 beats/minute.²⁴

Rhythm control. Antiarrhythmic agents or procedural interventions can be used in patients who fail or remain symptomatic despite rate control.²⁶ Surgical measures include AV node ablation with placement of a pacemaker; atrial pacing with an implantable atrial defibrillator; the Maze procedure (open-heart surgery) to interrupt reentrant circuits in the left atrium; and percutaneous radiofrequency or cryotherapy ablation of arrhythmogenic foci in and around the junction of the pulmonary veins and left atrium.²⁷

There is no significant benefit to immediate catheter ablation over standard medical therapy in adults with symptomatic AF in reducing the composite outcome of death, stroke, serious bleeding, and cardiac arrest. Catheter ablation is associated with a lower AF recurrence rate (50%) than drug therapy (69%) at 3 years.²⁸

Anticoagulation. Patients at high risk of embolic stroke based on their score on the CHA2DS2-VASc^a risk stratification tool (ie, a score ≥ 2) should be anticoagulated.^29,30 Options include a novel oral anticoagulant (dabigatran, rivaroxaban, apixaban, or edoxaban), the preferred class of agents for nonvalvular AF, and warfarin, with a target International Normalized Ratio of 2 to 3. Novel oral anticoagulants have been compared to warfarin for prevention of stroke in AF and were found more effective than warfarin, although at the expense of an increased risk of gastrointestinal bleeding.³¹ Percutaneous left atrial appendage closure, using a device such as the Watchman implant, is a noninferior surgical method to prevent embolic stroke in patients who are intolerant of, or have a contraindication to, anticoagulation.³²

CORRESPONDENCE
Anne Mounsey, MD, Department of Family Medicine, University of North Carolina, 590 Manning Drive, Chapel Hill, NC 27599; [email protected].

Atopic dermatitis (AD), also known as eczema, is a chronic inflammatory skin condition that is well known for its relapsing, pruritic rash in children and adults. Less recognized are its associated conditions—allergic rhinitis, asthma, food allergies, attention-deficit/hyperactivity disorder (ADHD), depression, and anxiety—and its burden on patients and their families. In fact, families that have children with AD report lower overall quality of life than those with otherwise healthy children.¹ Given AD’s prevalence across age groups and its effect on the family, family physicians are uniquely positioned to diagnose, care for, and counsel patients with AD and its associated maladies.

The prevalence and pathogenesis of AD

AD affects up to 20% of children and 5% of adults in the United States.² AD typically manifests before a child reaches age 5 (often in the first 6 months of life), and it is slightly more common in females (1.3:1). A family history of atopy (eczema, asthma, allergic rhinitis) is common. In fact, children with one atopic parent have a 2- to 3-fold increased risk of atopic dermatitis; those with 2 atopic parents have a 3- to 5-fold increased risk.³

The pathophysiology of AD is complex, culminating in impaired barrier function of the skin and transepidermal water loss resulting in dry and inflamed skin. Additionally, alterations in a cell-mediated immune response leading to an immunoglobulin (Ig) E-mediated hypersensitivity is also theorized to play a role in the development of AD.

Signs and symptoms

Signs at birth. Physical signs of atopic dermatitis typically appear between birth and 6 months. In infancy, lesions generally occur on the scalp, face (FIGURES 1A and 1B), neck, and extensor surfaces of the extremities. Lesions are typically papules and vesicles, sometimes accompanied by serous exudate and crusting. Eczematous lesions typically spare the groin and diaper area, and their presence in this area should raise suspicion for an alternative diagnosis.

Beginning at age 2 years, eczematous lesions are more commonly limited to the folds of the flexor surfaces. Instead of the weeping and crusting lesions seen in infancy, eczema in older children manifests as dry, lichenified papules and plaques in areas that are typically affected in adults: the wrist, hands, ankles, and popliteal and antecubital fossa.²

Although lesions in adults are similar to those of childhood, they may manifest in a more localized area (hand or eyelid, for example). As is the case in childhood, the lesions are dry, sometimes lichenified, and found on the flexural surfaces (FIGURES 2A and 2B).²

Symptom triggers are unproven

While anecdotal reports cite various triggers for AD flares, a systematic review found little scientific evidence to substantiate identifiable triggers.⁴ Triggers often cited and studied are foods, dust mite exposure, airborne allergens, detergents, sunlight, fabrics, bacterial infections, and stress. While as many as one-third of people with AD who also have confirmed dust mite allergy report worsening of symptoms when exposed to dust, a Cochrane review of 7 randomized controlled trials totaling 324 adults and children with eczema found that efforts at dust mite mitigation (laundering of bed covers, increased vacuuming, spraying for mites) were not effective in reducing symptoms.⁵

Continue to: How quality of life diminishes with AD

How quality of life diminishes with AD

AD substantially lessens quality of life. For children, the most distressing physical symptoms include itching that inhibits sleep and provokes scratching, pain, and bleeding. Emotional distress can cause irritability, crying, and uncooperativeness with treatments. Parents also report that they frequently restrict their children from activities, such as playing in the heat or swimming, that may lead to worsening of their eczema.⁶

The loss of sleep associated with AD is not completely understood but is likely multifactorial. Pruritus and scratching leading to sleeplessness is the most obvious culprit, but an altered circadian rhythm, immune system response, and changes in skin physiology are also likely factors.⁷ Whatever the cause, sleep disturbance is reported in as many as 60% of patients with AD, and the degree of sleep disturbance is proportional to increases in disease severity and worsening of quality-of-life scores.⁸ Lost sleep is not limited to patients; parents of children with AD also report significant loss of sleep and subsequent decreased work productivity and quality of life.⁹

Children with AD are often the target of bullying.¹⁰ A 2015 survey by the National Eczema Association indicates that 1 in 5 children reported being bullied due to their AD.¹¹

Associated conditions and comorbidities

AD increases patients’ risks for other illnesses, due either to their underlying atopy or to the effects of AD symptoms (TABLE^12-17).

Atopic march

Atopic march—the clinical succession of AD, allergic rhinitis, and asthma—is a well-­established clinical progression. The presence of all 3 conditions appears to be more common in children diagnosed with AD before 2 years of age.¹² Typically, allergic rhinitis manifests at around age 4, and asthma develops between ages 6 and 8. The severity of AD predicts progression. Compared with an 8% chance of asthma developing among the general population, children with mild AD have a 20% to 30% chance of developing asthma, and those with severe AD have about a 70% chance.¹²

Continue to: Food allergies

Patients with AD are at higher risk for food-induced anaphylaxis, with up to one-third of AD patients having an IgE-mediated food allergy.¹³ While it is theorized that the impaired skin barrier of an atopic child may allow for early sensitization and allergy development, a landmark 2015 study demonstrated that early allergen introduction (specifically, peanuts) may serve as a preventive strategy in those at high risk of food allergies.¹⁴ Current guidelines recommend that physicians be aware of the increased possibility of food allergies in those with AD, and consider evaluating a child for milk, egg, peanut, wheat, and soy allergy if the child is younger than 5 years and has eczema that does not resolve with treatment, or has eczema and a history of an allergic reaction to a specific food.¹⁵

Interestingly, despite the strong association between AD and food allergies, it is not clear that food allergies trigger atopic flares; as such, elimination diets are not universally recommended in those without a proven food allergy.

Psychiatric diagnoses

Children with AD have an increased prevalence of several psychiatric conditions, including ADHD, depression, anxiety, conduct disorder, and autism when compared with peers who do not have AD, and the probability correlates with the severity of AD.¹⁶ While there is a clear link—secondary to nocturnal pruritis—between AD and sleep deprivation, it is not clear whether the sleep deprivation leads to an increase in these psychiatric conditions or if AD is an independent risk factor.

Consider recommending bleach baths in cases of moderate-to-severe atopic dermatitis with frequent bacterial infections.

What we do know is that one of the strongest associations between AD and a psychiatric condition is with ADHD, with a recent pooled meta-analysis showing a 46% increase in risk.¹⁷ The incidence of depression among children with AD appears to correlate with the severity of AD symptoms: estimated at 5% with mild AD, 7% with moderate disease, and 14% with severe disease (compared with 3% without AD). Similar incremental increases are seen when correlating AD and anxiety.¹⁶

Nonpharmacologic care

Bathing

Bathing habits are critical to controlling AD. While bathing serves to both hydrate the skin and remove allergens, the water’s evaporation off the skin surface can lead to increased transepidermal water loss. Combining bathing and immediate application of a moisturizer improves skin hydration in patients with AD vs bathing alone.¹⁸ Thus, consensus guidelines recommend once-daily bathing (bath or shower) to remove scale and crust, followed by immediate application of a moisturizing emollient.¹⁹

Continue to: Emollients

Application of moisturizing emollients is the mainstay of nonpharmacologic care of AD, and there is strong evidence that their regimented use reduces disease burden and the need for prescription treatment.¹⁹ Emollient creams and ointments help retain moisture and improve the skin’s barrier. While ointments may provide a better barrier, patients tend to prefer creams as they are less greasy than ointments.

Emollient therapy may also help prevent development of AD, especially in those infants thought to be at high risk with a family history of atopy. In a multinational randomized controlled trial, infants who received daily full-body application of emollient beginning at 3 weeks of life were significantly less likely than controls to develop AD by 6 months.²⁰ While the mechanism of action is not clearly understood, it is believed that early emollient use prevents skin dehydration and maintains the skin’s barrier integrity, thus decreasing allergen epidermal penetration and subsequent inflammation.

Bleach bath

A bleach bath, prepared by adding 1/2 cup of unconcentrated bleach (5.25% sodium hypochlorite) to a standard 40-gallon bathtub, produces a chlorine mixture equivalent to an average swimming pool. Soaking in a bleach bath for 10 minutes once or twice weekly is thought to reduce inflammation and bacteria on the skin, but studies of its efficacy in improving atopic symptoms are mixed.

In a pooled analysis of 5 studies evaluating bleach baths vs standard baths, there was no significant difference in disease severity at 4 weeks.²¹ Thus, while bleach baths were effective in decreasing disease severity, they appeared to be no more effective than a standard water bath.²¹ Bleach baths may be helpful, however, in cases of moderate-to-severe disease with frequent bacterial infections.¹⁹

Pharmacologic therapy

Steroids

For symptoms refractory to nonpharmacologic skin care, topical steroids are the initial pharmacologic treatment for AD.19 Choose steroid potency based on symptom severity and disease location. Low- to medium-potency is appropriate for mild disease, and medium- to high-potency is useful for ­moderate-to-severe symptoms. High-­potency steroids are generally avoided on the face and skin folds; however, they can be used for short periods in these areas to induce remission. They must then be quickly tapered and discontinued.

Continue to: Frequency

Frequency. Topical corticosteroids are typically applied twice daily, although recent studies indicate that once-daily application is just as efficacious.²² In addition to treatment of an acute flare, topical steroids are useful as maintenance therapy for patients with recurrent outbreaks in the same anatomical site. Guidelines suggest once- or twice-weekly application of a medium-potency steroid to prolong time between flares.¹⁹

For children, a practical guide is for caregivers to apply the amount of steroid covering 1 adult fingertip to an area of the child’s skin equal to that of 2 adult palms.²³ Topical steroids are generally well tolerated and have a good safety profile. Adverse effects are proportional to the amount and duration of use and include purpura, telangiectasias, striae, and skin atrophy. The risk of skin atrophy increases with higher potency steroids, occlusion (covering affected area after steroid application), use on thin-skinned areas, and older patient age.²⁴

A Cochrane review found that efforts at dust mite mitigation (laundering of bed covers, increased vacuuming, spraying for mites) were not effective in reducing symptoms of atopic dermatitis.

Reassure patients/parents about the safety of topical steroids, as fears regarding the potential adverse effects can limit compliance. In one study of 200 patients with AD, 72.5% of respondents expressed fear of using steroids on their own skin or that of their child, and 24% admitted being noncompliant with therapy based on these concerns.²⁵

Treating flares. Oral steroids are sometimes needed to abort or control an AD flare in older children and adults. A tapering course of prednisone over 5 to 7 days, transitioning to medium- to high-dose topical steroids, may be needed to achieve symptom control.

Topical calcineurin inhibitors

Topical calcineurin inhibitors, including tacrolimus and pimecrolimus, are generally second-line therapy to topical corticosteroids. However, as nonsteroidal agents, topical calcineurin inhibitors do not cause skin atrophy and can be a first-line option in areas where atrophy is more common (face, eyelids, neck, and skin folds).²⁶

Continue to: A Cochrane review found...

Interestingly, despite the strong association between atopic dermatitis and food allergies, it is not clear that food allergies trigger atopic flares.

A Cochrane review found tacrolimus 0.1% to be better than low‐potency topical corticosteroids on the face and neck areas, while results were equivocal when compared with moderate‐potency topical corticosteroids on the trunk and extremities (no difference based on physician assessment, but marginal benefit favoring tacrolimus based on participant scoring).²⁷ When compared head-to-head, tacrolimus was more effective than pimecrolimus, although tacrolimus has a higher rate of local irritation. The most common adverse effects are stinging and burning at the application site, although these adverse effects generally improve with repeated application.

There have been long-term safety concerns with topical calcineurin inhibitors—chiefly a 2006 Food and Drug Administration (FDA) black box warning regarding a possible link between topical calcineurin inhibitors and cancer. However, while there may be a slight increased risk of lymphoma in AD patients, a recent meta-analysis did not find an association between topical calcineurin inhibitors use and lymphoma.²⁸ Given the initial concern—and pending additional data—the FDA currently recommends reserving topical calcineurin inhibitors for second-line therapy and only for the minimum amount of time to induce improvement. It also recommends avoiding their use in patients younger than 2 years and in those with compromised immune systems.

Cisaborole

Cisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor, received FDA approval in 2016 for mild-to-moderate AD. By inhibiting PDE4, the drug limits inflammation. In a multicenter randomized trial, patients applying cisaborole 2% twice a day noted reductions in pruritus, inflammation, excoriation, and lichenification.²⁹ Adverse effects are minimal and limited to application site irritation.

Systemic treatments

While beyond the care of a family physician, symptoms refractory to conservative, nonpharmacologic measures and combinations of topical pharmaceuticals can be treated with systemic immunomodulators such as cyclosporine, azathioprine, and methotrexate. Phototherapy is also effective in patients with more widespread skin involvement. Dupilumab, an injectable monoclonal antibody that binds to interleukin-4 receptor and inhibits inflammation, is approved to treat moderate-to-severe AD in adults.³⁰

Ineffective therapies: Oral montelukast and probiotics

While oral antihistamines are frequently prescribed and used, there are no studies evaluating the use of antihistamines (H1) as monotherapy for AD.³¹ Nonetheless, while not altering the disease process, the sedative effect of antihistamines may palliate the nocturnal pruritus frequently associated with AD. Although nonsedating antihistamines may still have a role for atopic patients with concurrent seasonal and environmental allergies, there is no evidence to support their use in the treatment of AD.

Continue to: Data are limited...

Data are limited on the effectiveness of leukotriene receptor antagonists for AD, and all studies meeting inclusion for a Cochrane review assessed oral montelukast. The review found no benefit with the use of montelukast 10 mg in terms of severity of disease, pruritus, or need for topical steroids.³²

A practical guide is for caregivers to apply the amount of steroid covering 1 adult fingertip to an area of the child’s skin equal to that of 2 adult palms.

A systematic review investigating the benefit of probiotics for the treatment of AD found no improvement in patient-rated eczema scores for quality of life.³³ Additionally, a review of 11 randomized controlled trials including 596 participants found no evidence to suggest efficacy of fish oil, zinc, selenium, vitamin D, vitamin E, pyridoxine, sea buckthorn oil, hempseed oil, or sunflower oil in the treatment of AD.³⁴

Education can reduce AD severity

Family physicians can be a source of education and support for patients and families of patients with AD. Support programs for adults with AD—including education, relaxation techniques, and cognitive behavioral therapy—have been shown to decrease disease severity.³⁵ Comparable improvement in disease severity has been demonstrated in children with AD when similar education is provided to them and their families.

CORRESPONDENCE
Franklin Berkey, DO, Penn State Health, 1850 East Park Avenue, Suite 207, State College, PA 16803; fberkey@ pennstatehealth.psu.edu.

Atopic dermatitis (AD), also known as eczema, is a chronic inflammatory skin condition that is well known for its relapsing, pruritic rash in children and adults. Less recognized are its associated conditions—allergic rhinitis, asthma, food allergies, attention-deficit/hyperactivity disorder (ADHD), depression, and anxiety—and its burden on patients and their families. In fact, families that have children with AD report lower overall quality of life than those with otherwise healthy children.¹ Given AD’s prevalence across age groups and its effect on the family, family physicians are uniquely positioned to diagnose, care for, and counsel patients with AD and its associated maladies.

The prevalence and pathogenesis of AD

AD affects up to 20% of children and 5% of adults in the United States.² AD typically manifests before a child reaches age 5 (often in the first 6 months of life), and it is slightly more common in females (1.3:1). A family history of atopy (eczema, asthma, allergic rhinitis) is common. In fact, children with one atopic parent have a 2- to 3-fold increased risk of atopic dermatitis; those with 2 atopic parents have a 3- to 5-fold increased risk.³

The pathophysiology of AD is complex, culminating in impaired barrier function of the skin and transepidermal water loss resulting in dry and inflamed skin. Additionally, alterations in a cell-mediated immune response leading to an immunoglobulin (Ig) E-mediated hypersensitivity is also theorized to play a role in the development of AD.

Signs and symptoms

Signs at birth. Physical signs of atopic dermatitis typically appear between birth and 6 months. In infancy, lesions generally occur on the scalp, face (FIGURES 1A and 1B), neck, and extensor surfaces of the extremities. Lesions are typically papules and vesicles, sometimes accompanied by serous exudate and crusting. Eczematous lesions typically spare the groin and diaper area, and their presence in this area should raise suspicion for an alternative diagnosis.

Beginning at age 2 years, eczematous lesions are more commonly limited to the folds of the flexor surfaces. Instead of the weeping and crusting lesions seen in infancy, eczema in older children manifests as dry, lichenified papules and plaques in areas that are typically affected in adults: the wrist, hands, ankles, and popliteal and antecubital fossa.²

Although lesions in adults are similar to those of childhood, they may manifest in a more localized area (hand or eyelid, for example). As is the case in childhood, the lesions are dry, sometimes lichenified, and found on the flexural surfaces (FIGURES 2A and 2B).²

Symptom triggers are unproven

While anecdotal reports cite various triggers for AD flares, a systematic review found little scientific evidence to substantiate identifiable triggers.⁴ Triggers often cited and studied are foods, dust mite exposure, airborne allergens, detergents, sunlight, fabrics, bacterial infections, and stress. While as many as one-third of people with AD who also have confirmed dust mite allergy report worsening of symptoms when exposed to dust, a Cochrane review of 7 randomized controlled trials totaling 324 adults and children with eczema found that efforts at dust mite mitigation (laundering of bed covers, increased vacuuming, spraying for mites) were not effective in reducing symptoms.⁵

Continue to: How quality of life diminishes with AD

How quality of life diminishes with AD

AD substantially lessens quality of life. For children, the most distressing physical symptoms include itching that inhibits sleep and provokes scratching, pain, and bleeding. Emotional distress can cause irritability, crying, and uncooperativeness with treatments. Parents also report that they frequently restrict their children from activities, such as playing in the heat or swimming, that may lead to worsening of their eczema.⁶

The loss of sleep associated with AD is not completely understood but is likely multifactorial. Pruritus and scratching leading to sleeplessness is the most obvious culprit, but an altered circadian rhythm, immune system response, and changes in skin physiology are also likely factors.⁷ Whatever the cause, sleep disturbance is reported in as many as 60% of patients with AD, and the degree of sleep disturbance is proportional to increases in disease severity and worsening of quality-of-life scores.⁸ Lost sleep is not limited to patients; parents of children with AD also report significant loss of sleep and subsequent decreased work productivity and quality of life.⁹

Children with AD are often the target of bullying.¹⁰ A 2015 survey by the National Eczema Association indicates that 1 in 5 children reported being bullied due to their AD.¹¹

Associated conditions and comorbidities

AD increases patients’ risks for other illnesses, due either to their underlying atopy or to the effects of AD symptoms (TABLE^12-17).

Atopic march

Atopic march—the clinical succession of AD, allergic rhinitis, and asthma—is a well-­established clinical progression. The presence of all 3 conditions appears to be more common in children diagnosed with AD before 2 years of age.¹² Typically, allergic rhinitis manifests at around age 4, and asthma develops between ages 6 and 8. The severity of AD predicts progression. Compared with an 8% chance of asthma developing among the general population, children with mild AD have a 20% to 30% chance of developing asthma, and those with severe AD have about a 70% chance.¹²

Continue to: Food allergies

Patients with AD are at higher risk for food-induced anaphylaxis, with up to one-third of AD patients having an IgE-mediated food allergy.¹³ While it is theorized that the impaired skin barrier of an atopic child may allow for early sensitization and allergy development, a landmark 2015 study demonstrated that early allergen introduction (specifically, peanuts) may serve as a preventive strategy in those at high risk of food allergies.¹⁴ Current guidelines recommend that physicians be aware of the increased possibility of food allergies in those with AD, and consider evaluating a child for milk, egg, peanut, wheat, and soy allergy if the child is younger than 5 years and has eczema that does not resolve with treatment, or has eczema and a history of an allergic reaction to a specific food.¹⁵

Interestingly, despite the strong association between AD and food allergies, it is not clear that food allergies trigger atopic flares; as such, elimination diets are not universally recommended in those without a proven food allergy.

Psychiatric diagnoses

Children with AD have an increased prevalence of several psychiatric conditions, including ADHD, depression, anxiety, conduct disorder, and autism when compared with peers who do not have AD, and the probability correlates with the severity of AD.¹⁶ While there is a clear link—secondary to nocturnal pruritis—between AD and sleep deprivation, it is not clear whether the sleep deprivation leads to an increase in these psychiatric conditions or if AD is an independent risk factor.

Consider recommending bleach baths in cases of moderate-to-severe atopic dermatitis with frequent bacterial infections.

What we do know is that one of the strongest associations between AD and a psychiatric condition is with ADHD, with a recent pooled meta-analysis showing a 46% increase in risk.¹⁷ The incidence of depression among children with AD appears to correlate with the severity of AD symptoms: estimated at 5% with mild AD, 7% with moderate disease, and 14% with severe disease (compared with 3% without AD). Similar incremental increases are seen when correlating AD and anxiety.¹⁶

Nonpharmacologic care

Bathing

Bathing habits are critical to controlling AD. While bathing serves to both hydrate the skin and remove allergens, the water’s evaporation off the skin surface can lead to increased transepidermal water loss. Combining bathing and immediate application of a moisturizer improves skin hydration in patients with AD vs bathing alone.¹⁸ Thus, consensus guidelines recommend once-daily bathing (bath or shower) to remove scale and crust, followed by immediate application of a moisturizing emollient.¹⁹

Continue to: Emollients

Application of moisturizing emollients is the mainstay of nonpharmacologic care of AD, and there is strong evidence that their regimented use reduces disease burden and the need for prescription treatment.¹⁹ Emollient creams and ointments help retain moisture and improve the skin’s barrier. While ointments may provide a better barrier, patients tend to prefer creams as they are less greasy than ointments.

Emollient therapy may also help prevent development of AD, especially in those infants thought to be at high risk with a family history of atopy. In a multinational randomized controlled trial, infants who received daily full-body application of emollient beginning at 3 weeks of life were significantly less likely than controls to develop AD by 6 months.²⁰ While the mechanism of action is not clearly understood, it is believed that early emollient use prevents skin dehydration and maintains the skin’s barrier integrity, thus decreasing allergen epidermal penetration and subsequent inflammation.

Bleach bath

A bleach bath, prepared by adding 1/2 cup of unconcentrated bleach (5.25% sodium hypochlorite) to a standard 40-gallon bathtub, produces a chlorine mixture equivalent to an average swimming pool. Soaking in a bleach bath for 10 minutes once or twice weekly is thought to reduce inflammation and bacteria on the skin, but studies of its efficacy in improving atopic symptoms are mixed.

In a pooled analysis of 5 studies evaluating bleach baths vs standard baths, there was no significant difference in disease severity at 4 weeks.²¹ Thus, while bleach baths were effective in decreasing disease severity, they appeared to be no more effective than a standard water bath.²¹ Bleach baths may be helpful, however, in cases of moderate-to-severe disease with frequent bacterial infections.¹⁹

Pharmacologic therapy

Steroids

For symptoms refractory to nonpharmacologic skin care, topical steroids are the initial pharmacologic treatment for AD.19 Choose steroid potency based on symptom severity and disease location. Low- to medium-potency is appropriate for mild disease, and medium- to high-potency is useful for ­moderate-to-severe symptoms. High-­potency steroids are generally avoided on the face and skin folds; however, they can be used for short periods in these areas to induce remission. They must then be quickly tapered and discontinued.

Continue to: Frequency

Frequency. Topical corticosteroids are typically applied twice daily, although recent studies indicate that once-daily application is just as efficacious.²² In addition to treatment of an acute flare, topical steroids are useful as maintenance therapy for patients with recurrent outbreaks in the same anatomical site. Guidelines suggest once- or twice-weekly application of a medium-potency steroid to prolong time between flares.¹⁹

For children, a practical guide is for caregivers to apply the amount of steroid covering 1 adult fingertip to an area of the child’s skin equal to that of 2 adult palms.²³ Topical steroids are generally well tolerated and have a good safety profile. Adverse effects are proportional to the amount and duration of use and include purpura, telangiectasias, striae, and skin atrophy. The risk of skin atrophy increases with higher potency steroids, occlusion (covering affected area after steroid application), use on thin-skinned areas, and older patient age.²⁴

A Cochrane review found that efforts at dust mite mitigation (laundering of bed covers, increased vacuuming, spraying for mites) were not effective in reducing symptoms of atopic dermatitis.

Reassure patients/parents about the safety of topical steroids, as fears regarding the potential adverse effects can limit compliance. In one study of 200 patients with AD, 72.5% of respondents expressed fear of using steroids on their own skin or that of their child, and 24% admitted being noncompliant with therapy based on these concerns.²⁵

Treating flares. Oral steroids are sometimes needed to abort or control an AD flare in older children and adults. A tapering course of prednisone over 5 to 7 days, transitioning to medium- to high-dose topical steroids, may be needed to achieve symptom control.

Topical calcineurin inhibitors

Topical calcineurin inhibitors, including tacrolimus and pimecrolimus, are generally second-line therapy to topical corticosteroids. However, as nonsteroidal agents, topical calcineurin inhibitors do not cause skin atrophy and can be a first-line option in areas where atrophy is more common (face, eyelids, neck, and skin folds).²⁶

Continue to: A Cochrane review found...

Interestingly, despite the strong association between atopic dermatitis and food allergies, it is not clear that food allergies trigger atopic flares.

A Cochrane review found tacrolimus 0.1% to be better than low‐potency topical corticosteroids on the face and neck areas, while results were equivocal when compared with moderate‐potency topical corticosteroids on the trunk and extremities (no difference based on physician assessment, but marginal benefit favoring tacrolimus based on participant scoring).²⁷ When compared head-to-head, tacrolimus was more effective than pimecrolimus, although tacrolimus has a higher rate of local irritation. The most common adverse effects are stinging and burning at the application site, although these adverse effects generally improve with repeated application.

There have been long-term safety concerns with topical calcineurin inhibitors—chiefly a 2006 Food and Drug Administration (FDA) black box warning regarding a possible link between topical calcineurin inhibitors and cancer. However, while there may be a slight increased risk of lymphoma in AD patients, a recent meta-analysis did not find an association between topical calcineurin inhibitors use and lymphoma.²⁸ Given the initial concern—and pending additional data—the FDA currently recommends reserving topical calcineurin inhibitors for second-line therapy and only for the minimum amount of time to induce improvement. It also recommends avoiding their use in patients younger than 2 years and in those with compromised immune systems.

Cisaborole

Cisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor, received FDA approval in 2016 for mild-to-moderate AD. By inhibiting PDE4, the drug limits inflammation. In a multicenter randomized trial, patients applying cisaborole 2% twice a day noted reductions in pruritus, inflammation, excoriation, and lichenification.²⁹ Adverse effects are minimal and limited to application site irritation.

Systemic treatments

While beyond the care of a family physician, symptoms refractory to conservative, nonpharmacologic measures and combinations of topical pharmaceuticals can be treated with systemic immunomodulators such as cyclosporine, azathioprine, and methotrexate. Phototherapy is also effective in patients with more widespread skin involvement. Dupilumab, an injectable monoclonal antibody that binds to interleukin-4 receptor and inhibits inflammation, is approved to treat moderate-to-severe AD in adults.³⁰

Ineffective therapies: Oral montelukast and probiotics

While oral antihistamines are frequently prescribed and used, there are no studies evaluating the use of antihistamines (H1) as monotherapy for AD.³¹ Nonetheless, while not altering the disease process, the sedative effect of antihistamines may palliate the nocturnal pruritus frequently associated with AD. Although nonsedating antihistamines may still have a role for atopic patients with concurrent seasonal and environmental allergies, there is no evidence to support their use in the treatment of AD.

Continue to: Data are limited...

Data are limited on the effectiveness of leukotriene receptor antagonists for AD, and all studies meeting inclusion for a Cochrane review assessed oral montelukast. The review found no benefit with the use of montelukast 10 mg in terms of severity of disease, pruritus, or need for topical steroids.³²

A practical guide is for caregivers to apply the amount of steroid covering 1 adult fingertip to an area of the child’s skin equal to that of 2 adult palms.

A systematic review investigating the benefit of probiotics for the treatment of AD found no improvement in patient-rated eczema scores for quality of life.³³ Additionally, a review of 11 randomized controlled trials including 596 participants found no evidence to suggest efficacy of fish oil, zinc, selenium, vitamin D, vitamin E, pyridoxine, sea buckthorn oil, hempseed oil, or sunflower oil in the treatment of AD.³⁴

Education can reduce AD severity

Family physicians can be a source of education and support for patients and families of patients with AD. Support programs for adults with AD—including education, relaxation techniques, and cognitive behavioral therapy—have been shown to decrease disease severity.³⁵ Comparable improvement in disease severity has been demonstrated in children with AD when similar education is provided to them and their families.

CORRESPONDENCE
Franklin Berkey, DO, Penn State Health, 1850 East Park Avenue, Suite 207, State College, PA 16803; fberkey@ pennstatehealth.psu.edu.

Atopic dermatitis (AD), also known as eczema, is a chronic inflammatory skin condition that is well known for its relapsing, pruritic rash in children and adults. Less recognized are its associated conditions—allergic rhinitis, asthma, food allergies, attention-deficit/hyperactivity disorder (ADHD), depression, and anxiety—and its burden on patients and their families. In fact, families that have children with AD report lower overall quality of life than those with otherwise healthy children.¹ Given AD’s prevalence across age groups and its effect on the family, family physicians are uniquely positioned to diagnose, care for, and counsel patients with AD and its associated maladies.

The prevalence and pathogenesis of AD

AD affects up to 20% of children and 5% of adults in the United States.² AD typically manifests before a child reaches age 5 (often in the first 6 months of life), and it is slightly more common in females (1.3:1). A family history of atopy (eczema, asthma, allergic rhinitis) is common. In fact, children with one atopic parent have a 2- to 3-fold increased risk of atopic dermatitis; those with 2 atopic parents have a 3- to 5-fold increased risk.³

The pathophysiology of AD is complex, culminating in impaired barrier function of the skin and transepidermal water loss resulting in dry and inflamed skin. Additionally, alterations in a cell-mediated immune response leading to an immunoglobulin (Ig) E-mediated hypersensitivity is also theorized to play a role in the development of AD.

Signs and symptoms

Signs at birth. Physical signs of atopic dermatitis typically appear between birth and 6 months. In infancy, lesions generally occur on the scalp, face (FIGURES 1A and 1B), neck, and extensor surfaces of the extremities. Lesions are typically papules and vesicles, sometimes accompanied by serous exudate and crusting. Eczematous lesions typically spare the groin and diaper area, and their presence in this area should raise suspicion for an alternative diagnosis.

Beginning at age 2 years, eczematous lesions are more commonly limited to the folds of the flexor surfaces. Instead of the weeping and crusting lesions seen in infancy, eczema in older children manifests as dry, lichenified papules and plaques in areas that are typically affected in adults: the wrist, hands, ankles, and popliteal and antecubital fossa.²

Although lesions in adults are similar to those of childhood, they may manifest in a more localized area (hand or eyelid, for example). As is the case in childhood, the lesions are dry, sometimes lichenified, and found on the flexural surfaces (FIGURES 2A and 2B).²

Symptom triggers are unproven

While anecdotal reports cite various triggers for AD flares, a systematic review found little scientific evidence to substantiate identifiable triggers.⁴ Triggers often cited and studied are foods, dust mite exposure, airborne allergens, detergents, sunlight, fabrics, bacterial infections, and stress. While as many as one-third of people with AD who also have confirmed dust mite allergy report worsening of symptoms when exposed to dust, a Cochrane review of 7 randomized controlled trials totaling 324 adults and children with eczema found that efforts at dust mite mitigation (laundering of bed covers, increased vacuuming, spraying for mites) were not effective in reducing symptoms.⁵

Continue to: How quality of life diminishes with AD

How quality of life diminishes with AD

AD substantially lessens quality of life. For children, the most distressing physical symptoms include itching that inhibits sleep and provokes scratching, pain, and bleeding. Emotional distress can cause irritability, crying, and uncooperativeness with treatments. Parents also report that they frequently restrict their children from activities, such as playing in the heat or swimming, that may lead to worsening of their eczema.⁶

The loss of sleep associated with AD is not completely understood but is likely multifactorial. Pruritus and scratching leading to sleeplessness is the most obvious culprit, but an altered circadian rhythm, immune system response, and changes in skin physiology are also likely factors.⁷ Whatever the cause, sleep disturbance is reported in as many as 60% of patients with AD, and the degree of sleep disturbance is proportional to increases in disease severity and worsening of quality-of-life scores.⁸ Lost sleep is not limited to patients; parents of children with AD also report significant loss of sleep and subsequent decreased work productivity and quality of life.⁹

Children with AD are often the target of bullying.¹⁰ A 2015 survey by the National Eczema Association indicates that 1 in 5 children reported being bullied due to their AD.¹¹

Associated conditions and comorbidities

AD increases patients’ risks for other illnesses, due either to their underlying atopy or to the effects of AD symptoms (TABLE^12-17).

Atopic march

Atopic march—the clinical succession of AD, allergic rhinitis, and asthma—is a well-­established clinical progression. The presence of all 3 conditions appears to be more common in children diagnosed with AD before 2 years of age.¹² Typically, allergic rhinitis manifests at around age 4, and asthma develops between ages 6 and 8. The severity of AD predicts progression. Compared with an 8% chance of asthma developing among the general population, children with mild AD have a 20% to 30% chance of developing asthma, and those with severe AD have about a 70% chance.¹²

Continue to: Food allergies

Patients with AD are at higher risk for food-induced anaphylaxis, with up to one-third of AD patients having an IgE-mediated food allergy.¹³ While it is theorized that the impaired skin barrier of an atopic child may allow for early sensitization and allergy development, a landmark 2015 study demonstrated that early allergen introduction (specifically, peanuts) may serve as a preventive strategy in those at high risk of food allergies.¹⁴ Current guidelines recommend that physicians be aware of the increased possibility of food allergies in those with AD, and consider evaluating a child for milk, egg, peanut, wheat, and soy allergy if the child is younger than 5 years and has eczema that does not resolve with treatment, or has eczema and a history of an allergic reaction to a specific food.¹⁵

Interestingly, despite the strong association between AD and food allergies, it is not clear that food allergies trigger atopic flares; as such, elimination diets are not universally recommended in those without a proven food allergy.

Psychiatric diagnoses

Children with AD have an increased prevalence of several psychiatric conditions, including ADHD, depression, anxiety, conduct disorder, and autism when compared with peers who do not have AD, and the probability correlates with the severity of AD.¹⁶ While there is a clear link—secondary to nocturnal pruritis—between AD and sleep deprivation, it is not clear whether the sleep deprivation leads to an increase in these psychiatric conditions or if AD is an independent risk factor.

Consider recommending bleach baths in cases of moderate-to-severe atopic dermatitis with frequent bacterial infections.

What we do know is that one of the strongest associations between AD and a psychiatric condition is with ADHD, with a recent pooled meta-analysis showing a 46% increase in risk.¹⁷ The incidence of depression among children with AD appears to correlate with the severity of AD symptoms: estimated at 5% with mild AD, 7% with moderate disease, and 14% with severe disease (compared with 3% without AD). Similar incremental increases are seen when correlating AD and anxiety.¹⁶

Nonpharmacologic care

Bathing

Bathing habits are critical to controlling AD. While bathing serves to both hydrate the skin and remove allergens, the water’s evaporation off the skin surface can lead to increased transepidermal water loss. Combining bathing and immediate application of a moisturizer improves skin hydration in patients with AD vs bathing alone.¹⁸ Thus, consensus guidelines recommend once-daily bathing (bath or shower) to remove scale and crust, followed by immediate application of a moisturizing emollient.¹⁹

Continue to: Emollients

Application of moisturizing emollients is the mainstay of nonpharmacologic care of AD, and there is strong evidence that their regimented use reduces disease burden and the need for prescription treatment.¹⁹ Emollient creams and ointments help retain moisture and improve the skin’s barrier. While ointments may provide a better barrier, patients tend to prefer creams as they are less greasy than ointments.

Emollient therapy may also help prevent development of AD, especially in those infants thought to be at high risk with a family history of atopy. In a multinational randomized controlled trial, infants who received daily full-body application of emollient beginning at 3 weeks of life were significantly less likely than controls to develop AD by 6 months.²⁰ While the mechanism of action is not clearly understood, it is believed that early emollient use prevents skin dehydration and maintains the skin’s barrier integrity, thus decreasing allergen epidermal penetration and subsequent inflammation.

Bleach bath

A bleach bath, prepared by adding 1/2 cup of unconcentrated bleach (5.25% sodium hypochlorite) to a standard 40-gallon bathtub, produces a chlorine mixture equivalent to an average swimming pool. Soaking in a bleach bath for 10 minutes once or twice weekly is thought to reduce inflammation and bacteria on the skin, but studies of its efficacy in improving atopic symptoms are mixed.

In a pooled analysis of 5 studies evaluating bleach baths vs standard baths, there was no significant difference in disease severity at 4 weeks.²¹ Thus, while bleach baths were effective in decreasing disease severity, they appeared to be no more effective than a standard water bath.²¹ Bleach baths may be helpful, however, in cases of moderate-to-severe disease with frequent bacterial infections.¹⁹

Pharmacologic therapy

Steroids

For symptoms refractory to nonpharmacologic skin care, topical steroids are the initial pharmacologic treatment for AD.19 Choose steroid potency based on symptom severity and disease location. Low- to medium-potency is appropriate for mild disease, and medium- to high-potency is useful for ­moderate-to-severe symptoms. High-­potency steroids are generally avoided on the face and skin folds; however, they can be used for short periods in these areas to induce remission. They must then be quickly tapered and discontinued.

Continue to: Frequency

Frequency. Topical corticosteroids are typically applied twice daily, although recent studies indicate that once-daily application is just as efficacious.²² In addition to treatment of an acute flare, topical steroids are useful as maintenance therapy for patients with recurrent outbreaks in the same anatomical site. Guidelines suggest once- or twice-weekly application of a medium-potency steroid to prolong time between flares.¹⁹

For children, a practical guide is for caregivers to apply the amount of steroid covering 1 adult fingertip to an area of the child’s skin equal to that of 2 adult palms.²³ Topical steroids are generally well tolerated and have a good safety profile. Adverse effects are proportional to the amount and duration of use and include purpura, telangiectasias, striae, and skin atrophy. The risk of skin atrophy increases with higher potency steroids, occlusion (covering affected area after steroid application), use on thin-skinned areas, and older patient age.²⁴

A Cochrane review found that efforts at dust mite mitigation (laundering of bed covers, increased vacuuming, spraying for mites) were not effective in reducing symptoms of atopic dermatitis.

Reassure patients/parents about the safety of topical steroids, as fears regarding the potential adverse effects can limit compliance. In one study of 200 patients with AD, 72.5% of respondents expressed fear of using steroids on their own skin or that of their child, and 24% admitted being noncompliant with therapy based on these concerns.²⁵

Treating flares. Oral steroids are sometimes needed to abort or control an AD flare in older children and adults. A tapering course of prednisone over 5 to 7 days, transitioning to medium- to high-dose topical steroids, may be needed to achieve symptom control.

Topical calcineurin inhibitors

Topical calcineurin inhibitors, including tacrolimus and pimecrolimus, are generally second-line therapy to topical corticosteroids. However, as nonsteroidal agents, topical calcineurin inhibitors do not cause skin atrophy and can be a first-line option in areas where atrophy is more common (face, eyelids, neck, and skin folds).²⁶

Continue to: A Cochrane review found...

Interestingly, despite the strong association between atopic dermatitis and food allergies, it is not clear that food allergies trigger atopic flares.

A Cochrane review found tacrolimus 0.1% to be better than low‐potency topical corticosteroids on the face and neck areas, while results were equivocal when compared with moderate‐potency topical corticosteroids on the trunk and extremities (no difference based on physician assessment, but marginal benefit favoring tacrolimus based on participant scoring).²⁷ When compared head-to-head, tacrolimus was more effective than pimecrolimus, although tacrolimus has a higher rate of local irritation. The most common adverse effects are stinging and burning at the application site, although these adverse effects generally improve with repeated application.

There have been long-term safety concerns with topical calcineurin inhibitors—chiefly a 2006 Food and Drug Administration (FDA) black box warning regarding a possible link between topical calcineurin inhibitors and cancer. However, while there may be a slight increased risk of lymphoma in AD patients, a recent meta-analysis did not find an association between topical calcineurin inhibitors use and lymphoma.²⁸ Given the initial concern—and pending additional data—the FDA currently recommends reserving topical calcineurin inhibitors for second-line therapy and only for the minimum amount of time to induce improvement. It also recommends avoiding their use in patients younger than 2 years and in those with compromised immune systems.

Cisaborole

Cisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor, received FDA approval in 2016 for mild-to-moderate AD. By inhibiting PDE4, the drug limits inflammation. In a multicenter randomized trial, patients applying cisaborole 2% twice a day noted reductions in pruritus, inflammation, excoriation, and lichenification.²⁹ Adverse effects are minimal and limited to application site irritation.

Systemic treatments

While beyond the care of a family physician, symptoms refractory to conservative, nonpharmacologic measures and combinations of topical pharmaceuticals can be treated with systemic immunomodulators such as cyclosporine, azathioprine, and methotrexate. Phototherapy is also effective in patients with more widespread skin involvement. Dupilumab, an injectable monoclonal antibody that binds to interleukin-4 receptor and inhibits inflammation, is approved to treat moderate-to-severe AD in adults.³⁰

Ineffective therapies: Oral montelukast and probiotics

While oral antihistamines are frequently prescribed and used, there are no studies evaluating the use of antihistamines (H1) as monotherapy for AD.³¹ Nonetheless, while not altering the disease process, the sedative effect of antihistamines may palliate the nocturnal pruritus frequently associated with AD. Although nonsedating antihistamines may still have a role for atopic patients with concurrent seasonal and environmental allergies, there is no evidence to support their use in the treatment of AD.

Continue to: Data are limited...

Data are limited on the effectiveness of leukotriene receptor antagonists for AD, and all studies meeting inclusion for a Cochrane review assessed oral montelukast. The review found no benefit with the use of montelukast 10 mg in terms of severity of disease, pruritus, or need for topical steroids.³²

A practical guide is for caregivers to apply the amount of steroid covering 1 adult fingertip to an area of the child’s skin equal to that of 2 adult palms.

A systematic review investigating the benefit of probiotics for the treatment of AD found no improvement in patient-rated eczema scores for quality of life.³³ Additionally, a review of 11 randomized controlled trials including 596 participants found no evidence to suggest efficacy of fish oil, zinc, selenium, vitamin D, vitamin E, pyridoxine, sea buckthorn oil, hempseed oil, or sunflower oil in the treatment of AD.³⁴

Education can reduce AD severity

Family physicians can be a source of education and support for patients and families of patients with AD. Support programs for adults with AD—including education, relaxation techniques, and cognitive behavioral therapy—have been shown to decrease disease severity.³⁵ Comparable improvement in disease severity has been demonstrated in children with AD when similar education is provided to them and their families.

CORRESPONDENCE
Franklin Berkey, DO, Penn State Health, 1850 East Park Avenue, Suite 207, State College, PA 16803; fberkey@ pennstatehealth.psu.edu.

Chronic kidney disease (CKD) is a significant comorbidity of diabetes mellitus. The Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation defines CKD as the presence of kidney damage or decreased kidney function for ≥ 3 months. CKD caused by diabetes is called diabetic kidney disease (DKD), which is 1 of 3 principal microvascular complications of diabetes. DKD can progress to end-stage renal disease (ESRD), requiring kidney replacement therapy, and is the leading cause of CKD and ESRD in the United States.^1-3 Studies have also shown that, particularly in patients with diabetes, CKD considerably increases the risk of cardiovascular events, which often occur prior to ESRD.^1,4

This article provides the latest recommendations for evaluating and managing DKD to help you prevent or slow its progression.

Defining and categorizing diabetic kidney disease

CKD is defined as persistently elevated excretion of urinary albumin (albuminuria) and decreased estimated glomerular filtration rate (eGFR), or as the presence of signs of progressive kidney damage.^5,6 DKD, also known as diabetic nephropathy, is CKD attributed to long-term diabetes. A patient’s eGFR is the established basis for assignment to a stage (1, 2, 3a, 3b, 4, or 5) of CKD (TABLE 1⁷) and, along with the category of albuminuria (A1, A2, or A3), can indicate prognosis.

Taking its toll in diabetes

As many as 40% of patients with diabetes develop DKD.^8-10 Most studies of DKD have been conducted in patients with type 1 diabetes (T1D), because the time of clinical onset is typically known.

Type 1 diabetes. DKD usually occurs 10 to 15 years, or later, after the onset of diabetes.⁶ As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.^5,11 After approximately 22.5 years without albuminuria, patients with T1D have approximately a 1% annual risk of DKD.¹²

Type 2 diabetes (T2D). DKD is often present at diagnosis, likely due to a delay in diagnosis and briefer clinical exposure, compared to T1D. Albuminuria has been reported in as many as 40% of patients with T2D approximately 10 years after onset of diabetes.^12,13

Multiple risk factors with no standout “predictor”

Genetic susceptibility, ethnicity, glycemic control, smoking, blood pressure (BP), and the eGFR have been identified as risk factors for renal involvement in diabetes; obesity, oral contraceptives, and age can also contribute. Although each risk factor increases the risk of DKD, no single factor is adequately predictive. Moderately increased albuminuria, the earliest sign of DKD, is associated with progressive nephropathy.¹²

Continue to: How great is the risk?

How great is the risk? From disease onset to proteinuria and from proteinuria to ESRD, the risk of DKD in T1D and T2D is similar. With appropriate treatment, albuminuria can regress, and the risk of ESRD can be < 20% at 10 years in T1D.¹² As in T1D, good glycemic control might result in regression of albuminuria in T2D.¹⁴

As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.

For unknown reasons, the degree of albuminuria can exist independent of the progression of DKD. Factors responsible for a progressive decline in eGFR in DKD without albuminuria are unknown.^12,15

Patient evaluation with an eye toward comorbidities

A comprehensive initial medical evaluation for DKD includes a review of microvascular complications; visits to specialists; lifestyle and behavior patterns (eg, diet, sleep, substance use, and social support); and medication adherence, adverse drug effects, and alternative medicines. Although DKD is often a clinical diagnosis, it can be ruled in by persistent albuminuria or decreased eGFR, or both, in established diabetes or diabetic retinopathy when other causes are unlikely (see “Recommended DKD screening protocol,” below).

Screening for mental health conditions and barriers to self-management is also key.⁶

Comorbidities, of course, can complicate disease management in patients with diabetes.^16-20 Providers and patients therefore need to be aware of potential diabetic comorbidities. For example, DKD and even moderately increased albuminuria significantly increase the risk of cardiovascular disease (CVD).¹² Other possible comorbidities include (but are not limited to) nonalcoholic steatohepatitis, fracture, hearing impairment, cancer (eg, liver, pancreas, endometrium, colon, rectum, breast, and bladder), pancreatitis, hypogonadism, obstructive sleep apnea, periodontal disease, anxiety, depression, and eating disorders.⁶

Continue to: Recommended DKD screening protocol

In all cases of T2D, in cases of T1D of ≥ 5 years’ duration, and in patients with diabetes and comorbid hypertension, perform annual screening for albuminuria, an elevated creatinine level, and a decline in eGFR.

Screen for potential comorbidities of DKD: For example, the risk of cardiovascular disease is significantly elevated in even moderately increased albuminuria.

To confirm the diagnosis of DKD, at least 2 of 3 urine specimens must demonstrate an elevated urinary albumin:creatinine ratio (UACR) over a 3- to 6-month period.²¹ Apart from renal damage, exercise within 24 hours before specimen collection, infection, fever, congestive heart failure, hyperglycemia, menstruation, and hypertension can elevate the UACR.⁶

Levels of the UACR are established as follows²²:

• Normal UACR is defined as < 30 milligrams of albumin per gram of creatinine (expressed as “mg/g”).
• Increased urinary albumin excretion is defined as ≥ 30 mg/g.
• Moderately increased albuminuria, a predictor of potential nephropathy, is the excretion of 30 to 300 mg/g.
• Severely increased albuminuria is excretion > 300 mg/g; it is often followed by a gradual decline in eGFR that, without treatment, eventually leads to ESRD.

The rate of decline in eGFR once albuminuria is severely increased is equivalent in T1D and T2D.¹² Without intervention, the time from severely increased albuminuria to ESRD in T1D and T2D averages approximately 6 or 7 years.

Clinical features

DKD is typically a clinical diagnosis seen in patients with longstanding diabetes, albuminuria, retinopathy, or a reduced eGFR in the absence of another primary cause of kidney damage. In patients with T1D and DKD, signs of retinopathy and neuropathy are almost always present at diagnosis, unless a diagnosis is made early in the course of diabetes.¹² Therefore, the presence of retinopathy suggests that diabetes is the likely cause of CKD.

Continue to: The presence of microvascular disease...

The presence of microvascular disease in patients with T2D and DKD is less predictable.¹² In T2D patients who do not have retinopathy, consider causes of CKD other than DKD. Features suggesting that the cause of CKD is an underlying condition other than diabetes are rapidly increasing albuminuria or decreasing eGFR; urinary sediment comprising red blood cells or white blood cells; and nephrotic syndrome.⁶

As the prevalence of diabetes increases, it has become more common to diagnose DKD by eGFR without albuminuria—underscoring the importance of routine monitoring of eGFR in patients with diabetes.⁶

Sources of expert guidance. The Chronic Kidney Disease Epidemiology Collaboration equation²³ is preferred for calculating eGFR from serum creatinine: An eGFR < 60 mL/min/1.73 m² is considered abnormal.^3,12 At these rates, the prevalence of complications related to CKD rises and screening for complications becomes necessary.

A more comprehensive classification of the stages of CKD, incorporating albuminuria and progression of CKD, has been recommended by Kidney Disease: Improving Global Outcomes (KDIGO).⁷ Because eGFR and excretion of albumin vary, abnormal test results need to be verified over time to stage the degree of CKD.^3,12 Kidney damage often manifests as albuminuria, but also as hematuria, other types of abnormal urinary sediment, radiographic abnormalities, and other abnormal presentations.

Management

Nutritional factors

Excessive protein intake has been shown to increase albuminuria, worsen renal function, and increase CVD mortality in DKD.^24-26 Therefore, daily dietary protein intake of 0.8 g/kg body weight is recommended for patients who are not on dialysis.³ Patients on dialysis might require higher protein intake to preserve muscle mass caused by protein-energy wasting, which is common in dialysis patients.⁶

Continue to: Low sodium intake

Low sodium intake in CKD patients has been shown to decrease BP and thus slow the progression of renal disease and lower the risk of CVD. The recommended dietary sodium intake in CKD patients is 1500-3000 mg/d.³

Low potassium intake. Hyperkalemia is a serious complication of CKD. A low-potassium diet is recommended in ESRD patients who have a potassium level > 5.5 mEq/L.⁶

Blood pressure

Preventing and treating hypertension is critical to slowing the progression of CKD and reducing cardiovascular risk. BP should be measured at every clinic visit. Aside from lifestyle changes, medication might be needed to reach target BP.

The American Diabetes Association recommends a BP goal of ≤ 140/90 mm Hg for hypertensive patients with diabetes, although they do state that a lower BP target (≤ 130/80 mm Hg) might be more appropriate for patients with DKD.²⁷

The American College of Cardiology recommends that hypertensive patients with CKD have a BP target of ≤ 130/80 mm Hg.²⁸

Continue to: ACE inhibitors and ARBs

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have renoprotective benefits. These agents are recommended as first-line medications for patients with diabetes, hypertension, and an eGFR < 60 mL/min/1.73 m² and a UACR > 300 mg/g.^29-31 Evidence also supports their use when the UACR is 30 to 299 mg/g.

Studies have shown that, in patients with DKD, ACE inhibitors and ARBs can slow the progression of renal disease.^29,30,32 There is no difference between ACE inhibitors and ARBs in their effectiveness for preventing progression of DKD.⁶ There is no added benefit in combining an ACE inhibitor and an ARB³³; notably, combination ACE inhibitor and ARB therapy can increase the risk of adverse events, such as hyperkalemia and acute kidney injury, especially in patients with DKD.³³

There is no evidence for starting an ACE inhibitor or ARB to prevent CKD in patients with diabetes who are not hypertensive.⁵

ACE inhibitors and ARBs should be used with caution in women of childbearing age, who should use a reliable form of contraception if taking one of these drugs.

Diuretics. Thiazide-type and loop diuretics might potentiate the positive effects of ACE inhibitors and ARBs. KDOQI guidelines recommend that, in patients who require a second agent to control BP, a diuretic should be considered in combination with an ACE inhibitor or an ARB.²⁰ A loop diuretic is preferred if the eGFR is < 30 mL/min/1.73 m².

Continue to: Nondihydropyridine calcium-channel blockers

Nondihydropyridine calcium-channel blockers (CCBs), such as diltiazem and verapamil, have been shown to be more effective then dihydrophyridine CCBs, such as amlodipine and nifedipine, in slowing the progression of renal disease because of their antiproteinuric effects. However, the antiproteinuric effects of nondihydropyridine CCBs are not as strong as those of ACE inhibitors or ARBs, and these drugs do not appear to potentiate the effects of an ACE inhibitor or ARB when used in combination.²⁰

Confirmation of suspected DKD requires an elevated albumin:creatinine ratio in at least 2 of 3 urine specimens over a 3- to 6-month period.

Nondihydropyridine CCBs might be a reasonable alternative in patients who cannot tolerate an ACE inhibitor or an ARB.

Mineralocorticoid receptor antagonists in combination with an ACE inhibitor or ARB have been demonstrated to reduce albuminuria in short-term studies.^34,35

Glycemic levels

Studies conducted in patients with T1D, and others in patients with T2D, have shown that tight glycemic control can delay the onset and slow the progression of albuminuria and a decline in the eGFR.^10,36-39 The target glycated hemoglobin (A1C) should be < 7% to prevent or slow progression of DKD.⁴⁰ However, patients with DKD have an increased risk of hypoglycemic events and increased mortality with more intensive glycemic control.^40,41 Given those findings, some patients with DKD and significant comorbidities, ESRD, or limited life expectancy might need to have an A1C target set at 8%.^6,42

Adjustments to antidiabetes medications in DKD

In patients with stages 3 to 5 DKD, several common antidiabetic medications might need to be adjusted or discontinued because they decrease creatinine clearance.

Continue to: First-generation sulfonylureas

First-generation sulfonylureas should be avoided in DKD. Glipizide and gliclazide are preferred among second-generation sulfonylureas because they do not increase the risk of hypoglycemia in DKD patients, although patients taking these medications still require close monitoring of their blood glucose level.²⁰

Metformin. In 2016, recommendations changed for the use of metformin in patients with DKD: The eGFR, not the serum creatinine level, should guide treatment.⁴³ Metformin can be used safely in patients with (1) an eGFR of < 60 mL/min/1.73 m² and (2) an eGFR of 30 mL/min/1.73 m² with close monitoring. Metformin should not be initiated if the eGFR is < 45 mL/min/1.73 m².⁴³ 

Antidiabetes medications with direct effect on the kidney

Several antidiabetes medications have a direct effect on the kidney apart from their effect on the blood glucose level.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce albuminuria and slow the decrease of eGFR independent of glycemic control. In addition, SGLT2 inhibitors have also been shown to have cardiovascular benefits in patients with DKD.^44,45 

Glucagon-like peptide 1 (GLP-1) receptor agonists have been shown to delay and decrease the progression of DKD.^46-48 Also, similar to what is seen with SGLT2 inhibitors, GLP-1 agonists have demonstrable cardiovascular benefit in patients with DKD.^46,48

Continue to: Dyslipidemia and DKD

Because the risk of CVD is increased in patients with DKD, addressing other modifiable risk factors, including dyslipidemia, is recommended in these patients. Patients with diabetes and stages 1 to 4 DKD should be treated with a high-intensity statin or a combination of a statin and ezetimibe.^49,50

Tight glycemic control in T1D and T2D can delay the onset, and slow the progression, of albuminuria and a decline in the eGFR.

If a patient is taking a statin and starting dialysis, it’s important to discuss with him or her whether to continue the statin, based on perceived benefits and risks. It is not recommended that statins be initiated in patients on dialysis unless there is a specific cardiovascular indication for doing so. Risk reduction with a statin has been shown to be significantly less in dialysis patients than in patients who are not being treated with dialysis.⁴⁹

Complications of CKD

Anemia is a common complication of CKD. KDIGO recommends measuring the ­hemoglobin concentration annually in DKD stage 3 patients without anemia; at least every 6 months in stage 4 patients; and at least every 3 months in stage 5. DKD patients with anemia should have additional laboratory testing: the absolute reticulocyte count, serum ferritin, serum transferrin saturation, vitamin B12, and folate.⁵¹

Mineral and bone disorder should be screened for in patients with DKD. TABLE 2⁵² outlines when clinical laboratory tests should be ordered to assess for mineral bone disease.

When to refer to a nephrologist

Refer patients with stage 4 or 5 CKD (eGFR, ≤ 30 mL/min/1.73 m²) to a nephrologist for discussion of kidney replacement therapy.⁶ Patients with stage 3a CKD and severely increased albuminuria or with stage 3b CKD and moderately or severely increased albuminuria should also be referred to a nephrologist for intervention to delay disease progression.

Continue to: Identifying the need for early referral...

Nutritional control is important in DKD: A lowsodium diet can slow progression of DKD, and a low-potassium diet can prevent hyperkalemia in end-stage renal disease.

Identifying the need for early referral to a nephrologist has been shown to reduce the cost, and improve the quality, of care.⁵³ Other indications for earlier referral include uncertainty about the etiology of renal disease, persistent or severe albuminuria, persistent hematuria, a rapid decline in eGFR, and acute kidney injury. Additionally, referral at an earlier stage of DKD might be needed to assist with complications associated with DKD, such as anemia, secondary hyperparathyroidism, mineral and bone disorder, resistant hypertension, fluid overload, and electrolyte disturbances.⁶

ACKNOWLEDGEMENT
The authors thank Colleen Colbert, PhD, and Iqbal Ahmad, PhD, for their review and critique of the manuscript of this article. They also thank Christopher Babiuch, MD, for his guidance in the preparation of the manuscript.

CORRESPONDENCE
Faraz Ahmad, MD, MPH, Care Point East Family Medicine, 543 Taylor Avenue, 2nd floor, Columbus, OH 43203; faraz. [email protected].

Chronic kidney disease (CKD) is a significant comorbidity of diabetes mellitus. The Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation defines CKD as the presence of kidney damage or decreased kidney function for ≥ 3 months. CKD caused by diabetes is called diabetic kidney disease (DKD), which is 1 of 3 principal microvascular complications of diabetes. DKD can progress to end-stage renal disease (ESRD), requiring kidney replacement therapy, and is the leading cause of CKD and ESRD in the United States.^1-3 Studies have also shown that, particularly in patients with diabetes, CKD considerably increases the risk of cardiovascular events, which often occur prior to ESRD.^1,4

This article provides the latest recommendations for evaluating and managing DKD to help you prevent or slow its progression.

Defining and categorizing diabetic kidney disease

CKD is defined as persistently elevated excretion of urinary albumin (albuminuria) and decreased estimated glomerular filtration rate (eGFR), or as the presence of signs of progressive kidney damage.^5,6 DKD, also known as diabetic nephropathy, is CKD attributed to long-term diabetes. A patient’s eGFR is the established basis for assignment to a stage (1, 2, 3a, 3b, 4, or 5) of CKD (TABLE 1⁷) and, along with the category of albuminuria (A1, A2, or A3), can indicate prognosis.

Taking its toll in diabetes

As many as 40% of patients with diabetes develop DKD.^8-10 Most studies of DKD have been conducted in patients with type 1 diabetes (T1D), because the time of clinical onset is typically known.

Type 1 diabetes. DKD usually occurs 10 to 15 years, or later, after the onset of diabetes.⁶ As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.^5,11 After approximately 22.5 years without albuminuria, patients with T1D have approximately a 1% annual risk of DKD.¹²

Type 2 diabetes (T2D). DKD is often present at diagnosis, likely due to a delay in diagnosis and briefer clinical exposure, compared to T1D. Albuminuria has been reported in as many as 40% of patients with T2D approximately 10 years after onset of diabetes.^12,13

Multiple risk factors with no standout “predictor”

Genetic susceptibility, ethnicity, glycemic control, smoking, blood pressure (BP), and the eGFR have been identified as risk factors for renal involvement in diabetes; obesity, oral contraceptives, and age can also contribute. Although each risk factor increases the risk of DKD, no single factor is adequately predictive. Moderately increased albuminuria, the earliest sign of DKD, is associated with progressive nephropathy.¹²

Continue to: How great is the risk?

How great is the risk? From disease onset to proteinuria and from proteinuria to ESRD, the risk of DKD in T1D and T2D is similar. With appropriate treatment, albuminuria can regress, and the risk of ESRD can be < 20% at 10 years in T1D.¹² As in T1D, good glycemic control might result in regression of albuminuria in T2D.¹⁴

As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.

For unknown reasons, the degree of albuminuria can exist independent of the progression of DKD. Factors responsible for a progressive decline in eGFR in DKD without albuminuria are unknown.^12,15

Patient evaluation with an eye toward comorbidities

A comprehensive initial medical evaluation for DKD includes a review of microvascular complications; visits to specialists; lifestyle and behavior patterns (eg, diet, sleep, substance use, and social support); and medication adherence, adverse drug effects, and alternative medicines. Although DKD is often a clinical diagnosis, it can be ruled in by persistent albuminuria or decreased eGFR, or both, in established diabetes or diabetic retinopathy when other causes are unlikely (see “Recommended DKD screening protocol,” below).

Screening for mental health conditions and barriers to self-management is also key.⁶

Comorbidities, of course, can complicate disease management in patients with diabetes.^16-20 Providers and patients therefore need to be aware of potential diabetic comorbidities. For example, DKD and even moderately increased albuminuria significantly increase the risk of cardiovascular disease (CVD).¹² Other possible comorbidities include (but are not limited to) nonalcoholic steatohepatitis, fracture, hearing impairment, cancer (eg, liver, pancreas, endometrium, colon, rectum, breast, and bladder), pancreatitis, hypogonadism, obstructive sleep apnea, periodontal disease, anxiety, depression, and eating disorders.⁶

Continue to: Recommended DKD screening protocol

In all cases of T2D, in cases of T1D of ≥ 5 years’ duration, and in patients with diabetes and comorbid hypertension, perform annual screening for albuminuria, an elevated creatinine level, and a decline in eGFR.

Screen for potential comorbidities of DKD: For example, the risk of cardiovascular disease is significantly elevated in even moderately increased albuminuria.

To confirm the diagnosis of DKD, at least 2 of 3 urine specimens must demonstrate an elevated urinary albumin:creatinine ratio (UACR) over a 3- to 6-month period.²¹ Apart from renal damage, exercise within 24 hours before specimen collection, infection, fever, congestive heart failure, hyperglycemia, menstruation, and hypertension can elevate the UACR.⁶

Levels of the UACR are established as follows²²:

• Normal UACR is defined as < 30 milligrams of albumin per gram of creatinine (expressed as “mg/g”).
• Increased urinary albumin excretion is defined as ≥ 30 mg/g.
• Moderately increased albuminuria, a predictor of potential nephropathy, is the excretion of 30 to 300 mg/g.
• Severely increased albuminuria is excretion > 300 mg/g; it is often followed by a gradual decline in eGFR that, without treatment, eventually leads to ESRD.

The rate of decline in eGFR once albuminuria is severely increased is equivalent in T1D and T2D.¹² Without intervention, the time from severely increased albuminuria to ESRD in T1D and T2D averages approximately 6 or 7 years.

Clinical features

DKD is typically a clinical diagnosis seen in patients with longstanding diabetes, albuminuria, retinopathy, or a reduced eGFR in the absence of another primary cause of kidney damage. In patients with T1D and DKD, signs of retinopathy and neuropathy are almost always present at diagnosis, unless a diagnosis is made early in the course of diabetes.¹² Therefore, the presence of retinopathy suggests that diabetes is the likely cause of CKD.

Continue to: The presence of microvascular disease...

The presence of microvascular disease in patients with T2D and DKD is less predictable.¹² In T2D patients who do not have retinopathy, consider causes of CKD other than DKD. Features suggesting that the cause of CKD is an underlying condition other than diabetes are rapidly increasing albuminuria or decreasing eGFR; urinary sediment comprising red blood cells or white blood cells; and nephrotic syndrome.⁶

As the prevalence of diabetes increases, it has become more common to diagnose DKD by eGFR without albuminuria—underscoring the importance of routine monitoring of eGFR in patients with diabetes.⁶

Sources of expert guidance. The Chronic Kidney Disease Epidemiology Collaboration equation²³ is preferred for calculating eGFR from serum creatinine: An eGFR < 60 mL/min/1.73 m² is considered abnormal.^3,12 At these rates, the prevalence of complications related to CKD rises and screening for complications becomes necessary.

A more comprehensive classification of the stages of CKD, incorporating albuminuria and progression of CKD, has been recommended by Kidney Disease: Improving Global Outcomes (KDIGO).⁷ Because eGFR and excretion of albumin vary, abnormal test results need to be verified over time to stage the degree of CKD.^3,12 Kidney damage often manifests as albuminuria, but also as hematuria, other types of abnormal urinary sediment, radiographic abnormalities, and other abnormal presentations.

Management

Nutritional factors

Excessive protein intake has been shown to increase albuminuria, worsen renal function, and increase CVD mortality in DKD.^24-26 Therefore, daily dietary protein intake of 0.8 g/kg body weight is recommended for patients who are not on dialysis.³ Patients on dialysis might require higher protein intake to preserve muscle mass caused by protein-energy wasting, which is common in dialysis patients.⁶

Continue to: Low sodium intake

Low sodium intake in CKD patients has been shown to decrease BP and thus slow the progression of renal disease and lower the risk of CVD. The recommended dietary sodium intake in CKD patients is 1500-3000 mg/d.³

Low potassium intake. Hyperkalemia is a serious complication of CKD. A low-potassium diet is recommended in ESRD patients who have a potassium level > 5.5 mEq/L.⁶

Blood pressure

Preventing and treating hypertension is critical to slowing the progression of CKD and reducing cardiovascular risk. BP should be measured at every clinic visit. Aside from lifestyle changes, medication might be needed to reach target BP.

The American Diabetes Association recommends a BP goal of ≤ 140/90 mm Hg for hypertensive patients with diabetes, although they do state that a lower BP target (≤ 130/80 mm Hg) might be more appropriate for patients with DKD.²⁷

The American College of Cardiology recommends that hypertensive patients with CKD have a BP target of ≤ 130/80 mm Hg.²⁸

Continue to: ACE inhibitors and ARBs

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have renoprotective benefits. These agents are recommended as first-line medications for patients with diabetes, hypertension, and an eGFR < 60 mL/min/1.73 m² and a UACR > 300 mg/g.^29-31 Evidence also supports their use when the UACR is 30 to 299 mg/g.

Studies have shown that, in patients with DKD, ACE inhibitors and ARBs can slow the progression of renal disease.^29,30,32 There is no difference between ACE inhibitors and ARBs in their effectiveness for preventing progression of DKD.⁶ There is no added benefit in combining an ACE inhibitor and an ARB³³; notably, combination ACE inhibitor and ARB therapy can increase the risk of adverse events, such as hyperkalemia and acute kidney injury, especially in patients with DKD.³³

There is no evidence for starting an ACE inhibitor or ARB to prevent CKD in patients with diabetes who are not hypertensive.⁵

ACE inhibitors and ARBs should be used with caution in women of childbearing age, who should use a reliable form of contraception if taking one of these drugs.

Diuretics. Thiazide-type and loop diuretics might potentiate the positive effects of ACE inhibitors and ARBs. KDOQI guidelines recommend that, in patients who require a second agent to control BP, a diuretic should be considered in combination with an ACE inhibitor or an ARB.²⁰ A loop diuretic is preferred if the eGFR is < 30 mL/min/1.73 m².

Continue to: Nondihydropyridine calcium-channel blockers

Nondihydropyridine calcium-channel blockers (CCBs), such as diltiazem and verapamil, have been shown to be more effective then dihydrophyridine CCBs, such as amlodipine and nifedipine, in slowing the progression of renal disease because of their antiproteinuric effects. However, the antiproteinuric effects of nondihydropyridine CCBs are not as strong as those of ACE inhibitors or ARBs, and these drugs do not appear to potentiate the effects of an ACE inhibitor or ARB when used in combination.²⁰

Confirmation of suspected DKD requires an elevated albumin:creatinine ratio in at least 2 of 3 urine specimens over a 3- to 6-month period.

Nondihydropyridine CCBs might be a reasonable alternative in patients who cannot tolerate an ACE inhibitor or an ARB.

Mineralocorticoid receptor antagonists in combination with an ACE inhibitor or ARB have been demonstrated to reduce albuminuria in short-term studies.^34,35

Glycemic levels

Studies conducted in patients with T1D, and others in patients with T2D, have shown that tight glycemic control can delay the onset and slow the progression of albuminuria and a decline in the eGFR.^10,36-39 The target glycated hemoglobin (A1C) should be < 7% to prevent or slow progression of DKD.⁴⁰ However, patients with DKD have an increased risk of hypoglycemic events and increased mortality with more intensive glycemic control.^40,41 Given those findings, some patients with DKD and significant comorbidities, ESRD, or limited life expectancy might need to have an A1C target set at 8%.^6,42

Adjustments to antidiabetes medications in DKD

In patients with stages 3 to 5 DKD, several common antidiabetic medications might need to be adjusted or discontinued because they decrease creatinine clearance.

Continue to: First-generation sulfonylureas

First-generation sulfonylureas should be avoided in DKD. Glipizide and gliclazide are preferred among second-generation sulfonylureas because they do not increase the risk of hypoglycemia in DKD patients, although patients taking these medications still require close monitoring of their blood glucose level.²⁰

Metformin. In 2016, recommendations changed for the use of metformin in patients with DKD: The eGFR, not the serum creatinine level, should guide treatment.⁴³ Metformin can be used safely in patients with (1) an eGFR of < 60 mL/min/1.73 m² and (2) an eGFR of 30 mL/min/1.73 m² with close monitoring. Metformin should not be initiated if the eGFR is < 45 mL/min/1.73 m².⁴³ 

Antidiabetes medications with direct effect on the kidney

Several antidiabetes medications have a direct effect on the kidney apart from their effect on the blood glucose level.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce albuminuria and slow the decrease of eGFR independent of glycemic control. In addition, SGLT2 inhibitors have also been shown to have cardiovascular benefits in patients with DKD.^44,45 

Glucagon-like peptide 1 (GLP-1) receptor agonists have been shown to delay and decrease the progression of DKD.^46-48 Also, similar to what is seen with SGLT2 inhibitors, GLP-1 agonists have demonstrable cardiovascular benefit in patients with DKD.^46,48

Continue to: Dyslipidemia and DKD

Because the risk of CVD is increased in patients with DKD, addressing other modifiable risk factors, including dyslipidemia, is recommended in these patients. Patients with diabetes and stages 1 to 4 DKD should be treated with a high-intensity statin or a combination of a statin and ezetimibe.^49,50

Tight glycemic control in T1D and T2D can delay the onset, and slow the progression, of albuminuria and a decline in the eGFR.

If a patient is taking a statin and starting dialysis, it’s important to discuss with him or her whether to continue the statin, based on perceived benefits and risks. It is not recommended that statins be initiated in patients on dialysis unless there is a specific cardiovascular indication for doing so. Risk reduction with a statin has been shown to be significantly less in dialysis patients than in patients who are not being treated with dialysis.⁴⁹

Complications of CKD

Anemia is a common complication of CKD. KDIGO recommends measuring the ­hemoglobin concentration annually in DKD stage 3 patients without anemia; at least every 6 months in stage 4 patients; and at least every 3 months in stage 5. DKD patients with anemia should have additional laboratory testing: the absolute reticulocyte count, serum ferritin, serum transferrin saturation, vitamin B12, and folate.⁵¹

Mineral and bone disorder should be screened for in patients with DKD. TABLE 2⁵² outlines when clinical laboratory tests should be ordered to assess for mineral bone disease.

When to refer to a nephrologist

Refer patients with stage 4 or 5 CKD (eGFR, ≤ 30 mL/min/1.73 m²) to a nephrologist for discussion of kidney replacement therapy.⁶ Patients with stage 3a CKD and severely increased albuminuria or with stage 3b CKD and moderately or severely increased albuminuria should also be referred to a nephrologist for intervention to delay disease progression.

Continue to: Identifying the need for early referral...

Nutritional control is important in DKD: A lowsodium diet can slow progression of DKD, and a low-potassium diet can prevent hyperkalemia in end-stage renal disease.

Identifying the need for early referral to a nephrologist has been shown to reduce the cost, and improve the quality, of care.⁵³ Other indications for earlier referral include uncertainty about the etiology of renal disease, persistent or severe albuminuria, persistent hematuria, a rapid decline in eGFR, and acute kidney injury. Additionally, referral at an earlier stage of DKD might be needed to assist with complications associated with DKD, such as anemia, secondary hyperparathyroidism, mineral and bone disorder, resistant hypertension, fluid overload, and electrolyte disturbances.⁶

ACKNOWLEDGEMENT
The authors thank Colleen Colbert, PhD, and Iqbal Ahmad, PhD, for their review and critique of the manuscript of this article. They also thank Christopher Babiuch, MD, for his guidance in the preparation of the manuscript.

CORRESPONDENCE
Faraz Ahmad, MD, MPH, Care Point East Family Medicine, 543 Taylor Avenue, 2nd floor, Columbus, OH 43203; faraz. [email protected].

Chronic kidney disease (CKD) is a significant comorbidity of diabetes mellitus. The Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation defines CKD as the presence of kidney damage or decreased kidney function for ≥ 3 months. CKD caused by diabetes is called diabetic kidney disease (DKD), which is 1 of 3 principal microvascular complications of diabetes. DKD can progress to end-stage renal disease (ESRD), requiring kidney replacement therapy, and is the leading cause of CKD and ESRD in the United States.^1-3 Studies have also shown that, particularly in patients with diabetes, CKD considerably increases the risk of cardiovascular events, which often occur prior to ESRD.^1,4

This article provides the latest recommendations for evaluating and managing DKD to help you prevent or slow its progression.

Defining and categorizing diabetic kidney disease

CKD is defined as persistently elevated excretion of urinary albumin (albuminuria) and decreased estimated glomerular filtration rate (eGFR), or as the presence of signs of progressive kidney damage.^5,6 DKD, also known as diabetic nephropathy, is CKD attributed to long-term diabetes. A patient’s eGFR is the established basis for assignment to a stage (1, 2, 3a, 3b, 4, or 5) of CKD (TABLE 1⁷) and, along with the category of albuminuria (A1, A2, or A3), can indicate prognosis.

Taking its toll in diabetes

As many as 40% of patients with diabetes develop DKD.^8-10 Most studies of DKD have been conducted in patients with type 1 diabetes (T1D), because the time of clinical onset is typically known.

Type 1 diabetes. DKD usually occurs 10 to 15 years, or later, after the onset of diabetes.⁶ As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.^5,11 After approximately 22.5 years without albuminuria, patients with T1D have approximately a 1% annual risk of DKD.¹²

Type 2 diabetes (T2D). DKD is often present at diagnosis, likely due to a delay in diagnosis and briefer clinical exposure, compared to T1D. Albuminuria has been reported in as many as 40% of patients with T2D approximately 10 years after onset of diabetes.^12,13

Multiple risk factors with no standout “predictor”

Genetic susceptibility, ethnicity, glycemic control, smoking, blood pressure (BP), and the eGFR have been identified as risk factors for renal involvement in diabetes; obesity, oral contraceptives, and age can also contribute. Although each risk factor increases the risk of DKD, no single factor is adequately predictive. Moderately increased albuminuria, the earliest sign of DKD, is associated with progressive nephropathy.¹²

Continue to: How great is the risk?

How great is the risk? From disease onset to proteinuria and from proteinuria to ESRD, the risk of DKD in T1D and T2D is similar. With appropriate treatment, albuminuria can regress, and the risk of ESRD can be < 20% at 10 years in T1D.¹² As in T1D, good glycemic control might result in regression of albuminuria in T2D.¹⁴

As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.

For unknown reasons, the degree of albuminuria can exist independent of the progression of DKD. Factors responsible for a progressive decline in eGFR in DKD without albuminuria are unknown.^12,15

Patient evaluation with an eye toward comorbidities

A comprehensive initial medical evaluation for DKD includes a review of microvascular complications; visits to specialists; lifestyle and behavior patterns (eg, diet, sleep, substance use, and social support); and medication adherence, adverse drug effects, and alternative medicines. Although DKD is often a clinical diagnosis, it can be ruled in by persistent albuminuria or decreased eGFR, or both, in established diabetes or diabetic retinopathy when other causes are unlikely (see “Recommended DKD screening protocol,” below).

Screening for mental health conditions and barriers to self-management is also key.⁶

Comorbidities, of course, can complicate disease management in patients with diabetes.^16-20 Providers and patients therefore need to be aware of potential diabetic comorbidities. For example, DKD and even moderately increased albuminuria significantly increase the risk of cardiovascular disease (CVD).¹² Other possible comorbidities include (but are not limited to) nonalcoholic steatohepatitis, fracture, hearing impairment, cancer (eg, liver, pancreas, endometrium, colon, rectum, breast, and bladder), pancreatitis, hypogonadism, obstructive sleep apnea, periodontal disease, anxiety, depression, and eating disorders.⁶

Continue to: Recommended DKD screening protocol

In all cases of T2D, in cases of T1D of ≥ 5 years’ duration, and in patients with diabetes and comorbid hypertension, perform annual screening for albuminuria, an elevated creatinine level, and a decline in eGFR.

Screen for potential comorbidities of DKD: For example, the risk of cardiovascular disease is significantly elevated in even moderately increased albuminuria.

To confirm the diagnosis of DKD, at least 2 of 3 urine specimens must demonstrate an elevated urinary albumin:creatinine ratio (UACR) over a 3- to 6-month period.²¹ Apart from renal damage, exercise within 24 hours before specimen collection, infection, fever, congestive heart failure, hyperglycemia, menstruation, and hypertension can elevate the UACR.⁶

Levels of the UACR are established as follows²²:

• Normal UACR is defined as < 30 milligrams of albumin per gram of creatinine (expressed as “mg/g”).
• Increased urinary albumin excretion is defined as ≥ 30 mg/g.
• Moderately increased albuminuria, a predictor of potential nephropathy, is the excretion of 30 to 300 mg/g.
• Severely increased albuminuria is excretion > 300 mg/g; it is often followed by a gradual decline in eGFR that, without treatment, eventually leads to ESRD.

The rate of decline in eGFR once albuminuria is severely increased is equivalent in T1D and T2D.¹² Without intervention, the time from severely increased albuminuria to ESRD in T1D and T2D averages approximately 6 or 7 years.

Clinical features

DKD is typically a clinical diagnosis seen in patients with longstanding diabetes, albuminuria, retinopathy, or a reduced eGFR in the absence of another primary cause of kidney damage. In patients with T1D and DKD, signs of retinopathy and neuropathy are almost always present at diagnosis, unless a diagnosis is made early in the course of diabetes.¹² Therefore, the presence of retinopathy suggests that diabetes is the likely cause of CKD.

Continue to: The presence of microvascular disease...

The presence of microvascular disease in patients with T2D and DKD is less predictable.¹² In T2D patients who do not have retinopathy, consider causes of CKD other than DKD. Features suggesting that the cause of CKD is an underlying condition other than diabetes are rapidly increasing albuminuria or decreasing eGFR; urinary sediment comprising red blood cells or white blood cells; and nephrotic syndrome.⁶

As the prevalence of diabetes increases, it has become more common to diagnose DKD by eGFR without albuminuria—underscoring the importance of routine monitoring of eGFR in patients with diabetes.⁶

Sources of expert guidance. The Chronic Kidney Disease Epidemiology Collaboration equation²³ is preferred for calculating eGFR from serum creatinine: An eGFR < 60 mL/min/1.73 m² is considered abnormal.^3,12 At these rates, the prevalence of complications related to CKD rises and screening for complications becomes necessary.

A more comprehensive classification of the stages of CKD, incorporating albuminuria and progression of CKD, has been recommended by Kidney Disease: Improving Global Outcomes (KDIGO).⁷ Because eGFR and excretion of albumin vary, abnormal test results need to be verified over time to stage the degree of CKD.^3,12 Kidney damage often manifests as albuminuria, but also as hematuria, other types of abnormal urinary sediment, radiographic abnormalities, and other abnormal presentations.

Management

Nutritional factors

Excessive protein intake has been shown to increase albuminuria, worsen renal function, and increase CVD mortality in DKD.^24-26 Therefore, daily dietary protein intake of 0.8 g/kg body weight is recommended for patients who are not on dialysis.³ Patients on dialysis might require higher protein intake to preserve muscle mass caused by protein-energy wasting, which is common in dialysis patients.⁶

Continue to: Low sodium intake

Low sodium intake in CKD patients has been shown to decrease BP and thus slow the progression of renal disease and lower the risk of CVD. The recommended dietary sodium intake in CKD patients is 1500-3000 mg/d.³

Low potassium intake. Hyperkalemia is a serious complication of CKD. A low-potassium diet is recommended in ESRD patients who have a potassium level > 5.5 mEq/L.⁶

Blood pressure

Preventing and treating hypertension is critical to slowing the progression of CKD and reducing cardiovascular risk. BP should be measured at every clinic visit. Aside from lifestyle changes, medication might be needed to reach target BP.

The American Diabetes Association recommends a BP goal of ≤ 140/90 mm Hg for hypertensive patients with diabetes, although they do state that a lower BP target (≤ 130/80 mm Hg) might be more appropriate for patients with DKD.²⁷

The American College of Cardiology recommends that hypertensive patients with CKD have a BP target of ≤ 130/80 mm Hg.²⁸

Continue to: ACE inhibitors and ARBs

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have renoprotective benefits. These agents are recommended as first-line medications for patients with diabetes, hypertension, and an eGFR < 60 mL/min/1.73 m² and a UACR > 300 mg/g.^29-31 Evidence also supports their use when the UACR is 30 to 299 mg/g.

Studies have shown that, in patients with DKD, ACE inhibitors and ARBs can slow the progression of renal disease.^29,30,32 There is no difference between ACE inhibitors and ARBs in their effectiveness for preventing progression of DKD.⁶ There is no added benefit in combining an ACE inhibitor and an ARB³³; notably, combination ACE inhibitor and ARB therapy can increase the risk of adverse events, such as hyperkalemia and acute kidney injury, especially in patients with DKD.³³

There is no evidence for starting an ACE inhibitor or ARB to prevent CKD in patients with diabetes who are not hypertensive.⁵

ACE inhibitors and ARBs should be used with caution in women of childbearing age, who should use a reliable form of contraception if taking one of these drugs.

Diuretics. Thiazide-type and loop diuretics might potentiate the positive effects of ACE inhibitors and ARBs. KDOQI guidelines recommend that, in patients who require a second agent to control BP, a diuretic should be considered in combination with an ACE inhibitor or an ARB.²⁰ A loop diuretic is preferred if the eGFR is < 30 mL/min/1.73 m².

Continue to: Nondihydropyridine calcium-channel blockers

Nondihydropyridine calcium-channel blockers (CCBs), such as diltiazem and verapamil, have been shown to be more effective then dihydrophyridine CCBs, such as amlodipine and nifedipine, in slowing the progression of renal disease because of their antiproteinuric effects. However, the antiproteinuric effects of nondihydropyridine CCBs are not as strong as those of ACE inhibitors or ARBs, and these drugs do not appear to potentiate the effects of an ACE inhibitor or ARB when used in combination.²⁰

Confirmation of suspected DKD requires an elevated albumin:creatinine ratio in at least 2 of 3 urine specimens over a 3- to 6-month period.

Nondihydropyridine CCBs might be a reasonable alternative in patients who cannot tolerate an ACE inhibitor or an ARB.

Mineralocorticoid receptor antagonists in combination with an ACE inhibitor or ARB have been demonstrated to reduce albuminuria in short-term studies.^34,35

Glycemic levels

Studies conducted in patients with T1D, and others in patients with T2D, have shown that tight glycemic control can delay the onset and slow the progression of albuminuria and a decline in the eGFR.^10,36-39 The target glycated hemoglobin (A1C) should be < 7% to prevent or slow progression of DKD.⁴⁰ However, patients with DKD have an increased risk of hypoglycemic events and increased mortality with more intensive glycemic control.^40,41 Given those findings, some patients with DKD and significant comorbidities, ESRD, or limited life expectancy might need to have an A1C target set at 8%.^6,42

Adjustments to antidiabetes medications in DKD

In patients with stages 3 to 5 DKD, several common antidiabetic medications might need to be adjusted or discontinued because they decrease creatinine clearance.

Continue to: First-generation sulfonylureas

First-generation sulfonylureas should be avoided in DKD. Glipizide and gliclazide are preferred among second-generation sulfonylureas because they do not increase the risk of hypoglycemia in DKD patients, although patients taking these medications still require close monitoring of their blood glucose level.²⁰

Metformin. In 2016, recommendations changed for the use of metformin in patients with DKD: The eGFR, not the serum creatinine level, should guide treatment.⁴³ Metformin can be used safely in patients with (1) an eGFR of < 60 mL/min/1.73 m² and (2) an eGFR of 30 mL/min/1.73 m² with close monitoring. Metformin should not be initiated if the eGFR is < 45 mL/min/1.73 m².⁴³ 

Antidiabetes medications with direct effect on the kidney

Several antidiabetes medications have a direct effect on the kidney apart from their effect on the blood glucose level.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce albuminuria and slow the decrease of eGFR independent of glycemic control. In addition, SGLT2 inhibitors have also been shown to have cardiovascular benefits in patients with DKD.^44,45 

Glucagon-like peptide 1 (GLP-1) receptor agonists have been shown to delay and decrease the progression of DKD.^46-48 Also, similar to what is seen with SGLT2 inhibitors, GLP-1 agonists have demonstrable cardiovascular benefit in patients with DKD.^46,48

Continue to: Dyslipidemia and DKD

Because the risk of CVD is increased in patients with DKD, addressing other modifiable risk factors, including dyslipidemia, is recommended in these patients. Patients with diabetes and stages 1 to 4 DKD should be treated with a high-intensity statin or a combination of a statin and ezetimibe.^49,50

Tight glycemic control in T1D and T2D can delay the onset, and slow the progression, of albuminuria and a decline in the eGFR.

If a patient is taking a statin and starting dialysis, it’s important to discuss with him or her whether to continue the statin, based on perceived benefits and risks. It is not recommended that statins be initiated in patients on dialysis unless there is a specific cardiovascular indication for doing so. Risk reduction with a statin has been shown to be significantly less in dialysis patients than in patients who are not being treated with dialysis.⁴⁹

Complications of CKD

Anemia is a common complication of CKD. KDIGO recommends measuring the ­hemoglobin concentration annually in DKD stage 3 patients without anemia; at least every 6 months in stage 4 patients; and at least every 3 months in stage 5. DKD patients with anemia should have additional laboratory testing: the absolute reticulocyte count, serum ferritin, serum transferrin saturation, vitamin B12, and folate.⁵¹

Mineral and bone disorder should be screened for in patients with DKD. TABLE 2⁵² outlines when clinical laboratory tests should be ordered to assess for mineral bone disease.

When to refer to a nephrologist

Refer patients with stage 4 or 5 CKD (eGFR, ≤ 30 mL/min/1.73 m²) to a nephrologist for discussion of kidney replacement therapy.⁶ Patients with stage 3a CKD and severely increased albuminuria or with stage 3b CKD and moderately or severely increased albuminuria should also be referred to a nephrologist for intervention to delay disease progression.

Continue to: Identifying the need for early referral...

Nutritional control is important in DKD: A lowsodium diet can slow progression of DKD, and a low-potassium diet can prevent hyperkalemia in end-stage renal disease.

Identifying the need for early referral to a nephrologist has been shown to reduce the cost, and improve the quality, of care.⁵³ Other indications for earlier referral include uncertainty about the etiology of renal disease, persistent or severe albuminuria, persistent hematuria, a rapid decline in eGFR, and acute kidney injury. Additionally, referral at an earlier stage of DKD might be needed to assist with complications associated with DKD, such as anemia, secondary hyperparathyroidism, mineral and bone disorder, resistant hypertension, fluid overload, and electrolyte disturbances.⁶

ACKNOWLEDGEMENT
The authors thank Colleen Colbert, PhD, and Iqbal Ahmad, PhD, for their review and critique of the manuscript of this article. They also thank Christopher Babiuch, MD, for his guidance in the preparation of the manuscript.

CORRESPONDENCE
Faraz Ahmad, MD, MPH, Care Point East Family Medicine, 543 Taylor Avenue, 2nd floor, Columbus, OH 43203; faraz. [email protected].

Medication overuse headache (MOH), a secondary headache diagnosis, is a prevalent phenomenon that complicates headache diagnosis and treatment, increases the cost of care, and reduces quality of life. Effective abortive medication is essential for the headache sufferer; when an abortive is used too frequently, however, headache frequency increases—potentially beginning a cycle in which the patient then takes more medication to abort the headache. Over time, the patient suffers from an ever-­increasing number of headaches, takes even more abortive medication, and so on. In the presence of MOH, there is a reduction in pain response to preventive and abortive treatments; when medication overuse is eliminated, pain response improves.¹

Although MOH is well recognized among headache specialists, the condition is often overlooked in primary care. Since headache is a top complaint in primary care, however, and prevention is a major goal in family medicine, the opportunity for you to recognize, treat, and prevent MOH is significant. In fact, a randomized controlled trial showed that brief patient education about headache care and MOH provided by a primary care physician can lead to a significant reduction in headache frequency among patients with MOH.²

Although medication overuse headache is well recognized among headache specialists, the condition is often overlooked in primary care.

This article reviews the recognition and diagnosis of MOH, based on historical features and current criteria; addresses risk factors for abortive medication overuse and how to withdraw an offending agent; and explores the value of bridging and preventive therapies to reduce the overall frequency of headache.

IMAGE © ROY SCOTT

What defines MOH?

Typically, MOH is a chronification of a primary headache disorder. However, in patients with a history of migraine who are undergoing treatment for another chronic pain condition with an opioid or other analgesic, MOH can be induced.³ An increase in the frequency of headache raises the specter of a concomitant increase in the level of disability⁴; psychiatric comorbidity⁵; and more headache days, with time lost from school and work.

The Migraine Disability Assessment (MIDAS) questionnaire, a validated instrument that helps the provider (1) measure the impact that headache has on a patient’s life and (2) follow treatment progress, also provides information to employers and insurance companies on treatment coverage and the need for work modification. The MIDAS score is 3 times higher in patients with MOH than in patients with episodic migraine.^6,7

The annual associated cost per person of MOH has been estimated at $4000, resulting in billions of dollars in associated costs⁸; most of these costs are related to absenteeism and disability. After detoxification for MOH, annual outpatient medication costs are reduced by approximately 24%.⁹

Efforts to solve a common problem create another

Headache affects nearly 50% of the general population worldwide,¹⁰ accounting for about 4% of primary care visits¹¹ and approximately 20% of outpatient neurology consultations.¹² Although inpatient stays for headache are approximately half the duration of the overall average hospital stay, headache accounts for 3% of admissions.¹³ According to the Global Burden of Disease study, tension-type headache, migraine, and MOH are the 3 most common headache disorders.¹⁰ Headache is the second leading cause of disability among people 15 to 49 years of age.¹⁰

Continue to: The prevalence of MOH...

The prevalence of MOH in the general population is 2%.^7,14,15 A population-based study showed that the rate of progression from episodic headache (< 15 d/mo) to chronic headache (≥ 15 d/mo) in the general population is 2.5% per year¹⁶; however, progression to chronic headache is 14% per year in patients with medication overuse. One-third of the general population with chronic migraine overuses symptomatic medication; in US headache clinics, roughly one-half of patients with chronic headache overuse acute medication.⁶

Definitions and diagnosis

MOH is a secondary headache diagnosis in the third edition of the International Classification of Headache Disorders (ICHD-3) (TABLE 1),¹⁷ which lists diagnostic criteria for recognized headache disorders.

Terminology. MOH has also been called rebound headache, drug-induced headache, and transformed migraine, but these terms are outdated and are not formal diagnoses. Patients sometimes refer to substance-withdrawal headaches (not discussed in this article) as rebound headaches, so clarity is important when discussing headache with patients: namely, that MOH is an exacerbation of an existing headache condition caused by overuse of abortive headache medications, including analgesics, combination analgesics, triptans, barbiturates, and opioids.

The time it takes to develop medication overuse headache is shortest with triptans, followed by ergots, then analgesics.

MOH was recognized in the early 1950s and fully differentiated as a diagnosis in 2005 in the second edition of the ICHD. The disorder is subcategorized by offending abortive agent (TABLE 2¹⁷) because the frequency of analgesic use required to develop MOH differs by agent.

Risk factors for MOH and chronification of a primary headache ­disorder. There are several risk factors for developing MOH, and others that contribute to increasing headache frequency in general (TABLE 3^5,14,18-23). Some risk factors are common to each. All are important to address because some are modifiable.

Continue to: Pathophysiology

Pathophysiology. The pathophysiology and psychology behind MOH are largely unknown. Physiologic changes in pain processing and functional imaging changes have been demonstrated in patients with MOH, both of which are reversible upon withdrawal of medication.²³ Genetic factors and changes in hormone and neurotransmitter levels are found in MOH patients; this is not the case in patients who have an episodic headache pattern only.²⁴

Presentation. Diagnostic criteria for MOH do not include clinical characteristics. Typically, the phenotype of MOH in a given patient is similar to the underlying primary headache²⁵—although this principle can be complicated to tease out because these medications can suppress some symptoms. Diagnosis of a primary headache disorder should be documented along with the diagnosis of MOH.

Medication overuse can exist without MOH: Not every patient who frequently uses an abortive medication develops MOH.

Treatment is multifaceted—and can become complex

Mainstays of treatment of MOH are education about the disorder and detoxification from the overused agent, although specific treatments can differ depending on the agent involved, the frequency and duration of its use, and a patient’s behavioral patterns and psychiatric comorbidities. Often, a daily medication to prevent headache is considered upon, or after, withdrawal of the offending agent. The timing of introducing a preventive might impact its effectiveness. Some refractory cases require more intensive therapy, including hospitalization at a specialized tertiary center.

But before we look at detoxification from an overused agent, it’s important to review one of the best strategies of all in combatting MOH.

Continue to: First and best strategy

Select an appropriate abortive to reduce the risk of MOH. With regard to specific acute headache medications, some nuances other than type of headache should be considered. Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended as abortive therapy by the American Headache Society for their efficacy, favorable adverse effect profile, and low cost. NSAIDs are protective against development of MOH if a patient’s baseline headache frequency is < 10/mo; at a frequency of 10 to 14 d/mo, however, the risk of MOH increases when using an NSAID.⁶ A similar effect has been seen with triptans.¹⁶ Longer-acting NSAIDs, such as nabumetone and naproxen, have been proposed as less likely to cause MOH, and are even used as bridging therapy sometimes (as long as neither of these was the overused medication).²⁶

The time it takes to develop MOH is shortest with triptans, followed by ergots, then analgesics.²⁷

Prospective cohort studies^6,16 have shown that barbiturates and opioids are more likely to induce MOH; for that reason, agents in these analgesic classes are almost universally avoided unless no other medically acceptable options exist. Using barbiturate-containing compounds or opioids > 4 d/mo exponentially increases the likelihood of MOH.

Promising preclinical data demonstrate that the gepant, or small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, class of medications used as abortive therapy does not induce medication overuse cutaneous allodynia.²⁸

Provide education. Primary prevention of MOH involves (1) increasing patients’ awareness of how to take medications appropriately and (2) restricting intake of over-the-counter abortive medications. Often, the expert recommendation is to limit abortives to approximately 2 d/wk because more frequent use places patients at risk of further increased use and subsequent MOH.

Continue to: A randomized controlled trial in Norway...

A randomized controlled trial in Norway compared outcomes in 2 groups of patients with MOH: One group was given advice on the disorder by a physician; the other group was not provided with advice. In the “business-as-usual” group, there was no significant improvement; however, when general practitioners provided simple advice (lasting roughly 9 minutes) about reducing abortive medication use to a safe level and cautioned patients that they would be “feeling worse before feeling better,” headache days were reduced by approximately 8 per month and medication days, by 16 per month.²

A subsequent, long-term follow-up study²⁹ of patients from the Norway trial² who had been given advice and education showed a relapse rate (ie, into overuse of headache medication) of only 8% and sustained reduction of headache days and medication use at 16 months.

Offer support and other nondrug interventions. A recent review of 3 studies²³ recommended that extra support for patients from a headache nurse, close follow-up, keeping an electronic diary that provides feedback, and undertaking a short course of psychotherapy can reduce medication overuse and prevent relapse.

If MOH develops, initiate withdrawal, introduce a preventive

Withdraw overused medication. Most current evidence suggests that withdrawal of the offending agent is the most effective factor in reducing headache days and improving quality of life. A randomized controlled trial compared the effects of (1) complete and immediate withdrawal of an abortive medication with (2) reducing its use (ie, limiting intake to 2 d/wk), on headache frequency, disability, and quality of life.³⁰ There was a reduction of headache days in both groups; however, reduction was much greater at 2 months in the complete withdrawal group than in the restricted intake group (respectively, a 41% and a 26% reduction in headache days per month). This effect was sustained at 6 and 12 months in both groups. The study confirmed the results of earlier research^2,15: Abrupt withdrawal leads to reversion to an episodic pattern at 2 to 6 months in approximately 40% to 60% of patients.

More studies are needed to determine the most appropriate treatment course for MOH; however, complete withdrawal of the causative drug is the most important intervention.

Continue to: Consider withdrawal plus preventive treatment

Consider withdrawal plus preventive treatment. Use of sodium valproate, in addition to medication overuse detoxification, led to a significant reduction in headache days and improvement in quality of life at 12 weeks but no difference after 24 weeks, compared with detoxification alone in a randomized, double-blind, placebo-controlled study.³¹

A study of 61 patients showed a larger reduction (by 7.2 d/mo) in headache frequency with any preventive medication in addition to medication withdrawal, compared to withdrawal alone (by 4.1 d/mo) after 3 months; however, the relative benefit was gone at 6 months.³²

A study of 98 patients compared immediate and delayed initiation of preventive medication upon withdrawal of overused abortive medication.³³ Response was defined as a > 50% reduction in headache frequency and was similar in both groups; results showed a 28% response with immediate initiation of a preventive; a 23% response with delayed (ie, 2 months after withdrawal) initiation; and a 48% response in both groups at 12 months.

Collectively, these studies suggest that adding a preventive medication at the time of withdrawal has the potential to reduce headache frequency more quickly than withdrawal alone. However, after 3 to 6 months, the outcome of reduced headache frequency is the same whether or not a preventive medication is used—as long as the offending agent has been withdrawn.

Do preventives work without withdrawing overused medication? Patients with MOH often show little or no improvement with addition of a preventive medication only; their response to a preventive improves after withdrawal of the overused medication. Patients without previous headache improvement after addition of a preventive, who also did not improve 2 months after withdrawal, then demonstrated an overall reduction in headache by 26% when a preventive was reintroduced after withdrawal.²

Continue to: The research evidence for preventives

The research evidence for preventives. Medications for headache prevention have not been extensively evaluated specifically for treating MOH. Here is what’s known:

• Flunarizine, amitriptyline, and beta-blockers usually are ineffective for MOH.²⁴
• Results for topiramate are mixed: A small, double-blind, placebo-controlled chronic migraine study in Europe showed that, in a subgroup of patients with MOH, topiramate led to a small but significant reduction (3.5 d/mo) in headache frequency, compared to placebo.²⁷ A similar study done in the United States did not show a significant difference between the active-treatment and placebo groups.³⁴
• Findings regarding onabotulinumtoxinA are intriguing: In a posthoc analysis of onabotulinumtoxinA to treat chronic migraine, patients with MOH who did not undergo detoxification had an 8 d/mo greater reduction in headache, compared to placebo.³⁵ However, when compared to placebo in conjunction with detoxification, onabotulinumtoxinA demonstrated no benefit.³⁶
• Newer CGRP antagonist and CGRP receptor antagonist monoclonal antibodies are successful preventive medications that have demonstrated a reduction in acute medication use days per month and headache days per month³⁷; these compounds have not been compared to withdrawal alone.

Reducing the severity and duration of withdrawal symptoms

Withdrawal from overused abortive headache medications can lead to worsening headache, nausea, vomiting, hypotension, tachycardia, sleep disturbances, restlessness, anxiety, and nervousness. Symptoms usually last 2 to 10 days but can persist for as long as 4 weeks; duration of withdrawal symptoms varies with the medication that is being overused. In patients who have used a triptan, for example, mean duration of withdrawal is 4.1 days; ergotamine, 6.7 days; and NSAIDs, 9.5 days.²³ Tapered withdrawal is sometimes recommended with opioids and barbiturates to reduce withdrawal symptoms. It is unclear whether starting a preventive medication during withdrawal assists in reducing withdrawal symptoms.³⁸

Bridging therapy to reduce symptoms of withdrawal is often provided despite debatable utility. Available evidence does not favor one agent or method but suggests some strategies that could be helpful:

• A prednisone taper has a potential role during the first 6 days of withdrawal by reducing rebound headache and withdrawal symptoms³⁹; however, oral prednisolone has been shown to have no benefit.⁴⁰
• Alone, IV methylprednisolone seems not to be of benefit; however, in a retrospective study of 94 patients, IV methylprednisolone plus diazepam for 5 days led to a significant reduction in headache frequency and drug consumption that was sustained after 3 months.⁴¹
• Celecoxib was compared to prednisone over a 20-day course: a celecoxib dosage of 400 mg/d for the first 5 days, tapered by 100 mg every 5 days, and an oral prednisone dosage of 75 mg/d for the first 5 days, then tapered every 5 days. Patients taking celecoxib had lower headache intensity but there was no difference in headache frequency and acute medication intake between the groups.⁴²

Other strategies. Using antiemetics and NSAIDs to reduce withdrawal symptoms is widely practiced, but no placebo-­controlled trials have been conducted to support this strategy.

Reduce the risk of medication overuse headache by selecting an appropriate abortive; NSAIDs are recommended for their efficacy, favorable adverse effect profile, and low cost.

Patients in withdrawal might be more likely to benefit from inpatient care if they have a severe comorbidity, such as opioid or barbiturate use; failure to respond to, tolerate, or adhere to treatment; or relapse after withdrawal.³⁸

Continue to: Cognitive behavioral therapy...

Cognitive behavioral therapy, exercise, a headache diary, and biofeedback should be considered in every patient’s treatment strategy because a multidisciplinary approach increases adherence and leads to improvement in headache frequency and a decrease in disability and medication use.⁴³

Predictors of Tx success

A prospective cohort study determined that the rate of MOH relapse is 31% at 6 months, 41% at 1 year, and 45% at 4 years, with the highest risk of relapse during the first year.⁴⁴ Looking at the correlation between type of medication overused and relapse rate, the research indicates that

• triptans have the lowest risk of relapse,⁴⁴
• simple analgesics have a higher risk of relapse than triptans,^22,44 and
• opioids have the highest risk of relapse.²²

Where the data don’t agree. Data on combination analgesics and on ergots are conflicting.²² In addition, data on whether the primary type of headache predicts relapse rate conflict; however, migraine might predict a better outcome than tension-type headache.²²

To recap and expand: Management pearls

The major goals of headache management generally are to rule out secondary headache, reach a correct diagnosis, reduce overall headache frequency, and provide effective abortive medication. A large component of reducing headache frequency is addressing and treating medication overuse.

Seek to understand the nature of the patient’s headache disorder. Components of the history are key in identifying the underlying headache diagnosis and ruling out other, more concerning secondary headache diagnoses. The ICHD-3 is an excellent resource for treating headache disorders because the classification lists specific diagnostic criteria for all recognized headache diagnoses.

Continue to: Medication withdrawal...

Medication withdrawal—with or without preventive medication—should reduce the frequency of MOH in 2 or 3 months. If headache does not become less frequent, however, the headache diagnosis might need to be reconsidered. Minimizing the use of abortive medication is generally recommended, but reduction or withdrawal of these medications does not guarantee that patients will revert to an episodic pattern of headache.

Inpatient care of withdrawal might be beneficial when a patient has a severe comorbidity; does not respond to, tolerate, or adhere to treatment; or relapses after withdrawal.

Treating withdrawal symptoms is a reasonable approach in some patients, but evidence does not support routinely providing bridging therapy.

Apply preventives carefully. Abortive medication withdrawal should generally be completed before initiating preventive medication; however, over the short term, starting preventive therapy while withdrawing the overused medication could assist in reducing headache frequency rapidly. This strategy can put patients at risk of medication adverse effects and using the medications longer than necessary, yet might be reasonable in certain patients, given their comorbidities, risk of relapse, and physician and patient preference. A preventive medication for an individual patient should generally be chosen in line with recommendations of the American Academy of Neurology⁴⁵ and on the basis of the history and comorbidities.

Provide education, which is essential to lowering barriers to success. Patients with MOH must be counseled to understand that (1) a headache treatment that is supposed to be making them feel better is, in fact, making them feel worse and (2) they will get worse before they get better. Many patients are afraid to be without medication to use as needed. It is helpful to educate them on the different types of treatments (abortive, preventive); how MOH interferes with headache prophylaxis and medication efficacy; how MOH alters brain function (ie, aforementioned physiologic changes in pain processing and functional imaging changes²³); and that such change is reversible when medication is withdrawn.

ACKNOWLEDGEMENT
The author thanks Jeffrey Curtis, MD, MPH, for his support and editing assistance with the manuscript.

CORRESPONDENCE
Allison Crain, MD, 2927 N 7th Avenue, Phoenix, AZ 85013; [email protected].

Medication overuse headache (MOH), a secondary headache diagnosis, is a prevalent phenomenon that complicates headache diagnosis and treatment, increases the cost of care, and reduces quality of life. Effective abortive medication is essential for the headache sufferer; when an abortive is used too frequently, however, headache frequency increases—potentially beginning a cycle in which the patient then takes more medication to abort the headache. Over time, the patient suffers from an ever-­increasing number of headaches, takes even more abortive medication, and so on. In the presence of MOH, there is a reduction in pain response to preventive and abortive treatments; when medication overuse is eliminated, pain response improves.¹

Although MOH is well recognized among headache specialists, the condition is often overlooked in primary care. Since headache is a top complaint in primary care, however, and prevention is a major goal in family medicine, the opportunity for you to recognize, treat, and prevent MOH is significant. In fact, a randomized controlled trial showed that brief patient education about headache care and MOH provided by a primary care physician can lead to a significant reduction in headache frequency among patients with MOH.²

Although medication overuse headache is well recognized among headache specialists, the condition is often overlooked in primary care.

This article reviews the recognition and diagnosis of MOH, based on historical features and current criteria; addresses risk factors for abortive medication overuse and how to withdraw an offending agent; and explores the value of bridging and preventive therapies to reduce the overall frequency of headache.

IMAGE © ROY SCOTT

What defines MOH?

Typically, MOH is a chronification of a primary headache disorder. However, in patients with a history of migraine who are undergoing treatment for another chronic pain condition with an opioid or other analgesic, MOH can be induced.³ An increase in the frequency of headache raises the specter of a concomitant increase in the level of disability⁴; psychiatric comorbidity⁵; and more headache days, with time lost from school and work.

The Migraine Disability Assessment (MIDAS) questionnaire, a validated instrument that helps the provider (1) measure the impact that headache has on a patient’s life and (2) follow treatment progress, also provides information to employers and insurance companies on treatment coverage and the need for work modification. The MIDAS score is 3 times higher in patients with MOH than in patients with episodic migraine.^6,7

The annual associated cost per person of MOH has been estimated at $4000, resulting in billions of dollars in associated costs⁸; most of these costs are related to absenteeism and disability. After detoxification for MOH, annual outpatient medication costs are reduced by approximately 24%.⁹

Efforts to solve a common problem create another

Headache affects nearly 50% of the general population worldwide,¹⁰ accounting for about 4% of primary care visits¹¹ and approximately 20% of outpatient neurology consultations.¹² Although inpatient stays for headache are approximately half the duration of the overall average hospital stay, headache accounts for 3% of admissions.¹³ According to the Global Burden of Disease study, tension-type headache, migraine, and MOH are the 3 most common headache disorders.¹⁰ Headache is the second leading cause of disability among people 15 to 49 years of age.¹⁰

Continue to: The prevalence of MOH...

The prevalence of MOH in the general population is 2%.^7,14,15 A population-based study showed that the rate of progression from episodic headache (< 15 d/mo) to chronic headache (≥ 15 d/mo) in the general population is 2.5% per year¹⁶; however, progression to chronic headache is 14% per year in patients with medication overuse. One-third of the general population with chronic migraine overuses symptomatic medication; in US headache clinics, roughly one-half of patients with chronic headache overuse acute medication.⁶

Definitions and diagnosis

MOH is a secondary headache diagnosis in the third edition of the International Classification of Headache Disorders (ICHD-3) (TABLE 1),¹⁷ which lists diagnostic criteria for recognized headache disorders.

Terminology. MOH has also been called rebound headache, drug-induced headache, and transformed migraine, but these terms are outdated and are not formal diagnoses. Patients sometimes refer to substance-withdrawal headaches (not discussed in this article) as rebound headaches, so clarity is important when discussing headache with patients: namely, that MOH is an exacerbation of an existing headache condition caused by overuse of abortive headache medications, including analgesics, combination analgesics, triptans, barbiturates, and opioids.

The time it takes to develop medication overuse headache is shortest with triptans, followed by ergots, then analgesics.

MOH was recognized in the early 1950s and fully differentiated as a diagnosis in 2005 in the second edition of the ICHD. The disorder is subcategorized by offending abortive agent (TABLE 2¹⁷) because the frequency of analgesic use required to develop MOH differs by agent.

Risk factors for MOH and chronification of a primary headache ­disorder. There are several risk factors for developing MOH, and others that contribute to increasing headache frequency in general (TABLE 3^5,14,18-23). Some risk factors are common to each. All are important to address because some are modifiable.

Continue to: Pathophysiology

Pathophysiology. The pathophysiology and psychology behind MOH are largely unknown. Physiologic changes in pain processing and functional imaging changes have been demonstrated in patients with MOH, both of which are reversible upon withdrawal of medication.²³ Genetic factors and changes in hormone and neurotransmitter levels are found in MOH patients; this is not the case in patients who have an episodic headache pattern only.²⁴

Presentation. Diagnostic criteria for MOH do not include clinical characteristics. Typically, the phenotype of MOH in a given patient is similar to the underlying primary headache²⁵—although this principle can be complicated to tease out because these medications can suppress some symptoms. Diagnosis of a primary headache disorder should be documented along with the diagnosis of MOH.

Medication overuse can exist without MOH: Not every patient who frequently uses an abortive medication develops MOH.

Treatment is multifaceted—and can become complex

Mainstays of treatment of MOH are education about the disorder and detoxification from the overused agent, although specific treatments can differ depending on the agent involved, the frequency and duration of its use, and a patient’s behavioral patterns and psychiatric comorbidities. Often, a daily medication to prevent headache is considered upon, or after, withdrawal of the offending agent. The timing of introducing a preventive might impact its effectiveness. Some refractory cases require more intensive therapy, including hospitalization at a specialized tertiary center.

But before we look at detoxification from an overused agent, it’s important to review one of the best strategies of all in combatting MOH.

Continue to: First and best strategy

Select an appropriate abortive to reduce the risk of MOH. With regard to specific acute headache medications, some nuances other than type of headache should be considered. Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended as abortive therapy by the American Headache Society for their efficacy, favorable adverse effect profile, and low cost. NSAIDs are protective against development of MOH if a patient’s baseline headache frequency is < 10/mo; at a frequency of 10 to 14 d/mo, however, the risk of MOH increases when using an NSAID.⁶ A similar effect has been seen with triptans.¹⁶ Longer-acting NSAIDs, such as nabumetone and naproxen, have been proposed as less likely to cause MOH, and are even used as bridging therapy sometimes (as long as neither of these was the overused medication).²⁶

The time it takes to develop MOH is shortest with triptans, followed by ergots, then analgesics.²⁷

Prospective cohort studies^6,16 have shown that barbiturates and opioids are more likely to induce MOH; for that reason, agents in these analgesic classes are almost universally avoided unless no other medically acceptable options exist. Using barbiturate-containing compounds or opioids > 4 d/mo exponentially increases the likelihood of MOH.

Promising preclinical data demonstrate that the gepant, or small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, class of medications used as abortive therapy does not induce medication overuse cutaneous allodynia.²⁸

Provide education. Primary prevention of MOH involves (1) increasing patients’ awareness of how to take medications appropriately and (2) restricting intake of over-the-counter abortive medications. Often, the expert recommendation is to limit abortives to approximately 2 d/wk because more frequent use places patients at risk of further increased use and subsequent MOH.

Continue to: A randomized controlled trial in Norway...

A randomized controlled trial in Norway compared outcomes in 2 groups of patients with MOH: One group was given advice on the disorder by a physician; the other group was not provided with advice. In the “business-as-usual” group, there was no significant improvement; however, when general practitioners provided simple advice (lasting roughly 9 minutes) about reducing abortive medication use to a safe level and cautioned patients that they would be “feeling worse before feeling better,” headache days were reduced by approximately 8 per month and medication days, by 16 per month.²

A subsequent, long-term follow-up study²⁹ of patients from the Norway trial² who had been given advice and education showed a relapse rate (ie, into overuse of headache medication) of only 8% and sustained reduction of headache days and medication use at 16 months.

Offer support and other nondrug interventions. A recent review of 3 studies²³ recommended that extra support for patients from a headache nurse, close follow-up, keeping an electronic diary that provides feedback, and undertaking a short course of psychotherapy can reduce medication overuse and prevent relapse.

If MOH develops, initiate withdrawal, introduce a preventive

Withdraw overused medication. Most current evidence suggests that withdrawal of the offending agent is the most effective factor in reducing headache days and improving quality of life. A randomized controlled trial compared the effects of (1) complete and immediate withdrawal of an abortive medication with (2) reducing its use (ie, limiting intake to 2 d/wk), on headache frequency, disability, and quality of life.³⁰ There was a reduction of headache days in both groups; however, reduction was much greater at 2 months in the complete withdrawal group than in the restricted intake group (respectively, a 41% and a 26% reduction in headache days per month). This effect was sustained at 6 and 12 months in both groups. The study confirmed the results of earlier research^2,15: Abrupt withdrawal leads to reversion to an episodic pattern at 2 to 6 months in approximately 40% to 60% of patients.

More studies are needed to determine the most appropriate treatment course for MOH; however, complete withdrawal of the causative drug is the most important intervention.

Continue to: Consider withdrawal plus preventive treatment

Consider withdrawal plus preventive treatment. Use of sodium valproate, in addition to medication overuse detoxification, led to a significant reduction in headache days and improvement in quality of life at 12 weeks but no difference after 24 weeks, compared with detoxification alone in a randomized, double-blind, placebo-controlled study.³¹

A study of 61 patients showed a larger reduction (by 7.2 d/mo) in headache frequency with any preventive medication in addition to medication withdrawal, compared to withdrawal alone (by 4.1 d/mo) after 3 months; however, the relative benefit was gone at 6 months.³²

A study of 98 patients compared immediate and delayed initiation of preventive medication upon withdrawal of overused abortive medication.³³ Response was defined as a > 50% reduction in headache frequency and was similar in both groups; results showed a 28% response with immediate initiation of a preventive; a 23% response with delayed (ie, 2 months after withdrawal) initiation; and a 48% response in both groups at 12 months.

Collectively, these studies suggest that adding a preventive medication at the time of withdrawal has the potential to reduce headache frequency more quickly than withdrawal alone. However, after 3 to 6 months, the outcome of reduced headache frequency is the same whether or not a preventive medication is used—as long as the offending agent has been withdrawn.

Do preventives work without withdrawing overused medication? Patients with MOH often show little or no improvement with addition of a preventive medication only; their response to a preventive improves after withdrawal of the overused medication. Patients without previous headache improvement after addition of a preventive, who also did not improve 2 months after withdrawal, then demonstrated an overall reduction in headache by 26% when a preventive was reintroduced after withdrawal.²

Continue to: The research evidence for preventives

The research evidence for preventives. Medications for headache prevention have not been extensively evaluated specifically for treating MOH. Here is what’s known:

• Flunarizine, amitriptyline, and beta-blockers usually are ineffective for MOH.²⁴
• Results for topiramate are mixed: A small, double-blind, placebo-controlled chronic migraine study in Europe showed that, in a subgroup of patients with MOH, topiramate led to a small but significant reduction (3.5 d/mo) in headache frequency, compared to placebo.²⁷ A similar study done in the United States did not show a significant difference between the active-treatment and placebo groups.³⁴
• Findings regarding onabotulinumtoxinA are intriguing: In a posthoc analysis of onabotulinumtoxinA to treat chronic migraine, patients with MOH who did not undergo detoxification had an 8 d/mo greater reduction in headache, compared to placebo.³⁵ However, when compared to placebo in conjunction with detoxification, onabotulinumtoxinA demonstrated no benefit.³⁶
• Newer CGRP antagonist and CGRP receptor antagonist monoclonal antibodies are successful preventive medications that have demonstrated a reduction in acute medication use days per month and headache days per month³⁷; these compounds have not been compared to withdrawal alone.

Reducing the severity and duration of withdrawal symptoms

Withdrawal from overused abortive headache medications can lead to worsening headache, nausea, vomiting, hypotension, tachycardia, sleep disturbances, restlessness, anxiety, and nervousness. Symptoms usually last 2 to 10 days but can persist for as long as 4 weeks; duration of withdrawal symptoms varies with the medication that is being overused. In patients who have used a triptan, for example, mean duration of withdrawal is 4.1 days; ergotamine, 6.7 days; and NSAIDs, 9.5 days.²³ Tapered withdrawal is sometimes recommended with opioids and barbiturates to reduce withdrawal symptoms. It is unclear whether starting a preventive medication during withdrawal assists in reducing withdrawal symptoms.³⁸

Bridging therapy to reduce symptoms of withdrawal is often provided despite debatable utility. Available evidence does not favor one agent or method but suggests some strategies that could be helpful:

• A prednisone taper has a potential role during the first 6 days of withdrawal by reducing rebound headache and withdrawal symptoms³⁹; however, oral prednisolone has been shown to have no benefit.⁴⁰
• Alone, IV methylprednisolone seems not to be of benefit; however, in a retrospective study of 94 patients, IV methylprednisolone plus diazepam for 5 days led to a significant reduction in headache frequency and drug consumption that was sustained after 3 months.⁴¹
• Celecoxib was compared to prednisone over a 20-day course: a celecoxib dosage of 400 mg/d for the first 5 days, tapered by 100 mg every 5 days, and an oral prednisone dosage of 75 mg/d for the first 5 days, then tapered every 5 days. Patients taking celecoxib had lower headache intensity but there was no difference in headache frequency and acute medication intake between the groups.⁴²

Other strategies. Using antiemetics and NSAIDs to reduce withdrawal symptoms is widely practiced, but no placebo-­controlled trials have been conducted to support this strategy.

Reduce the risk of medication overuse headache by selecting an appropriate abortive; NSAIDs are recommended for their efficacy, favorable adverse effect profile, and low cost.

Patients in withdrawal might be more likely to benefit from inpatient care if they have a severe comorbidity, such as opioid or barbiturate use; failure to respond to, tolerate, or adhere to treatment; or relapse after withdrawal.³⁸

Continue to: Cognitive behavioral therapy...

Cognitive behavioral therapy, exercise, a headache diary, and biofeedback should be considered in every patient’s treatment strategy because a multidisciplinary approach increases adherence and leads to improvement in headache frequency and a decrease in disability and medication use.⁴³

Predictors of Tx success

A prospective cohort study determined that the rate of MOH relapse is 31% at 6 months, 41% at 1 year, and 45% at 4 years, with the highest risk of relapse during the first year.⁴⁴ Looking at the correlation between type of medication overused and relapse rate, the research indicates that

• triptans have the lowest risk of relapse,⁴⁴
• simple analgesics have a higher risk of relapse than triptans,^22,44 and
• opioids have the highest risk of relapse.²²

Where the data don’t agree. Data on combination analgesics and on ergots are conflicting.²² In addition, data on whether the primary type of headache predicts relapse rate conflict; however, migraine might predict a better outcome than tension-type headache.²²

To recap and expand: Management pearls

The major goals of headache management generally are to rule out secondary headache, reach a correct diagnosis, reduce overall headache frequency, and provide effective abortive medication. A large component of reducing headache frequency is addressing and treating medication overuse.

Seek to understand the nature of the patient’s headache disorder. Components of the history are key in identifying the underlying headache diagnosis and ruling out other, more concerning secondary headache diagnoses. The ICHD-3 is an excellent resource for treating headache disorders because the classification lists specific diagnostic criteria for all recognized headache diagnoses.

Continue to: Medication withdrawal...

Medication withdrawal—with or without preventive medication—should reduce the frequency of MOH in 2 or 3 months. If headache does not become less frequent, however, the headache diagnosis might need to be reconsidered. Minimizing the use of abortive medication is generally recommended, but reduction or withdrawal of these medications does not guarantee that patients will revert to an episodic pattern of headache.

Inpatient care of withdrawal might be beneficial when a patient has a severe comorbidity; does not respond to, tolerate, or adhere to treatment; or relapses after withdrawal.

Treating withdrawal symptoms is a reasonable approach in some patients, but evidence does not support routinely providing bridging therapy.

Apply preventives carefully. Abortive medication withdrawal should generally be completed before initiating preventive medication; however, over the short term, starting preventive therapy while withdrawing the overused medication could assist in reducing headache frequency rapidly. This strategy can put patients at risk of medication adverse effects and using the medications longer than necessary, yet might be reasonable in certain patients, given their comorbidities, risk of relapse, and physician and patient preference. A preventive medication for an individual patient should generally be chosen in line with recommendations of the American Academy of Neurology⁴⁵ and on the basis of the history and comorbidities.

Provide education, which is essential to lowering barriers to success. Patients with MOH must be counseled to understand that (1) a headache treatment that is supposed to be making them feel better is, in fact, making them feel worse and (2) they will get worse before they get better. Many patients are afraid to be without medication to use as needed. It is helpful to educate them on the different types of treatments (abortive, preventive); how MOH interferes with headache prophylaxis and medication efficacy; how MOH alters brain function (ie, aforementioned physiologic changes in pain processing and functional imaging changes²³); and that such change is reversible when medication is withdrawn.

ACKNOWLEDGEMENT
The author thanks Jeffrey Curtis, MD, MPH, for his support and editing assistance with the manuscript.

CORRESPONDENCE
Allison Crain, MD, 2927 N 7th Avenue, Phoenix, AZ 85013; [email protected].

Medication overuse headache (MOH), a secondary headache diagnosis, is a prevalent phenomenon that complicates headache diagnosis and treatment, increases the cost of care, and reduces quality of life. Effective abortive medication is essential for the headache sufferer; when an abortive is used too frequently, however, headache frequency increases—potentially beginning a cycle in which the patient then takes more medication to abort the headache. Over time, the patient suffers from an ever-­increasing number of headaches, takes even more abortive medication, and so on. In the presence of MOH, there is a reduction in pain response to preventive and abortive treatments; when medication overuse is eliminated, pain response improves.¹

Although MOH is well recognized among headache specialists, the condition is often overlooked in primary care. Since headache is a top complaint in primary care, however, and prevention is a major goal in family medicine, the opportunity for you to recognize, treat, and prevent MOH is significant. In fact, a randomized controlled trial showed that brief patient education about headache care and MOH provided by a primary care physician can lead to a significant reduction in headache frequency among patients with MOH.²

Although medication overuse headache is well recognized among headache specialists, the condition is often overlooked in primary care.

This article reviews the recognition and diagnosis of MOH, based on historical features and current criteria; addresses risk factors for abortive medication overuse and how to withdraw an offending agent; and explores the value of bridging and preventive therapies to reduce the overall frequency of headache.

IMAGE © ROY SCOTT

What defines MOH?

Typically, MOH is a chronification of a primary headache disorder. However, in patients with a history of migraine who are undergoing treatment for another chronic pain condition with an opioid or other analgesic, MOH can be induced.³ An increase in the frequency of headache raises the specter of a concomitant increase in the level of disability⁴; psychiatric comorbidity⁵; and more headache days, with time lost from school and work.

The Migraine Disability Assessment (MIDAS) questionnaire, a validated instrument that helps the provider (1) measure the impact that headache has on a patient’s life and (2) follow treatment progress, also provides information to employers and insurance companies on treatment coverage and the need for work modification. The MIDAS score is 3 times higher in patients with MOH than in patients with episodic migraine.^6,7

The annual associated cost per person of MOH has been estimated at $4000, resulting in billions of dollars in associated costs⁸; most of these costs are related to absenteeism and disability. After detoxification for MOH, annual outpatient medication costs are reduced by approximately 24%.⁹

Efforts to solve a common problem create another

Headache affects nearly 50% of the general population worldwide,¹⁰ accounting for about 4% of primary care visits¹¹ and approximately 20% of outpatient neurology consultations.¹² Although inpatient stays for headache are approximately half the duration of the overall average hospital stay, headache accounts for 3% of admissions.¹³ According to the Global Burden of Disease study, tension-type headache, migraine, and MOH are the 3 most common headache disorders.¹⁰ Headache is the second leading cause of disability among people 15 to 49 years of age.¹⁰

Continue to: The prevalence of MOH...

The prevalence of MOH in the general population is 2%.^7,14,15 A population-based study showed that the rate of progression from episodic headache (< 15 d/mo) to chronic headache (≥ 15 d/mo) in the general population is 2.5% per year¹⁶; however, progression to chronic headache is 14% per year in patients with medication overuse. One-third of the general population with chronic migraine overuses symptomatic medication; in US headache clinics, roughly one-half of patients with chronic headache overuse acute medication.⁶

Definitions and diagnosis

MOH is a secondary headache diagnosis in the third edition of the International Classification of Headache Disorders (ICHD-3) (TABLE 1),¹⁷ which lists diagnostic criteria for recognized headache disorders.

Terminology. MOH has also been called rebound headache, drug-induced headache, and transformed migraine, but these terms are outdated and are not formal diagnoses. Patients sometimes refer to substance-withdrawal headaches (not discussed in this article) as rebound headaches, so clarity is important when discussing headache with patients: namely, that MOH is an exacerbation of an existing headache condition caused by overuse of abortive headache medications, including analgesics, combination analgesics, triptans, barbiturates, and opioids.

The time it takes to develop medication overuse headache is shortest with triptans, followed by ergots, then analgesics.

MOH was recognized in the early 1950s and fully differentiated as a diagnosis in 2005 in the second edition of the ICHD. The disorder is subcategorized by offending abortive agent (TABLE 2¹⁷) because the frequency of analgesic use required to develop MOH differs by agent.

Risk factors for MOH and chronification of a primary headache ­disorder. There are several risk factors for developing MOH, and others that contribute to increasing headache frequency in general (TABLE 3^5,14,18-23). Some risk factors are common to each. All are important to address because some are modifiable.

Continue to: Pathophysiology

Pathophysiology. The pathophysiology and psychology behind MOH are largely unknown. Physiologic changes in pain processing and functional imaging changes have been demonstrated in patients with MOH, both of which are reversible upon withdrawal of medication.²³ Genetic factors and changes in hormone and neurotransmitter levels are found in MOH patients; this is not the case in patients who have an episodic headache pattern only.²⁴

Presentation. Diagnostic criteria for MOH do not include clinical characteristics. Typically, the phenotype of MOH in a given patient is similar to the underlying primary headache²⁵—although this principle can be complicated to tease out because these medications can suppress some symptoms. Diagnosis of a primary headache disorder should be documented along with the diagnosis of MOH.

Medication overuse can exist without MOH: Not every patient who frequently uses an abortive medication develops MOH.

Treatment is multifaceted—and can become complex

Mainstays of treatment of MOH are education about the disorder and detoxification from the overused agent, although specific treatments can differ depending on the agent involved, the frequency and duration of its use, and a patient’s behavioral patterns and psychiatric comorbidities. Often, a daily medication to prevent headache is considered upon, or after, withdrawal of the offending agent. The timing of introducing a preventive might impact its effectiveness. Some refractory cases require more intensive therapy, including hospitalization at a specialized tertiary center.

But before we look at detoxification from an overused agent, it’s important to review one of the best strategies of all in combatting MOH.

Continue to: First and best strategy

Select an appropriate abortive to reduce the risk of MOH. With regard to specific acute headache medications, some nuances other than type of headache should be considered. Nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended as abortive therapy by the American Headache Society for their efficacy, favorable adverse effect profile, and low cost. NSAIDs are protective against development of MOH if a patient’s baseline headache frequency is < 10/mo; at a frequency of 10 to 14 d/mo, however, the risk of MOH increases when using an NSAID.⁶ A similar effect has been seen with triptans.¹⁶ Longer-acting NSAIDs, such as nabumetone and naproxen, have been proposed as less likely to cause MOH, and are even used as bridging therapy sometimes (as long as neither of these was the overused medication).²⁶

The time it takes to develop MOH is shortest with triptans, followed by ergots, then analgesics.²⁷

Prospective cohort studies^6,16 have shown that barbiturates and opioids are more likely to induce MOH; for that reason, agents in these analgesic classes are almost universally avoided unless no other medically acceptable options exist. Using barbiturate-containing compounds or opioids > 4 d/mo exponentially increases the likelihood of MOH.

Promising preclinical data demonstrate that the gepant, or small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, class of medications used as abortive therapy does not induce medication overuse cutaneous allodynia.²⁸

Provide education. Primary prevention of MOH involves (1) increasing patients’ awareness of how to take medications appropriately and (2) restricting intake of over-the-counter abortive medications. Often, the expert recommendation is to limit abortives to approximately 2 d/wk because more frequent use places patients at risk of further increased use and subsequent MOH.

Continue to: A randomized controlled trial in Norway...

A randomized controlled trial in Norway compared outcomes in 2 groups of patients with MOH: One group was given advice on the disorder by a physician; the other group was not provided with advice. In the “business-as-usual” group, there was no significant improvement; however, when general practitioners provided simple advice (lasting roughly 9 minutes) about reducing abortive medication use to a safe level and cautioned patients that they would be “feeling worse before feeling better,” headache days were reduced by approximately 8 per month and medication days, by 16 per month.²

A subsequent, long-term follow-up study²⁹ of patients from the Norway trial² who had been given advice and education showed a relapse rate (ie, into overuse of headache medication) of only 8% and sustained reduction of headache days and medication use at 16 months.

Offer support and other nondrug interventions. A recent review of 3 studies²³ recommended that extra support for patients from a headache nurse, close follow-up, keeping an electronic diary that provides feedback, and undertaking a short course of psychotherapy can reduce medication overuse and prevent relapse.

If MOH develops, initiate withdrawal, introduce a preventive

Withdraw overused medication. Most current evidence suggests that withdrawal of the offending agent is the most effective factor in reducing headache days and improving quality of life. A randomized controlled trial compared the effects of (1) complete and immediate withdrawal of an abortive medication with (2) reducing its use (ie, limiting intake to 2 d/wk), on headache frequency, disability, and quality of life.³⁰ There was a reduction of headache days in both groups; however, reduction was much greater at 2 months in the complete withdrawal group than in the restricted intake group (respectively, a 41% and a 26% reduction in headache days per month). This effect was sustained at 6 and 12 months in both groups. The study confirmed the results of earlier research^2,15: Abrupt withdrawal leads to reversion to an episodic pattern at 2 to 6 months in approximately 40% to 60% of patients.

More studies are needed to determine the most appropriate treatment course for MOH; however, complete withdrawal of the causative drug is the most important intervention.

Continue to: Consider withdrawal plus preventive treatment

Consider withdrawal plus preventive treatment. Use of sodium valproate, in addition to medication overuse detoxification, led to a significant reduction in headache days and improvement in quality of life at 12 weeks but no difference after 24 weeks, compared with detoxification alone in a randomized, double-blind, placebo-controlled study.³¹

A study of 61 patients showed a larger reduction (by 7.2 d/mo) in headache frequency with any preventive medication in addition to medication withdrawal, compared to withdrawal alone (by 4.1 d/mo) after 3 months; however, the relative benefit was gone at 6 months.³²

A study of 98 patients compared immediate and delayed initiation of preventive medication upon withdrawal of overused abortive medication.³³ Response was defined as a > 50% reduction in headache frequency and was similar in both groups; results showed a 28% response with immediate initiation of a preventive; a 23% response with delayed (ie, 2 months after withdrawal) initiation; and a 48% response in both groups at 12 months.

Collectively, these studies suggest that adding a preventive medication at the time of withdrawal has the potential to reduce headache frequency more quickly than withdrawal alone. However, after 3 to 6 months, the outcome of reduced headache frequency is the same whether or not a preventive medication is used—as long as the offending agent has been withdrawn.

Do preventives work without withdrawing overused medication? Patients with MOH often show little or no improvement with addition of a preventive medication only; their response to a preventive improves after withdrawal of the overused medication. Patients without previous headache improvement after addition of a preventive, who also did not improve 2 months after withdrawal, then demonstrated an overall reduction in headache by 26% when a preventive was reintroduced after withdrawal.²

Continue to: The research evidence for preventives

The research evidence for preventives. Medications for headache prevention have not been extensively evaluated specifically for treating MOH. Here is what’s known:

• Flunarizine, amitriptyline, and beta-blockers usually are ineffective for MOH.²⁴
• Results for topiramate are mixed: A small, double-blind, placebo-controlled chronic migraine study in Europe showed that, in a subgroup of patients with MOH, topiramate led to a small but significant reduction (3.5 d/mo) in headache frequency, compared to placebo.²⁷ A similar study done in the United States did not show a significant difference between the active-treatment and placebo groups.³⁴
• Findings regarding onabotulinumtoxinA are intriguing: In a posthoc analysis of onabotulinumtoxinA to treat chronic migraine, patients with MOH who did not undergo detoxification had an 8 d/mo greater reduction in headache, compared to placebo.³⁵ However, when compared to placebo in conjunction with detoxification, onabotulinumtoxinA demonstrated no benefit.³⁶
• Newer CGRP antagonist and CGRP receptor antagonist monoclonal antibodies are successful preventive medications that have demonstrated a reduction in acute medication use days per month and headache days per month³⁷; these compounds have not been compared to withdrawal alone.

Reducing the severity and duration of withdrawal symptoms

Withdrawal from overused abortive headache medications can lead to worsening headache, nausea, vomiting, hypotension, tachycardia, sleep disturbances, restlessness, anxiety, and nervousness. Symptoms usually last 2 to 10 days but can persist for as long as 4 weeks; duration of withdrawal symptoms varies with the medication that is being overused. In patients who have used a triptan, for example, mean duration of withdrawal is 4.1 days; ergotamine, 6.7 days; and NSAIDs, 9.5 days.²³ Tapered withdrawal is sometimes recommended with opioids and barbiturates to reduce withdrawal symptoms. It is unclear whether starting a preventive medication during withdrawal assists in reducing withdrawal symptoms.³⁸

Bridging therapy to reduce symptoms of withdrawal is often provided despite debatable utility. Available evidence does not favor one agent or method but suggests some strategies that could be helpful:

• A prednisone taper has a potential role during the first 6 days of withdrawal by reducing rebound headache and withdrawal symptoms³⁹; however, oral prednisolone has been shown to have no benefit.⁴⁰
• Alone, IV methylprednisolone seems not to be of benefit; however, in a retrospective study of 94 patients, IV methylprednisolone plus diazepam for 5 days led to a significant reduction in headache frequency and drug consumption that was sustained after 3 months.⁴¹
• Celecoxib was compared to prednisone over a 20-day course: a celecoxib dosage of 400 mg/d for the first 5 days, tapered by 100 mg every 5 days, and an oral prednisone dosage of 75 mg/d for the first 5 days, then tapered every 5 days. Patients taking celecoxib had lower headache intensity but there was no difference in headache frequency and acute medication intake between the groups.⁴²

Other strategies. Using antiemetics and NSAIDs to reduce withdrawal symptoms is widely practiced, but no placebo-­controlled trials have been conducted to support this strategy.

Reduce the risk of medication overuse headache by selecting an appropriate abortive; NSAIDs are recommended for their efficacy, favorable adverse effect profile, and low cost.

Patients in withdrawal might be more likely to benefit from inpatient care if they have a severe comorbidity, such as opioid or barbiturate use; failure to respond to, tolerate, or adhere to treatment; or relapse after withdrawal.³⁸

Continue to: Cognitive behavioral therapy...

Cognitive behavioral therapy, exercise, a headache diary, and biofeedback should be considered in every patient’s treatment strategy because a multidisciplinary approach increases adherence and leads to improvement in headache frequency and a decrease in disability and medication use.⁴³

Predictors of Tx success

A prospective cohort study determined that the rate of MOH relapse is 31% at 6 months, 41% at 1 year, and 45% at 4 years, with the highest risk of relapse during the first year.⁴⁴ Looking at the correlation between type of medication overused and relapse rate, the research indicates that

• triptans have the lowest risk of relapse,⁴⁴
• simple analgesics have a higher risk of relapse than triptans,^22,44 and
• opioids have the highest risk of relapse.²²

Where the data don’t agree. Data on combination analgesics and on ergots are conflicting.²² In addition, data on whether the primary type of headache predicts relapse rate conflict; however, migraine might predict a better outcome than tension-type headache.²²

To recap and expand: Management pearls

The major goals of headache management generally are to rule out secondary headache, reach a correct diagnosis, reduce overall headache frequency, and provide effective abortive medication. A large component of reducing headache frequency is addressing and treating medication overuse.

Seek to understand the nature of the patient’s headache disorder. Components of the history are key in identifying the underlying headache diagnosis and ruling out other, more concerning secondary headache diagnoses. The ICHD-3 is an excellent resource for treating headache disorders because the classification lists specific diagnostic criteria for all recognized headache diagnoses.

Continue to: Medication withdrawal...

Medication withdrawal—with or without preventive medication—should reduce the frequency of MOH in 2 or 3 months. If headache does not become less frequent, however, the headache diagnosis might need to be reconsidered. Minimizing the use of abortive medication is generally recommended, but reduction or withdrawal of these medications does not guarantee that patients will revert to an episodic pattern of headache.

Inpatient care of withdrawal might be beneficial when a patient has a severe comorbidity; does not respond to, tolerate, or adhere to treatment; or relapses after withdrawal.

Treating withdrawal symptoms is a reasonable approach in some patients, but evidence does not support routinely providing bridging therapy.

Apply preventives carefully. Abortive medication withdrawal should generally be completed before initiating preventive medication; however, over the short term, starting preventive therapy while withdrawing the overused medication could assist in reducing headache frequency rapidly. This strategy can put patients at risk of medication adverse effects and using the medications longer than necessary, yet might be reasonable in certain patients, given their comorbidities, risk of relapse, and physician and patient preference. A preventive medication for an individual patient should generally be chosen in line with recommendations of the American Academy of Neurology⁴⁵ and on the basis of the history and comorbidities.

Provide education, which is essential to lowering barriers to success. Patients with MOH must be counseled to understand that (1) a headache treatment that is supposed to be making them feel better is, in fact, making them feel worse and (2) they will get worse before they get better. Many patients are afraid to be without medication to use as needed. It is helpful to educate them on the different types of treatments (abortive, preventive); how MOH interferes with headache prophylaxis and medication efficacy; how MOH alters brain function (ie, aforementioned physiologic changes in pain processing and functional imaging changes²³); and that such change is reversible when medication is withdrawn.

ACKNOWLEDGEMENT
The author thanks Jeffrey Curtis, MD, MPH, for his support and editing assistance with the manuscript.

CORRESPONDENCE
Allison Crain, MD, 2927 N 7th Avenue, Phoenix, AZ 85013; [email protected].

The mainstay of treatment for many musculoskeletal (MSK) complaints is physical or occupational therapy. But often an individual’s underlying biomechanical issue is one that can be easily addressed with a home exercise plan, and, in light of the COVID-19 pandemic, patients may wish to avoid in-person physical therapy. This article describes the rationale for, and methods of providing, home exercises for several MSK conditions commonly seen in the primary care setting.

General rehabilitation principles: First things first

With basic MSK complaints, focus on controlling pain and swelling before undertaking restoration of function. Tailor pharmacologic and nonpharmacologic options to the patient’s needs, using first-line modalities such as ice and compression to reduce inflammation, and prescribing scheduled doses of an anti-inflammatory medication to help with both pain and inflammation.

Once pain is sufficiently controlled, have patients begin basic rehabilitation with simple range-of-motion exercises that move the injured region through normal patterns, as tolerated. Later, the patient can progress through more specific exercises to return the injured region to full functional capacity.

Explain to patients that it takes about 7 to 10 days of consistent care to decrease inflammation, but that they should begin prescribed exercises once they are able to tolerate them. Plan a follow-up visit in 2 to 3 weeks to check on the patient’s response to prescribed care.

Which is better, ice or heat?

Ice and heat are both commonly used to treat MSK injuries and pain, although scrutiny of the use of either intervention has increased. Despite the widespread use of these modalities, there is little evidence to support their effect on patient outcomes. The historical consensus has been that ice decreases pain, inflammation, and edema,while heat can facilitate movement in rehabilitation by improving blood flow and decreasing stiffness.^1-3 In our practice, we encourage use of both topical modalities as a way to start exercise therapy when pain from the acute injury limits participation. Patients often ask which modality they should use. Ice is generally applied in the acute injury phase (48-72 hours after injury), while heat has been thought to be more beneficial in the chronic stages.

Ccontinue to: When and how to apply ice

When and how to apply ice. Applying an ice pack or a bag of frozen vegetables directly to the affected area will help control pain and swelling. Ice should be applied for 15 to 20 minutes at a time, once an hour. If a patient has sensitivity to cold or if the ice pack is a gel-type, have the patient place a layer (eg, towel) between the ice and skin to avoid injury to the skin. Additional caution should be exercised in patients with peripheral vascular disease, cryoglobulinemia, Raynaud disease, or a history of frostbite at the site.⁴

An alternative method we sometimes recommend is ice-cup massage. The patient can fill a small paper cup with water and freeze it. The cup is then used to massage the injured area, providing a more active method of icing whereby the cold can penetrate more quickly. Ice-cup massage should be done for 5 to 10 minutes, 3 to 4 times a day.

When and how to apply heat. Heat will help relax and loosen muscles and is a preferred treatment for older injuries, chronic pain, muscle tension, and spasms.⁵ Because heat can increase blood flow and, likely, inflammation, it should not be used in the acute injury phase. A heating pad or a warm, wet towel can be applied for up to 20 minutes at a time to help relieve pain and tension. Heat is also beneficial before participating in rehab activities as a method of “warming up” a recently injured area.⁶ However, ice should still be used following activity to prevent any new inflammation.

Anti-inflammatory medications

For an acute injury, nonsteroidal anti-­inflammatory drugs (NSAIDs) not only can decrease inflammation and aid in healing but can alleviate pain. We typically start with over-the-counter (OTC) NSAIDs taken on a schedule. A good suggestion is to have the patient take the scheduled NSAID with food for 7 to 10 days or until symptoms subside.

Topical analgesics

Because oral medications can occasionally cause adverse effects or be contraindicated in some patients, topical analgesics can be a good substitute due to their minimal adverse effects. Acceptable topical medications include NSAIDs, lidocaine, menthol, and arnica. Other than prescribed topical NSAIDs, these products can be applied directly to the painful area on an as-needed basis. Often, a topical patch is a nice option to recommend for use during work or school, and a topical cream or ointment can be used at bedtime.

Continue to: Graduated rehabilitation

Graduated rehabilitation

The following 4 common MSK injuries are ones that can benefit from a graduated approach to rehabilitation at home.

Lateral ankle sprain

Lateral ankle sprain, usually resulting from an inversion mechanism, is the most common type of acute ankle sprain seen in primary care and sports medicine settings.^7-9 The injury causes lateral ankle pain and swelling, decreased range of motion and strength, and pain with weight-bearing activities.

Have patients avoid using heat in the acute injury phase because it can increase inflammation due to increased blood flow.

Treatment and rehabilitation after this type of injury are critical to restoring normal function and increasing the likelihood of returning to pre-injury levels of activity.^9,10 Goals for an acute ankle sprain include controlling swelling, regaining full range of motion, increasing muscle strength and power, and improving balance.

Phase 1: Immediately following injury, have the patient protect the injured area with rest, ice, compression, and elevation (RICE). This will help to decrease swelling and pain. Exercises to regain range of motion, such as stretching and doing ankle “ABCs,” should begin within 48 to 72 hours of the initial injury (TABLE 1).^9-11

Continue to: Phase 2

Phase 2: Once the patient has achieved full range of motion and pain is controlled, begin the process of regaining strength. The 4-way ankle exercise program (with elastic tubing) is an easy at-home exercise that has been shown to improve strength in plantar flexion, dorsiflexion, eversion, and inversion (TABLE 1).^9-11

Phase 3: Once your patient is able to bear full weight with little to no pain, begin a balance program (TABLE 1^9-11). This is the most frequently neglected component of rehabilitation and the most common reason patients return with chronic ankle pain or repeat ankle injuries. Deficits in postural stability and balance have been reported in unstable ankles following acute ankle sprains,^10,12-15 and studies have shown that individuals with poor stability are at a greater risk of injury.^13-16

For most lateral ankle sprains, patients can expect time to recovery to range from 2 to 8 weeks. Longer recoveries are associated with more severe injuries or those that involve the syndesmosis.

Plantar fasciitis

Plantar fasciitis (PF) of the foot can be frustrating for a patient due to its chronic nature. Most patients will present with pain in the heel that is aggravated by weight-bearing activities. A conservative management program that focuses on reducing pain and inflammation, reducing tissue stress, and restoring strength and flexibility has been shown to be effective for this type of injury.^17,18

Step 1: Reduce pain and inflammation. Deep-tissue massage and cryotherapy are easy ways to help with pain and inflammation. Deep-tissue massage can be accomplished by rolling the bottom of the foot on a golf or lacrosse ball. A favorite recommendation of ours to reduce inflammation is to use the ice-cup massage, mentioned earlier, for 5 minutes. Or rolling the bottom of the foot on a frozen water bottle will accomplish both tasks at once (TABLE 2^17,18).

Step 2: Reduce tissue stress. Management tools commonly used to reduce tissue stress are OTC orthotics and night splints. The night splint has been shown to improve symptoms,but patients often stop using it due to discomfort.¹⁹ Many kinds of night splints are available, but we have found that the sock variety with a strap to keep the foot in dorsiflexion is best tolerated, and it should be covered by most care plans.

Continue to: Step 3

Step 3: Restore muscle strength and flexibility. Restoring flexibility of the gastrocnemius and soleus is most frequently recommended for treating PF. Strengthening exercises that involve intrinsic and extrinsic muscles of the foot and ankle are also essential.^17,18 Helpful exercises include those listed in TABLE 1.^9-11 Additionally, an eccentric heel stretch can help to alleviate PF symptoms (TABLE 2^17,18).

A reasonable timeline for follow-up on newly diagnosed PF is 4 to 6 weeks. While many patients will not have recovered in that time, the goal is to document progress in recovery. If no progress is made, consider other treatment modalities.

Patellofemoral pain syndrome

Patellofemoral pain syndrome (PFPS) is one of the most common orthopedic complaints, estimated to comprise 7.3% of all orthopedic visits.²⁰ Commonly called “runner’s knee,” PFPS is the leading cause of anterior knee pain in active individuals. Studies suggest a gender bias, with PFPS being diagnosed more frequently in females than in males, particularly between the ages of 10 and 19.²⁰ Often, there is vague anterior knee pain, or pain that worsens with activities such as climbing hills or stairs, or with long sitting or when fatigued.

In general, unbalanced patellar tracking within the trochlear groove likely leads to this pain. Multiple contributory factors have been described; however, evidence increasingly has shown that deficiencies in hip strength may contribute significantly to maltracking of the patella with resultant pain. Specifically, weakness in hip external rotators and abductors is associated with abnormal lower extremity mechanics.²¹ One randomized controlled trial by Ferber et al found that therapy protocols directed at hip and core strength showed earlier resolution of pain and greater strength when compared with knee protocols alone.²²

We routinely talk to patients about how the knee is the “victim” caught between weak hips and/or flat feet. It is prudent to look for both in the office visit. This can be done with one simple maneuver: Ask your patient to do a squat followed by 3 or 4 single-leg squats on each side. This will often reveal dysfunction at the foot/ankle or weakness in the hips/core as demonstrated by pronated feet (along with valgus tracking of the knees inward) or loss of balance upon squatting.

There is general consensus that a nonsurgical approach is the mainstay of treatment for PFPS.²³ Pelvic stabilization and hip strengthening are standard components along with treatment protocols of exercises tailored to one’s individual weaknesses.

Numerous types of exercises do not require specialized equipment and can be taught in the office (TABLE 3²⁴). Explain to patients that the recovery process may take several months. Monthly follow-up to document progress is essential and helps to ensure compliance with one’s home program.

Continue to : Neck pain

Neck pain

The annual prevalence of nonspecific neck pain ranges from 27% to 48%, with 70% of individuals being afflicted at some time in their lives.²⁵ First rule out any neurologic factors that might suggest cervical disc disease or spinal stenosis. If a patient describes weakness or sensory changes along one or both upper extremities, obtain imaging and consider more formalized therapy with a physical therapist.

In patients without any red flags, investigate possible biomechanical causes. It is essential to review the patient’s work and home habits, particularly in light of COVID-19, to determine if adjustments may be needed. Factors to consider are desk and computer setups at work or home, reading or laptop use in bed, sleep habits, and frequency of cellular phone calls/texting.²⁶ A formal ergonomic assessment of the patient’s workplace may be helpful.

A mainstay in treating mechanical neck pain is alleviating trapezial tightness or spasm. Manipulative therapies such as osteopathic manipulation, massage, and chiropractic care can provide pain relief in the acute setting as well as help with control of chronic symptoms.²⁷ A simple self-care tool is using a tennis ball to massage the trapezial muscles. This can be accomplished by having the patient position the tennis ball along the upper trapezial muscles, holding it in place by leaning against a wall, and initiating self-massage. Another method of self-massage is to put 2 tennis balls in an athletic tube sock and tie off the end, place the sock on the floor, and lie on it in the supine position.

There is also evidence that exercise of any kind can help control neck pain.^28,29 The easiest exercises one can offer a patient with neck stiffness, or even mild cervical strains, is self-directed stretching through gentle pressure applied in all 4 directions on the neck. This technique can be repeated hourly both at work and at home (TABLE 4).

Reminders that can help ensure success

You can use the approaches described here for numerous other MSK conditions in helping patients on the road to recovery.

After the acute phase, advise patients to

• apply heat to the affected area before exercising. This can help bring blood flow to the region and promote ease of movement.

• continue icing the area following rehabilitation exercises in order to control exercise-induced inflammation.

• report any changing symptoms such as worsening pain, numbness, or weakness.


These techniques are one step in the recovery process. A home program can benefit the patient either alone or in combination with more advanced techniques that are best accomplished under the watchful eye of a physical or occupational therapist.
 

CORRESPONDENCE

Carrie A. Jaworski, MD, FAAFP, FACSM, 2180 Pfingsten Road, Suite 3100, Glenview, IL 60026; [email protected]

The mainstay of treatment for many musculoskeletal (MSK) complaints is physical or occupational therapy. But often an individual’s underlying biomechanical issue is one that can be easily addressed with a home exercise plan, and, in light of the COVID-19 pandemic, patients may wish to avoid in-person physical therapy. This article describes the rationale for, and methods of providing, home exercises for several MSK conditions commonly seen in the primary care setting.

General rehabilitation principles: First things first

With basic MSK complaints, focus on controlling pain and swelling before undertaking restoration of function. Tailor pharmacologic and nonpharmacologic options to the patient’s needs, using first-line modalities such as ice and compression to reduce inflammation, and prescribing scheduled doses of an anti-inflammatory medication to help with both pain and inflammation.

Once pain is sufficiently controlled, have patients begin basic rehabilitation with simple range-of-motion exercises that move the injured region through normal patterns, as tolerated. Later, the patient can progress through more specific exercises to return the injured region to full functional capacity.

Explain to patients that it takes about 7 to 10 days of consistent care to decrease inflammation, but that they should begin prescribed exercises once they are able to tolerate them. Plan a follow-up visit in 2 to 3 weeks to check on the patient’s response to prescribed care.

Which is better, ice or heat?

Ice and heat are both commonly used to treat MSK injuries and pain, although scrutiny of the use of either intervention has increased. Despite the widespread use of these modalities, there is little evidence to support their effect on patient outcomes. The historical consensus has been that ice decreases pain, inflammation, and edema,while heat can facilitate movement in rehabilitation by improving blood flow and decreasing stiffness.^1-3 In our practice, we encourage use of both topical modalities as a way to start exercise therapy when pain from the acute injury limits participation. Patients often ask which modality they should use. Ice is generally applied in the acute injury phase (48-72 hours after injury), while heat has been thought to be more beneficial in the chronic stages.

Ccontinue to: When and how to apply ice

When and how to apply ice. Applying an ice pack or a bag of frozen vegetables directly to the affected area will help control pain and swelling. Ice should be applied for 15 to 20 minutes at a time, once an hour. If a patient has sensitivity to cold or if the ice pack is a gel-type, have the patient place a layer (eg, towel) between the ice and skin to avoid injury to the skin. Additional caution should be exercised in patients with peripheral vascular disease, cryoglobulinemia, Raynaud disease, or a history of frostbite at the site.⁴

An alternative method we sometimes recommend is ice-cup massage. The patient can fill a small paper cup with water and freeze it. The cup is then used to massage the injured area, providing a more active method of icing whereby the cold can penetrate more quickly. Ice-cup massage should be done for 5 to 10 minutes, 3 to 4 times a day.

When and how to apply heat. Heat will help relax and loosen muscles and is a preferred treatment for older injuries, chronic pain, muscle tension, and spasms.⁵ Because heat can increase blood flow and, likely, inflammation, it should not be used in the acute injury phase. A heating pad or a warm, wet towel can be applied for up to 20 minutes at a time to help relieve pain and tension. Heat is also beneficial before participating in rehab activities as a method of “warming up” a recently injured area.⁶ However, ice should still be used following activity to prevent any new inflammation.

Anti-inflammatory medications

For an acute injury, nonsteroidal anti-­inflammatory drugs (NSAIDs) not only can decrease inflammation and aid in healing but can alleviate pain. We typically start with over-the-counter (OTC) NSAIDs taken on a schedule. A good suggestion is to have the patient take the scheduled NSAID with food for 7 to 10 days or until symptoms subside.

Topical analgesics

Because oral medications can occasionally cause adverse effects or be contraindicated in some patients, topical analgesics can be a good substitute due to their minimal adverse effects. Acceptable topical medications include NSAIDs, lidocaine, menthol, and arnica. Other than prescribed topical NSAIDs, these products can be applied directly to the painful area on an as-needed basis. Often, a topical patch is a nice option to recommend for use during work or school, and a topical cream or ointment can be used at bedtime.

Continue to: Graduated rehabilitation

Graduated rehabilitation

The following 4 common MSK injuries are ones that can benefit from a graduated approach to rehabilitation at home.

Lateral ankle sprain

Lateral ankle sprain, usually resulting from an inversion mechanism, is the most common type of acute ankle sprain seen in primary care and sports medicine settings.^7-9 The injury causes lateral ankle pain and swelling, decreased range of motion and strength, and pain with weight-bearing activities.

Have patients avoid using heat in the acute injury phase because it can increase inflammation due to increased blood flow.

Treatment and rehabilitation after this type of injury are critical to restoring normal function and increasing the likelihood of returning to pre-injury levels of activity.^9,10 Goals for an acute ankle sprain include controlling swelling, regaining full range of motion, increasing muscle strength and power, and improving balance.

Phase 1: Immediately following injury, have the patient protect the injured area with rest, ice, compression, and elevation (RICE). This will help to decrease swelling and pain. Exercises to regain range of motion, such as stretching and doing ankle “ABCs,” should begin within 48 to 72 hours of the initial injury (TABLE 1).^9-11

Continue to: Phase 2

Phase 2: Once the patient has achieved full range of motion and pain is controlled, begin the process of regaining strength. The 4-way ankle exercise program (with elastic tubing) is an easy at-home exercise that has been shown to improve strength in plantar flexion, dorsiflexion, eversion, and inversion (TABLE 1).^9-11

Phase 3: Once your patient is able to bear full weight with little to no pain, begin a balance program (TABLE 1^9-11). This is the most frequently neglected component of rehabilitation and the most common reason patients return with chronic ankle pain or repeat ankle injuries. Deficits in postural stability and balance have been reported in unstable ankles following acute ankle sprains,^10,12-15 and studies have shown that individuals with poor stability are at a greater risk of injury.^13-16

For most lateral ankle sprains, patients can expect time to recovery to range from 2 to 8 weeks. Longer recoveries are associated with more severe injuries or those that involve the syndesmosis.

Plantar fasciitis

Plantar fasciitis (PF) of the foot can be frustrating for a patient due to its chronic nature. Most patients will present with pain in the heel that is aggravated by weight-bearing activities. A conservative management program that focuses on reducing pain and inflammation, reducing tissue stress, and restoring strength and flexibility has been shown to be effective for this type of injury.^17,18

Step 1: Reduce pain and inflammation. Deep-tissue massage and cryotherapy are easy ways to help with pain and inflammation. Deep-tissue massage can be accomplished by rolling the bottom of the foot on a golf or lacrosse ball. A favorite recommendation of ours to reduce inflammation is to use the ice-cup massage, mentioned earlier, for 5 minutes. Or rolling the bottom of the foot on a frozen water bottle will accomplish both tasks at once (TABLE 2^17,18).

Step 2: Reduce tissue stress. Management tools commonly used to reduce tissue stress are OTC orthotics and night splints. The night splint has been shown to improve symptoms,but patients often stop using it due to discomfort.¹⁹ Many kinds of night splints are available, but we have found that the sock variety with a strap to keep the foot in dorsiflexion is best tolerated, and it should be covered by most care plans.

Continue to: Step 3

Step 3: Restore muscle strength and flexibility. Restoring flexibility of the gastrocnemius and soleus is most frequently recommended for treating PF. Strengthening exercises that involve intrinsic and extrinsic muscles of the foot and ankle are also essential.^17,18 Helpful exercises include those listed in TABLE 1.^9-11 Additionally, an eccentric heel stretch can help to alleviate PF symptoms (TABLE 2^17,18).

A reasonable timeline for follow-up on newly diagnosed PF is 4 to 6 weeks. While many patients will not have recovered in that time, the goal is to document progress in recovery. If no progress is made, consider other treatment modalities.

Patellofemoral pain syndrome

Patellofemoral pain syndrome (PFPS) is one of the most common orthopedic complaints, estimated to comprise 7.3% of all orthopedic visits.²⁰ Commonly called “runner’s knee,” PFPS is the leading cause of anterior knee pain in active individuals. Studies suggest a gender bias, with PFPS being diagnosed more frequently in females than in males, particularly between the ages of 10 and 19.²⁰ Often, there is vague anterior knee pain, or pain that worsens with activities such as climbing hills or stairs, or with long sitting or when fatigued.

In general, unbalanced patellar tracking within the trochlear groove likely leads to this pain. Multiple contributory factors have been described; however, evidence increasingly has shown that deficiencies in hip strength may contribute significantly to maltracking of the patella with resultant pain. Specifically, weakness in hip external rotators and abductors is associated with abnormal lower extremity mechanics.²¹ One randomized controlled trial by Ferber et al found that therapy protocols directed at hip and core strength showed earlier resolution of pain and greater strength when compared with knee protocols alone.²²

We routinely talk to patients about how the knee is the “victim” caught between weak hips and/or flat feet. It is prudent to look for both in the office visit. This can be done with one simple maneuver: Ask your patient to do a squat followed by 3 or 4 single-leg squats on each side. This will often reveal dysfunction at the foot/ankle or weakness in the hips/core as demonstrated by pronated feet (along with valgus tracking of the knees inward) or loss of balance upon squatting.

There is general consensus that a nonsurgical approach is the mainstay of treatment for PFPS.²³ Pelvic stabilization and hip strengthening are standard components along with treatment protocols of exercises tailored to one’s individual weaknesses.

Numerous types of exercises do not require specialized equipment and can be taught in the office (TABLE 3²⁴). Explain to patients that the recovery process may take several months. Monthly follow-up to document progress is essential and helps to ensure compliance with one’s home program.

Continue to : Neck pain

Neck pain

The annual prevalence of nonspecific neck pain ranges from 27% to 48%, with 70% of individuals being afflicted at some time in their lives.²⁵ First rule out any neurologic factors that might suggest cervical disc disease or spinal stenosis. If a patient describes weakness or sensory changes along one or both upper extremities, obtain imaging and consider more formalized therapy with a physical therapist.

In patients without any red flags, investigate possible biomechanical causes. It is essential to review the patient’s work and home habits, particularly in light of COVID-19, to determine if adjustments may be needed. Factors to consider are desk and computer setups at work or home, reading or laptop use in bed, sleep habits, and frequency of cellular phone calls/texting.²⁶ A formal ergonomic assessment of the patient’s workplace may be helpful.

A mainstay in treating mechanical neck pain is alleviating trapezial tightness or spasm. Manipulative therapies such as osteopathic manipulation, massage, and chiropractic care can provide pain relief in the acute setting as well as help with control of chronic symptoms.²⁷ A simple self-care tool is using a tennis ball to massage the trapezial muscles. This can be accomplished by having the patient position the tennis ball along the upper trapezial muscles, holding it in place by leaning against a wall, and initiating self-massage. Another method of self-massage is to put 2 tennis balls in an athletic tube sock and tie off the end, place the sock on the floor, and lie on it in the supine position.

There is also evidence that exercise of any kind can help control neck pain.^28,29 The easiest exercises one can offer a patient with neck stiffness, or even mild cervical strains, is self-directed stretching through gentle pressure applied in all 4 directions on the neck. This technique can be repeated hourly both at work and at home (TABLE 4).

Reminders that can help ensure success

You can use the approaches described here for numerous other MSK conditions in helping patients on the road to recovery.

After the acute phase, advise patients to

• apply heat to the affected area before exercising. This can help bring blood flow to the region and promote ease of movement.

• continue icing the area following rehabilitation exercises in order to control exercise-induced inflammation.

• report any changing symptoms such as worsening pain, numbness, or weakness.


These techniques are one step in the recovery process. A home program can benefit the patient either alone or in combination with more advanced techniques that are best accomplished under the watchful eye of a physical or occupational therapist.
 

CORRESPONDENCE

Carrie A. Jaworski, MD, FAAFP, FACSM, 2180 Pfingsten Road, Suite 3100, Glenview, IL 60026; [email protected]

The mainstay of treatment for many musculoskeletal (MSK) complaints is physical or occupational therapy. But often an individual’s underlying biomechanical issue is one that can be easily addressed with a home exercise plan, and, in light of the COVID-19 pandemic, patients may wish to avoid in-person physical therapy. This article describes the rationale for, and methods of providing, home exercises for several MSK conditions commonly seen in the primary care setting.

General rehabilitation principles: First things first

With basic MSK complaints, focus on controlling pain and swelling before undertaking restoration of function. Tailor pharmacologic and nonpharmacologic options to the patient’s needs, using first-line modalities such as ice and compression to reduce inflammation, and prescribing scheduled doses of an anti-inflammatory medication to help with both pain and inflammation.

Once pain is sufficiently controlled, have patients begin basic rehabilitation with simple range-of-motion exercises that move the injured region through normal patterns, as tolerated. Later, the patient can progress through more specific exercises to return the injured region to full functional capacity.

Explain to patients that it takes about 7 to 10 days of consistent care to decrease inflammation, but that they should begin prescribed exercises once they are able to tolerate them. Plan a follow-up visit in 2 to 3 weeks to check on the patient’s response to prescribed care.

Which is better, ice or heat?

Ice and heat are both commonly used to treat MSK injuries and pain, although scrutiny of the use of either intervention has increased. Despite the widespread use of these modalities, there is little evidence to support their effect on patient outcomes. The historical consensus has been that ice decreases pain, inflammation, and edema,while heat can facilitate movement in rehabilitation by improving blood flow and decreasing stiffness.^1-3 In our practice, we encourage use of both topical modalities as a way to start exercise therapy when pain from the acute injury limits participation. Patients often ask which modality they should use. Ice is generally applied in the acute injury phase (48-72 hours after injury), while heat has been thought to be more beneficial in the chronic stages.

Ccontinue to: When and how to apply ice

When and how to apply ice. Applying an ice pack or a bag of frozen vegetables directly to the affected area will help control pain and swelling. Ice should be applied for 15 to 20 minutes at a time, once an hour. If a patient has sensitivity to cold or if the ice pack is a gel-type, have the patient place a layer (eg, towel) between the ice and skin to avoid injury to the skin. Additional caution should be exercised in patients with peripheral vascular disease, cryoglobulinemia, Raynaud disease, or a history of frostbite at the site.⁴

An alternative method we sometimes recommend is ice-cup massage. The patient can fill a small paper cup with water and freeze it. The cup is then used to massage the injured area, providing a more active method of icing whereby the cold can penetrate more quickly. Ice-cup massage should be done for 5 to 10 minutes, 3 to 4 times a day.

When and how to apply heat. Heat will help relax and loosen muscles and is a preferred treatment for older injuries, chronic pain, muscle tension, and spasms.⁵ Because heat can increase blood flow and, likely, inflammation, it should not be used in the acute injury phase. A heating pad or a warm, wet towel can be applied for up to 20 minutes at a time to help relieve pain and tension. Heat is also beneficial before participating in rehab activities as a method of “warming up” a recently injured area.⁶ However, ice should still be used following activity to prevent any new inflammation.

Anti-inflammatory medications

For an acute injury, nonsteroidal anti-­inflammatory drugs (NSAIDs) not only can decrease inflammation and aid in healing but can alleviate pain. We typically start with over-the-counter (OTC) NSAIDs taken on a schedule. A good suggestion is to have the patient take the scheduled NSAID with food for 7 to 10 days or until symptoms subside.

Topical analgesics

Because oral medications can occasionally cause adverse effects or be contraindicated in some patients, topical analgesics can be a good substitute due to their minimal adverse effects. Acceptable topical medications include NSAIDs, lidocaine, menthol, and arnica. Other than prescribed topical NSAIDs, these products can be applied directly to the painful area on an as-needed basis. Often, a topical patch is a nice option to recommend for use during work or school, and a topical cream or ointment can be used at bedtime.

Continue to: Graduated rehabilitation

Graduated rehabilitation

The following 4 common MSK injuries are ones that can benefit from a graduated approach to rehabilitation at home.

Lateral ankle sprain

Lateral ankle sprain, usually resulting from an inversion mechanism, is the most common type of acute ankle sprain seen in primary care and sports medicine settings.^7-9 The injury causes lateral ankle pain and swelling, decreased range of motion and strength, and pain with weight-bearing activities.

Have patients avoid using heat in the acute injury phase because it can increase inflammation due to increased blood flow.

Treatment and rehabilitation after this type of injury are critical to restoring normal function and increasing the likelihood of returning to pre-injury levels of activity.^9,10 Goals for an acute ankle sprain include controlling swelling, regaining full range of motion, increasing muscle strength and power, and improving balance.

Phase 1: Immediately following injury, have the patient protect the injured area with rest, ice, compression, and elevation (RICE). This will help to decrease swelling and pain. Exercises to regain range of motion, such as stretching and doing ankle “ABCs,” should begin within 48 to 72 hours of the initial injury (TABLE 1).^9-11

Continue to: Phase 2

Phase 2: Once the patient has achieved full range of motion and pain is controlled, begin the process of regaining strength. The 4-way ankle exercise program (with elastic tubing) is an easy at-home exercise that has been shown to improve strength in plantar flexion, dorsiflexion, eversion, and inversion (TABLE 1).^9-11

Phase 3: Once your patient is able to bear full weight with little to no pain, begin a balance program (TABLE 1^9-11). This is the most frequently neglected component of rehabilitation and the most common reason patients return with chronic ankle pain or repeat ankle injuries. Deficits in postural stability and balance have been reported in unstable ankles following acute ankle sprains,^10,12-15 and studies have shown that individuals with poor stability are at a greater risk of injury.^13-16

For most lateral ankle sprains, patients can expect time to recovery to range from 2 to 8 weeks. Longer recoveries are associated with more severe injuries or those that involve the syndesmosis.

Plantar fasciitis

Plantar fasciitis (PF) of the foot can be frustrating for a patient due to its chronic nature. Most patients will present with pain in the heel that is aggravated by weight-bearing activities. A conservative management program that focuses on reducing pain and inflammation, reducing tissue stress, and restoring strength and flexibility has been shown to be effective for this type of injury.^17,18

Step 1: Reduce pain and inflammation. Deep-tissue massage and cryotherapy are easy ways to help with pain and inflammation. Deep-tissue massage can be accomplished by rolling the bottom of the foot on a golf or lacrosse ball. A favorite recommendation of ours to reduce inflammation is to use the ice-cup massage, mentioned earlier, for 5 minutes. Or rolling the bottom of the foot on a frozen water bottle will accomplish both tasks at once (TABLE 2^17,18).

Step 2: Reduce tissue stress. Management tools commonly used to reduce tissue stress are OTC orthotics and night splints. The night splint has been shown to improve symptoms,but patients often stop using it due to discomfort.¹⁹ Many kinds of night splints are available, but we have found that the sock variety with a strap to keep the foot in dorsiflexion is best tolerated, and it should be covered by most care plans.

Continue to: Step 3

Step 3: Restore muscle strength and flexibility. Restoring flexibility of the gastrocnemius and soleus is most frequently recommended for treating PF. Strengthening exercises that involve intrinsic and extrinsic muscles of the foot and ankle are also essential.^17,18 Helpful exercises include those listed in TABLE 1.^9-11 Additionally, an eccentric heel stretch can help to alleviate PF symptoms (TABLE 2^17,18).

A reasonable timeline for follow-up on newly diagnosed PF is 4 to 6 weeks. While many patients will not have recovered in that time, the goal is to document progress in recovery. If no progress is made, consider other treatment modalities.

Patellofemoral pain syndrome

Patellofemoral pain syndrome (PFPS) is one of the most common orthopedic complaints, estimated to comprise 7.3% of all orthopedic visits.²⁰ Commonly called “runner’s knee,” PFPS is the leading cause of anterior knee pain in active individuals. Studies suggest a gender bias, with PFPS being diagnosed more frequently in females than in males, particularly between the ages of 10 and 19.²⁰ Often, there is vague anterior knee pain, or pain that worsens with activities such as climbing hills or stairs, or with long sitting or when fatigued.

In general, unbalanced patellar tracking within the trochlear groove likely leads to this pain. Multiple contributory factors have been described; however, evidence increasingly has shown that deficiencies in hip strength may contribute significantly to maltracking of the patella with resultant pain. Specifically, weakness in hip external rotators and abductors is associated with abnormal lower extremity mechanics.²¹ One randomized controlled trial by Ferber et al found that therapy protocols directed at hip and core strength showed earlier resolution of pain and greater strength when compared with knee protocols alone.²²

We routinely talk to patients about how the knee is the “victim” caught between weak hips and/or flat feet. It is prudent to look for both in the office visit. This can be done with one simple maneuver: Ask your patient to do a squat followed by 3 or 4 single-leg squats on each side. This will often reveal dysfunction at the foot/ankle or weakness in the hips/core as demonstrated by pronated feet (along with valgus tracking of the knees inward) or loss of balance upon squatting.

There is general consensus that a nonsurgical approach is the mainstay of treatment for PFPS.²³ Pelvic stabilization and hip strengthening are standard components along with treatment protocols of exercises tailored to one’s individual weaknesses.

Numerous types of exercises do not require specialized equipment and can be taught in the office (TABLE 3²⁴). Explain to patients that the recovery process may take several months. Monthly follow-up to document progress is essential and helps to ensure compliance with one’s home program.

Continue to : Neck pain

Neck pain

The annual prevalence of nonspecific neck pain ranges from 27% to 48%, with 70% of individuals being afflicted at some time in their lives.²⁵ First rule out any neurologic factors that might suggest cervical disc disease or spinal stenosis. If a patient describes weakness or sensory changes along one or both upper extremities, obtain imaging and consider more formalized therapy with a physical therapist.

In patients without any red flags, investigate possible biomechanical causes. It is essential to review the patient’s work and home habits, particularly in light of COVID-19, to determine if adjustments may be needed. Factors to consider are desk and computer setups at work or home, reading or laptop use in bed, sleep habits, and frequency of cellular phone calls/texting.²⁶ A formal ergonomic assessment of the patient’s workplace may be helpful.

A mainstay in treating mechanical neck pain is alleviating trapezial tightness or spasm. Manipulative therapies such as osteopathic manipulation, massage, and chiropractic care can provide pain relief in the acute setting as well as help with control of chronic symptoms.²⁷ A simple self-care tool is using a tennis ball to massage the trapezial muscles. This can be accomplished by having the patient position the tennis ball along the upper trapezial muscles, holding it in place by leaning against a wall, and initiating self-massage. Another method of self-massage is to put 2 tennis balls in an athletic tube sock and tie off the end, place the sock on the floor, and lie on it in the supine position.

There is also evidence that exercise of any kind can help control neck pain.^28,29 The easiest exercises one can offer a patient with neck stiffness, or even mild cervical strains, is self-directed stretching through gentle pressure applied in all 4 directions on the neck. This technique can be repeated hourly both at work and at home (TABLE 4).

Reminders that can help ensure success

You can use the approaches described here for numerous other MSK conditions in helping patients on the road to recovery.

After the acute phase, advise patients to

• apply heat to the affected area before exercising. This can help bring blood flow to the region and promote ease of movement.

• continue icing the area following rehabilitation exercises in order to control exercise-induced inflammation.

• report any changing symptoms such as worsening pain, numbness, or weakness.


These techniques are one step in the recovery process. A home program can benefit the patient either alone or in combination with more advanced techniques that are best accomplished under the watchful eye of a physical or occupational therapist.
 

CORRESPONDENCE

Carrie A. Jaworski, MD, FAAFP, FACSM, 2180 Pfingsten Road, Suite 3100, Glenview, IL 60026; [email protected]

Peripheral arterial disease (PAD), the progressive disorder that results in ischemia to distal vascular territories as a result of atherosclerosis, spans a wide range of presentations, from minimally symptomatic disease to limb ischemia secondary to acute or chronic occlusion.

The prevalence of PAD is variable, due to differing diagnostic criteria used in studies, but PAD appears to affect 1 in every 22 people older than age 40.¹ However, since PAD incidence increases with age, it is increasing in prevalence as the US population ages.^1-3

PAD is associated with increased hospitalizations and decreased quality of life.⁴ Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.³

Screening. Although PAD is underdiagnosed and appears to be undertreated,³ population-based screening for PAD in asymptomatic patients is not recommended. A Cochrane review found no studies evaluating the benefit of ­asymptomatic population-based screening.⁵ Similarly, in 2018, the USPSTF performed a comprehensive review and found no studies to support routine screening and determined there was insufficient evidence to recommend it.^6,7

Risk factors and associated comorbidities

PAD risk factors, like the ones detailed below, have a potentiating effect. The presence of 2 risk factors doubles PAD risk, while 3 or more risk factors increase PAD risk by a factor of 10.¹

Increasing age is the greatest single risk factor for PAD.^1,2,8,9 Researchers using data from the National Health and Nutrition Examination Survey (NHANES) found that the prevalence of PAD increased from 1.4% in individuals ages 40 to 49 years to almost 17% in those age 70 or older.¹

© kostudios

Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.

Demographic characteristics. Most studies demonstrate a higher risk for PAD in men.^1-3,10 African-American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases such as hypertension and diabetes in this population.^1-3,10

Continue to: Genetics...

Genetics. A study performed by the National Heart Lung and Blood Institute suggested that genetic correlations between twins were more important than environmental factors in the development of PAD.¹¹

Smoking. Most population studies show smoking to be the greatest modifiable risk factor for PAD. An analysis of the NHANES data yielded an odds ratio (OR) of 4.1 for current smokers and of 1.8 for former smokers.¹ Risk increases linearly with cumulative years of smoking.^1,2,9,10

Diabetes is another significant modifiable risk factor, increasing PAD risk by 2.5 times.² Diabetes is also associated with increases in functional limitation from claudication, risk for acute coronary syndrome, and progression to amputation.¹

Hypertension nearly doubles the risk for PAD, and poor control further increases this risk.^2,9,10

Chronic kidney disease (CKD). Patients with CKD have a progressively higher prevalence of PAD with worsening renal function.¹ There is also an association between CKD and increased morbidity, revascularization failure, and increased mortality.¹

Two additional risk factors that are less well understood are dyslipidemia and chronic inflammation. There is conflicting data regarding the role of individual components of cholesterol and their effect on PAD, although lipoprotein (a) has been shown to be an independent risk factor for both the development and progression of PAD.¹² Similarly, chronic inflammation has been shown to play a role in the initiation and progression of the disease, although the role of inflammatory markers in evaluation and treatment is unclear and assessment for these purposes is not currently recommended.^12,13

Continue to: Diagnosis...

Diagnosis

Clinical presentation

Lower extremity pain is the hallmark symptom of PAD, but presentation varies. The classic presentation is claudication, pain within a defined muscle group that occurs with exertion and is relieved by rest. Claudication is most common in the calf but also occurs in the buttock/thigh and the foot.

African- American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases in this population.

However, most patients with PAD present with pain that does not fit the definition of claudication. Patients with comorbidities, physical inactivity, and neuropathy are more likely to present with atypical pain.¹⁴ These patients may demonstrate critical or acute limb ischemia, characterized by pain at rest and most often localized to the forefoot and toes. Patients with critical limb ischemia may also present with nonhealing wounds/ulcers or gangrene.¹⁵

Physical exam findings can support the diagnosis of PAD, but none are reliable enough to rule the diagnosis in or out. Findings suggestive of PAD include cool skin, presence of a bruit (iliac, femoral, or popliteal), and palpable pulse abnormality. Multiple abnormal physical exam findings increase the likelihood of PAD, while the absence of a bruit or palpable pulse abnormality makes PAD less likely.¹⁶ In patients with PAD, an associated wound/ulcer is most often distal in the foot and usually appears dry.¹⁷

The differential diagnosis for intermittent leg pain is broad and includes neurologic, musculoskeletal, and venous etiologies. Table 1¹⁸ lists some common alternate diagnoses for patients presenting with leg pain or claudication.

Continue to: Diagnostic testing...

Diagnostic testing

An ankle-brachial index (ABI) test should be performed in patients with history or physical exam findings suggestive of PAD. A resting ABI is performed with the patient in the supine position, with measurement of systolic blood pressure in both arms and ankles using a Doppler ultrasound device. Table 2¹³ outlines ABI scoring and interpretation.

An ABI > 1.4 is an invalid measurement, indicating that the arteries are too calcified to be compressed. These highly elevated ABI measurements are common in patients with diabetes and/or advanced CKD. In these patients, a toe-brachial index (TBI) test should be performed, because the digital arteries are almost always compressible.¹³

Patients with symptomatic PAD who are under consideration for revascularization may benefit from radiologic imaging of the lower extremities with duplex ultrasound, computed tomography angiography, or magnetic resonance angiography to determine the anatomic location and severity of stenosis.¹³

Management of PAD

Lifestyle interventions

For patients with PAD, lifestyle modifications are an essential—but challenging—component of disease management.

Continue to: Smoking cessation...

Smoking cessation. As with other atherosclerotic diseases, PAD progression is strongly correlated with smoking. A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year, with numbers needed to treat (NNT) of 6 for mortality and 5 for amputation.¹⁹ Because of this dramatic effect, American College of Cardiology/American Heart Association (ACC/AHA) guidelines encourage providers to address smoking at every visit and use cessation programs and medication to increase quit rates.¹³

Exercise may be the most important intervention for PAD. A 2017 Cochrane review found that supervised, structured exercise programs increase pain-free and maximal walking distances by at least 20% and also improve physical and mental quality of life.²⁰ In a trial involving 111 patients with aortoiliac PAD, supervised exercise plus medical care led to greater functional improvement than either revascularization plus medical care or medical care alone.²¹ In a 2018 Cochrane review, neither revascularization or revascularization added to supervised exercise were better than supervised exercise alone.²² ACC/AHA guidelines recommend supervised exercise programs for claudication prior to considering revascularization.¹³TABLE 3¹³ outlines the components of a structured exercise program.

Unfortunately, the benefit of these programs has been difficult to reproduce without supervision. Another 2018 Cochrane review demonstrated significant improvement with supervised exercise and no clear improvement in patients given home exercise or advice to walk.²³ A recent study examined the effect of having patients use a wearable fitness tracker for home exercise and demonstrated no benefit over usual care.²⁴

Diet. There is some evidence that dietary interventions can prevent and possibly improve PAD. A large randomized controlled trial showed that a Mediterranean diet lowered rates of PAD over 1 year compared to a low-fat diet, with an NNT of 336 if supplemented with extra-virgin olive oil and 448 if supplemented with nuts.²⁵ A small trial of 25 patients who consumed non-soy legumes daily for 8 weeks showed average ABI improvement of 6%, although there was no control group.²⁶

Medical therapy to address peripheral and cardiovascular events

Standard medical therapy for coronary artery disease (CAD) is recommended for patients with PAD to reduce cardiovascular and limb events. For example, treatment of hypertension reduces cardiovascular and cerebrovascular events, and studies verify that lowering blood pressure does not worsen claudication or limb perfusion.

A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year.

¹³TABLE 4^13,27-30 outlines the options for medical therapy.

Continue to: Statins...

Statins reduce cardiovascular events in PAD patients. A large study demonstrated that 40 mg of simvastatin has an NNT of 21 to prevent a coronary or cerebrovascular event in PAD, similar to the NNT of 23 seen in treatment of CAD.²⁷ Statins also reduce adverse limb outcomes. A registry of atherosclerosis patients showed that statins have an NNT of 56 to prevent amputation in PAD and an NNT of 28 to prevent worsening claudication, critical limb ischemia, revascularization, or amputation.²⁸

Antiplatelet therapy with low-dose aspirin or clopidogrel is recommended for symptomatic patients and for asymptomatic patients with an ABI ≤ 0.9.¹³ A Cochrane review demonstrated significantly reduced mortality with nonaspirin antiplatelet agents vs aspirin (NNT = 94) without increase in major bleeding.²⁹ Only British guidelines specifically recommend clopidogrel over aspirin.³¹

Dual antiplatelet therapy has not shown consistent benefits over aspirin alone. ACC/AHA guidelines state that dual antiplatelet therapy is not well established for PAD but may be reasonable after revascularization.¹³

Voraxapar is a novel antiplatelet agent that targets the thrombin-binding receptor on platelets. However, trials show no significant coronary benefit, and slight reductions in acute limb ischemia are offset by increases in major bleeding.¹³

For patients receiving medical therapy, ongoing evaluation and treatment should be based on claudication symptoms and clinical assessment.

Medical therapy for claudication

Several medications have been proposed for symptomatic treatment of intermittent claudication. Cilostazol is a phosphodiesterase inhibitor with the best risk-benefit ratio. A Cochrane review showed improvements in maximal and pain-free walking distances compared to placebo and improvements in quality of life with cilostazol 100 mg taken twice daily.³² Adverse effects included headache, dizziness, palpitations, and diarrhea.²⁹

Continue to: Pentoxifylline...

Pentoxifylline is another phosphodiesterase inhibitor with less evidence of improvement, higher adverse effect rates, and more frequent dosing. It is not recommended for treatment of intermittent claudication.^13,33

Supplements. Padma 28, a Tibetan herbal formulation, appears to improve maximal walking distance with adverse effect rates similar to placebo.³⁴ Other supplements, including vitamin E, ginkgo biloba, and omega-3 fatty acids, have no evidence of benefit.^35-37

When revascularizationis needed

Patients who develop limb ischemia or lifestyle-limiting claudication despite conservative therapy are candidates for revascularization. Endovascular techniques include angioplasty, stenting, atherectomy, and precise medication delivery. Surgical approaches mainly consist of thrombectomy and bypass grafting. For intermittent claudication despite conservative care, ACC/AHA guidelines state endovascular procedures are appropriate for aortoiliac disease and reasonable for femoropopliteal disease, but unproven for infrapopliteal disease.¹³

Acute limb ischemia is an emergency requiring immediate intervention. Two trials revealed identical overall and amputation-free survival rates for percutaneous thrombolysis and surgical thrombectomy.^38,39 ACC/AHA guidelines recommend anticoagulation with heparin followed by the revascularization technique that will most rapidly restore arterial flow.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. However, surgical mortality was lower after 2 years.⁴⁰ ACC/AHA guidelines recommend either surgery or endovascular procedures and propose initial endovascular treatment followed by surgery if needed.¹³ After revascularization, the patient should be followed periodically with a clinical evaluation and ABI measurement with further consideration for routine duplex ultrasound surveillance.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. Surgical mortality was lower after 2 years.

Outcomes

Patients with PAD have variable outcomes. About 70% to 80% of patients with this diagnosis will have a stable disease process with no worsening of symptoms, 10% to 20% will experience worsening symptoms over time, 5% to 10% will require revascularization within 5 years of diagnosis, and 1% to 5% will progress to critical limb ischemia, which has a 5-year amputation rate of 1% to 4%.² Patients who require amputation have poor outcomes: Within 2 years, 30% are dead and 15% have had further amputations.¹⁸

In addition to the morbidity and mortality from its own progression, PAD is an important predictor of CAD and is associated with a significant elevation in morbidity and mortality from CAD. One small but well-designed prospective cohort study found that patients with PAD had a more than 6-fold increased risk of death from CAD than did patients without PAD.⁴¹

Acknowledgement
The authors thank Francesca Cimino, MD, FAAFP, for her help in reviewing this manuscript.

CORRESPONDENCE
Dustin K. Smith, DO, 2080 Child Street, Jacksonville, FL 32214; [email protected]

Peripheral arterial disease (PAD), the progressive disorder that results in ischemia to distal vascular territories as a result of atherosclerosis, spans a wide range of presentations, from minimally symptomatic disease to limb ischemia secondary to acute or chronic occlusion.

The prevalence of PAD is variable, due to differing diagnostic criteria used in studies, but PAD appears to affect 1 in every 22 people older than age 40.¹ However, since PAD incidence increases with age, it is increasing in prevalence as the US population ages.^1-3

PAD is associated with increased hospitalizations and decreased quality of life.⁴ Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.³

Screening. Although PAD is underdiagnosed and appears to be undertreated,³ population-based screening for PAD in asymptomatic patients is not recommended. A Cochrane review found no studies evaluating the benefit of ­asymptomatic population-based screening.⁵ Similarly, in 2018, the USPSTF performed a comprehensive review and found no studies to support routine screening and determined there was insufficient evidence to recommend it.^6,7

Risk factors and associated comorbidities

PAD risk factors, like the ones detailed below, have a potentiating effect. The presence of 2 risk factors doubles PAD risk, while 3 or more risk factors increase PAD risk by a factor of 10.¹

Increasing age is the greatest single risk factor for PAD.^1,2,8,9 Researchers using data from the National Health and Nutrition Examination Survey (NHANES) found that the prevalence of PAD increased from 1.4% in individuals ages 40 to 49 years to almost 17% in those age 70 or older.¹

© kostudios

Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.

Demographic characteristics. Most studies demonstrate a higher risk for PAD in men.^1-3,10 African-American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases such as hypertension and diabetes in this population.^1-3,10

Continue to: Genetics...

Genetics. A study performed by the National Heart Lung and Blood Institute suggested that genetic correlations between twins were more important than environmental factors in the development of PAD.¹¹

Smoking. Most population studies show smoking to be the greatest modifiable risk factor for PAD. An analysis of the NHANES data yielded an odds ratio (OR) of 4.1 for current smokers and of 1.8 for former smokers.¹ Risk increases linearly with cumulative years of smoking.^1,2,9,10

Diabetes is another significant modifiable risk factor, increasing PAD risk by 2.5 times.² Diabetes is also associated with increases in functional limitation from claudication, risk for acute coronary syndrome, and progression to amputation.¹

Hypertension nearly doubles the risk for PAD, and poor control further increases this risk.^2,9,10

Chronic kidney disease (CKD). Patients with CKD have a progressively higher prevalence of PAD with worsening renal function.¹ There is also an association between CKD and increased morbidity, revascularization failure, and increased mortality.¹

Two additional risk factors that are less well understood are dyslipidemia and chronic inflammation. There is conflicting data regarding the role of individual components of cholesterol and their effect on PAD, although lipoprotein (a) has been shown to be an independent risk factor for both the development and progression of PAD.¹² Similarly, chronic inflammation has been shown to play a role in the initiation and progression of the disease, although the role of inflammatory markers in evaluation and treatment is unclear and assessment for these purposes is not currently recommended.^12,13

Continue to: Diagnosis...

Diagnosis

Clinical presentation

Lower extremity pain is the hallmark symptom of PAD, but presentation varies. The classic presentation is claudication, pain within a defined muscle group that occurs with exertion and is relieved by rest. Claudication is most common in the calf but also occurs in the buttock/thigh and the foot.

African- American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases in this population.

However, most patients with PAD present with pain that does not fit the definition of claudication. Patients with comorbidities, physical inactivity, and neuropathy are more likely to present with atypical pain.¹⁴ These patients may demonstrate critical or acute limb ischemia, characterized by pain at rest and most often localized to the forefoot and toes. Patients with critical limb ischemia may also present with nonhealing wounds/ulcers or gangrene.¹⁵

Physical exam findings can support the diagnosis of PAD, but none are reliable enough to rule the diagnosis in or out. Findings suggestive of PAD include cool skin, presence of a bruit (iliac, femoral, or popliteal), and palpable pulse abnormality. Multiple abnormal physical exam findings increase the likelihood of PAD, while the absence of a bruit or palpable pulse abnormality makes PAD less likely.¹⁶ In patients with PAD, an associated wound/ulcer is most often distal in the foot and usually appears dry.¹⁷

The differential diagnosis for intermittent leg pain is broad and includes neurologic, musculoskeletal, and venous etiologies. Table 1¹⁸ lists some common alternate diagnoses for patients presenting with leg pain or claudication.

Continue to: Diagnostic testing...

Diagnostic testing

An ankle-brachial index (ABI) test should be performed in patients with history or physical exam findings suggestive of PAD. A resting ABI is performed with the patient in the supine position, with measurement of systolic blood pressure in both arms and ankles using a Doppler ultrasound device. Table 2¹³ outlines ABI scoring and interpretation.

An ABI > 1.4 is an invalid measurement, indicating that the arteries are too calcified to be compressed. These highly elevated ABI measurements are common in patients with diabetes and/or advanced CKD. In these patients, a toe-brachial index (TBI) test should be performed, because the digital arteries are almost always compressible.¹³

Patients with symptomatic PAD who are under consideration for revascularization may benefit from radiologic imaging of the lower extremities with duplex ultrasound, computed tomography angiography, or magnetic resonance angiography to determine the anatomic location and severity of stenosis.¹³

Management of PAD

Lifestyle interventions

For patients with PAD, lifestyle modifications are an essential—but challenging—component of disease management.

Continue to: Smoking cessation...

Smoking cessation. As with other atherosclerotic diseases, PAD progression is strongly correlated with smoking. A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year, with numbers needed to treat (NNT) of 6 for mortality and 5 for amputation.¹⁹ Because of this dramatic effect, American College of Cardiology/American Heart Association (ACC/AHA) guidelines encourage providers to address smoking at every visit and use cessation programs and medication to increase quit rates.¹³

Exercise may be the most important intervention for PAD. A 2017 Cochrane review found that supervised, structured exercise programs increase pain-free and maximal walking distances by at least 20% and also improve physical and mental quality of life.²⁰ In a trial involving 111 patients with aortoiliac PAD, supervised exercise plus medical care led to greater functional improvement than either revascularization plus medical care or medical care alone.²¹ In a 2018 Cochrane review, neither revascularization or revascularization added to supervised exercise were better than supervised exercise alone.²² ACC/AHA guidelines recommend supervised exercise programs for claudication prior to considering revascularization.¹³TABLE 3¹³ outlines the components of a structured exercise program.

Unfortunately, the benefit of these programs has been difficult to reproduce without supervision. Another 2018 Cochrane review demonstrated significant improvement with supervised exercise and no clear improvement in patients given home exercise or advice to walk.²³ A recent study examined the effect of having patients use a wearable fitness tracker for home exercise and demonstrated no benefit over usual care.²⁴

Diet. There is some evidence that dietary interventions can prevent and possibly improve PAD. A large randomized controlled trial showed that a Mediterranean diet lowered rates of PAD over 1 year compared to a low-fat diet, with an NNT of 336 if supplemented with extra-virgin olive oil and 448 if supplemented with nuts.²⁵ A small trial of 25 patients who consumed non-soy legumes daily for 8 weeks showed average ABI improvement of 6%, although there was no control group.²⁶

Medical therapy to address peripheral and cardiovascular events

Standard medical therapy for coronary artery disease (CAD) is recommended for patients with PAD to reduce cardiovascular and limb events. For example, treatment of hypertension reduces cardiovascular and cerebrovascular events, and studies verify that lowering blood pressure does not worsen claudication or limb perfusion.

A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year.

¹³TABLE 4^13,27-30 outlines the options for medical therapy.

Continue to: Statins...

Statins reduce cardiovascular events in PAD patients. A large study demonstrated that 40 mg of simvastatin has an NNT of 21 to prevent a coronary or cerebrovascular event in PAD, similar to the NNT of 23 seen in treatment of CAD.²⁷ Statins also reduce adverse limb outcomes. A registry of atherosclerosis patients showed that statins have an NNT of 56 to prevent amputation in PAD and an NNT of 28 to prevent worsening claudication, critical limb ischemia, revascularization, or amputation.²⁸

Antiplatelet therapy with low-dose aspirin or clopidogrel is recommended for symptomatic patients and for asymptomatic patients with an ABI ≤ 0.9.¹³ A Cochrane review demonstrated significantly reduced mortality with nonaspirin antiplatelet agents vs aspirin (NNT = 94) without increase in major bleeding.²⁹ Only British guidelines specifically recommend clopidogrel over aspirin.³¹

Dual antiplatelet therapy has not shown consistent benefits over aspirin alone. ACC/AHA guidelines state that dual antiplatelet therapy is not well established for PAD but may be reasonable after revascularization.¹³

Voraxapar is a novel antiplatelet agent that targets the thrombin-binding receptor on platelets. However, trials show no significant coronary benefit, and slight reductions in acute limb ischemia are offset by increases in major bleeding.¹³

For patients receiving medical therapy, ongoing evaluation and treatment should be based on claudication symptoms and clinical assessment.

Medical therapy for claudication

Several medications have been proposed for symptomatic treatment of intermittent claudication. Cilostazol is a phosphodiesterase inhibitor with the best risk-benefit ratio. A Cochrane review showed improvements in maximal and pain-free walking distances compared to placebo and improvements in quality of life with cilostazol 100 mg taken twice daily.³² Adverse effects included headache, dizziness, palpitations, and diarrhea.²⁹

Continue to: Pentoxifylline...

Pentoxifylline is another phosphodiesterase inhibitor with less evidence of improvement, higher adverse effect rates, and more frequent dosing. It is not recommended for treatment of intermittent claudication.^13,33

Supplements. Padma 28, a Tibetan herbal formulation, appears to improve maximal walking distance with adverse effect rates similar to placebo.³⁴ Other supplements, including vitamin E, ginkgo biloba, and omega-3 fatty acids, have no evidence of benefit.^35-37

When revascularizationis needed

Patients who develop limb ischemia or lifestyle-limiting claudication despite conservative therapy are candidates for revascularization. Endovascular techniques include angioplasty, stenting, atherectomy, and precise medication delivery. Surgical approaches mainly consist of thrombectomy and bypass grafting. For intermittent claudication despite conservative care, ACC/AHA guidelines state endovascular procedures are appropriate for aortoiliac disease and reasonable for femoropopliteal disease, but unproven for infrapopliteal disease.¹³

Acute limb ischemia is an emergency requiring immediate intervention. Two trials revealed identical overall and amputation-free survival rates for percutaneous thrombolysis and surgical thrombectomy.^38,39 ACC/AHA guidelines recommend anticoagulation with heparin followed by the revascularization technique that will most rapidly restore arterial flow.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. However, surgical mortality was lower after 2 years.⁴⁰ ACC/AHA guidelines recommend either surgery or endovascular procedures and propose initial endovascular treatment followed by surgery if needed.¹³ After revascularization, the patient should be followed periodically with a clinical evaluation and ABI measurement with further consideration for routine duplex ultrasound surveillance.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. Surgical mortality was lower after 2 years.

Outcomes

Patients with PAD have variable outcomes. About 70% to 80% of patients with this diagnosis will have a stable disease process with no worsening of symptoms, 10% to 20% will experience worsening symptoms over time, 5% to 10% will require revascularization within 5 years of diagnosis, and 1% to 5% will progress to critical limb ischemia, which has a 5-year amputation rate of 1% to 4%.² Patients who require amputation have poor outcomes: Within 2 years, 30% are dead and 15% have had further amputations.¹⁸

In addition to the morbidity and mortality from its own progression, PAD is an important predictor of CAD and is associated with a significant elevation in morbidity and mortality from CAD. One small but well-designed prospective cohort study found that patients with PAD had a more than 6-fold increased risk of death from CAD than did patients without PAD.⁴¹

Acknowledgement
The authors thank Francesca Cimino, MD, FAAFP, for her help in reviewing this manuscript.

CORRESPONDENCE
Dustin K. Smith, DO, 2080 Child Street, Jacksonville, FL 32214; [email protected]

Peripheral arterial disease (PAD), the progressive disorder that results in ischemia to distal vascular territories as a result of atherosclerosis, spans a wide range of presentations, from minimally symptomatic disease to limb ischemia secondary to acute or chronic occlusion.

The prevalence of PAD is variable, due to differing diagnostic criteria used in studies, but PAD appears to affect 1 in every 22 people older than age 40.¹ However, since PAD incidence increases with age, it is increasing in prevalence as the US population ages.^1-3

PAD is associated with increased hospitalizations and decreased quality of life.⁴ Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.³

Screening. Although PAD is underdiagnosed and appears to be undertreated,³ population-based screening for PAD in asymptomatic patients is not recommended. A Cochrane review found no studies evaluating the benefit of ­asymptomatic population-based screening.⁵ Similarly, in 2018, the USPSTF performed a comprehensive review and found no studies to support routine screening and determined there was insufficient evidence to recommend it.^6,7

Risk factors and associated comorbidities

PAD risk factors, like the ones detailed below, have a potentiating effect. The presence of 2 risk factors doubles PAD risk, while 3 or more risk factors increase PAD risk by a factor of 10.¹

Increasing age is the greatest single risk factor for PAD.^1,2,8,9 Researchers using data from the National Health and Nutrition Examination Survey (NHANES) found that the prevalence of PAD increased from 1.4% in individuals ages 40 to 49 years to almost 17% in those age 70 or older.¹

© kostudios

Patients with PAD have an estimated 30% 5-year risk for myocardial infarction, stroke, or death from a vascular cause.

Demographic characteristics. Most studies demonstrate a higher risk for PAD in men.^1-3,10 African-American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases such as hypertension and diabetes in this population.^1-3,10

Continue to: Genetics...

Genetics. A study performed by the National Heart Lung and Blood Institute suggested that genetic correlations between twins were more important than environmental factors in the development of PAD.¹¹

Smoking. Most population studies show smoking to be the greatest modifiable risk factor for PAD. An analysis of the NHANES data yielded an odds ratio (OR) of 4.1 for current smokers and of 1.8 for former smokers.¹ Risk increases linearly with cumulative years of smoking.^1,2,9,10

Diabetes is another significant modifiable risk factor, increasing PAD risk by 2.5 times.² Diabetes is also associated with increases in functional limitation from claudication, risk for acute coronary syndrome, and progression to amputation.¹

Hypertension nearly doubles the risk for PAD, and poor control further increases this risk.^2,9,10

Chronic kidney disease (CKD). Patients with CKD have a progressively higher prevalence of PAD with worsening renal function.¹ There is also an association between CKD and increased morbidity, revascularization failure, and increased mortality.¹

Two additional risk factors that are less well understood are dyslipidemia and chronic inflammation. There is conflicting data regarding the role of individual components of cholesterol and their effect on PAD, although lipoprotein (a) has been shown to be an independent risk factor for both the development and progression of PAD.¹² Similarly, chronic inflammation has been shown to play a role in the initiation and progression of the disease, although the role of inflammatory markers in evaluation and treatment is unclear and assessment for these purposes is not currently recommended.^12,13

Continue to: Diagnosis...

Diagnosis

Clinical presentation

Lower extremity pain is the hallmark symptom of PAD, but presentation varies. The classic presentation is claudication, pain within a defined muscle group that occurs with exertion and is relieved by rest. Claudication is most common in the calf but also occurs in the buttock/thigh and the foot.

African- American patients have more than twice the risk for PAD, compared with Whites, even after adjustment for the increased prevalence of associated diseases in this population.

However, most patients with PAD present with pain that does not fit the definition of claudication. Patients with comorbidities, physical inactivity, and neuropathy are more likely to present with atypical pain.¹⁴ These patients may demonstrate critical or acute limb ischemia, characterized by pain at rest and most often localized to the forefoot and toes. Patients with critical limb ischemia may also present with nonhealing wounds/ulcers or gangrene.¹⁵

Physical exam findings can support the diagnosis of PAD, but none are reliable enough to rule the diagnosis in or out. Findings suggestive of PAD include cool skin, presence of a bruit (iliac, femoral, or popliteal), and palpable pulse abnormality. Multiple abnormal physical exam findings increase the likelihood of PAD, while the absence of a bruit or palpable pulse abnormality makes PAD less likely.¹⁶ In patients with PAD, an associated wound/ulcer is most often distal in the foot and usually appears dry.¹⁷

The differential diagnosis for intermittent leg pain is broad and includes neurologic, musculoskeletal, and venous etiologies. Table 1¹⁸ lists some common alternate diagnoses for patients presenting with leg pain or claudication.

Continue to: Diagnostic testing...

Diagnostic testing

An ankle-brachial index (ABI) test should be performed in patients with history or physical exam findings suggestive of PAD. A resting ABI is performed with the patient in the supine position, with measurement of systolic blood pressure in both arms and ankles using a Doppler ultrasound device. Table 2¹³ outlines ABI scoring and interpretation.

An ABI > 1.4 is an invalid measurement, indicating that the arteries are too calcified to be compressed. These highly elevated ABI measurements are common in patients with diabetes and/or advanced CKD. In these patients, a toe-brachial index (TBI) test should be performed, because the digital arteries are almost always compressible.¹³

Patients with symptomatic PAD who are under consideration for revascularization may benefit from radiologic imaging of the lower extremities with duplex ultrasound, computed tomography angiography, or magnetic resonance angiography to determine the anatomic location and severity of stenosis.¹³

Management of PAD

Lifestyle interventions

For patients with PAD, lifestyle modifications are an essential—but challenging—component of disease management.

Continue to: Smoking cessation...

Smoking cessation. As with other atherosclerotic diseases, PAD progression is strongly correlated with smoking. A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year, with numbers needed to treat (NNT) of 6 for mortality and 5 for amputation.¹⁹ Because of this dramatic effect, American College of Cardiology/American Heart Association (ACC/AHA) guidelines encourage providers to address smoking at every visit and use cessation programs and medication to increase quit rates.¹³

Exercise may be the most important intervention for PAD. A 2017 Cochrane review found that supervised, structured exercise programs increase pain-free and maximal walking distances by at least 20% and also improve physical and mental quality of life.²⁰ In a trial involving 111 patients with aortoiliac PAD, supervised exercise plus medical care led to greater functional improvement than either revascularization plus medical care or medical care alone.²¹ In a 2018 Cochrane review, neither revascularization or revascularization added to supervised exercise were better than supervised exercise alone.²² ACC/AHA guidelines recommend supervised exercise programs for claudication prior to considering revascularization.¹³TABLE 3¹³ outlines the components of a structured exercise program.

Unfortunately, the benefit of these programs has been difficult to reproduce without supervision. Another 2018 Cochrane review demonstrated significant improvement with supervised exercise and no clear improvement in patients given home exercise or advice to walk.²³ A recent study examined the effect of having patients use a wearable fitness tracker for home exercise and demonstrated no benefit over usual care.²⁴

Diet. There is some evidence that dietary interventions can prevent and possibly improve PAD. A large randomized controlled trial showed that a Mediterranean diet lowered rates of PAD over 1 year compared to a low-fat diet, with an NNT of 336 if supplemented with extra-virgin olive oil and 448 if supplemented with nuts.²⁵ A small trial of 25 patients who consumed non-soy legumes daily for 8 weeks showed average ABI improvement of 6%, although there was no control group.²⁶

Medical therapy to address peripheral and cardiovascular events

Standard medical therapy for coronary artery disease (CAD) is recommended for patients with PAD to reduce cardiovascular and limb events. For example, treatment of hypertension reduces cardiovascular and cerebrovascular events, and studies verify that lowering blood pressure does not worsen claudication or limb perfusion.

A trial involving 204 active smokers with PAD showed that 5-year mortality and amputation rates dropped by more than half in those who quit smoking within a year.

¹³TABLE 4^13,27-30 outlines the options for medical therapy.

Continue to: Statins...

Statins reduce cardiovascular events in PAD patients. A large study demonstrated that 40 mg of simvastatin has an NNT of 21 to prevent a coronary or cerebrovascular event in PAD, similar to the NNT of 23 seen in treatment of CAD.²⁷ Statins also reduce adverse limb outcomes. A registry of atherosclerosis patients showed that statins have an NNT of 56 to prevent amputation in PAD and an NNT of 28 to prevent worsening claudication, critical limb ischemia, revascularization, or amputation.²⁸

Antiplatelet therapy with low-dose aspirin or clopidogrel is recommended for symptomatic patients and for asymptomatic patients with an ABI ≤ 0.9.¹³ A Cochrane review demonstrated significantly reduced mortality with nonaspirin antiplatelet agents vs aspirin (NNT = 94) without increase in major bleeding.²⁹ Only British guidelines specifically recommend clopidogrel over aspirin.³¹

Dual antiplatelet therapy has not shown consistent benefits over aspirin alone. ACC/AHA guidelines state that dual antiplatelet therapy is not well established for PAD but may be reasonable after revascularization.¹³

Voraxapar is a novel antiplatelet agent that targets the thrombin-binding receptor on platelets. However, trials show no significant coronary benefit, and slight reductions in acute limb ischemia are offset by increases in major bleeding.¹³

For patients receiving medical therapy, ongoing evaluation and treatment should be based on claudication symptoms and clinical assessment.

Medical therapy for claudication

Several medications have been proposed for symptomatic treatment of intermittent claudication. Cilostazol is a phosphodiesterase inhibitor with the best risk-benefit ratio. A Cochrane review showed improvements in maximal and pain-free walking distances compared to placebo and improvements in quality of life with cilostazol 100 mg taken twice daily.³² Adverse effects included headache, dizziness, palpitations, and diarrhea.²⁹

Continue to: Pentoxifylline...

Pentoxifylline is another phosphodiesterase inhibitor with less evidence of improvement, higher adverse effect rates, and more frequent dosing. It is not recommended for treatment of intermittent claudication.^13,33

Supplements. Padma 28, a Tibetan herbal formulation, appears to improve maximal walking distance with adverse effect rates similar to placebo.³⁴ Other supplements, including vitamin E, ginkgo biloba, and omega-3 fatty acids, have no evidence of benefit.^35-37

When revascularizationis needed

Patients who develop limb ischemia or lifestyle-limiting claudication despite conservative therapy are candidates for revascularization. Endovascular techniques include angioplasty, stenting, atherectomy, and precise medication delivery. Surgical approaches mainly consist of thrombectomy and bypass grafting. For intermittent claudication despite conservative care, ACC/AHA guidelines state endovascular procedures are appropriate for aortoiliac disease and reasonable for femoropopliteal disease, but unproven for infrapopliteal disease.¹³

Acute limb ischemia is an emergency requiring immediate intervention. Two trials revealed identical overall and amputation-free survival rates for percutaneous thrombolysis and surgical thrombectomy.^38,39 ACC/AHA guidelines recommend anticoagulation with heparin followed by the revascularization technique that will most rapidly restore arterial flow.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. However, surgical mortality was lower after 2 years.⁴⁰ ACC/AHA guidelines recommend either surgery or endovascular procedures and propose initial endovascular treatment followed by surgery if needed.¹³ After revascularization, the patient should be followed periodically with a clinical evaluation and ABI measurement with further consideration for routine duplex ultrasound surveillance.¹³

For chronic limb ischemia, a large trial showed angioplasty had lower initial morbidity, length of hospitalization, and cost than surgical repair. Surgical mortality was lower after 2 years.

Outcomes

Patients with PAD have variable outcomes. About 70% to 80% of patients with this diagnosis will have a stable disease process with no worsening of symptoms, 10% to 20% will experience worsening symptoms over time, 5% to 10% will require revascularization within 5 years of diagnosis, and 1% to 5% will progress to critical limb ischemia, which has a 5-year amputation rate of 1% to 4%.² Patients who require amputation have poor outcomes: Within 2 years, 30% are dead and 15% have had further amputations.¹⁸

In addition to the morbidity and mortality from its own progression, PAD is an important predictor of CAD and is associated with a significant elevation in morbidity and mortality from CAD. One small but well-designed prospective cohort study found that patients with PAD had a more than 6-fold increased risk of death from CAD than did patients without PAD.⁴¹

Acknowledgement
The authors thank Francesca Cimino, MD, FAAFP, for her help in reviewing this manuscript.

CORRESPONDENCE
Dustin K. Smith, DO, 2080 Child Street, Jacksonville, FL 32214; [email protected]