Applied Evidence

Heart failure (HF) affects nearly 6 million Americans and accounts for one million hospital admissions each year.¹ The condition, which results from a structural or functional disorder that impairs the ventricles’ ability to fill, empty, or both,² is a major cause of morbidity and mortality. The 5-year mortality rate ranges from 44% to 77%.^3,4

Growing evidence demonstrates reduced morbidity and mortality when patients with HF with reduced ejection fraction (HFrEF) are treated with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB); a beta-blocker; and a mineralocorticoid/aldosterone receptor antagonist (MRA) in appropriate doses.⁵ In addition, 2 new medications representing novel drug classes have recently entered the market and are recommended in select patients who remain symptomatic despite standard treatment.

The first is sacubitril, which is available in a combination pill with the ARB valsartan, and the second is ivabradine.⁶ Additionally, implanted medical devices are proving useful, particularly in the management of patients with refractory symptoms.

Two new medications representing novel drug classes have recently entered the market and have rapidly become important components of care.

This article will briefly review the diagnosis and initial evaluation of the patient with suspected HF and then describe how newer treatments fit within HF management priorities and strategies. But first, a word about what causes HF.

Causes are many and diverse

HF has a variety of cardiac and non-cardiac etiologies.^2,7,8 Some important cardiac causes include hypertension (HTN), coronary artery disease (CAD), valvular heart disease, arrhythmias, myocarditis, Takotsubo cardiomyopathy, and postpartum cardiomyopathy. Common and important non-cardiac causes of HF include alcoholic cardiomyopathy, pulmonary embolism, pulmonary hypertension, obstructive sleep apnea, anemia, hemochromatosis, amyloidosis, sarcoidosis, thyroid dysfunction, nephrotic syndrome, and cardiac toxins (especially stimulants and certain chemotherapy drugs).^2,7,8

Diagnosing an elusive culprit

HF remains a clinical diagnosis. Common symptoms include dyspnea, cough, pedal edema, and decreased exercise tolerance, but these symptoms are not at all specific. Given the varied causes and manifestations of HF, the diagnosis can be somewhat elusive. Fortunately, there are a number of objective methods to help identify patients with HF.

Framingham criteria. One commonly used tool for making the diagnosis of HF is the Framingham criteria (see https://www.mdcalc.com/framingham-heart-failure-diagnostic-criteria),⁹ which diagnoses HF based on historical and physical exam findings. Another well-validated decision tool is the Heart Failure Diagnostic Rule (see http://circ.ahajournals.org/content/124/25/2865.long),¹⁰ which incorporates N-terminal pro–B-type natriuretic peptide (NT-proBNP) results, as well as exam findings.

Measurement of natriuretic peptides, either B-type natriuretic peptide (BNP) or NT-proBNP, aids in the diagnosis of HF.⁵ Although several factors (including age, weight, and renal function) can affect BNP levels, a normal BNP value effectively rules out HF^5,7 and an elevated BNP can help to make the diagnosis in the context of a patient with corresponding symptoms.

The initial evaluation: Necessary lab work and imaging studies

The purpose of the initial evaluation of the patient with suspected HF is to establish the diagnosis, look for underlying etiologies of HF, identify comorbidities, and establish baseline values (eg, of potassium and creatinine) for elements monitored during treatment.^5,7 TABLE 1^5,7 lists the lab work and imaging tests that are commonly ordered in the initial evaluation of the patient with HF.

Echocardiography is useful in determining the ejection fraction (EF), which is essential in guiding treatment. Echocardiography can also identify important structural abnormalities including significant valvular disease. Refer patients with severe valvular disease for evaluation for valve repair/replacement, regardless of EF.⁸

Use MRAs as add-on therapy for symptomatic patients with an EF ≤35% or an EF ≤40% following an acute MI.

Noninvasive testing (stress nuclear imaging or echocardiography) to evaluate for underlying CAD is reasonable in patients with unknown CAD status.^8,11 Patients for whom there is a high suspicion of obstructive CAD should undergo coronary angiography if they are candidates for revascularization.^5,7 Noninvasive testing may also be an acceptable option for assessing ischemia in patients presenting with HF who have known CAD and no angina.⁵

Classification of HF is determined by ejection fraction

Physicians have traditionally classified patients with HF as having either systolic or diastolic dysfunction. Patients with HF symptoms and a reduced EF were said to have systolic dysfunction; those with a normal EF were said to have diastolic dysfunction.

More recently, researchers have learned that patients with reduced EF and those with preserved EF can have both systolic and diastolic dysfunction simultaneously.⁸ Therefore, the current preferred terminology is HFpEF (heart failure with preserved ejection fraction) for those with an EF ≥50% and HFrEF (heart failure with reduced ejection fraction) for those with an EF ≤40%.⁵ Both the American Heart Association (AHA) and the European Society of Cardiology recognize a category of HF with moderately reduced ejection fraction defined as an EF between 40% and 50%.^5,7 Practically speaking, this group is treated as per the guidelines for HFrEF.⁵

The cornerstone of medical treatment for HFrEF is the combination of an ACE inhibitor or ARB with a beta-blocker.^2,5,7,8 Several early trials showed clear benefits of these medications. For example, the Studies Of Left Ventricular Dysfunction trial (SOLVD), compared enalapril to placebo in patients receiving standard therapy (consisting chiefly of digitalis, diuretics, and nitrates). This study demonstrated a reduction in all-cause mortality or first hospitalization for HF (number needed to treat [NNT]=21) in the enalapril group vs the placebo group.¹²

Consider hydralazine combined with isosorbide dinitrate as an alternative in patients for whom ACE inhibitor/ARB therapy is contraindicated.

Similarly, a subgroup analysis of the Valsartan Heart Failure Treatment (Val-HeFT) trial demonstrated morbidity (NNT=10) and all-cause mortality benefits (NNT=6) when valsartan (an ARB) was given to patients who were not receiving an ACE inhibitor.¹³

MERIT-HF (Metoprolol CR/XL Randomised Intervention Trial in congestive Heart Failure) compared the beta-blocker metoprolol succinate to placebo and found fewer deaths from HF and lower all-cause mortality (NNT=26) associated with the treatment group vs the placebo group.¹⁴

And a comparison of 2 beta-blockers—carvedilol and metoprolol tartrate—on clinical outcomes in patients with chronic HF in the Carvedilol Or Metoprolol European Trial (COMET) showed that carvedilol extended survival compared with metoprolol tartrate (NNT=19).¹⁵

Unlike ACE inhibitors and ARBs, which seem to show a class benefit, only 3 beta-blockers available in the United States have been proven to reduce mortality: sustained-release metoprolol succinate, carvedilol, and bisoprolol.^2,7,8

Unless contraindicated, all patients with a reduced EF—even those without symptoms—should receive a beta-blocker and an ACE inhibitor or ARB.^5,7,8

Cautionary notes

Remember the following caveats when treating patients with ACE inhibitors, ARBs, and beta-blockers:

• Use ACE inhibitors and ARBs with caution in patients with impaired renal function (serum creatinine >2.5 mg/dL) or elevated serum potassium (>5 mEq/L).^16,17
• ARBs are associated with a much lower incidence of cough and angioedema than ACE inhibitors.¹⁸
• Although physicians frequently start patients on low doses of beta-blockers and ACE inhibitors or ARBs to minimize hypotension and other adverse effects, the goal of therapy is to titrate up to the therapeutic doses used in clinical trials.^5-7 (For dosages of medications commonly used in the treatment of heart failure, see Table 3 in the American College of Cardiology/AHA/Heart Failure Society of America guidelines available at https://www.sciencedirect.com/science/article/pii/S0735109717370870?via%3Dihub#tbl3 and Table 7.2 in the European Society of Cardiology guidelines available at https://academic.oup.com/eurheartj/article/37/27/2129/1748921.)
• Because beta-blockers can exacerbate fluid retention, do not initiate them in patients with fluid overload unless such patients are being treated with diuretics.^5,19

When more Tx is needed

For patients who remain symptomatic despite treatment with an ACE inhibitor or ARB and a beta-blocker, consider the following add-on therapies.

Diuretics are the only medications used in the treatment of HF that adequately reduce fluid overload.^2,7 While thiazide diuretics confer greater blood pressure control, loop diuretics are generally preferred in the treatment of HF because they are more efficacious.⁵ Loop diuretics should be prescribed to all patients with fluid overload, as few patients can maintain their target (“dry”) weight without diuretic therapy.^5,7 Common adverse effects include hypokalemia, dehydration, and azotemia.

Two MRAs are currently available in the United States: spironolactone and eplerenone. MRAs are used as add-on therapy for symptomatic patients with an EF ≤35% or an EF ≤40% following an acute myocardial infarction (MI).⁵ They significantly reduce all-cause mortality (NNT=26).²⁰

Consider ARNI treatment for all patients with an EF ≤40% who remain symptomatic despite appropriate doses of an ACE inhibitor or ARB plus a beta-blocker.

Because hyperkalemia is a risk with MRAs, do not prescribe them for patients who are already taking both an ACE inhibitor and an ARB.⁵ Also, do not initiate MRA therapy in patients who have an elevated creatinine level (≥2.5 mg/dL in men; ≥2 mg/dL in women) or a potassium level ≥5 mEq/L.^5,7,8 Discontinue MRA therapy if a patient’s potassium level rises to ≥5.5 mEq/L.⁵

Hydralazine combined with isosorbide dinitrate (H/ID) is an alternative in patients for whom ACE inhibitor/ARB therapy is contraindicated.^5,8

H/ID is also an add-on option in African American patients. Trials have demonstrated that H/ID reduces both first hospitalization for HF (NNT=13) and all-cause mortality (NNT=25) when it is used as add-on therapy in African Americans already receiving standard therapy with an ACE inhibitor or ARB, a beta-blocker, and an MRA.²¹ Headache and dizziness are commonly reported adverse effects.

Digoxin does not reduce mortality, but it does improve both quality of life and exercise tolerance and reduces hospital admissions for patients with HF.^5,7 Significant adverse effects of digoxin include anorexia, nausea, visual disturbances, and cardiac arrhythmias.²²

Also, hypokalemia can intensify digoxin toxicity.²³ Because of these concerns, digoxin is typically dosed at 0.125 mg/d (0.125 mg every other day in patients >70 years or patients with impaired renal function or low body weight) with a target therapeutic range of 0.5 to 0.9 ng/mL.⁵

New classes, new agents

Sacubitril, a neprilysin inhibitor, is the first drug from this class approved for use in the United States. Neprilysin is the enzyme responsible for the degradation of natriuretic peptides; as such it increases endogenous NPs, promoting diuresis and lowering blood pressure.^24,25 Early trials with sacubitril alone showed limited clinical efficacy;²⁵ however, when it was combined with the ARB, valsartan (the combination being called angiotensin receptor blocker + neprilysin inhibitor [ARNI] therapy), it was found to be of significant benefit.^6,25

The PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial compared outcomes in patients receiving ARNI therapy to those receiving enalapril.²⁶ The authors stopped the trial early due to the overwhelming benefit seen in the ARNI arm.

After a median follow-up of 27 months, the researchers found a reduction in the primary outcomes of either cardiovascular death or first hospitalization for HF (26.5% in the enalapril-treated group vs 21.8% in the ARNI-treated group; NNT=21).²⁶ There were slightly more cases of angioedema in the ARNI arm than in the enalapril arm (0.5% vs 0.2%), although there were no patients in the trial who required endotracheal intubation.²⁶

Recommend ivabradine as add-on therapy to all patients with an EF ≤35% who remain symptomatic despite taking the maximum-tolerated dose of a beta-blocker.

Because of this increased risk, do not prescribe ARNI therapy for any patient with a history of angioedema.⁶ Hypotension was more common in the ARNI-treated group than in the enalapril group (14% vs 9.2%), but there were lower rates of hyperkalemia, elevated serum creatinine, and cough in the ARNI-treated group than in the enalapril group.²⁶

Consider ARNI treatment for all patients with an EF ≤40% who remain symptomatic despite appropriate doses of an ACE inhibitor or ARB plus a beta-blocker. Do not administer ARNI therapy concomitantly with an ACE inhibitor or ARB. When switching, do not start ARNI therapy for at least 36 hours after the last dose of an ACE inhibitor or ARB.⁶

Ivabradine is a sinoatrial node modulator that provides additional heart rate reduction. It does not affect ventricular repolarization or myocardial contractility.²⁷ Early trials with this medication have shown reduced cardiac mortality and an NNT to prevent one first HF hospitalization within one year of 27.²⁸ Adverse effects include symptomatic and asymptomatic bradycardia and luminous phenomena.²⁸

Recommend ivabradine as add-on therapy to all patients with an EF ≤35%, normal sinus rhythm, and resting heart rate ≥70 bpm who remain symptomatic despite taking the maximum-tolerated dose of a beta-blocker.⁶ The dose is adjusted to achieve a resting heart rate of 50 to 60 bpm.²⁷

Nonpharmacologic options

Implantable cardioverter defibrillators (ICDs) are recommended as primary prevention in select HFrEF patients to reduce the risk of sudden cardiac death and all-cause mortality. The 2013 American College of Cardiology Foundation/AHA Guideline for the Management of Heart Failure recommends an ICD for primary prevention for: 1) patients with symptomatic HF and an LVEF ≤35% despite ≥3 months of optimal medical therapy, and 2) patients at least 40 days post-MI with an LVEF of ≤30%.^5,29 ICDs are not recommended for patients who have a life expectancy of less than one year, and the devices are of unclear benefit for patients ≥75 years of age.⁵

Cardiac resynchronization therapy (CRT), although not new to the field of cardiology, is new to the treatment of heart failure. A number of patients with HFrEF have QRS prolongation and in particular, left bundle branch block (LBBB).⁵ CRT uses biventricular pacing to restore synchronous contraction of the left and right ventricles.³⁰ It is strongly recommended for patients with an EF ≤35%, sinus rhythm, LBBB, QRS ≥150 ms, and a life expectancy of at least one year.^5,7 It is weakly recommended for patients with an EF ≤35% and a QRS ≥150 ms but without LBBB. It’s also weakly recommended for patients with an EF ≤35% and LBBB with a QRS of 120 to 150 ms.^5,31

Left ventricular assist devices (LVADs) and cardiac transplantation are considerations for patients with severe symptoms refractory to all other interventions.⁵ LVADs may be used either while awaiting cardiac transplantation (bridge therapy) or as definitive treatment (destination therapy). Appropriate patient selection for such therapies requires a team of experts that ideally includes HF and transplantation cardiologists, cardiothoracic surgeons, nurses, social workers, and palliative care clinicians.⁵

Treatment of HFpEF: Evidence is lacking

While HFpEF is common—affecting about half of all patients with HF—ideal treatment remains unclear.³² Some trials have shown promise, but to date no unequivocal evidence exists that any standard therapy reduces mortality in patients with HFpEF.^33-37 Underlying mechanisms of action of HFpEF include cardiac rate and rhythm abnormalities, atrial dysfunction, and stiffening of the ventricles. In a sense, it represents an exaggerated expression of the pathophysiology seen with the normal aging of the heart and can be conceptualized as “presbycardia.”³⁷ Indeed, HFpEF is more common in the elderly, but it is also more common in patients of African descent.^38,39 Common contributing causes (which we’ll get to in a bit) include HTN, CAD, atrial fibrillation (AF), obesity, and obstructive sleep apnea (OSA).

Recommend cardiac rehabilitation to all symptomatic patients with HF who are clinically stable.

Trials have failed to show clear benefit for ACE inhibitors, ARBs, or beta-blockers.^7,33 The evidence for MRAs is somewhat unclear; however, they have recently been recommended as an option for patients who have been hospitalized in the last year to reduce the risk of subsequent hospitalizations.⁴⁰ Digoxin is used primarily for rate control in the setting of AF, but otherwise is of unclear benefit.⁷ A low-sodium diet (ie, ≤2 g/d) may be useful in those patients who are prone to fluid overload.^5,7 The cornerstone of treatment of HFpEF is the relief of volume overload with diuretics and the treatment of coexisting conditions.³³

Common contributing causes of HFpEF

HTN is not only a common contributing cause, but also the most common comorbid condition affecting patients with HFpEF. As such, treatment of HTN represents the most important management goal.^33,34 Based on recent data, the American College of Cardiology, the AHA, and the Heart Failure Society of America have recommended a systolic blood pressure goal <130 mm Hg for patients with HFpEF.⁴⁰ Most patients with HFpEF and HTN will have some degree of fluid overload and, therefore, should receive a diuretic.

CAD. Patients with HFpEF should be evaluated for CAD and treated with medical management and coronary revascularization, as appropriate.

AF is poorly tolerated by patients with HFpEF.³⁷ Patients with AF should receive anticoagulation and rate control medications, and those with persistent HF symptoms should be evaluated for rhythm control.³³

Obesity is more prevalent in patients with HFpEF than in those with HFrEF.⁴¹ Although there is indirect evidence that weight loss improves cardiac function,^34,42,43 and studies have shown bariatric surgery to improve diastolic function,^44,45 there are no studies reporting clinical outcomes.

Treatment of OSA with continuous positive airway pressure appears to alleviate some symptoms of HF and to reduce all-cause mortality.^46,47

Keeping HF patients out of the hospital

Many readmissions to the hospital for HF exacerbation are preventable. Patients often do not understand hospital discharge instructions or the nature of their chronic disease and its management.^48-51 Routine follow-up in the office or clinic provides an opportunity to improve quality of life for patients and decrease admissions.^7,52

A major role for the family physician is in the co-creation of, and adherence to, an individualized, comprehensive care plan. Make sure such a plan is easily understood not only by the patient with HF, but also by his or her care team. In addition, it should be evidence-based and reflect the patient’s culture, values, and goals of treatment.^5,7

At each visit, the family physician or a member of the health care team should assess adherence to guideline-directed medical therapy, measure weight, evaluate fluid status, and provide ongoing patient education including information on the importance of activity, monitoring weight daily, and moderating fluid, salt, and alcohol intake.^5,52

Research shows that cardiac rehabilitation improves functional capacity, exercise duration, quality of life, and mortality. Therefore, recommend it to all symptomatic patients with HF who are clinically stable.²

Consider collaboration with a subspecialist. Patients who remain symptomatic despite optimal medical management and patients with recurrent hospitalizations are best managed in conjunction with a subspecialist in HF treatment.^2,5

CORRESPONDENCE
Darin Brink, MD, 420 Delaware St. SE, MMC 381, Minneapolis, MN 55455; [email protected].

Heart failure (HF) affects nearly 6 million Americans and accounts for one million hospital admissions each year.¹ The condition, which results from a structural or functional disorder that impairs the ventricles’ ability to fill, empty, or both,² is a major cause of morbidity and mortality. The 5-year mortality rate ranges from 44% to 77%.^3,4

Growing evidence demonstrates reduced morbidity and mortality when patients with HF with reduced ejection fraction (HFrEF) are treated with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB); a beta-blocker; and a mineralocorticoid/aldosterone receptor antagonist (MRA) in appropriate doses.⁵ In addition, 2 new medications representing novel drug classes have recently entered the market and are recommended in select patients who remain symptomatic despite standard treatment.

The first is sacubitril, which is available in a combination pill with the ARB valsartan, and the second is ivabradine.⁶ Additionally, implanted medical devices are proving useful, particularly in the management of patients with refractory symptoms.

Two new medications representing novel drug classes have recently entered the market and have rapidly become important components of care.

This article will briefly review the diagnosis and initial evaluation of the patient with suspected HF and then describe how newer treatments fit within HF management priorities and strategies. But first, a word about what causes HF.

Causes are many and diverse

HF has a variety of cardiac and non-cardiac etiologies.^2,7,8 Some important cardiac causes include hypertension (HTN), coronary artery disease (CAD), valvular heart disease, arrhythmias, myocarditis, Takotsubo cardiomyopathy, and postpartum cardiomyopathy. Common and important non-cardiac causes of HF include alcoholic cardiomyopathy, pulmonary embolism, pulmonary hypertension, obstructive sleep apnea, anemia, hemochromatosis, amyloidosis, sarcoidosis, thyroid dysfunction, nephrotic syndrome, and cardiac toxins (especially stimulants and certain chemotherapy drugs).^2,7,8

Diagnosing an elusive culprit

HF remains a clinical diagnosis. Common symptoms include dyspnea, cough, pedal edema, and decreased exercise tolerance, but these symptoms are not at all specific. Given the varied causes and manifestations of HF, the diagnosis can be somewhat elusive. Fortunately, there are a number of objective methods to help identify patients with HF.

Framingham criteria. One commonly used tool for making the diagnosis of HF is the Framingham criteria (see https://www.mdcalc.com/framingham-heart-failure-diagnostic-criteria),⁹ which diagnoses HF based on historical and physical exam findings. Another well-validated decision tool is the Heart Failure Diagnostic Rule (see http://circ.ahajournals.org/content/124/25/2865.long),¹⁰ which incorporates N-terminal pro–B-type natriuretic peptide (NT-proBNP) results, as well as exam findings.

Measurement of natriuretic peptides, either B-type natriuretic peptide (BNP) or NT-proBNP, aids in the diagnosis of HF.⁵ Although several factors (including age, weight, and renal function) can affect BNP levels, a normal BNP value effectively rules out HF^5,7 and an elevated BNP can help to make the diagnosis in the context of a patient with corresponding symptoms.

The initial evaluation: Necessary lab work and imaging studies

The purpose of the initial evaluation of the patient with suspected HF is to establish the diagnosis, look for underlying etiologies of HF, identify comorbidities, and establish baseline values (eg, of potassium and creatinine) for elements monitored during treatment.^5,7 TABLE 1^5,7 lists the lab work and imaging tests that are commonly ordered in the initial evaluation of the patient with HF.

Echocardiography is useful in determining the ejection fraction (EF), which is essential in guiding treatment. Echocardiography can also identify important structural abnormalities including significant valvular disease. Refer patients with severe valvular disease for evaluation for valve repair/replacement, regardless of EF.⁸

Use MRAs as add-on therapy for symptomatic patients with an EF ≤35% or an EF ≤40% following an acute MI.

Noninvasive testing (stress nuclear imaging or echocardiography) to evaluate for underlying CAD is reasonable in patients with unknown CAD status.^8,11 Patients for whom there is a high suspicion of obstructive CAD should undergo coronary angiography if they are candidates for revascularization.^5,7 Noninvasive testing may also be an acceptable option for assessing ischemia in patients presenting with HF who have known CAD and no angina.⁵

Classification of HF is determined by ejection fraction

Physicians have traditionally classified patients with HF as having either systolic or diastolic dysfunction. Patients with HF symptoms and a reduced EF were said to have systolic dysfunction; those with a normal EF were said to have diastolic dysfunction.

More recently, researchers have learned that patients with reduced EF and those with preserved EF can have both systolic and diastolic dysfunction simultaneously.⁸ Therefore, the current preferred terminology is HFpEF (heart failure with preserved ejection fraction) for those with an EF ≥50% and HFrEF (heart failure with reduced ejection fraction) for those with an EF ≤40%.⁵ Both the American Heart Association (AHA) and the European Society of Cardiology recognize a category of HF with moderately reduced ejection fraction defined as an EF between 40% and 50%.^5,7 Practically speaking, this group is treated as per the guidelines for HFrEF.⁵

The cornerstone of medical treatment for HFrEF is the combination of an ACE inhibitor or ARB with a beta-blocker.^2,5,7,8 Several early trials showed clear benefits of these medications. For example, the Studies Of Left Ventricular Dysfunction trial (SOLVD), compared enalapril to placebo in patients receiving standard therapy (consisting chiefly of digitalis, diuretics, and nitrates). This study demonstrated a reduction in all-cause mortality or first hospitalization for HF (number needed to treat [NNT]=21) in the enalapril group vs the placebo group.¹²

Consider hydralazine combined with isosorbide dinitrate as an alternative in patients for whom ACE inhibitor/ARB therapy is contraindicated.

Similarly, a subgroup analysis of the Valsartan Heart Failure Treatment (Val-HeFT) trial demonstrated morbidity (NNT=10) and all-cause mortality benefits (NNT=6) when valsartan (an ARB) was given to patients who were not receiving an ACE inhibitor.¹³

MERIT-HF (Metoprolol CR/XL Randomised Intervention Trial in congestive Heart Failure) compared the beta-blocker metoprolol succinate to placebo and found fewer deaths from HF and lower all-cause mortality (NNT=26) associated with the treatment group vs the placebo group.¹⁴

And a comparison of 2 beta-blockers—carvedilol and metoprolol tartrate—on clinical outcomes in patients with chronic HF in the Carvedilol Or Metoprolol European Trial (COMET) showed that carvedilol extended survival compared with metoprolol tartrate (NNT=19).¹⁵

Unlike ACE inhibitors and ARBs, which seem to show a class benefit, only 3 beta-blockers available in the United States have been proven to reduce mortality: sustained-release metoprolol succinate, carvedilol, and bisoprolol.^2,7,8

Unless contraindicated, all patients with a reduced EF—even those without symptoms—should receive a beta-blocker and an ACE inhibitor or ARB.^5,7,8

Cautionary notes

Remember the following caveats when treating patients with ACE inhibitors, ARBs, and beta-blockers:

• Use ACE inhibitors and ARBs with caution in patients with impaired renal function (serum creatinine >2.5 mg/dL) or elevated serum potassium (>5 mEq/L).^16,17
• ARBs are associated with a much lower incidence of cough and angioedema than ACE inhibitors.¹⁸
• Although physicians frequently start patients on low doses of beta-blockers and ACE inhibitors or ARBs to minimize hypotension and other adverse effects, the goal of therapy is to titrate up to the therapeutic doses used in clinical trials.^5-7 (For dosages of medications commonly used in the treatment of heart failure, see Table 3 in the American College of Cardiology/AHA/Heart Failure Society of America guidelines available at https://www.sciencedirect.com/science/article/pii/S0735109717370870?via%3Dihub#tbl3 and Table 7.2 in the European Society of Cardiology guidelines available at https://academic.oup.com/eurheartj/article/37/27/2129/1748921.)
• Because beta-blockers can exacerbate fluid retention, do not initiate them in patients with fluid overload unless such patients are being treated with diuretics.^5,19

When more Tx is needed

For patients who remain symptomatic despite treatment with an ACE inhibitor or ARB and a beta-blocker, consider the following add-on therapies.

Diuretics are the only medications used in the treatment of HF that adequately reduce fluid overload.^2,7 While thiazide diuretics confer greater blood pressure control, loop diuretics are generally preferred in the treatment of HF because they are more efficacious.⁵ Loop diuretics should be prescribed to all patients with fluid overload, as few patients can maintain their target (“dry”) weight without diuretic therapy.^5,7 Common adverse effects include hypokalemia, dehydration, and azotemia.

Two MRAs are currently available in the United States: spironolactone and eplerenone. MRAs are used as add-on therapy for symptomatic patients with an EF ≤35% or an EF ≤40% following an acute myocardial infarction (MI).⁵ They significantly reduce all-cause mortality (NNT=26).²⁰

Consider ARNI treatment for all patients with an EF ≤40% who remain symptomatic despite appropriate doses of an ACE inhibitor or ARB plus a beta-blocker.

Because hyperkalemia is a risk with MRAs, do not prescribe them for patients who are already taking both an ACE inhibitor and an ARB.⁵ Also, do not initiate MRA therapy in patients who have an elevated creatinine level (≥2.5 mg/dL in men; ≥2 mg/dL in women) or a potassium level ≥5 mEq/L.^5,7,8 Discontinue MRA therapy if a patient’s potassium level rises to ≥5.5 mEq/L.⁵

Hydralazine combined with isosorbide dinitrate (H/ID) is an alternative in patients for whom ACE inhibitor/ARB therapy is contraindicated.^5,8

H/ID is also an add-on option in African American patients. Trials have demonstrated that H/ID reduces both first hospitalization for HF (NNT=13) and all-cause mortality (NNT=25) when it is used as add-on therapy in African Americans already receiving standard therapy with an ACE inhibitor or ARB, a beta-blocker, and an MRA.²¹ Headache and dizziness are commonly reported adverse effects.

Digoxin does not reduce mortality, but it does improve both quality of life and exercise tolerance and reduces hospital admissions for patients with HF.^5,7 Significant adverse effects of digoxin include anorexia, nausea, visual disturbances, and cardiac arrhythmias.²²

Also, hypokalemia can intensify digoxin toxicity.²³ Because of these concerns, digoxin is typically dosed at 0.125 mg/d (0.125 mg every other day in patients >70 years or patients with impaired renal function or low body weight) with a target therapeutic range of 0.5 to 0.9 ng/mL.⁵

New classes, new agents

Sacubitril, a neprilysin inhibitor, is the first drug from this class approved for use in the United States. Neprilysin is the enzyme responsible for the degradation of natriuretic peptides; as such it increases endogenous NPs, promoting diuresis and lowering blood pressure.^24,25 Early trials with sacubitril alone showed limited clinical efficacy;²⁵ however, when it was combined with the ARB, valsartan (the combination being called angiotensin receptor blocker + neprilysin inhibitor [ARNI] therapy), it was found to be of significant benefit.^6,25

The PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial compared outcomes in patients receiving ARNI therapy to those receiving enalapril.²⁶ The authors stopped the trial early due to the overwhelming benefit seen in the ARNI arm.

After a median follow-up of 27 months, the researchers found a reduction in the primary outcomes of either cardiovascular death or first hospitalization for HF (26.5% in the enalapril-treated group vs 21.8% in the ARNI-treated group; NNT=21).²⁶ There were slightly more cases of angioedema in the ARNI arm than in the enalapril arm (0.5% vs 0.2%), although there were no patients in the trial who required endotracheal intubation.²⁶

Recommend ivabradine as add-on therapy to all patients with an EF ≤35% who remain symptomatic despite taking the maximum-tolerated dose of a beta-blocker.

Because of this increased risk, do not prescribe ARNI therapy for any patient with a history of angioedema.⁶ Hypotension was more common in the ARNI-treated group than in the enalapril group (14% vs 9.2%), but there were lower rates of hyperkalemia, elevated serum creatinine, and cough in the ARNI-treated group than in the enalapril group.²⁶

Consider ARNI treatment for all patients with an EF ≤40% who remain symptomatic despite appropriate doses of an ACE inhibitor or ARB plus a beta-blocker. Do not administer ARNI therapy concomitantly with an ACE inhibitor or ARB. When switching, do not start ARNI therapy for at least 36 hours after the last dose of an ACE inhibitor or ARB.⁶

Ivabradine is a sinoatrial node modulator that provides additional heart rate reduction. It does not affect ventricular repolarization or myocardial contractility.²⁷ Early trials with this medication have shown reduced cardiac mortality and an NNT to prevent one first HF hospitalization within one year of 27.²⁸ Adverse effects include symptomatic and asymptomatic bradycardia and luminous phenomena.²⁸

Recommend ivabradine as add-on therapy to all patients with an EF ≤35%, normal sinus rhythm, and resting heart rate ≥70 bpm who remain symptomatic despite taking the maximum-tolerated dose of a beta-blocker.⁶ The dose is adjusted to achieve a resting heart rate of 50 to 60 bpm.²⁷

Nonpharmacologic options

Implantable cardioverter defibrillators (ICDs) are recommended as primary prevention in select HFrEF patients to reduce the risk of sudden cardiac death and all-cause mortality. The 2013 American College of Cardiology Foundation/AHA Guideline for the Management of Heart Failure recommends an ICD for primary prevention for: 1) patients with symptomatic HF and an LVEF ≤35% despite ≥3 months of optimal medical therapy, and 2) patients at least 40 days post-MI with an LVEF of ≤30%.^5,29 ICDs are not recommended for patients who have a life expectancy of less than one year, and the devices are of unclear benefit for patients ≥75 years of age.⁵

Cardiac resynchronization therapy (CRT), although not new to the field of cardiology, is new to the treatment of heart failure. A number of patients with HFrEF have QRS prolongation and in particular, left bundle branch block (LBBB).⁵ CRT uses biventricular pacing to restore synchronous contraction of the left and right ventricles.³⁰ It is strongly recommended for patients with an EF ≤35%, sinus rhythm, LBBB, QRS ≥150 ms, and a life expectancy of at least one year.^5,7 It is weakly recommended for patients with an EF ≤35% and a QRS ≥150 ms but without LBBB. It’s also weakly recommended for patients with an EF ≤35% and LBBB with a QRS of 120 to 150 ms.^5,31

Left ventricular assist devices (LVADs) and cardiac transplantation are considerations for patients with severe symptoms refractory to all other interventions.⁵ LVADs may be used either while awaiting cardiac transplantation (bridge therapy) or as definitive treatment (destination therapy). Appropriate patient selection for such therapies requires a team of experts that ideally includes HF and transplantation cardiologists, cardiothoracic surgeons, nurses, social workers, and palliative care clinicians.⁵

Treatment of HFpEF: Evidence is lacking

While HFpEF is common—affecting about half of all patients with HF—ideal treatment remains unclear.³² Some trials have shown promise, but to date no unequivocal evidence exists that any standard therapy reduces mortality in patients with HFpEF.^33-37 Underlying mechanisms of action of HFpEF include cardiac rate and rhythm abnormalities, atrial dysfunction, and stiffening of the ventricles. In a sense, it represents an exaggerated expression of the pathophysiology seen with the normal aging of the heart and can be conceptualized as “presbycardia.”³⁷ Indeed, HFpEF is more common in the elderly, but it is also more common in patients of African descent.^38,39 Common contributing causes (which we’ll get to in a bit) include HTN, CAD, atrial fibrillation (AF), obesity, and obstructive sleep apnea (OSA).

Recommend cardiac rehabilitation to all symptomatic patients with HF who are clinically stable.

Trials have failed to show clear benefit for ACE inhibitors, ARBs, or beta-blockers.^7,33 The evidence for MRAs is somewhat unclear; however, they have recently been recommended as an option for patients who have been hospitalized in the last year to reduce the risk of subsequent hospitalizations.⁴⁰ Digoxin is used primarily for rate control in the setting of AF, but otherwise is of unclear benefit.⁷ A low-sodium diet (ie, ≤2 g/d) may be useful in those patients who are prone to fluid overload.^5,7 The cornerstone of treatment of HFpEF is the relief of volume overload with diuretics and the treatment of coexisting conditions.³³

Common contributing causes of HFpEF

HTN is not only a common contributing cause, but also the most common comorbid condition affecting patients with HFpEF. As such, treatment of HTN represents the most important management goal.^33,34 Based on recent data, the American College of Cardiology, the AHA, and the Heart Failure Society of America have recommended a systolic blood pressure goal <130 mm Hg for patients with HFpEF.⁴⁰ Most patients with HFpEF and HTN will have some degree of fluid overload and, therefore, should receive a diuretic.

CAD. Patients with HFpEF should be evaluated for CAD and treated with medical management and coronary revascularization, as appropriate.

AF is poorly tolerated by patients with HFpEF.³⁷ Patients with AF should receive anticoagulation and rate control medications, and those with persistent HF symptoms should be evaluated for rhythm control.³³

Obesity is more prevalent in patients with HFpEF than in those with HFrEF.⁴¹ Although there is indirect evidence that weight loss improves cardiac function,^34,42,43 and studies have shown bariatric surgery to improve diastolic function,^44,45 there are no studies reporting clinical outcomes.

Treatment of OSA with continuous positive airway pressure appears to alleviate some symptoms of HF and to reduce all-cause mortality.^46,47

Keeping HF patients out of the hospital

Many readmissions to the hospital for HF exacerbation are preventable. Patients often do not understand hospital discharge instructions or the nature of their chronic disease and its management.^48-51 Routine follow-up in the office or clinic provides an opportunity to improve quality of life for patients and decrease admissions.^7,52

A major role for the family physician is in the co-creation of, and adherence to, an individualized, comprehensive care plan. Make sure such a plan is easily understood not only by the patient with HF, but also by his or her care team. In addition, it should be evidence-based and reflect the patient’s culture, values, and goals of treatment.^5,7

At each visit, the family physician or a member of the health care team should assess adherence to guideline-directed medical therapy, measure weight, evaluate fluid status, and provide ongoing patient education including information on the importance of activity, monitoring weight daily, and moderating fluid, salt, and alcohol intake.^5,52

Research shows that cardiac rehabilitation improves functional capacity, exercise duration, quality of life, and mortality. Therefore, recommend it to all symptomatic patients with HF who are clinically stable.²

Consider collaboration with a subspecialist. Patients who remain symptomatic despite optimal medical management and patients with recurrent hospitalizations are best managed in conjunction with a subspecialist in HF treatment.^2,5

CORRESPONDENCE
Darin Brink, MD, 420 Delaware St. SE, MMC 381, Minneapolis, MN 55455; [email protected].

Heart failure (HF) affects nearly 6 million Americans and accounts for one million hospital admissions each year.¹ The condition, which results from a structural or functional disorder that impairs the ventricles’ ability to fill, empty, or both,² is a major cause of morbidity and mortality. The 5-year mortality rate ranges from 44% to 77%.^3,4

Growing evidence demonstrates reduced morbidity and mortality when patients with HF with reduced ejection fraction (HFrEF) are treated with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB); a beta-blocker; and a mineralocorticoid/aldosterone receptor antagonist (MRA) in appropriate doses.⁵ In addition, 2 new medications representing novel drug classes have recently entered the market and are recommended in select patients who remain symptomatic despite standard treatment.

The first is sacubitril, which is available in a combination pill with the ARB valsartan, and the second is ivabradine.⁶ Additionally, implanted medical devices are proving useful, particularly in the management of patients with refractory symptoms.

Two new medications representing novel drug classes have recently entered the market and have rapidly become important components of care.

This article will briefly review the diagnosis and initial evaluation of the patient with suspected HF and then describe how newer treatments fit within HF management priorities and strategies. But first, a word about what causes HF.

Causes are many and diverse

HF has a variety of cardiac and non-cardiac etiologies.^2,7,8 Some important cardiac causes include hypertension (HTN), coronary artery disease (CAD), valvular heart disease, arrhythmias, myocarditis, Takotsubo cardiomyopathy, and postpartum cardiomyopathy. Common and important non-cardiac causes of HF include alcoholic cardiomyopathy, pulmonary embolism, pulmonary hypertension, obstructive sleep apnea, anemia, hemochromatosis, amyloidosis, sarcoidosis, thyroid dysfunction, nephrotic syndrome, and cardiac toxins (especially stimulants and certain chemotherapy drugs).^2,7,8

Diagnosing an elusive culprit

HF remains a clinical diagnosis. Common symptoms include dyspnea, cough, pedal edema, and decreased exercise tolerance, but these symptoms are not at all specific. Given the varied causes and manifestations of HF, the diagnosis can be somewhat elusive. Fortunately, there are a number of objective methods to help identify patients with HF.

Framingham criteria. One commonly used tool for making the diagnosis of HF is the Framingham criteria (see https://www.mdcalc.com/framingham-heart-failure-diagnostic-criteria),⁹ which diagnoses HF based on historical and physical exam findings. Another well-validated decision tool is the Heart Failure Diagnostic Rule (see http://circ.ahajournals.org/content/124/25/2865.long),¹⁰ which incorporates N-terminal pro–B-type natriuretic peptide (NT-proBNP) results, as well as exam findings.

Measurement of natriuretic peptides, either B-type natriuretic peptide (BNP) or NT-proBNP, aids in the diagnosis of HF.⁵ Although several factors (including age, weight, and renal function) can affect BNP levels, a normal BNP value effectively rules out HF^5,7 and an elevated BNP can help to make the diagnosis in the context of a patient with corresponding symptoms.

The initial evaluation: Necessary lab work and imaging studies

The purpose of the initial evaluation of the patient with suspected HF is to establish the diagnosis, look for underlying etiologies of HF, identify comorbidities, and establish baseline values (eg, of potassium and creatinine) for elements monitored during treatment.^5,7 TABLE 1^5,7 lists the lab work and imaging tests that are commonly ordered in the initial evaluation of the patient with HF.

Echocardiography is useful in determining the ejection fraction (EF), which is essential in guiding treatment. Echocardiography can also identify important structural abnormalities including significant valvular disease. Refer patients with severe valvular disease for evaluation for valve repair/replacement, regardless of EF.⁸

Use MRAs as add-on therapy for symptomatic patients with an EF ≤35% or an EF ≤40% following an acute MI.

Noninvasive testing (stress nuclear imaging or echocardiography) to evaluate for underlying CAD is reasonable in patients with unknown CAD status.^8,11 Patients for whom there is a high suspicion of obstructive CAD should undergo coronary angiography if they are candidates for revascularization.^5,7 Noninvasive testing may also be an acceptable option for assessing ischemia in patients presenting with HF who have known CAD and no angina.⁵

Classification of HF is determined by ejection fraction

Physicians have traditionally classified patients with HF as having either systolic or diastolic dysfunction. Patients with HF symptoms and a reduced EF were said to have systolic dysfunction; those with a normal EF were said to have diastolic dysfunction.

More recently, researchers have learned that patients with reduced EF and those with preserved EF can have both systolic and diastolic dysfunction simultaneously.⁸ Therefore, the current preferred terminology is HFpEF (heart failure with preserved ejection fraction) for those with an EF ≥50% and HFrEF (heart failure with reduced ejection fraction) for those with an EF ≤40%.⁵ Both the American Heart Association (AHA) and the European Society of Cardiology recognize a category of HF with moderately reduced ejection fraction defined as an EF between 40% and 50%.^5,7 Practically speaking, this group is treated as per the guidelines for HFrEF.⁵

The cornerstone of medical treatment for HFrEF is the combination of an ACE inhibitor or ARB with a beta-blocker.^2,5,7,8 Several early trials showed clear benefits of these medications. For example, the Studies Of Left Ventricular Dysfunction trial (SOLVD), compared enalapril to placebo in patients receiving standard therapy (consisting chiefly of digitalis, diuretics, and nitrates). This study demonstrated a reduction in all-cause mortality or first hospitalization for HF (number needed to treat [NNT]=21) in the enalapril group vs the placebo group.¹²

Consider hydralazine combined with isosorbide dinitrate as an alternative in patients for whom ACE inhibitor/ARB therapy is contraindicated.

Similarly, a subgroup analysis of the Valsartan Heart Failure Treatment (Val-HeFT) trial demonstrated morbidity (NNT=10) and all-cause mortality benefits (NNT=6) when valsartan (an ARB) was given to patients who were not receiving an ACE inhibitor.¹³

MERIT-HF (Metoprolol CR/XL Randomised Intervention Trial in congestive Heart Failure) compared the beta-blocker metoprolol succinate to placebo and found fewer deaths from HF and lower all-cause mortality (NNT=26) associated with the treatment group vs the placebo group.¹⁴

And a comparison of 2 beta-blockers—carvedilol and metoprolol tartrate—on clinical outcomes in patients with chronic HF in the Carvedilol Or Metoprolol European Trial (COMET) showed that carvedilol extended survival compared with metoprolol tartrate (NNT=19).¹⁵

Unlike ACE inhibitors and ARBs, which seem to show a class benefit, only 3 beta-blockers available in the United States have been proven to reduce mortality: sustained-release metoprolol succinate, carvedilol, and bisoprolol.^2,7,8

Unless contraindicated, all patients with a reduced EF—even those without symptoms—should receive a beta-blocker and an ACE inhibitor or ARB.^5,7,8

Cautionary notes

Remember the following caveats when treating patients with ACE inhibitors, ARBs, and beta-blockers:

• Use ACE inhibitors and ARBs with caution in patients with impaired renal function (serum creatinine >2.5 mg/dL) or elevated serum potassium (>5 mEq/L).^16,17
• ARBs are associated with a much lower incidence of cough and angioedema than ACE inhibitors.¹⁸
• Although physicians frequently start patients on low doses of beta-blockers and ACE inhibitors or ARBs to minimize hypotension and other adverse effects, the goal of therapy is to titrate up to the therapeutic doses used in clinical trials.^5-7 (For dosages of medications commonly used in the treatment of heart failure, see Table 3 in the American College of Cardiology/AHA/Heart Failure Society of America guidelines available at https://www.sciencedirect.com/science/article/pii/S0735109717370870?via%3Dihub#tbl3 and Table 7.2 in the European Society of Cardiology guidelines available at https://academic.oup.com/eurheartj/article/37/27/2129/1748921.)
• Because beta-blockers can exacerbate fluid retention, do not initiate them in patients with fluid overload unless such patients are being treated with diuretics.^5,19

When more Tx is needed

For patients who remain symptomatic despite treatment with an ACE inhibitor or ARB and a beta-blocker, consider the following add-on therapies.

Diuretics are the only medications used in the treatment of HF that adequately reduce fluid overload.^2,7 While thiazide diuretics confer greater blood pressure control, loop diuretics are generally preferred in the treatment of HF because they are more efficacious.⁵ Loop diuretics should be prescribed to all patients with fluid overload, as few patients can maintain their target (“dry”) weight without diuretic therapy.^5,7 Common adverse effects include hypokalemia, dehydration, and azotemia.

Two MRAs are currently available in the United States: spironolactone and eplerenone. MRAs are used as add-on therapy for symptomatic patients with an EF ≤35% or an EF ≤40% following an acute myocardial infarction (MI).⁵ They significantly reduce all-cause mortality (NNT=26).²⁰

Consider ARNI treatment for all patients with an EF ≤40% who remain symptomatic despite appropriate doses of an ACE inhibitor or ARB plus a beta-blocker.

Because hyperkalemia is a risk with MRAs, do not prescribe them for patients who are already taking both an ACE inhibitor and an ARB.⁵ Also, do not initiate MRA therapy in patients who have an elevated creatinine level (≥2.5 mg/dL in men; ≥2 mg/dL in women) or a potassium level ≥5 mEq/L.^5,7,8 Discontinue MRA therapy if a patient’s potassium level rises to ≥5.5 mEq/L.⁵

Hydralazine combined with isosorbide dinitrate (H/ID) is an alternative in patients for whom ACE inhibitor/ARB therapy is contraindicated.^5,8

H/ID is also an add-on option in African American patients. Trials have demonstrated that H/ID reduces both first hospitalization for HF (NNT=13) and all-cause mortality (NNT=25) when it is used as add-on therapy in African Americans already receiving standard therapy with an ACE inhibitor or ARB, a beta-blocker, and an MRA.²¹ Headache and dizziness are commonly reported adverse effects.

Digoxin does not reduce mortality, but it does improve both quality of life and exercise tolerance and reduces hospital admissions for patients with HF.^5,7 Significant adverse effects of digoxin include anorexia, nausea, visual disturbances, and cardiac arrhythmias.²²

Also, hypokalemia can intensify digoxin toxicity.²³ Because of these concerns, digoxin is typically dosed at 0.125 mg/d (0.125 mg every other day in patients >70 years or patients with impaired renal function or low body weight) with a target therapeutic range of 0.5 to 0.9 ng/mL.⁵

New classes, new agents

Sacubitril, a neprilysin inhibitor, is the first drug from this class approved for use in the United States. Neprilysin is the enzyme responsible for the degradation of natriuretic peptides; as such it increases endogenous NPs, promoting diuresis and lowering blood pressure.^24,25 Early trials with sacubitril alone showed limited clinical efficacy;²⁵ however, when it was combined with the ARB, valsartan (the combination being called angiotensin receptor blocker + neprilysin inhibitor [ARNI] therapy), it was found to be of significant benefit.^6,25

The PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial compared outcomes in patients receiving ARNI therapy to those receiving enalapril.²⁶ The authors stopped the trial early due to the overwhelming benefit seen in the ARNI arm.

After a median follow-up of 27 months, the researchers found a reduction in the primary outcomes of either cardiovascular death or first hospitalization for HF (26.5% in the enalapril-treated group vs 21.8% in the ARNI-treated group; NNT=21).²⁶ There were slightly more cases of angioedema in the ARNI arm than in the enalapril arm (0.5% vs 0.2%), although there were no patients in the trial who required endotracheal intubation.²⁶

Recommend ivabradine as add-on therapy to all patients with an EF ≤35% who remain symptomatic despite taking the maximum-tolerated dose of a beta-blocker.

Because of this increased risk, do not prescribe ARNI therapy for any patient with a history of angioedema.⁶ Hypotension was more common in the ARNI-treated group than in the enalapril group (14% vs 9.2%), but there were lower rates of hyperkalemia, elevated serum creatinine, and cough in the ARNI-treated group than in the enalapril group.²⁶

Consider ARNI treatment for all patients with an EF ≤40% who remain symptomatic despite appropriate doses of an ACE inhibitor or ARB plus a beta-blocker. Do not administer ARNI therapy concomitantly with an ACE inhibitor or ARB. When switching, do not start ARNI therapy for at least 36 hours after the last dose of an ACE inhibitor or ARB.⁶

Ivabradine is a sinoatrial node modulator that provides additional heart rate reduction. It does not affect ventricular repolarization or myocardial contractility.²⁷ Early trials with this medication have shown reduced cardiac mortality and an NNT to prevent one first HF hospitalization within one year of 27.²⁸ Adverse effects include symptomatic and asymptomatic bradycardia and luminous phenomena.²⁸

Recommend ivabradine as add-on therapy to all patients with an EF ≤35%, normal sinus rhythm, and resting heart rate ≥70 bpm who remain symptomatic despite taking the maximum-tolerated dose of a beta-blocker.⁶ The dose is adjusted to achieve a resting heart rate of 50 to 60 bpm.²⁷

Nonpharmacologic options

Implantable cardioverter defibrillators (ICDs) are recommended as primary prevention in select HFrEF patients to reduce the risk of sudden cardiac death and all-cause mortality. The 2013 American College of Cardiology Foundation/AHA Guideline for the Management of Heart Failure recommends an ICD for primary prevention for: 1) patients with symptomatic HF and an LVEF ≤35% despite ≥3 months of optimal medical therapy, and 2) patients at least 40 days post-MI with an LVEF of ≤30%.^5,29 ICDs are not recommended for patients who have a life expectancy of less than one year, and the devices are of unclear benefit for patients ≥75 years of age.⁵

Cardiac resynchronization therapy (CRT), although not new to the field of cardiology, is new to the treatment of heart failure. A number of patients with HFrEF have QRS prolongation and in particular, left bundle branch block (LBBB).⁵ CRT uses biventricular pacing to restore synchronous contraction of the left and right ventricles.³⁰ It is strongly recommended for patients with an EF ≤35%, sinus rhythm, LBBB, QRS ≥150 ms, and a life expectancy of at least one year.^5,7 It is weakly recommended for patients with an EF ≤35% and a QRS ≥150 ms but without LBBB. It’s also weakly recommended for patients with an EF ≤35% and LBBB with a QRS of 120 to 150 ms.^5,31

Left ventricular assist devices (LVADs) and cardiac transplantation are considerations for patients with severe symptoms refractory to all other interventions.⁵ LVADs may be used either while awaiting cardiac transplantation (bridge therapy) or as definitive treatment (destination therapy). Appropriate patient selection for such therapies requires a team of experts that ideally includes HF and transplantation cardiologists, cardiothoracic surgeons, nurses, social workers, and palliative care clinicians.⁵

Treatment of HFpEF: Evidence is lacking

While HFpEF is common—affecting about half of all patients with HF—ideal treatment remains unclear.³² Some trials have shown promise, but to date no unequivocal evidence exists that any standard therapy reduces mortality in patients with HFpEF.^33-37 Underlying mechanisms of action of HFpEF include cardiac rate and rhythm abnormalities, atrial dysfunction, and stiffening of the ventricles. In a sense, it represents an exaggerated expression of the pathophysiology seen with the normal aging of the heart and can be conceptualized as “presbycardia.”³⁷ Indeed, HFpEF is more common in the elderly, but it is also more common in patients of African descent.^38,39 Common contributing causes (which we’ll get to in a bit) include HTN, CAD, atrial fibrillation (AF), obesity, and obstructive sleep apnea (OSA).

Recommend cardiac rehabilitation to all symptomatic patients with HF who are clinically stable.

Trials have failed to show clear benefit for ACE inhibitors, ARBs, or beta-blockers.^7,33 The evidence for MRAs is somewhat unclear; however, they have recently been recommended as an option for patients who have been hospitalized in the last year to reduce the risk of subsequent hospitalizations.⁴⁰ Digoxin is used primarily for rate control in the setting of AF, but otherwise is of unclear benefit.⁷ A low-sodium diet (ie, ≤2 g/d) may be useful in those patients who are prone to fluid overload.^5,7 The cornerstone of treatment of HFpEF is the relief of volume overload with diuretics and the treatment of coexisting conditions.³³

Common contributing causes of HFpEF

HTN is not only a common contributing cause, but also the most common comorbid condition affecting patients with HFpEF. As such, treatment of HTN represents the most important management goal.^33,34 Based on recent data, the American College of Cardiology, the AHA, and the Heart Failure Society of America have recommended a systolic blood pressure goal <130 mm Hg for patients with HFpEF.⁴⁰ Most patients with HFpEF and HTN will have some degree of fluid overload and, therefore, should receive a diuretic.

CAD. Patients with HFpEF should be evaluated for CAD and treated with medical management and coronary revascularization, as appropriate.

AF is poorly tolerated by patients with HFpEF.³⁷ Patients with AF should receive anticoagulation and rate control medications, and those with persistent HF symptoms should be evaluated for rhythm control.³³

Obesity is more prevalent in patients with HFpEF than in those with HFrEF.⁴¹ Although there is indirect evidence that weight loss improves cardiac function,^34,42,43 and studies have shown bariatric surgery to improve diastolic function,^44,45 there are no studies reporting clinical outcomes.

Treatment of OSA with continuous positive airway pressure appears to alleviate some symptoms of HF and to reduce all-cause mortality.^46,47

Keeping HF patients out of the hospital

Many readmissions to the hospital for HF exacerbation are preventable. Patients often do not understand hospital discharge instructions or the nature of their chronic disease and its management.^48-51 Routine follow-up in the office or clinic provides an opportunity to improve quality of life for patients and decrease admissions.^7,52

A major role for the family physician is in the co-creation of, and adherence to, an individualized, comprehensive care plan. Make sure such a plan is easily understood not only by the patient with HF, but also by his or her care team. In addition, it should be evidence-based and reflect the patient’s culture, values, and goals of treatment.^5,7

At each visit, the family physician or a member of the health care team should assess adherence to guideline-directed medical therapy, measure weight, evaluate fluid status, and provide ongoing patient education including information on the importance of activity, monitoring weight daily, and moderating fluid, salt, and alcohol intake.^5,52

Research shows that cardiac rehabilitation improves functional capacity, exercise duration, quality of life, and mortality. Therefore, recommend it to all symptomatic patients with HF who are clinically stable.²

Consider collaboration with a subspecialist. Patients who remain symptomatic despite optimal medical management and patients with recurrent hospitalizations are best managed in conjunction with a subspecialist in HF treatment.^2,5

CORRESPONDENCE
Darin Brink, MD, 420 Delaware St. SE, MMC 381, Minneapolis, MN 55455; [email protected].

The National Center for Complementary and Integrative Health, a division of the National Institutes of Medicine, estimates that about 38% of American adults use complementary and alternative medicine.¹ That statistic includes 17.7% who say they use natural products. Despite their popularity, many physicians remain skeptical—and for good reason. Enthusiasts frequently offer dramatic anecdotes to “prove” their supplements' worth, but little scientific support is available for most herbal remedies. There are, however, exceptions. As this review of the medical literature will reveal, there is evidence to support the use of capsaicin to relieve osteoarthritis (OA) and postherpetic neuralgia (PHN) and support for green tea to serve as a lipid-lowering agent and help treat diabetes. Similarly, researchers have found that peppermint may be of value in the management of irritable bowel syndrome (IBS). (We also review the literature on butterbur for migraine headaches, but serious safety issues exist; TABLE.)

In the second part of this series, which is available here, we explore what the evidence tells us about the use of turmeric, chamomile, rosemary, coffee, and cocoa.

Worth noting as you consider this—or any—review of herbals is that while there is limited scientific evidence to establish the safety and efficacy of most herbal products, they are nonetheless freely sold without US Food & Drug Administration (FDA) approval because under current regulations, they are considered dietary supplements. That legal designation means companies can manufacture, sell, and market herbs without first demonstrating safety and efficacy, as is required for pharmaceutical drugs. Because herbal medications do not require the same testing through the large randomized controlled trials (RCTs) required for pharmaceuticals, evidence is often based on smaller RCTs and other studies of lower overall quality. Despite these limitations, we believe it’s worth keeping an open mind about the value of evidence-based herbal and botanical treatments.

Overview

Capsaicin, an active compound in chili peppers, provokes a burning sensation, but also has a long history of use in pain treatment.² Qutenza, an FDA-approved chemically synthesized 8% capsaicin patch, is identical to the naturally occurring molecule.² Topically applied capsaicin exerts its therapeutic effect by rapidly depleting substance P, thus reducing the transmission of pain from C fibers to higher neurologic centers in the area of administration.³

Capsaicin provided mild to moderate efficacy in randomized trials for patients with hand and knee OA when compared with placebo.

Meta-analyses and systematic reviews have shown capsaicin is effective for various painful conditions, including peripheral diabetic neuropathy, OA, and PHN.

Peripheral neuropathy. A Cochrane review of 6 randomized, double-blind, placebo-controlled studies of at least 6 weeks' duration using topical 8% capsaicin to treat neuropathic pain concluded that high-concentration topical capsaicin used to treat PHN and human immunodeficiency virus (HIV)-associated neuropathy provided more relief in patients with high pain levels than control patients who received placebo, which was a subtherapeutic (0.04%) capsaicin cream. Number-needed-to-treat values were between 8 and 12. Local adverse events were common, but not consistently reported enough to calculate a number needed to harm.⁴

OA. Capsaicin provides mild to moderate efficacy in randomized trials for patients with hand and knee OA, when compared with placebo.^5-7 A systematic review of capsaicin for all osteoarthritic conditions noted that there was consistent evidence that capsaicin gel was effective for OA.⁸ However, a 2013 Cochrane review of only knee OA noted that capsicum extract did not provide significant clinical improvement for pain or function in knee OA and resulted in a significant number of adverse events.⁹

Low back pain (LBP). Based on a 2014 Cochrane review of 3 trials (755 subjects) of moderate quality, capsicum frutescens cream or plaster appeared more efficacious than placebo in people with chronic LBP.¹⁰ Based on current (low-quality) evidence in one trial, however, it’s not clear whether topical capsicum cream is more beneficial for acute LBP than a placebo.¹⁰

PHN. Topical 8% capsaicin is an FDA-approved treatment for PHN. A review and cost-effectiveness analysis demonstrated that 8% capsaicin had significantly higher effectiveness rates than the oral agents (tricyclic antidepressants, duloxetine, gabapentin, pregabalin) used to treat PHN.¹¹ In addition, the cost-effectiveness analysis found that the capsaicin patch was similar in cost to a topical lidocaine patch and oral products for PHN.¹¹

A meta-analysis of 7 RCTs indicated that 8% topical capsaicin was superior to the low-dose capsaicin patch for relieving pain associated with PHN.¹²

Adverse effects

Very few toxic effects have been reported during a half century of capsaicin use. Those that have been reported are mainly limited to mild local reactions.² The most common adverse effect of topical capsaicin is local irritation (burning, stinging, and erythema), which had been reported to occur in approximately 40% of patients.⁶ Nevertheless, more than 90% of the subjects in clinical studies were able to complete the studies, and pain rapidly resolved after patch removal.² Washing with soap and water may help prevent the compound from spreading to other parts of the body unintentionally.

The safety of the patch has been demonstrated with repeated dosing every 3 months for up to one year. However, the long-term risks of chronic capsaicin use and its effect on epidermal innervation are uncertain.⁵

The bottom line

Capsaicin appears to be an effective treatment for neuropathy and chronic LBP. It is FDA approved for the treatment of PHN. It may also benefit patients with OA and acute LBP. Serious adverse effects are uncommon with topical use. Common adverse effects include burning pain and irritation in the area of application, which can be intense and cause discontinuation.²

Overview

Petasites hybridus, also known as butterbur, is a member of the daisy family, Asteraceae, and is a perennial plant found throughout Europe and Asia.¹³ It was used as a remedy for ulcers, wounds, and inflammation in ancient Greece. Its calcium channel-blocking effects may counteract vasoconstriction and play a role in preventing hyper-excitation of neurons.¹⁴ Sesquiterpenes, the pharmacologically active compounds in butterbur, have strong anti-inflammatory and vasodilatory effects through lipoxygenase and leukotriene inhibition.¹⁴

Migraine headache. Butterbur appears to be effective in migraine prophylaxis. Several studies have shown butterbur to significantly reduce the number of migraine attacks per month when compared with placebo. In a small, randomized, placebo-controlled, parallel-group study on the efficacy and tolerability of a special butterbur root extract (Petadolex) for the prevention of migraine, response rate was 45% in the butterbur group vs 15% in the placebo group. Butterbur was well tolerated.¹⁵ Similar results were found in another RCT in which Petasites (butterbur) 75 mg bid significantly reduced migraine attack frequency by 48%, compared with 26% for the placebo group.¹⁶ Petadolex was well tolerated in this study, too, and no serious adverse events occurred. Findings suggest that 75 mg bid may be a good option for migraine prevention given the agent's safety profile.

Butterbur appears to be effective in migraine prophylaxis, but there are serious concerns about liver toxicity.

Petadolex may also be a good option in pediatric migraine. A 2005 study in children and adolescents found that 77% of patients experienced a reduction in attacks by at least 50% with butterbur. Patients were treated with 50 mg to 150 mg over 4 months.¹⁷

In their guidelines for migraine prevention, the American Academy of Neurology (AAN) and American Headache Society gave butterbur a Level A recommendation and concluded that butterbur should be offered to patients with migraine to reduce the frequency and severity of migraine attacks.¹⁸ However, the AAN has since changed its position, stating that “The 2012 AAN guideline, ‘Evidence-based guideline update: NSAIDS and other complementary treatments for episodic migraine prevention in adults’ has been retired by the AAN Board of Directors on September 16, 2015, due to serious safety concerns with a preventative treatment, butterbur, recommended by this guideline. The recommendations and conclusions in all retired guidelines are considered no longer valid and no longer supported by the AAN.”¹⁹

Allergic rhinitis. Although the data is not convincing, some studies have shown that butterbur may be beneficial for the treatment of allergic rhinitis.^20,21

Adverse effects

While the butterbur plant itself contains pyrrolizidine alkaloids (PA), which are hepatotoxic and carcinogenic, extracts of butterbur root that are almost completely free from these alkaloids are available. (Patients who choose to use butterbur should be advised to use only products that are certified and labeled pyrrolizidine alkaloids free.)

Petadolex, the medication used in migraine studies, was initially approved by the German health regulatory authority, but approval was later withdrawn due to concerns about liver toxicity.²² In 2012, the United Kingdom’s Medicines and Health Care Products Regulatory Agency withdrew all butterbur products from the market due to associated cases of liver toxicity.²² Petasites (butterbur) products are still available in the US market, and the risks and benefits should be discussed with all patients considering this treatment. Liver function monitoring is recommended for all patients using butterbur.²²

The herb can also cause dyspepsia, headache, itchy eyes, gastrointestinal symptoms, asthma, fatigue, and drowsiness. Additionally, people who are allergic to ragweed and daisies may have allergic reactions to butterbur. Eructation (belching) occurred in 7% of patients in a pediatric study.¹⁷

The bottom line

Butterbur appears to be efficacious for migraine prophylaxis, but long-term safety is unknown and serious concerns exist for liver toxicity.

Overview

Most tea leaves come from the Camellia sinensis bush, but green and black tea are processed differently to produce different end products.²³ It is estimated that green tea accounts for approximately a quarter of all tea consumption, and is most commonly consumed in Asian countries.²³ The health-promoting effects of green tea are mainly attributed to its polyphenol content.²⁴ While there are many types of tea due to how they are processed, green tea has the highest concentration of polyphenols, including catechins, which are powerful antioxidants.^23,24 Green tea has been used in traditional Chinese and Indian medicine to control bleeding, improve digestion, and promote overall health.²³

Dementia. Green tea polyphenols may enhance cognition and may protect against the development of dementia. In-vitro studies have shown that green tea reduces hydrogen peroxide and beta-amyloid peptides, which are significant in the development of Alzheimer’s disease.²⁵ A 12-subject double-blind study found green tea increased working memory and had an impact on frontoparietal brain connections.²⁶ Furthermore, a cohort study with 13,645 Japanese participants over a 5-year period found that frequent green tea consumption (>5 cups per day) was associated with a lower risk of dementa.²⁷ Additional studies are needed, but green tea may be useful in the treatment or prevention of dementia in the future.

Coronary artery disease. In one study, green tea plasma and urinary concentrations were associated with plasma biomarkers of cardiovascular disease and diabetes.²⁸ In one review, the consumption of green tea was associated with a statistically significant reduction in low-density lipoprotein cholesterol.²⁹ Furthermore, a 2015 systematic review and meta-analysis of prospective observational studies concluded that increased tea consumption (of any type) is associated with a reduced risk of coronary heart disease, cardiac death, stroke, and total mortality.³⁰

Cancer. Many studies have shown that green tea may reduce the risk of cancer development, although epidemiologic evidence is inconsistent. Studies have shown that cancer rates tend to be lower in those who consume higher levels of green tea.^31,32 Whether this can be attributed solely to green tea remains debatable. Several other studies have shown that polyphenols in green tea can inhibit the growth of cancer cells, but the exact mechanisms by which tea interacts with cancerous cells is unknown.²³

Many studies have shown that green tea may reduce the risk of cancer development, although epidemiologic evidence is inconsistent.

Several population-based studies have been performed, mostly in Japan, which showed green tea consumption reduced the risk of developing cancer. Fewer prostate cancer cases have been reported in men who consume green tea.³³ While studies have been performed to determine whether green tea has effects on pancreatic, esophageal, ovarian, breast, bladder, and colorectal cancer, the evidence remains inadequate.³²

Diabetes. Green tea has been shown in several studies to have a beneficial effect on diabetes. A retrospective Japanese cohort study showed that those who consumed green tea were one-third less likely to develop type 2 diabetes mellitus.³⁴ A 10-year study from Taiwan found lower body fat and smaller waist circumference in those who consumed green tea regularly.³⁵ A 2014 meta-analysis and systematic review of tea (any type) consumption and the risk of diabetes concluded that 3 cups or more of tea per day was associated with a lower risk of diabetes.³⁶ Another meta-analysis that included 17 RCTs and that focused on green tea concluded that green tea improves glucose control and A1C values.³⁷

Adverse effects

There have been concerns about potential hepatotoxicity induced by green tea intake.³⁸ However, a systematic review of 34 RCTs on liver-related adverse events from green tea showed only a slight elevation in liver function tests; no serious liver-related adverse events were reported.³⁸ This review suggested that liver-related adverse events after intake of green tea extracts are rare.³⁸

A meta-analysis that included 17 RCTs found that green tea improves glucose control and A1C values.

Consuming green tea in the diet may lower the risk of adverse effects since the concentration consumed is generally much lower than that found in extracts.

Contraindications to drinking green tea are few. Individuals with caffeine sensitivities could experience insomnia, anxiety, irritability, or upset stomach. Additionally, patients who are taking anticoagulation drugs, such as warfarin, should avoid green tea due to its vitamin K content, which can counter the effects of warfarin. Pregnant or breastfeeding women, those with heart problems or high blood pressure, kidney or liver problems, stomach ulcers, or anxiety disorders should use caution with green tea consumption.

The bottom line

Green tea consumption in the diet appears to be safe and may have beneficial effects on weight, diabetes mellitus risk, cancer risk, dementia, and cardiovascular risk. Patients may want to consider drinking green tea as part of a healthy diet, in combination with exercise.

Overview

Mentha piperita, also known as peppermint, is a hybrid between water mint and spearmint. It is found throughout Europe and North America and is commonly used in tea and toothpaste and as a flavoring for gum. It is used both orally and topically. Menthol and methyl salicylate are the main active ingredients in peppermint, and peppermint has calcium channel-blocker effects.³⁹ Menthol has been shown to help regulate cold and pain sensation through the TRPM8 receptor.⁴⁰ The peppermint herb has been studied in the treatment of multiple conditions.

IBS. It appears that peppermint inhibits spontaneous peristaltic activity, which reduces gastric emptying, decreases basal tone in the gastrointestinal tract, and slows down peristalsis in the gut.³⁹

The American College of Gastroenterology guidelines currently note that there is moderate-quality evidence for peppermint oil in the treatment of IBS.⁴¹ A Cochrane review concluded that peppermint appears to be beneficial for IBS-related symptoms and pain.⁴² In a systematic review of 9 studies from 2014, peppermint oil was found to be more effective than placebo for IBS symptoms such as pain, bloating, gas, and diarrhea.⁴³ The review also indicated that peppermint oil is safe, with heartburn being the most common complaint.⁴³ A 2016 study also found that triple-coated microspheres containing peppermint oil reduced the frequency and intensity of IBS symptoms.⁴⁴

Non-ulcer dyspepsia. In combination with caraway oil, peppermint oil can be used to reduce symptoms of non-ulcer dyspepsia.^45,46 A multicenter, randomized, placebo-controlled, double-blind study found that 43.3% of subjects improved with a peppermint-caraway oil combination after 8 weeks, compared with 3.5% receiving placebo.⁴⁶

Barium enema-related colonic spasm. Peppermint can relax the lower esophageal sphincter, and it has been shown to be useful as an antispasmodic agent for barium enema-related colonic spasm.^47,48

Itching/skin irritation. Peppermint, when applied topically, has been used to calm pruritus and relieve irritation and inflammation. It has a soothing and cooling effect on the skin. At least one study found it to be effective in the treatment of pruritus gravidarum, although the study population consisted of only 96 subjects.⁴⁹

Migraine headache. Initial small trials suggest that menthol is likely beneficial for migraine headaches. A pilot trial of 25 patients treated with topical menthol 6% gel for an acute migraine attack showed a significant improvement in headache intensity by 2 hours after gel application.⁵⁰ In a randomized, triple-blind, placebo-controlled, crossover study of 35 patients, a menthol 10% solution was shown to be more efficacious as abortive treatment of migraine headaches than placebo.⁵¹

Tension headache. A randomized, placebo-controlled double-blind crossover study of topical peppermint oil showed a significant clinical reduction in tension headache pain.⁵² Another small randomized, double-blind trial showed that tiger balm (containing menthol as the main ingredient) also produced statistically significant improvement in tension headache discomfort compared with placebo.⁵³

Musculoskeletal pain. A small study comparing topical menthol to ice for muscle soreness noted decreased perceived discomfort with menthol.⁵⁴ Menthol has also been shown to reduce pain in patients with knee OA.⁵⁵

Carpal tunnel syndrome (CTS). A triple-blind, randomized, placebo-controlled trial concluded that topical menthol acutely reduced pain intensity during the working day in slaughterhouse workers with CTS and should be considered as an effective non-systemic alternative to regular analgesics in the workplace management of chronic and neuropathic pain.⁵⁶

Adverse effects

Peppermint appears to be safe for most adults when used in small doses, and serious adverse effects are rare.^43,57 While peppermint tea appears to be safe in moderate to large amounts, people allergic to plants in the peppermint family (eg, mint, thyme, sage, rosemary, marjoram, basil, lavender) may experience allergic reactions with swelling, wheals, or erythema. Peppermint may also cause heartburn due to relaxation of the cardiac sphincter.

There is moderate-quality evidence for peppermint oil in the treatment of IBS.

Other symptoms may include nausea, vomiting, flushing, and headache.⁵⁸ The herb may also be both hepatotoxic and nephrotoxic at extremely high doses.⁵⁹ Other considerations for women are that it can trigger menstruation and should be avoided during pregnancy. Due to uncertain efficacy in this population, peppermint oil should not be used on the face of infants, young children, or pregnant women.^58,59

The bottom line

Peppermint appears to be safe and well-tolerated. It is useful in alleviating IBS symptoms and may be effective in the treatment of non-ulcerative dyspepsia, musculoskeletal pain, headache, and carpal tunnel syndrome.^54,55

Read part 2 here.

CORRESPONDENCE
Michael Malone, MD, Family and Community Medicine, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033; [email protected].

The National Center for Complementary and Integrative Health, a division of the National Institutes of Medicine, estimates that about 38% of American adults use complementary and alternative medicine.¹ That statistic includes 17.7% who say they use natural products. Despite their popularity, many physicians remain skeptical—and for good reason. Enthusiasts frequently offer dramatic anecdotes to “prove” their supplements' worth, but little scientific support is available for most herbal remedies. There are, however, exceptions. As this review of the medical literature will reveal, there is evidence to support the use of capsaicin to relieve osteoarthritis (OA) and postherpetic neuralgia (PHN) and support for green tea to serve as a lipid-lowering agent and help treat diabetes. Similarly, researchers have found that peppermint may be of value in the management of irritable bowel syndrome (IBS). (We also review the literature on butterbur for migraine headaches, but serious safety issues exist; TABLE.)

In the second part of this series, which is available here, we explore what the evidence tells us about the use of turmeric, chamomile, rosemary, coffee, and cocoa.

Worth noting as you consider this—or any—review of herbals is that while there is limited scientific evidence to establish the safety and efficacy of most herbal products, they are nonetheless freely sold without US Food & Drug Administration (FDA) approval because under current regulations, they are considered dietary supplements. That legal designation means companies can manufacture, sell, and market herbs without first demonstrating safety and efficacy, as is required for pharmaceutical drugs. Because herbal medications do not require the same testing through the large randomized controlled trials (RCTs) required for pharmaceuticals, evidence is often based on smaller RCTs and other studies of lower overall quality. Despite these limitations, we believe it’s worth keeping an open mind about the value of evidence-based herbal and botanical treatments.

Overview

Capsaicin, an active compound in chili peppers, provokes a burning sensation, but also has a long history of use in pain treatment.² Qutenza, an FDA-approved chemically synthesized 8% capsaicin patch, is identical to the naturally occurring molecule.² Topically applied capsaicin exerts its therapeutic effect by rapidly depleting substance P, thus reducing the transmission of pain from C fibers to higher neurologic centers in the area of administration.³

Capsaicin provided mild to moderate efficacy in randomized trials for patients with hand and knee OA when compared with placebo.

Meta-analyses and systematic reviews have shown capsaicin is effective for various painful conditions, including peripheral diabetic neuropathy, OA, and PHN.

Peripheral neuropathy. A Cochrane review of 6 randomized, double-blind, placebo-controlled studies of at least 6 weeks' duration using topical 8% capsaicin to treat neuropathic pain concluded that high-concentration topical capsaicin used to treat PHN and human immunodeficiency virus (HIV)-associated neuropathy provided more relief in patients with high pain levels than control patients who received placebo, which was a subtherapeutic (0.04%) capsaicin cream. Number-needed-to-treat values were between 8 and 12. Local adverse events were common, but not consistently reported enough to calculate a number needed to harm.⁴

OA. Capsaicin provides mild to moderate efficacy in randomized trials for patients with hand and knee OA, when compared with placebo.^5-7 A systematic review of capsaicin for all osteoarthritic conditions noted that there was consistent evidence that capsaicin gel was effective for OA.⁸ However, a 2013 Cochrane review of only knee OA noted that capsicum extract did not provide significant clinical improvement for pain or function in knee OA and resulted in a significant number of adverse events.⁹

Low back pain (LBP). Based on a 2014 Cochrane review of 3 trials (755 subjects) of moderate quality, capsicum frutescens cream or plaster appeared more efficacious than placebo in people with chronic LBP.¹⁰ Based on current (low-quality) evidence in one trial, however, it’s not clear whether topical capsicum cream is more beneficial for acute LBP than a placebo.¹⁰

PHN. Topical 8% capsaicin is an FDA-approved treatment for PHN. A review and cost-effectiveness analysis demonstrated that 8% capsaicin had significantly higher effectiveness rates than the oral agents (tricyclic antidepressants, duloxetine, gabapentin, pregabalin) used to treat PHN.¹¹ In addition, the cost-effectiveness analysis found that the capsaicin patch was similar in cost to a topical lidocaine patch and oral products for PHN.¹¹

A meta-analysis of 7 RCTs indicated that 8% topical capsaicin was superior to the low-dose capsaicin patch for relieving pain associated with PHN.¹²

Adverse effects

Very few toxic effects have been reported during a half century of capsaicin use. Those that have been reported are mainly limited to mild local reactions.² The most common adverse effect of topical capsaicin is local irritation (burning, stinging, and erythema), which had been reported to occur in approximately 40% of patients.⁶ Nevertheless, more than 90% of the subjects in clinical studies were able to complete the studies, and pain rapidly resolved after patch removal.² Washing with soap and water may help prevent the compound from spreading to other parts of the body unintentionally.

The safety of the patch has been demonstrated with repeated dosing every 3 months for up to one year. However, the long-term risks of chronic capsaicin use and its effect on epidermal innervation are uncertain.⁵

The bottom line

Capsaicin appears to be an effective treatment for neuropathy and chronic LBP. It is FDA approved for the treatment of PHN. It may also benefit patients with OA and acute LBP. Serious adverse effects are uncommon with topical use. Common adverse effects include burning pain and irritation in the area of application, which can be intense and cause discontinuation.²

Overview

Petasites hybridus, also known as butterbur, is a member of the daisy family, Asteraceae, and is a perennial plant found throughout Europe and Asia.¹³ It was used as a remedy for ulcers, wounds, and inflammation in ancient Greece. Its calcium channel-blocking effects may counteract vasoconstriction and play a role in preventing hyper-excitation of neurons.¹⁴ Sesquiterpenes, the pharmacologically active compounds in butterbur, have strong anti-inflammatory and vasodilatory effects through lipoxygenase and leukotriene inhibition.¹⁴

Migraine headache. Butterbur appears to be effective in migraine prophylaxis. Several studies have shown butterbur to significantly reduce the number of migraine attacks per month when compared with placebo. In a small, randomized, placebo-controlled, parallel-group study on the efficacy and tolerability of a special butterbur root extract (Petadolex) for the prevention of migraine, response rate was 45% in the butterbur group vs 15% in the placebo group. Butterbur was well tolerated.¹⁵ Similar results were found in another RCT in which Petasites (butterbur) 75 mg bid significantly reduced migraine attack frequency by 48%, compared with 26% for the placebo group.¹⁶ Petadolex was well tolerated in this study, too, and no serious adverse events occurred. Findings suggest that 75 mg bid may be a good option for migraine prevention given the agent's safety profile.

Butterbur appears to be effective in migraine prophylaxis, but there are serious concerns about liver toxicity.

Petadolex may also be a good option in pediatric migraine. A 2005 study in children and adolescents found that 77% of patients experienced a reduction in attacks by at least 50% with butterbur. Patients were treated with 50 mg to 150 mg over 4 months.¹⁷

In their guidelines for migraine prevention, the American Academy of Neurology (AAN) and American Headache Society gave butterbur a Level A recommendation and concluded that butterbur should be offered to patients with migraine to reduce the frequency and severity of migraine attacks.¹⁸ However, the AAN has since changed its position, stating that “The 2012 AAN guideline, ‘Evidence-based guideline update: NSAIDS and other complementary treatments for episodic migraine prevention in adults’ has been retired by the AAN Board of Directors on September 16, 2015, due to serious safety concerns with a preventative treatment, butterbur, recommended by this guideline. The recommendations and conclusions in all retired guidelines are considered no longer valid and no longer supported by the AAN.”¹⁹

Allergic rhinitis. Although the data is not convincing, some studies have shown that butterbur may be beneficial for the treatment of allergic rhinitis.^20,21

Adverse effects

While the butterbur plant itself contains pyrrolizidine alkaloids (PA), which are hepatotoxic and carcinogenic, extracts of butterbur root that are almost completely free from these alkaloids are available. (Patients who choose to use butterbur should be advised to use only products that are certified and labeled pyrrolizidine alkaloids free.)

Petadolex, the medication used in migraine studies, was initially approved by the German health regulatory authority, but approval was later withdrawn due to concerns about liver toxicity.²² In 2012, the United Kingdom’s Medicines and Health Care Products Regulatory Agency withdrew all butterbur products from the market due to associated cases of liver toxicity.²² Petasites (butterbur) products are still available in the US market, and the risks and benefits should be discussed with all patients considering this treatment. Liver function monitoring is recommended for all patients using butterbur.²²

The herb can also cause dyspepsia, headache, itchy eyes, gastrointestinal symptoms, asthma, fatigue, and drowsiness. Additionally, people who are allergic to ragweed and daisies may have allergic reactions to butterbur. Eructation (belching) occurred in 7% of patients in a pediatric study.¹⁷

The bottom line

Butterbur appears to be efficacious for migraine prophylaxis, but long-term safety is unknown and serious concerns exist for liver toxicity.

Overview

Most tea leaves come from the Camellia sinensis bush, but green and black tea are processed differently to produce different end products.²³ It is estimated that green tea accounts for approximately a quarter of all tea consumption, and is most commonly consumed in Asian countries.²³ The health-promoting effects of green tea are mainly attributed to its polyphenol content.²⁴ While there are many types of tea due to how they are processed, green tea has the highest concentration of polyphenols, including catechins, which are powerful antioxidants.^23,24 Green tea has been used in traditional Chinese and Indian medicine to control bleeding, improve digestion, and promote overall health.²³

Dementia. Green tea polyphenols may enhance cognition and may protect against the development of dementia. In-vitro studies have shown that green tea reduces hydrogen peroxide and beta-amyloid peptides, which are significant in the development of Alzheimer’s disease.²⁵ A 12-subject double-blind study found green tea increased working memory and had an impact on frontoparietal brain connections.²⁶ Furthermore, a cohort study with 13,645 Japanese participants over a 5-year period found that frequent green tea consumption (>5 cups per day) was associated with a lower risk of dementa.²⁷ Additional studies are needed, but green tea may be useful in the treatment or prevention of dementia in the future.

Coronary artery disease. In one study, green tea plasma and urinary concentrations were associated with plasma biomarkers of cardiovascular disease and diabetes.²⁸ In one review, the consumption of green tea was associated with a statistically significant reduction in low-density lipoprotein cholesterol.²⁹ Furthermore, a 2015 systematic review and meta-analysis of prospective observational studies concluded that increased tea consumption (of any type) is associated with a reduced risk of coronary heart disease, cardiac death, stroke, and total mortality.³⁰

Cancer. Many studies have shown that green tea may reduce the risk of cancer development, although epidemiologic evidence is inconsistent. Studies have shown that cancer rates tend to be lower in those who consume higher levels of green tea.^31,32 Whether this can be attributed solely to green tea remains debatable. Several other studies have shown that polyphenols in green tea can inhibit the growth of cancer cells, but the exact mechanisms by which tea interacts with cancerous cells is unknown.²³

Many studies have shown that green tea may reduce the risk of cancer development, although epidemiologic evidence is inconsistent.

Several population-based studies have been performed, mostly in Japan, which showed green tea consumption reduced the risk of developing cancer. Fewer prostate cancer cases have been reported in men who consume green tea.³³ While studies have been performed to determine whether green tea has effects on pancreatic, esophageal, ovarian, breast, bladder, and colorectal cancer, the evidence remains inadequate.³²

Diabetes. Green tea has been shown in several studies to have a beneficial effect on diabetes. A retrospective Japanese cohort study showed that those who consumed green tea were one-third less likely to develop type 2 diabetes mellitus.³⁴ A 10-year study from Taiwan found lower body fat and smaller waist circumference in those who consumed green tea regularly.³⁵ A 2014 meta-analysis and systematic review of tea (any type) consumption and the risk of diabetes concluded that 3 cups or more of tea per day was associated with a lower risk of diabetes.³⁶ Another meta-analysis that included 17 RCTs and that focused on green tea concluded that green tea improves glucose control and A1C values.³⁷

Adverse effects

There have been concerns about potential hepatotoxicity induced by green tea intake.³⁸ However, a systematic review of 34 RCTs on liver-related adverse events from green tea showed only a slight elevation in liver function tests; no serious liver-related adverse events were reported.³⁸ This review suggested that liver-related adverse events after intake of green tea extracts are rare.³⁸

A meta-analysis that included 17 RCTs found that green tea improves glucose control and A1C values.

Consuming green tea in the diet may lower the risk of adverse effects since the concentration consumed is generally much lower than that found in extracts.

Contraindications to drinking green tea are few. Individuals with caffeine sensitivities could experience insomnia, anxiety, irritability, or upset stomach. Additionally, patients who are taking anticoagulation drugs, such as warfarin, should avoid green tea due to its vitamin K content, which can counter the effects of warfarin. Pregnant or breastfeeding women, those with heart problems or high blood pressure, kidney or liver problems, stomach ulcers, or anxiety disorders should use caution with green tea consumption.

The bottom line

Green tea consumption in the diet appears to be safe and may have beneficial effects on weight, diabetes mellitus risk, cancer risk, dementia, and cardiovascular risk. Patients may want to consider drinking green tea as part of a healthy diet, in combination with exercise.

Overview

Mentha piperita, also known as peppermint, is a hybrid between water mint and spearmint. It is found throughout Europe and North America and is commonly used in tea and toothpaste and as a flavoring for gum. It is used both orally and topically. Menthol and methyl salicylate are the main active ingredients in peppermint, and peppermint has calcium channel-blocker effects.³⁹ Menthol has been shown to help regulate cold and pain sensation through the TRPM8 receptor.⁴⁰ The peppermint herb has been studied in the treatment of multiple conditions.

IBS. It appears that peppermint inhibits spontaneous peristaltic activity, which reduces gastric emptying, decreases basal tone in the gastrointestinal tract, and slows down peristalsis in the gut.³⁹

The American College of Gastroenterology guidelines currently note that there is moderate-quality evidence for peppermint oil in the treatment of IBS.⁴¹ A Cochrane review concluded that peppermint appears to be beneficial for IBS-related symptoms and pain.⁴² In a systematic review of 9 studies from 2014, peppermint oil was found to be more effective than placebo for IBS symptoms such as pain, bloating, gas, and diarrhea.⁴³ The review also indicated that peppermint oil is safe, with heartburn being the most common complaint.⁴³ A 2016 study also found that triple-coated microspheres containing peppermint oil reduced the frequency and intensity of IBS symptoms.⁴⁴

Non-ulcer dyspepsia. In combination with caraway oil, peppermint oil can be used to reduce symptoms of non-ulcer dyspepsia.^45,46 A multicenter, randomized, placebo-controlled, double-blind study found that 43.3% of subjects improved with a peppermint-caraway oil combination after 8 weeks, compared with 3.5% receiving placebo.⁴⁶

Barium enema-related colonic spasm. Peppermint can relax the lower esophageal sphincter, and it has been shown to be useful as an antispasmodic agent for barium enema-related colonic spasm.^47,48

Itching/skin irritation. Peppermint, when applied topically, has been used to calm pruritus and relieve irritation and inflammation. It has a soothing and cooling effect on the skin. At least one study found it to be effective in the treatment of pruritus gravidarum, although the study population consisted of only 96 subjects.⁴⁹

Migraine headache. Initial small trials suggest that menthol is likely beneficial for migraine headaches. A pilot trial of 25 patients treated with topical menthol 6% gel for an acute migraine attack showed a significant improvement in headache intensity by 2 hours after gel application.⁵⁰ In a randomized, triple-blind, placebo-controlled, crossover study of 35 patients, a menthol 10% solution was shown to be more efficacious as abortive treatment of migraine headaches than placebo.⁵¹

Tension headache. A randomized, placebo-controlled double-blind crossover study of topical peppermint oil showed a significant clinical reduction in tension headache pain.⁵² Another small randomized, double-blind trial showed that tiger balm (containing menthol as the main ingredient) also produced statistically significant improvement in tension headache discomfort compared with placebo.⁵³

Musculoskeletal pain. A small study comparing topical menthol to ice for muscle soreness noted decreased perceived discomfort with menthol.⁵⁴ Menthol has also been shown to reduce pain in patients with knee OA.⁵⁵

Carpal tunnel syndrome (CTS). A triple-blind, randomized, placebo-controlled trial concluded that topical menthol acutely reduced pain intensity during the working day in slaughterhouse workers with CTS and should be considered as an effective non-systemic alternative to regular analgesics in the workplace management of chronic and neuropathic pain.⁵⁶

Adverse effects

Peppermint appears to be safe for most adults when used in small doses, and serious adverse effects are rare.^43,57 While peppermint tea appears to be safe in moderate to large amounts, people allergic to plants in the peppermint family (eg, mint, thyme, sage, rosemary, marjoram, basil, lavender) may experience allergic reactions with swelling, wheals, or erythema. Peppermint may also cause heartburn due to relaxation of the cardiac sphincter.

There is moderate-quality evidence for peppermint oil in the treatment of IBS.

Other symptoms may include nausea, vomiting, flushing, and headache.⁵⁸ The herb may also be both hepatotoxic and nephrotoxic at extremely high doses.⁵⁹ Other considerations for women are that it can trigger menstruation and should be avoided during pregnancy. Due to uncertain efficacy in this population, peppermint oil should not be used on the face of infants, young children, or pregnant women.^58,59

The bottom line

Peppermint appears to be safe and well-tolerated. It is useful in alleviating IBS symptoms and may be effective in the treatment of non-ulcerative dyspepsia, musculoskeletal pain, headache, and carpal tunnel syndrome.^54,55

Read part 2 here.

CORRESPONDENCE
Michael Malone, MD, Family and Community Medicine, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033; [email protected].

The National Center for Complementary and Integrative Health, a division of the National Institutes of Medicine, estimates that about 38% of American adults use complementary and alternative medicine.¹ That statistic includes 17.7% who say they use natural products. Despite their popularity, many physicians remain skeptical—and for good reason. Enthusiasts frequently offer dramatic anecdotes to “prove” their supplements' worth, but little scientific support is available for most herbal remedies. There are, however, exceptions. As this review of the medical literature will reveal, there is evidence to support the use of capsaicin to relieve osteoarthritis (OA) and postherpetic neuralgia (PHN) and support for green tea to serve as a lipid-lowering agent and help treat diabetes. Similarly, researchers have found that peppermint may be of value in the management of irritable bowel syndrome (IBS). (We also review the literature on butterbur for migraine headaches, but serious safety issues exist; TABLE.)

In the second part of this series, which is available here, we explore what the evidence tells us about the use of turmeric, chamomile, rosemary, coffee, and cocoa.

Worth noting as you consider this—or any—review of herbals is that while there is limited scientific evidence to establish the safety and efficacy of most herbal products, they are nonetheless freely sold without US Food & Drug Administration (FDA) approval because under current regulations, they are considered dietary supplements. That legal designation means companies can manufacture, sell, and market herbs without first demonstrating safety and efficacy, as is required for pharmaceutical drugs. Because herbal medications do not require the same testing through the large randomized controlled trials (RCTs) required for pharmaceuticals, evidence is often based on smaller RCTs and other studies of lower overall quality. Despite these limitations, we believe it’s worth keeping an open mind about the value of evidence-based herbal and botanical treatments.

Overview

Capsaicin, an active compound in chili peppers, provokes a burning sensation, but also has a long history of use in pain treatment.² Qutenza, an FDA-approved chemically synthesized 8% capsaicin patch, is identical to the naturally occurring molecule.² Topically applied capsaicin exerts its therapeutic effect by rapidly depleting substance P, thus reducing the transmission of pain from C fibers to higher neurologic centers in the area of administration.³

Capsaicin provided mild to moderate efficacy in randomized trials for patients with hand and knee OA when compared with placebo.

Meta-analyses and systematic reviews have shown capsaicin is effective for various painful conditions, including peripheral diabetic neuropathy, OA, and PHN.

Peripheral neuropathy. A Cochrane review of 6 randomized, double-blind, placebo-controlled studies of at least 6 weeks' duration using topical 8% capsaicin to treat neuropathic pain concluded that high-concentration topical capsaicin used to treat PHN and human immunodeficiency virus (HIV)-associated neuropathy provided more relief in patients with high pain levels than control patients who received placebo, which was a subtherapeutic (0.04%) capsaicin cream. Number-needed-to-treat values were between 8 and 12. Local adverse events were common, but not consistently reported enough to calculate a number needed to harm.⁴

OA. Capsaicin provides mild to moderate efficacy in randomized trials for patients with hand and knee OA, when compared with placebo.^5-7 A systematic review of capsaicin for all osteoarthritic conditions noted that there was consistent evidence that capsaicin gel was effective for OA.⁸ However, a 2013 Cochrane review of only knee OA noted that capsicum extract did not provide significant clinical improvement for pain or function in knee OA and resulted in a significant number of adverse events.⁹

Low back pain (LBP). Based on a 2014 Cochrane review of 3 trials (755 subjects) of moderate quality, capsicum frutescens cream or plaster appeared more efficacious than placebo in people with chronic LBP.¹⁰ Based on current (low-quality) evidence in one trial, however, it’s not clear whether topical capsicum cream is more beneficial for acute LBP than a placebo.¹⁰

PHN. Topical 8% capsaicin is an FDA-approved treatment for PHN. A review and cost-effectiveness analysis demonstrated that 8% capsaicin had significantly higher effectiveness rates than the oral agents (tricyclic antidepressants, duloxetine, gabapentin, pregabalin) used to treat PHN.¹¹ In addition, the cost-effectiveness analysis found that the capsaicin patch was similar in cost to a topical lidocaine patch and oral products for PHN.¹¹

A meta-analysis of 7 RCTs indicated that 8% topical capsaicin was superior to the low-dose capsaicin patch for relieving pain associated with PHN.¹²

Adverse effects

Very few toxic effects have been reported during a half century of capsaicin use. Those that have been reported are mainly limited to mild local reactions.² The most common adverse effect of topical capsaicin is local irritation (burning, stinging, and erythema), which had been reported to occur in approximately 40% of patients.⁶ Nevertheless, more than 90% of the subjects in clinical studies were able to complete the studies, and pain rapidly resolved after patch removal.² Washing with soap and water may help prevent the compound from spreading to other parts of the body unintentionally.

The safety of the patch has been demonstrated with repeated dosing every 3 months for up to one year. However, the long-term risks of chronic capsaicin use and its effect on epidermal innervation are uncertain.⁵

The bottom line

Capsaicin appears to be an effective treatment for neuropathy and chronic LBP. It is FDA approved for the treatment of PHN. It may also benefit patients with OA and acute LBP. Serious adverse effects are uncommon with topical use. Common adverse effects include burning pain and irritation in the area of application, which can be intense and cause discontinuation.²

Overview

Petasites hybridus, also known as butterbur, is a member of the daisy family, Asteraceae, and is a perennial plant found throughout Europe and Asia.¹³ It was used as a remedy for ulcers, wounds, and inflammation in ancient Greece. Its calcium channel-blocking effects may counteract vasoconstriction and play a role in preventing hyper-excitation of neurons.¹⁴ Sesquiterpenes, the pharmacologically active compounds in butterbur, have strong anti-inflammatory and vasodilatory effects through lipoxygenase and leukotriene inhibition.¹⁴

Migraine headache. Butterbur appears to be effective in migraine prophylaxis. Several studies have shown butterbur to significantly reduce the number of migraine attacks per month when compared with placebo. In a small, randomized, placebo-controlled, parallel-group study on the efficacy and tolerability of a special butterbur root extract (Petadolex) for the prevention of migraine, response rate was 45% in the butterbur group vs 15% in the placebo group. Butterbur was well tolerated.¹⁵ Similar results were found in another RCT in which Petasites (butterbur) 75 mg bid significantly reduced migraine attack frequency by 48%, compared with 26% for the placebo group.¹⁶ Petadolex was well tolerated in this study, too, and no serious adverse events occurred. Findings suggest that 75 mg bid may be a good option for migraine prevention given the agent's safety profile.

Butterbur appears to be effective in migraine prophylaxis, but there are serious concerns about liver toxicity.

Petadolex may also be a good option in pediatric migraine. A 2005 study in children and adolescents found that 77% of patients experienced a reduction in attacks by at least 50% with butterbur. Patients were treated with 50 mg to 150 mg over 4 months.¹⁷

In their guidelines for migraine prevention, the American Academy of Neurology (AAN) and American Headache Society gave butterbur a Level A recommendation and concluded that butterbur should be offered to patients with migraine to reduce the frequency and severity of migraine attacks.¹⁸ However, the AAN has since changed its position, stating that “The 2012 AAN guideline, ‘Evidence-based guideline update: NSAIDS and other complementary treatments for episodic migraine prevention in adults’ has been retired by the AAN Board of Directors on September 16, 2015, due to serious safety concerns with a preventative treatment, butterbur, recommended by this guideline. The recommendations and conclusions in all retired guidelines are considered no longer valid and no longer supported by the AAN.”¹⁹

Allergic rhinitis. Although the data is not convincing, some studies have shown that butterbur may be beneficial for the treatment of allergic rhinitis.^20,21

Adverse effects

While the butterbur plant itself contains pyrrolizidine alkaloids (PA), which are hepatotoxic and carcinogenic, extracts of butterbur root that are almost completely free from these alkaloids are available. (Patients who choose to use butterbur should be advised to use only products that are certified and labeled pyrrolizidine alkaloids free.)

Petadolex, the medication used in migraine studies, was initially approved by the German health regulatory authority, but approval was later withdrawn due to concerns about liver toxicity.²² In 2012, the United Kingdom’s Medicines and Health Care Products Regulatory Agency withdrew all butterbur products from the market due to associated cases of liver toxicity.²² Petasites (butterbur) products are still available in the US market, and the risks and benefits should be discussed with all patients considering this treatment. Liver function monitoring is recommended for all patients using butterbur.²²

The herb can also cause dyspepsia, headache, itchy eyes, gastrointestinal symptoms, asthma, fatigue, and drowsiness. Additionally, people who are allergic to ragweed and daisies may have allergic reactions to butterbur. Eructation (belching) occurred in 7% of patients in a pediatric study.¹⁷

The bottom line

Butterbur appears to be efficacious for migraine prophylaxis, but long-term safety is unknown and serious concerns exist for liver toxicity.

Overview

Most tea leaves come from the Camellia sinensis bush, but green and black tea are processed differently to produce different end products.²³ It is estimated that green tea accounts for approximately a quarter of all tea consumption, and is most commonly consumed in Asian countries.²³ The health-promoting effects of green tea are mainly attributed to its polyphenol content.²⁴ While there are many types of tea due to how they are processed, green tea has the highest concentration of polyphenols, including catechins, which are powerful antioxidants.^23,24 Green tea has been used in traditional Chinese and Indian medicine to control bleeding, improve digestion, and promote overall health.²³

Dementia. Green tea polyphenols may enhance cognition and may protect against the development of dementia. In-vitro studies have shown that green tea reduces hydrogen peroxide and beta-amyloid peptides, which are significant in the development of Alzheimer’s disease.²⁵ A 12-subject double-blind study found green tea increased working memory and had an impact on frontoparietal brain connections.²⁶ Furthermore, a cohort study with 13,645 Japanese participants over a 5-year period found that frequent green tea consumption (>5 cups per day) was associated with a lower risk of dementa.²⁷ Additional studies are needed, but green tea may be useful in the treatment or prevention of dementia in the future.

Coronary artery disease. In one study, green tea plasma and urinary concentrations were associated with plasma biomarkers of cardiovascular disease and diabetes.²⁸ In one review, the consumption of green tea was associated with a statistically significant reduction in low-density lipoprotein cholesterol.²⁹ Furthermore, a 2015 systematic review and meta-analysis of prospective observational studies concluded that increased tea consumption (of any type) is associated with a reduced risk of coronary heart disease, cardiac death, stroke, and total mortality.³⁰

Cancer. Many studies have shown that green tea may reduce the risk of cancer development, although epidemiologic evidence is inconsistent. Studies have shown that cancer rates tend to be lower in those who consume higher levels of green tea.^31,32 Whether this can be attributed solely to green tea remains debatable. Several other studies have shown that polyphenols in green tea can inhibit the growth of cancer cells, but the exact mechanisms by which tea interacts with cancerous cells is unknown.²³

Many studies have shown that green tea may reduce the risk of cancer development, although epidemiologic evidence is inconsistent.

Several population-based studies have been performed, mostly in Japan, which showed green tea consumption reduced the risk of developing cancer. Fewer prostate cancer cases have been reported in men who consume green tea.³³ While studies have been performed to determine whether green tea has effects on pancreatic, esophageal, ovarian, breast, bladder, and colorectal cancer, the evidence remains inadequate.³²

Diabetes. Green tea has been shown in several studies to have a beneficial effect on diabetes. A retrospective Japanese cohort study showed that those who consumed green tea were one-third less likely to develop type 2 diabetes mellitus.³⁴ A 10-year study from Taiwan found lower body fat and smaller waist circumference in those who consumed green tea regularly.³⁵ A 2014 meta-analysis and systematic review of tea (any type) consumption and the risk of diabetes concluded that 3 cups or more of tea per day was associated with a lower risk of diabetes.³⁶ Another meta-analysis that included 17 RCTs and that focused on green tea concluded that green tea improves glucose control and A1C values.³⁷

Adverse effects

There have been concerns about potential hepatotoxicity induced by green tea intake.³⁸ However, a systematic review of 34 RCTs on liver-related adverse events from green tea showed only a slight elevation in liver function tests; no serious liver-related adverse events were reported.³⁸ This review suggested that liver-related adverse events after intake of green tea extracts are rare.³⁸

A meta-analysis that included 17 RCTs found that green tea improves glucose control and A1C values.

Consuming green tea in the diet may lower the risk of adverse effects since the concentration consumed is generally much lower than that found in extracts.

Contraindications to drinking green tea are few. Individuals with caffeine sensitivities could experience insomnia, anxiety, irritability, or upset stomach. Additionally, patients who are taking anticoagulation drugs, such as warfarin, should avoid green tea due to its vitamin K content, which can counter the effects of warfarin. Pregnant or breastfeeding women, those with heart problems or high blood pressure, kidney or liver problems, stomach ulcers, or anxiety disorders should use caution with green tea consumption.

The bottom line

Green tea consumption in the diet appears to be safe and may have beneficial effects on weight, diabetes mellitus risk, cancer risk, dementia, and cardiovascular risk. Patients may want to consider drinking green tea as part of a healthy diet, in combination with exercise.

Overview

Mentha piperita, also known as peppermint, is a hybrid between water mint and spearmint. It is found throughout Europe and North America and is commonly used in tea and toothpaste and as a flavoring for gum. It is used both orally and topically. Menthol and methyl salicylate are the main active ingredients in peppermint, and peppermint has calcium channel-blocker effects.³⁹ Menthol has been shown to help regulate cold and pain sensation through the TRPM8 receptor.⁴⁰ The peppermint herb has been studied in the treatment of multiple conditions.

IBS. It appears that peppermint inhibits spontaneous peristaltic activity, which reduces gastric emptying, decreases basal tone in the gastrointestinal tract, and slows down peristalsis in the gut.³⁹

The American College of Gastroenterology guidelines currently note that there is moderate-quality evidence for peppermint oil in the treatment of IBS.⁴¹ A Cochrane review concluded that peppermint appears to be beneficial for IBS-related symptoms and pain.⁴² In a systematic review of 9 studies from 2014, peppermint oil was found to be more effective than placebo for IBS symptoms such as pain, bloating, gas, and diarrhea.⁴³ The review also indicated that peppermint oil is safe, with heartburn being the most common complaint.⁴³ A 2016 study also found that triple-coated microspheres containing peppermint oil reduced the frequency and intensity of IBS symptoms.⁴⁴

Non-ulcer dyspepsia. In combination with caraway oil, peppermint oil can be used to reduce symptoms of non-ulcer dyspepsia.^45,46 A multicenter, randomized, placebo-controlled, double-blind study found that 43.3% of subjects improved with a peppermint-caraway oil combination after 8 weeks, compared with 3.5% receiving placebo.⁴⁶

Barium enema-related colonic spasm. Peppermint can relax the lower esophageal sphincter, and it has been shown to be useful as an antispasmodic agent for barium enema-related colonic spasm.^47,48

Itching/skin irritation. Peppermint, when applied topically, has been used to calm pruritus and relieve irritation and inflammation. It has a soothing and cooling effect on the skin. At least one study found it to be effective in the treatment of pruritus gravidarum, although the study population consisted of only 96 subjects.⁴⁹

Migraine headache. Initial small trials suggest that menthol is likely beneficial for migraine headaches. A pilot trial of 25 patients treated with topical menthol 6% gel for an acute migraine attack showed a significant improvement in headache intensity by 2 hours after gel application.⁵⁰ In a randomized, triple-blind, placebo-controlled, crossover study of 35 patients, a menthol 10% solution was shown to be more efficacious as abortive treatment of migraine headaches than placebo.⁵¹

Tension headache. A randomized, placebo-controlled double-blind crossover study of topical peppermint oil showed a significant clinical reduction in tension headache pain.⁵² Another small randomized, double-blind trial showed that tiger balm (containing menthol as the main ingredient) also produced statistically significant improvement in tension headache discomfort compared with placebo.⁵³

Musculoskeletal pain. A small study comparing topical menthol to ice for muscle soreness noted decreased perceived discomfort with menthol.⁵⁴ Menthol has also been shown to reduce pain in patients with knee OA.⁵⁵

Carpal tunnel syndrome (CTS). A triple-blind, randomized, placebo-controlled trial concluded that topical menthol acutely reduced pain intensity during the working day in slaughterhouse workers with CTS and should be considered as an effective non-systemic alternative to regular analgesics in the workplace management of chronic and neuropathic pain.⁵⁶

Adverse effects

Peppermint appears to be safe for most adults when used in small doses, and serious adverse effects are rare.^43,57 While peppermint tea appears to be safe in moderate to large amounts, people allergic to plants in the peppermint family (eg, mint, thyme, sage, rosemary, marjoram, basil, lavender) may experience allergic reactions with swelling, wheals, or erythema. Peppermint may also cause heartburn due to relaxation of the cardiac sphincter.

There is moderate-quality evidence for peppermint oil in the treatment of IBS.

Other symptoms may include nausea, vomiting, flushing, and headache.⁵⁸ The herb may also be both hepatotoxic and nephrotoxic at extremely high doses.⁵⁹ Other considerations for women are that it can trigger menstruation and should be avoided during pregnancy. Due to uncertain efficacy in this population, peppermint oil should not be used on the face of infants, young children, or pregnant women.^58,59

The bottom line

Peppermint appears to be safe and well-tolerated. It is useful in alleviating IBS symptoms and may be effective in the treatment of non-ulcerative dyspepsia, musculoskeletal pain, headache, and carpal tunnel syndrome.^54,55

Read part 2 here.

CORRESPONDENCE
Michael Malone, MD, Family and Community Medicine, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033; [email protected].

More than a third of American adults use complementary and alternative medicine.¹ Unfortunately, the public’s enthusiasm for herbal products is not always consistent with the scientific evidence supporting their use. In part one of this series, we discussed the studies that have been done on capsaicin, butterbur, green tea, and peppermint. In this installment, we outline the research on 5 additional remedies: turmeric/curcumin, which may be of benefit in ulcerative colitis; chamomile, which appears to offer relief to patients with anxiety; rosemary, which may help treat alopecia; as well as coffee and cocoa, which may have some cardiovascular benefits (TABLE).

Turmeric/curcumin

Overview

Turmeric (Curcuma longa), a relative of ginger, has been used for 4000 years to treat a variety of conditions.^2,3 Curcumin is the yellow pigment isolated from the rhizomes of Curcuma longa, commonly known as turmeric.³ Turmeric powder contains 5% curcumin, which is the main biologically active compound. Although it grows in many tropical locations, most turmeric is grown in India, where it is used as a main ingredient in curry. The roots and bulbs of turmeric that are used in medicine are generally boiled and dried, which results in a yellow powder.

Turmeric has been used in both Ayurvedic and Chinese medicine for its anti-inflammatory properties, in the treatment of digestive and liver problems, to fight infections, and to help heal skin diseases and wounds.^3-7

Functional GI disorders. A recent review noted that curcumin has been shown in several preclinical studies and uncontrolled clinical trials to have effects on gut inflammation, gut permeability, and the brain-gut axis, especially in functional GI disorders.⁷ A double-blind, placebo-controlled study from 1989 found that turmeric reduced symptoms of bloating and gas in subjects suffering from undifferentiated dyspepsia.⁸

Ulcerative colitis (UC). A 2012 Cochrane review noted that curcumin appears to be a safe and effective therapy for maintenance of remission in quiescent UC when given as adjunctive therapy along with mesalamine or sulfasalazine.⁹ In a 2015 randomized controlled trial (RCT), the addition of curcumin to mesalamine therapy was superior to the combination of placebo and mesalamine in inducing clinical and endoscopic remission in patients with mild-to-moderate active UC, producing no apparent adverse effects.¹⁰

Osteoarthritis (OA). Because of turmeric’s ability to reduce inflammation, it may help relieve OA pain.³ Clinical evidence is scant for the anti-arthritic efficacy of turmeric dietary supplements, although animal studies indicate that turmeric prevents inflammation through regulation of NF-kappaB-regulated genes that regulate the immune and inflammatory response.⁶ Inflammatory cell influx, joint levels of prostaglandin E2, and periarticular osteoclast formation were also inhibited by turmeric extract treatment.⁶

A 2013 review of turmeric for OA concluded that observational studies and in vitro results are promising for the use of curcumin for OA, but well-designed clinical studies were lacking and are needed to support the efficacy of curcumin in OA patients.¹¹ How­ever, in a 2014 randomized trial of 367 patients, turmeric appeared to be similar in efficacy to ibuprofen for the treatment of pain and disability in adults with knee OA.¹² The curcumin (turmeric) group also had fewer adverse effects.¹²

Cancer. There has been a great deal of research on turmeric’s anti-cancer properties, but clinical evidence is lacking. In vitro evidence, animal studies, and small clinical trials suggest that curcumin may help prevent or treat several types of cancers, but the overall evidence is poor. Nonetheless, curcumin and turmeric have been or are currently being evaluated for the treatment or prevention of prostate, liver, breast, skin, gynecologic, hematologic, pulmonary, thymic, bone, brain, and colon cancer.^13-18

Oral submucous fibrosis. A small randomized trial found improvement in oral function with curcumin lozenges, when compared to placebo, indicating that turmeric may hold promise as a treatment of oral submucous fibrosis.¹⁹

Uveitis. A small pilot study of 32 patients suggested that oral curcumin may be as effective as corticosteroids for uveitis.²⁰

Heart disease. Curcumin may have a cardiovascular protective role, as it has been shown to reduce atherosclerosis, but a reduction in myocardial infarction or stroke has not been documented.²¹

Alzheimer’s dementia. Animal studies have shown a reduction in amyloid plaque formation with curcumin.²²

Adverse effects (and precautions)

Turmeric in food is considered safe. A variety of animal and human studies have also indicated that curcumin is safe and well tolerated, even at very high doses.¹³ However, taking large amounts of turmeric for long periods of time could cause stomach upset and gastric ulcers. In addition, patients with gallstones or bile obstruction should use it with caution due to increased bile production.⁷

Because turmeric may lower blood sugar levels, patients with diabetes should monitor for hypoglycemia when using turmeric in combination with diabetic medications. Similarly, those with bleeding disorders taking blood thinners should use turmeric and curcumin with caution, because it can inhibit platelet aggregation.²³

Although it is safe to eat foods with turmeric during pregnancy, pregnant and breastfeeding women should not take turmeric supplements, as the safety of large doses in pregnancy is unknown.

The bottom line

Turmeric/curcumin has anti-inflammatory properties and may be useful as an adjunct for ulcerative colitis and to improve the symptoms of OA. It may also have anti-carcinogenic properties, although definitive data are lacking. Those with a history of gastrointestinal conditions such as gastric ulcer, patients taking blood thinners, and patients with diabetes who are prone to low blood sugar levels should use turmeric/curcumin with caution.

Overview

Chamomile, a member of the Asteraceae/Compositae family, is one of the oldest herbal medicines. It has been used for hay fever, inflammation, muscle spasms, menstrual disorders, insomnia, ulcers, wounds, gastrointestinal disorders, rheumatic pain, and hemorrhoids. Essential oils of chamomile are used extensively in cosmetics and aromatherapy. Many different preparations have been developed, the most popular being herbal tea.²⁴

A controlled clinical trial of chamomile extract suggested that it may have modest anxiolytic activity in patients with mild to moderate generalized anxiety disorder.

Individuals with a hypersensitivity to plants of the Asteraceae (Compositae) family such as ragweed (Ambrosia spp.), marigold flower (Calendula officinalis), and chrysanthemum (Chrysanthemum spp.) may show a similar reaction to chamomile.²⁵

Anxiety. A controlled clinical trial of chamomile extract for generalized anxiety disorder (GAD) suggested that it may have modest anxiolytic activity in patients with mild to moderate GAD.²⁶ Another randomized, double-blind, placebo-controlled trial found oral chamomile extract was efficacious and well-tolerated in patients experiencing mild to moderate GAD and may provide an alternative therapeutic anxiolytic for patients with mild GAD.²⁵ In addition to its anxiolytic activity, chamomile may also provide clinically meaningful antidepressant activity.²⁶

Insomnia. Chamomile may have some impact on sleep diary measures (total sleep time, sleep efficiency, sleep latency, wake after sleep onset, sleep quality, and number of awakenings) relative to placebo in adults with chronic primary insomnia, according to a small randomized, double-blind, placebo-controlled pilot trial involving 34 patients.²⁷ However, a systematic review found no statistically significant difference between any herbal medicine (including chamomile) and placebo, for clinical efficacy in patients with insomnia. A similar, or smaller, number of adverse events per person were reported with chamomile compared with placebo, suggesting safe use.²⁸

Infantile colic. A small prospective double-blind study on the use of chamomile-containing tea on infantile colic showed statistically significant symptom improvement in tea-treated infants. The study did note, however, that prolonged ingestion of herbal teas may lead to decreased milk intake.^29,30

Adverse effects

As noted earlier, a systematic review found that the number of adverse events per person reported with chamomile was comparable to the number associated with placebo, suggesting that it is safe.²⁸

The bottom line

Chamomile appears to be safe with minimal adverse effects and may be effective for the treatment of anxiety, insomnia, and infantile colic.

Rosemary

Overview

Rosemary, officially known as Rosmarinus officinalis, is a medicinal evergreen plant native to the Mediterranean area that appears to increase microcapillary perfusion.³¹

Topical rosemary oil may be useful in the treatment of alopecia, with minimal adverse effects.

Alopecia. A randomized double-blind controlled trial found that essential oils including rosemary oil (as well as thyme, lavender, and cedarwood) massaged into the scalp improved hair growth in almost half of patients with alopecia areata after 7 months.³² Another randomized trial comparing rosemary oil to minoxidil 2% for androgenetic alopecia showed a significant increase in hair count at the 6-month endpoint compared with the baseline, but no significant difference was found between the study groups regarding hair count either at Month 3 or Month 6 (P >.05). ³¹

Adverse effects

In the randomized trial described above comparing rosemary oil to minoxidil 2%, adverse effects appeared to be rare for topical rosemary oil. Scalp itching was more frequent in the minoxidil group.³¹

The bottom line

Topical rosemary oil may be useful in the treatment of alopecia with minimal adverse effects.

Overview

Coffee is one of the most widely used botanicals with approximately 3.5 billion cups of coffee consumed per day worldwide. It is a popular beverage because of its unique aromatic taste and its use as a central nervous system stimulant. The coffee tree (genus coffea) is found throughout Latin America, Africa, and eastern Asia. Two of the most common commercially grown species are Coffea arabica (Arabicas) and Coffea canephora (Robusta). Processing and roasting methods may differ and produce variations in flavor and aroma. The degree of roasting also affects the caffeine content.

Coffee consumption leads to increased alertness and can boost mental performance. Based on the literature and US Food and Drug Administration recommendations, four 8-oz cups of coffee (about 400 mg of caffeine) daily is an acceptable average amount of caffeine. More than 500 mg/d is considered excessive use of coffee.^33,34

Overall mortality. A 2008 study showed that regular coffee was not associated with increased or decreased mortality in both men and women.³⁵ However, more recent studies show an inverse relationship between mortality and coffee consumption.

Specifically, a 2014 meta-analysis found an inverse relationship between coffee and mortality.³⁶ A large prospective cohort study from 2015 that included 79,234 women and 76,704 men found that drinking coffee was inversely associated with overall mortality.³⁷ In this cohort study, an inverse association were observed for deaths from heart disease, respiratory disease, diabetes, and self-harm.³⁷ While mechanisms were not analyzed, coffee may reduce mortality risk by affecting inflammation, lung function, insulin sensitivity, and depression.

Cardiovascular disease. Coffee consumption may modestly reduce the risk of stroke, according to a prospective cohort study of 83,076 women from the Nurses’ Health Study who were followed for 24 years.³⁸ Reduced cardiovascular mortality was also found in a large prospective cohort study, as noted in the mortality discussion above.³⁷ A 2014 meta-analysis concluded that coffee consumption is inversely associated with cardiovascular mortality. Drinking 3 or 4 cups a day appears to be the amount that may decrease one’s risk of death when compared to those who do not drink coffee at all.³⁶

Liver disease. Friedrich et al performed a study involving 379 patients with end stage liver disease, and found that coffee consumption delayed the progression of disease in patients with both alcoholic liver disease and primary sclerosing cholangitis.³⁹ Coffee consumption also increased long-term survival after liver transplantation.³⁹ However, the study found that coffee did not have any effect on patients with chronic viral hepatitis.

In a 2016 meta-analysis, caffeinated coffee consumption reduced hepatic fibrosis of nonalcoholic fatty liver disease, although caffeine consumption did not reduce the prevalence of nonalcoholic fatty liver disease.⁴⁰ Another meta-analysis, including 16 studies, also found caffeine reduced the risk for hepatic fibrosis and cirrhosis.⁴¹

Depression. Based on 2 different systematic reviews and meta-analyses from 2016, coffee consumption appears to have a significant protective effect, decreasing the risk of developing depression.^40,42

Alzheimer’s disease/dementia. Coffee, tea, and caffeine consumption show promise in reducing the risk of cognitive decline and dementia. Individuals who consume one to 2 cups of coffee per day had a decreased incidence of mild cognitive impairment compared to non-drinkers.⁴³ A 2015 Japanese study also found an inverse association between coffee consumption and dementia among women, nonsmokers, and those who do not drink alcohol.⁴⁴ Most recently, a 2016 study, the Women’s Health Initiative Memory Study, looked at incident dementia rates in women >65 years of age with high vs low caffeine intake. Women with higher caffeine intake were less likely to develop dementia or any cognitive impairment compared with those consuming <64 mg/day.⁴⁵

Type 2 diabetes. A 2009 prospective cohort study, which included 40,011 participants followed for more than 10 years, found that drinking at least 3 cups of coffee or tea was associated with a lowered risk of type 2 diabetes.⁴⁶ A 2009 systematic review of 20 cohort studies showed that high intakes of coffee, decaffeinated coffee, and tea are associated with a reduced risk of diabetes.⁴⁷

A meta-analysis of 12 studies involving 832,956 participants found an inverse relationship between cutaneous melanoma and coffee consumption.

Melanoma. A meta-analysis of 12 studies involving 832,956 participants demon­strated an inverse relationship between cutaneous melanoma and coffee consumption.⁴⁷ The risk of melanoma decreased by 3% and 4% for one cup/day of total coffee and caffeinated coffee consumption, respectively. Furthermore, a 2016 meta-analysis found that caffeinated coffee may have greater chemopreventive effects against melanoma than decaffeinated coffee.⁴⁸

Adverse effects

Despite the many potential benefits of coffee, caffeine is a potent drug that should be used with caution.⁴⁹ People with underlying heart problems should avoid caffeine due to concern that it may cause palpitations from tachycardia. It may worsen anxiety problems or depression. Coffee may increase the production of stomach acids, which can worsen acid reflux or stomach ulcers.

Regular coffee intake is associated with a lower risk of mortality, reduced CV events, and a reduction in liver disease progression.

Caffeine is a potent diuretic and may decrease absorption of calcium and cause OA. Caffeine may cause dependence and withdrawal symptoms. Some of the symptoms of withdrawal include drowsiness, headaches, irritability, nausea, and vomiting. It may disrupt sleeping patterns by causing jitters and sleeplessness.⁴⁹ Additionally, large amounts of caffeine may cause overdose and death.

The bottom line

Regular coffee intake is associated with a lower risk of mortality, reduced cardiovascular events, and a reduction in liver disease progression. Coffee may also have some utility for improving cognitive function and reducing the risk of type 2 diabetes. Caffeinated coffee should be limited to no more than 32 oz per day, due to the risk of insomnia, palpitations, anxiety, and gastritis.

Overview

Few natural products have been claimed to successfully treat as many disorders as chocolate. The modern concept of chocolate as food has overshadowed its traditional medicinal use, although recent trials have looked at evidence for some of its traditional uses. Chocolate is processed from the pod of the cacao plant. The earliest evidence for its medical use is in Mayan civilizations, and for most of its approximately 4000-year history, chocolate was consumed as a bitter drink referred to as the “drink of the Gods.” The traditional drink was mixed with water, vanilla, honey, chili peppers, and other spices. Important components in chocolate include flavonoids (antioxidants), cocoa butter, caffeine, theobromine, and phenylethylamine.  

Chocolate has stimulating, anti-inflammatory, neuroprotective, and cardioprotective effects, and improves the bioavailability of nitric oxide, which can improve blood pressure and platelet function.⁵⁰ Epicatechin (an antioxidant) in cocoa is primarily responsible for its favorable impact on vascular endothelium via its effect on both acute and chronic upregulation of nitric oxide production. Other cardiovascular effects are mediated by the anti-inflammatory effects of cocoa polyphenols, and modulated through the activity of NF-kappaB.⁵¹

Multiple studies have shown that chocolate is associated with a reduction in cardiovascular risk.

Dark chocolate appears to have the greatest benefit, as milk binds to antioxidants in chocolate, making them unavailable. Therefore, milk chocolate is not a good antioxidant source. There is no specific amount of chocolate that is known to be ideal, but an average of one to 2 ounces per day is often used in studies.

Cardiovascular effects. Chocolate does contain saturated fat, but a comparative, double-blind study found that short-term use of cocoa powder lowered plasma low-density lipoprotein (LDL) cholesterol, oxidized LDL, and apo B concentrations, and the plasma high-density lipoprotein (HDL) cholesterol concentration increased, relative to baseline in the low-, middle-, and high-cocoa groups.⁵² A small randomized crossover trial without clinical outcomes indicated that chocolate may increase HDL cholesterol without increasing weight.⁵³

A meta-analysis of short-term (2-12 weeks) treatment with dark chocolate/cocoa products showed reductions in LDL and total cholesterol, but no changes in HDL or triglycerides.⁵⁴ Another meta-analysis of RCTs, however, showed no short-term effect of cocoa/chocolate on lipid concentrations.⁵⁵ A randomized, placebo-controlled double-blind study of 62 patients with diabetes and hypertension showed that high polyphenol chocolate improved triglyceride levels.⁵⁶

Chocolate intake was associated with a lower risk of cognitive decline, with the greatest benefit noted in those who averaged more than one chocolate bar per week.

Multiple studies have shown that chocolate is associated with a reduction in cardiovascular risk.^57-59 A best case scenario analysis using a Markov model to predict the long-term effectiveness and cost effectiveness of daily dark chocolate consumption in a population with metabolic syndrome at high risk of cardiovascular disease concluded that daily consumption of dark chocolate can reduce cardiovascular events by 85 per 10,000 population treated over 10 years. The study concluded that $42 could be cost effectively spent per person per year on prevention strategies using dark chocolate.⁵⁹

In addition, a meta-analysis of 7 observational studies showed that high levels of chocolate consumption (any type) were associated with a 29% reduction in stroke compared with the lowest levels of chocolate intake.⁵⁷ Results of a similar meta-analysis from Neurology in 2012 also suggested that moderate chocolate consumption (any type) may lower the risk of stroke.⁶⁰

That said, 2 systematic reviews specifically relating to the risk of coronary heart disease and chocolate intake were inconclusive.^61-62

Blood pressure (BP). An RCT published in JAMA indicates that inclusion of small amounts of polyphenol-rich dark chocolate as part of a usual diet efficiently reduced BP and improved the formation of vasodilative nitric oxide.⁶³ A meta-analysis of 10 RCTs also showed mean BP change in the active cocoa treatment arms across all trials was -4.5 mm Hg (95% confidence interval (CI), -5.9 to -3.2; P<.001) for systolic BP and -2.5 mm Hg (95% CI, -3.9 to -1.2; P<.001) for diastolic BP.⁶⁴

A Cochrane Review meta-analysis of 20 studies revealed a statistically significant BP-reducing effect of flavanol-rich cocoa products compared with control in short-term trials of 2 to 18 weeks' duration.⁶⁵ Because studies have shown improvement in BP with chocolate intake, investigations into a role of chocolate in the prevention of preeclampsia have been undertaken. In some studies, chocolate intake was associated with reduced odds of preeclampsia and gestational hypertension.^66,67

Diabetes. Chocolate may exert significant vascular protection because of its antioxidant properties and possible increase of nitric oxide bioavailability, which can influence glucose uptake. A small trial comparing the effects of either dark or white chocolate bars (which do not contain the polyphenols) showed improved BP and glucose and insulin responses to an oral glucose tolerance test in healthy subjects on dark chocolate, but not white chocolate.⁶⁸ A comparison of chocolate consumption and risk of diabetes in the Physicians’ Health Study showed an inverse relationship between chocolate intake with incident disease, but this association appeared only to apply in younger and normal-body weight men after controlling for comprehensive lifestyles, including total energy consumption.⁶⁹

Fatigue. The effect of chocolate on a person’s energy level has been noted for centuries.⁷⁰ A small randomized trial showed improved energy levels in those treated with higher chocolate intakes. In a double-blind, randomized, clinical pilot crossover study, high cocoa liquor/polyphenol rich chocolate, reduced fatigue in subjects with chronic fatigue syndrome.⁷¹

Anxiety. A small randomized trial showed chocolate decreased anxiety in high-anxiety trait subjects and improved the anxiety level and the energy levels of low-anxiety trait participants.⁷²

Eye effects. The literature presents conflicting evidence regarding the effect of flavonoids on patients with glaucoma and ocular hypertension. However, a meta-analysis showed that flavonoids have a promising role in improving visual function in patients with glaucoma and ocular hypertension, and appear to play a part in both improving and slowing the progression of visual field loss.⁷³

Cognitive decline. Chocolate intake (any type) was associated with a lower risk of cognitive decline (RR = 0.59; 95% CI, 0.38-0.92) with the greatest benefit noted in those who averaged more than one chocolate bar or one tablespoon of cocoa powder per week. This protective effect was observed only among subjects with an average daily consumption of caffeine <75  mg (69% of the participants; RR = 0.50; 95% CI, 0.31-0.82).⁷⁴

The bottom line

Chocolate with high cocoa content (dark chocolate) appears to be safe and beneficial as part of a healthy diet and lifestyle that includes exercise and stress reduction to decrease cardiovascular risk and may improve energy levels.

CORRESPONDENCE
Michael Malone, MD, Family and Community Medicine, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033; [email protected].

More than a third of American adults use complementary and alternative medicine.¹ Unfortunately, the public’s enthusiasm for herbal products is not always consistent with the scientific evidence supporting their use. In part one of this series, we discussed the studies that have been done on capsaicin, butterbur, green tea, and peppermint. In this installment, we outline the research on 5 additional remedies: turmeric/curcumin, which may be of benefit in ulcerative colitis; chamomile, which appears to offer relief to patients with anxiety; rosemary, which may help treat alopecia; as well as coffee and cocoa, which may have some cardiovascular benefits (TABLE).

Turmeric/curcumin

Overview

Turmeric (Curcuma longa), a relative of ginger, has been used for 4000 years to treat a variety of conditions.^2,3 Curcumin is the yellow pigment isolated from the rhizomes of Curcuma longa, commonly known as turmeric.³ Turmeric powder contains 5% curcumin, which is the main biologically active compound. Although it grows in many tropical locations, most turmeric is grown in India, where it is used as a main ingredient in curry. The roots and bulbs of turmeric that are used in medicine are generally boiled and dried, which results in a yellow powder.

Turmeric has been used in both Ayurvedic and Chinese medicine for its anti-inflammatory properties, in the treatment of digestive and liver problems, to fight infections, and to help heal skin diseases and wounds.^3-7

Functional GI disorders. A recent review noted that curcumin has been shown in several preclinical studies and uncontrolled clinical trials to have effects on gut inflammation, gut permeability, and the brain-gut axis, especially in functional GI disorders.⁷ A double-blind, placebo-controlled study from 1989 found that turmeric reduced symptoms of bloating and gas in subjects suffering from undifferentiated dyspepsia.⁸

Ulcerative colitis (UC). A 2012 Cochrane review noted that curcumin appears to be a safe and effective therapy for maintenance of remission in quiescent UC when given as adjunctive therapy along with mesalamine or sulfasalazine.⁹ In a 2015 randomized controlled trial (RCT), the addition of curcumin to mesalamine therapy was superior to the combination of placebo and mesalamine in inducing clinical and endoscopic remission in patients with mild-to-moderate active UC, producing no apparent adverse effects.¹⁰

Osteoarthritis (OA). Because of turmeric’s ability to reduce inflammation, it may help relieve OA pain.³ Clinical evidence is scant for the anti-arthritic efficacy of turmeric dietary supplements, although animal studies indicate that turmeric prevents inflammation through regulation of NF-kappaB-regulated genes that regulate the immune and inflammatory response.⁶ Inflammatory cell influx, joint levels of prostaglandin E2, and periarticular osteoclast formation were also inhibited by turmeric extract treatment.⁶

A 2013 review of turmeric for OA concluded that observational studies and in vitro results are promising for the use of curcumin for OA, but well-designed clinical studies were lacking and are needed to support the efficacy of curcumin in OA patients.¹¹ How­ever, in a 2014 randomized trial of 367 patients, turmeric appeared to be similar in efficacy to ibuprofen for the treatment of pain and disability in adults with knee OA.¹² The curcumin (turmeric) group also had fewer adverse effects.¹²

Cancer. There has been a great deal of research on turmeric’s anti-cancer properties, but clinical evidence is lacking. In vitro evidence, animal studies, and small clinical trials suggest that curcumin may help prevent or treat several types of cancers, but the overall evidence is poor. Nonetheless, curcumin and turmeric have been or are currently being evaluated for the treatment or prevention of prostate, liver, breast, skin, gynecologic, hematologic, pulmonary, thymic, bone, brain, and colon cancer.^13-18

Oral submucous fibrosis. A small randomized trial found improvement in oral function with curcumin lozenges, when compared to placebo, indicating that turmeric may hold promise as a treatment of oral submucous fibrosis.¹⁹

Uveitis. A small pilot study of 32 patients suggested that oral curcumin may be as effective as corticosteroids for uveitis.²⁰

Heart disease. Curcumin may have a cardiovascular protective role, as it has been shown to reduce atherosclerosis, but a reduction in myocardial infarction or stroke has not been documented.²¹

Alzheimer’s dementia. Animal studies have shown a reduction in amyloid plaque formation with curcumin.²²

Adverse effects (and precautions)

Turmeric in food is considered safe. A variety of animal and human studies have also indicated that curcumin is safe and well tolerated, even at very high doses.¹³ However, taking large amounts of turmeric for long periods of time could cause stomach upset and gastric ulcers. In addition, patients with gallstones or bile obstruction should use it with caution due to increased bile production.⁷

Because turmeric may lower blood sugar levels, patients with diabetes should monitor for hypoglycemia when using turmeric in combination with diabetic medications. Similarly, those with bleeding disorders taking blood thinners should use turmeric and curcumin with caution, because it can inhibit platelet aggregation.²³

Although it is safe to eat foods with turmeric during pregnancy, pregnant and breastfeeding women should not take turmeric supplements, as the safety of large doses in pregnancy is unknown.

The bottom line

Turmeric/curcumin has anti-inflammatory properties and may be useful as an adjunct for ulcerative colitis and to improve the symptoms of OA. It may also have anti-carcinogenic properties, although definitive data are lacking. Those with a history of gastrointestinal conditions such as gastric ulcer, patients taking blood thinners, and patients with diabetes who are prone to low blood sugar levels should use turmeric/curcumin with caution.

Overview

Chamomile, a member of the Asteraceae/Compositae family, is one of the oldest herbal medicines. It has been used for hay fever, inflammation, muscle spasms, menstrual disorders, insomnia, ulcers, wounds, gastrointestinal disorders, rheumatic pain, and hemorrhoids. Essential oils of chamomile are used extensively in cosmetics and aromatherapy. Many different preparations have been developed, the most popular being herbal tea.²⁴

A controlled clinical trial of chamomile extract suggested that it may have modest anxiolytic activity in patients with mild to moderate generalized anxiety disorder.

Individuals with a hypersensitivity to plants of the Asteraceae (Compositae) family such as ragweed (Ambrosia spp.), marigold flower (Calendula officinalis), and chrysanthemum (Chrysanthemum spp.) may show a similar reaction to chamomile.²⁵

Anxiety. A controlled clinical trial of chamomile extract for generalized anxiety disorder (GAD) suggested that it may have modest anxiolytic activity in patients with mild to moderate GAD.²⁶ Another randomized, double-blind, placebo-controlled trial found oral chamomile extract was efficacious and well-tolerated in patients experiencing mild to moderate GAD and may provide an alternative therapeutic anxiolytic for patients with mild GAD.²⁵ In addition to its anxiolytic activity, chamomile may also provide clinically meaningful antidepressant activity.²⁶

Insomnia. Chamomile may have some impact on sleep diary measures (total sleep time, sleep efficiency, sleep latency, wake after sleep onset, sleep quality, and number of awakenings) relative to placebo in adults with chronic primary insomnia, according to a small randomized, double-blind, placebo-controlled pilot trial involving 34 patients.²⁷ However, a systematic review found no statistically significant difference between any herbal medicine (including chamomile) and placebo, for clinical efficacy in patients with insomnia. A similar, or smaller, number of adverse events per person were reported with chamomile compared with placebo, suggesting safe use.²⁸

Infantile colic. A small prospective double-blind study on the use of chamomile-containing tea on infantile colic showed statistically significant symptom improvement in tea-treated infants. The study did note, however, that prolonged ingestion of herbal teas may lead to decreased milk intake.^29,30

Adverse effects

As noted earlier, a systematic review found that the number of adverse events per person reported with chamomile was comparable to the number associated with placebo, suggesting that it is safe.²⁸

The bottom line

Chamomile appears to be safe with minimal adverse effects and may be effective for the treatment of anxiety, insomnia, and infantile colic.

Rosemary

Overview

Rosemary, officially known as Rosmarinus officinalis, is a medicinal evergreen plant native to the Mediterranean area that appears to increase microcapillary perfusion.³¹

Topical rosemary oil may be useful in the treatment of alopecia, with minimal adverse effects.

Alopecia. A randomized double-blind controlled trial found that essential oils including rosemary oil (as well as thyme, lavender, and cedarwood) massaged into the scalp improved hair growth in almost half of patients with alopecia areata after 7 months.³² Another randomized trial comparing rosemary oil to minoxidil 2% for androgenetic alopecia showed a significant increase in hair count at the 6-month endpoint compared with the baseline, but no significant difference was found between the study groups regarding hair count either at Month 3 or Month 6 (P >.05). ³¹

Adverse effects

In the randomized trial described above comparing rosemary oil to minoxidil 2%, adverse effects appeared to be rare for topical rosemary oil. Scalp itching was more frequent in the minoxidil group.³¹

The bottom line

Topical rosemary oil may be useful in the treatment of alopecia with minimal adverse effects.

Overview

Coffee is one of the most widely used botanicals with approximately 3.5 billion cups of coffee consumed per day worldwide. It is a popular beverage because of its unique aromatic taste and its use as a central nervous system stimulant. The coffee tree (genus coffea) is found throughout Latin America, Africa, and eastern Asia. Two of the most common commercially grown species are Coffea arabica (Arabicas) and Coffea canephora (Robusta). Processing and roasting methods may differ and produce variations in flavor and aroma. The degree of roasting also affects the caffeine content.

Coffee consumption leads to increased alertness and can boost mental performance. Based on the literature and US Food and Drug Administration recommendations, four 8-oz cups of coffee (about 400 mg of caffeine) daily is an acceptable average amount of caffeine. More than 500 mg/d is considered excessive use of coffee.^33,34

Overall mortality. A 2008 study showed that regular coffee was not associated with increased or decreased mortality in both men and women.³⁵ However, more recent studies show an inverse relationship between mortality and coffee consumption.

Specifically, a 2014 meta-analysis found an inverse relationship between coffee and mortality.³⁶ A large prospective cohort study from 2015 that included 79,234 women and 76,704 men found that drinking coffee was inversely associated with overall mortality.³⁷ In this cohort study, an inverse association were observed for deaths from heart disease, respiratory disease, diabetes, and self-harm.³⁷ While mechanisms were not analyzed, coffee may reduce mortality risk by affecting inflammation, lung function, insulin sensitivity, and depression.

Cardiovascular disease. Coffee consumption may modestly reduce the risk of stroke, according to a prospective cohort study of 83,076 women from the Nurses’ Health Study who were followed for 24 years.³⁸ Reduced cardiovascular mortality was also found in a large prospective cohort study, as noted in the mortality discussion above.³⁷ A 2014 meta-analysis concluded that coffee consumption is inversely associated with cardiovascular mortality. Drinking 3 or 4 cups a day appears to be the amount that may decrease one’s risk of death when compared to those who do not drink coffee at all.³⁶

Liver disease. Friedrich et al performed a study involving 379 patients with end stage liver disease, and found that coffee consumption delayed the progression of disease in patients with both alcoholic liver disease and primary sclerosing cholangitis.³⁹ Coffee consumption also increased long-term survival after liver transplantation.³⁹ However, the study found that coffee did not have any effect on patients with chronic viral hepatitis.

In a 2016 meta-analysis, caffeinated coffee consumption reduced hepatic fibrosis of nonalcoholic fatty liver disease, although caffeine consumption did not reduce the prevalence of nonalcoholic fatty liver disease.⁴⁰ Another meta-analysis, including 16 studies, also found caffeine reduced the risk for hepatic fibrosis and cirrhosis.⁴¹

Depression. Based on 2 different systematic reviews and meta-analyses from 2016, coffee consumption appears to have a significant protective effect, decreasing the risk of developing depression.^40,42

Alzheimer’s disease/dementia. Coffee, tea, and caffeine consumption show promise in reducing the risk of cognitive decline and dementia. Individuals who consume one to 2 cups of coffee per day had a decreased incidence of mild cognitive impairment compared to non-drinkers.⁴³ A 2015 Japanese study also found an inverse association between coffee consumption and dementia among women, nonsmokers, and those who do not drink alcohol.⁴⁴ Most recently, a 2016 study, the Women’s Health Initiative Memory Study, looked at incident dementia rates in women >65 years of age with high vs low caffeine intake. Women with higher caffeine intake were less likely to develop dementia or any cognitive impairment compared with those consuming <64 mg/day.⁴⁵

Type 2 diabetes. A 2009 prospective cohort study, which included 40,011 participants followed for more than 10 years, found that drinking at least 3 cups of coffee or tea was associated with a lowered risk of type 2 diabetes.⁴⁶ A 2009 systematic review of 20 cohort studies showed that high intakes of coffee, decaffeinated coffee, and tea are associated with a reduced risk of diabetes.⁴⁷

A meta-analysis of 12 studies involving 832,956 participants found an inverse relationship between cutaneous melanoma and coffee consumption.

Melanoma. A meta-analysis of 12 studies involving 832,956 participants demon­strated an inverse relationship between cutaneous melanoma and coffee consumption.⁴⁷ The risk of melanoma decreased by 3% and 4% for one cup/day of total coffee and caffeinated coffee consumption, respectively. Furthermore, a 2016 meta-analysis found that caffeinated coffee may have greater chemopreventive effects against melanoma than decaffeinated coffee.⁴⁸

Adverse effects

Despite the many potential benefits of coffee, caffeine is a potent drug that should be used with caution.⁴⁹ People with underlying heart problems should avoid caffeine due to concern that it may cause palpitations from tachycardia. It may worsen anxiety problems or depression. Coffee may increase the production of stomach acids, which can worsen acid reflux or stomach ulcers.

Regular coffee intake is associated with a lower risk of mortality, reduced CV events, and a reduction in liver disease progression.

Caffeine is a potent diuretic and may decrease absorption of calcium and cause OA. Caffeine may cause dependence and withdrawal symptoms. Some of the symptoms of withdrawal include drowsiness, headaches, irritability, nausea, and vomiting. It may disrupt sleeping patterns by causing jitters and sleeplessness.⁴⁹ Additionally, large amounts of caffeine may cause overdose and death.

The bottom line

Regular coffee intake is associated with a lower risk of mortality, reduced cardiovascular events, and a reduction in liver disease progression. Coffee may also have some utility for improving cognitive function and reducing the risk of type 2 diabetes. Caffeinated coffee should be limited to no more than 32 oz per day, due to the risk of insomnia, palpitations, anxiety, and gastritis.

Overview

Few natural products have been claimed to successfully treat as many disorders as chocolate. The modern concept of chocolate as food has overshadowed its traditional medicinal use, although recent trials have looked at evidence for some of its traditional uses. Chocolate is processed from the pod of the cacao plant. The earliest evidence for its medical use is in Mayan civilizations, and for most of its approximately 4000-year history, chocolate was consumed as a bitter drink referred to as the “drink of the Gods.” The traditional drink was mixed with water, vanilla, honey, chili peppers, and other spices. Important components in chocolate include flavonoids (antioxidants), cocoa butter, caffeine, theobromine, and phenylethylamine.  

Chocolate has stimulating, anti-inflammatory, neuroprotective, and cardioprotective effects, and improves the bioavailability of nitric oxide, which can improve blood pressure and platelet function.⁵⁰ Epicatechin (an antioxidant) in cocoa is primarily responsible for its favorable impact on vascular endothelium via its effect on both acute and chronic upregulation of nitric oxide production. Other cardiovascular effects are mediated by the anti-inflammatory effects of cocoa polyphenols, and modulated through the activity of NF-kappaB.⁵¹

Multiple studies have shown that chocolate is associated with a reduction in cardiovascular risk.

Dark chocolate appears to have the greatest benefit, as milk binds to antioxidants in chocolate, making them unavailable. Therefore, milk chocolate is not a good antioxidant source. There is no specific amount of chocolate that is known to be ideal, but an average of one to 2 ounces per day is often used in studies.

Cardiovascular effects. Chocolate does contain saturated fat, but a comparative, double-blind study found that short-term use of cocoa powder lowered plasma low-density lipoprotein (LDL) cholesterol, oxidized LDL, and apo B concentrations, and the plasma high-density lipoprotein (HDL) cholesterol concentration increased, relative to baseline in the low-, middle-, and high-cocoa groups.⁵² A small randomized crossover trial without clinical outcomes indicated that chocolate may increase HDL cholesterol without increasing weight.⁵³

A meta-analysis of short-term (2-12 weeks) treatment with dark chocolate/cocoa products showed reductions in LDL and total cholesterol, but no changes in HDL or triglycerides.⁵⁴ Another meta-analysis of RCTs, however, showed no short-term effect of cocoa/chocolate on lipid concentrations.⁵⁵ A randomized, placebo-controlled double-blind study of 62 patients with diabetes and hypertension showed that high polyphenol chocolate improved triglyceride levels.⁵⁶

Chocolate intake was associated with a lower risk of cognitive decline, with the greatest benefit noted in those who averaged more than one chocolate bar per week.

Multiple studies have shown that chocolate is associated with a reduction in cardiovascular risk.^57-59 A best case scenario analysis using a Markov model to predict the long-term effectiveness and cost effectiveness of daily dark chocolate consumption in a population with metabolic syndrome at high risk of cardiovascular disease concluded that daily consumption of dark chocolate can reduce cardiovascular events by 85 per 10,000 population treated over 10 years. The study concluded that $42 could be cost effectively spent per person per year on prevention strategies using dark chocolate.⁵⁹

In addition, a meta-analysis of 7 observational studies showed that high levels of chocolate consumption (any type) were associated with a 29% reduction in stroke compared with the lowest levels of chocolate intake.⁵⁷ Results of a similar meta-analysis from Neurology in 2012 also suggested that moderate chocolate consumption (any type) may lower the risk of stroke.⁶⁰

That said, 2 systematic reviews specifically relating to the risk of coronary heart disease and chocolate intake were inconclusive.^61-62

Blood pressure (BP). An RCT published in JAMA indicates that inclusion of small amounts of polyphenol-rich dark chocolate as part of a usual diet efficiently reduced BP and improved the formation of vasodilative nitric oxide.⁶³ A meta-analysis of 10 RCTs also showed mean BP change in the active cocoa treatment arms across all trials was -4.5 mm Hg (95% confidence interval (CI), -5.9 to -3.2; P<.001) for systolic BP and -2.5 mm Hg (95% CI, -3.9 to -1.2; P<.001) for diastolic BP.⁶⁴

A Cochrane Review meta-analysis of 20 studies revealed a statistically significant BP-reducing effect of flavanol-rich cocoa products compared with control in short-term trials of 2 to 18 weeks' duration.⁶⁵ Because studies have shown improvement in BP with chocolate intake, investigations into a role of chocolate in the prevention of preeclampsia have been undertaken. In some studies, chocolate intake was associated with reduced odds of preeclampsia and gestational hypertension.^66,67

Diabetes. Chocolate may exert significant vascular protection because of its antioxidant properties and possible increase of nitric oxide bioavailability, which can influence glucose uptake. A small trial comparing the effects of either dark or white chocolate bars (which do not contain the polyphenols) showed improved BP and glucose and insulin responses to an oral glucose tolerance test in healthy subjects on dark chocolate, but not white chocolate.⁶⁸ A comparison of chocolate consumption and risk of diabetes in the Physicians’ Health Study showed an inverse relationship between chocolate intake with incident disease, but this association appeared only to apply in younger and normal-body weight men after controlling for comprehensive lifestyles, including total energy consumption.⁶⁹

Fatigue. The effect of chocolate on a person’s energy level has been noted for centuries.⁷⁰ A small randomized trial showed improved energy levels in those treated with higher chocolate intakes. In a double-blind, randomized, clinical pilot crossover study, high cocoa liquor/polyphenol rich chocolate, reduced fatigue in subjects with chronic fatigue syndrome.⁷¹

Anxiety. A small randomized trial showed chocolate decreased anxiety in high-anxiety trait subjects and improved the anxiety level and the energy levels of low-anxiety trait participants.⁷²

Eye effects. The literature presents conflicting evidence regarding the effect of flavonoids on patients with glaucoma and ocular hypertension. However, a meta-analysis showed that flavonoids have a promising role in improving visual function in patients with glaucoma and ocular hypertension, and appear to play a part in both improving and slowing the progression of visual field loss.⁷³

Cognitive decline. Chocolate intake (any type) was associated with a lower risk of cognitive decline (RR = 0.59; 95% CI, 0.38-0.92) with the greatest benefit noted in those who averaged more than one chocolate bar or one tablespoon of cocoa powder per week. This protective effect was observed only among subjects with an average daily consumption of caffeine <75  mg (69% of the participants; RR = 0.50; 95% CI, 0.31-0.82).⁷⁴

The bottom line

Chocolate with high cocoa content (dark chocolate) appears to be safe and beneficial as part of a healthy diet and lifestyle that includes exercise and stress reduction to decrease cardiovascular risk and may improve energy levels.

CORRESPONDENCE
Michael Malone, MD, Family and Community Medicine, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033; [email protected].

More than a third of American adults use complementary and alternative medicine.¹ Unfortunately, the public’s enthusiasm for herbal products is not always consistent with the scientific evidence supporting their use. In part one of this series, we discussed the studies that have been done on capsaicin, butterbur, green tea, and peppermint. In this installment, we outline the research on 5 additional remedies: turmeric/curcumin, which may be of benefit in ulcerative colitis; chamomile, which appears to offer relief to patients with anxiety; rosemary, which may help treat alopecia; as well as coffee and cocoa, which may have some cardiovascular benefits (TABLE).

Turmeric/curcumin

Overview

Turmeric (Curcuma longa), a relative of ginger, has been used for 4000 years to treat a variety of conditions.^2,3 Curcumin is the yellow pigment isolated from the rhizomes of Curcuma longa, commonly known as turmeric.³ Turmeric powder contains 5% curcumin, which is the main biologically active compound. Although it grows in many tropical locations, most turmeric is grown in India, where it is used as a main ingredient in curry. The roots and bulbs of turmeric that are used in medicine are generally boiled and dried, which results in a yellow powder.

Turmeric has been used in both Ayurvedic and Chinese medicine for its anti-inflammatory properties, in the treatment of digestive and liver problems, to fight infections, and to help heal skin diseases and wounds.^3-7

Functional GI disorders. A recent review noted that curcumin has been shown in several preclinical studies and uncontrolled clinical trials to have effects on gut inflammation, gut permeability, and the brain-gut axis, especially in functional GI disorders.⁷ A double-blind, placebo-controlled study from 1989 found that turmeric reduced symptoms of bloating and gas in subjects suffering from undifferentiated dyspepsia.⁸

Ulcerative colitis (UC). A 2012 Cochrane review noted that curcumin appears to be a safe and effective therapy for maintenance of remission in quiescent UC when given as adjunctive therapy along with mesalamine or sulfasalazine.⁹ In a 2015 randomized controlled trial (RCT), the addition of curcumin to mesalamine therapy was superior to the combination of placebo and mesalamine in inducing clinical and endoscopic remission in patients with mild-to-moderate active UC, producing no apparent adverse effects.¹⁰

Osteoarthritis (OA). Because of turmeric’s ability to reduce inflammation, it may help relieve OA pain.³ Clinical evidence is scant for the anti-arthritic efficacy of turmeric dietary supplements, although animal studies indicate that turmeric prevents inflammation through regulation of NF-kappaB-regulated genes that regulate the immune and inflammatory response.⁶ Inflammatory cell influx, joint levels of prostaglandin E2, and periarticular osteoclast formation were also inhibited by turmeric extract treatment.⁶

A 2013 review of turmeric for OA concluded that observational studies and in vitro results are promising for the use of curcumin for OA, but well-designed clinical studies were lacking and are needed to support the efficacy of curcumin in OA patients.¹¹ How­ever, in a 2014 randomized trial of 367 patients, turmeric appeared to be similar in efficacy to ibuprofen for the treatment of pain and disability in adults with knee OA.¹² The curcumin (turmeric) group also had fewer adverse effects.¹²

Cancer. There has been a great deal of research on turmeric’s anti-cancer properties, but clinical evidence is lacking. In vitro evidence, animal studies, and small clinical trials suggest that curcumin may help prevent or treat several types of cancers, but the overall evidence is poor. Nonetheless, curcumin and turmeric have been or are currently being evaluated for the treatment or prevention of prostate, liver, breast, skin, gynecologic, hematologic, pulmonary, thymic, bone, brain, and colon cancer.^13-18

Oral submucous fibrosis. A small randomized trial found improvement in oral function with curcumin lozenges, when compared to placebo, indicating that turmeric may hold promise as a treatment of oral submucous fibrosis.¹⁹

Uveitis. A small pilot study of 32 patients suggested that oral curcumin may be as effective as corticosteroids for uveitis.²⁰

Heart disease. Curcumin may have a cardiovascular protective role, as it has been shown to reduce atherosclerosis, but a reduction in myocardial infarction or stroke has not been documented.²¹

Alzheimer’s dementia. Animal studies have shown a reduction in amyloid plaque formation with curcumin.²²

Adverse effects (and precautions)

Turmeric in food is considered safe. A variety of animal and human studies have also indicated that curcumin is safe and well tolerated, even at very high doses.¹³ However, taking large amounts of turmeric for long periods of time could cause stomach upset and gastric ulcers. In addition, patients with gallstones or bile obstruction should use it with caution due to increased bile production.⁷

Because turmeric may lower blood sugar levels, patients with diabetes should monitor for hypoglycemia when using turmeric in combination with diabetic medications. Similarly, those with bleeding disorders taking blood thinners should use turmeric and curcumin with caution, because it can inhibit platelet aggregation.²³

Although it is safe to eat foods with turmeric during pregnancy, pregnant and breastfeeding women should not take turmeric supplements, as the safety of large doses in pregnancy is unknown.

The bottom line

Turmeric/curcumin has anti-inflammatory properties and may be useful as an adjunct for ulcerative colitis and to improve the symptoms of OA. It may also have anti-carcinogenic properties, although definitive data are lacking. Those with a history of gastrointestinal conditions such as gastric ulcer, patients taking blood thinners, and patients with diabetes who are prone to low blood sugar levels should use turmeric/curcumin with caution.

Overview

Chamomile, a member of the Asteraceae/Compositae family, is one of the oldest herbal medicines. It has been used for hay fever, inflammation, muscle spasms, menstrual disorders, insomnia, ulcers, wounds, gastrointestinal disorders, rheumatic pain, and hemorrhoids. Essential oils of chamomile are used extensively in cosmetics and aromatherapy. Many different preparations have been developed, the most popular being herbal tea.²⁴

A controlled clinical trial of chamomile extract suggested that it may have modest anxiolytic activity in patients with mild to moderate generalized anxiety disorder.

Individuals with a hypersensitivity to plants of the Asteraceae (Compositae) family such as ragweed (Ambrosia spp.), marigold flower (Calendula officinalis), and chrysanthemum (Chrysanthemum spp.) may show a similar reaction to chamomile.²⁵

Anxiety. A controlled clinical trial of chamomile extract for generalized anxiety disorder (GAD) suggested that it may have modest anxiolytic activity in patients with mild to moderate GAD.²⁶ Another randomized, double-blind, placebo-controlled trial found oral chamomile extract was efficacious and well-tolerated in patients experiencing mild to moderate GAD and may provide an alternative therapeutic anxiolytic for patients with mild GAD.²⁵ In addition to its anxiolytic activity, chamomile may also provide clinically meaningful antidepressant activity.²⁶

Insomnia. Chamomile may have some impact on sleep diary measures (total sleep time, sleep efficiency, sleep latency, wake after sleep onset, sleep quality, and number of awakenings) relative to placebo in adults with chronic primary insomnia, according to a small randomized, double-blind, placebo-controlled pilot trial involving 34 patients.²⁷ However, a systematic review found no statistically significant difference between any herbal medicine (including chamomile) and placebo, for clinical efficacy in patients with insomnia. A similar, or smaller, number of adverse events per person were reported with chamomile compared with placebo, suggesting safe use.²⁸

Infantile colic. A small prospective double-blind study on the use of chamomile-containing tea on infantile colic showed statistically significant symptom improvement in tea-treated infants. The study did note, however, that prolonged ingestion of herbal teas may lead to decreased milk intake.^29,30

Adverse effects

As noted earlier, a systematic review found that the number of adverse events per person reported with chamomile was comparable to the number associated with placebo, suggesting that it is safe.²⁸

The bottom line

Chamomile appears to be safe with minimal adverse effects and may be effective for the treatment of anxiety, insomnia, and infantile colic.

Rosemary

Overview

Rosemary, officially known as Rosmarinus officinalis, is a medicinal evergreen plant native to the Mediterranean area that appears to increase microcapillary perfusion.³¹

Topical rosemary oil may be useful in the treatment of alopecia, with minimal adverse effects.

Alopecia. A randomized double-blind controlled trial found that essential oils including rosemary oil (as well as thyme, lavender, and cedarwood) massaged into the scalp improved hair growth in almost half of patients with alopecia areata after 7 months.³² Another randomized trial comparing rosemary oil to minoxidil 2% for androgenetic alopecia showed a significant increase in hair count at the 6-month endpoint compared with the baseline, but no significant difference was found between the study groups regarding hair count either at Month 3 or Month 6 (P >.05). ³¹

Adverse effects

In the randomized trial described above comparing rosemary oil to minoxidil 2%, adverse effects appeared to be rare for topical rosemary oil. Scalp itching was more frequent in the minoxidil group.³¹

The bottom line

Topical rosemary oil may be useful in the treatment of alopecia with minimal adverse effects.

Overview

Coffee is one of the most widely used botanicals with approximately 3.5 billion cups of coffee consumed per day worldwide. It is a popular beverage because of its unique aromatic taste and its use as a central nervous system stimulant. The coffee tree (genus coffea) is found throughout Latin America, Africa, and eastern Asia. Two of the most common commercially grown species are Coffea arabica (Arabicas) and Coffea canephora (Robusta). Processing and roasting methods may differ and produce variations in flavor and aroma. The degree of roasting also affects the caffeine content.

Coffee consumption leads to increased alertness and can boost mental performance. Based on the literature and US Food and Drug Administration recommendations, four 8-oz cups of coffee (about 400 mg of caffeine) daily is an acceptable average amount of caffeine. More than 500 mg/d is considered excessive use of coffee.^33,34

Overall mortality. A 2008 study showed that regular coffee was not associated with increased or decreased mortality in both men and women.³⁵ However, more recent studies show an inverse relationship between mortality and coffee consumption.

Specifically, a 2014 meta-analysis found an inverse relationship between coffee and mortality.³⁶ A large prospective cohort study from 2015 that included 79,234 women and 76,704 men found that drinking coffee was inversely associated with overall mortality.³⁷ In this cohort study, an inverse association were observed for deaths from heart disease, respiratory disease, diabetes, and self-harm.³⁷ While mechanisms were not analyzed, coffee may reduce mortality risk by affecting inflammation, lung function, insulin sensitivity, and depression.

Cardiovascular disease. Coffee consumption may modestly reduce the risk of stroke, according to a prospective cohort study of 83,076 women from the Nurses’ Health Study who were followed for 24 years.³⁸ Reduced cardiovascular mortality was also found in a large prospective cohort study, as noted in the mortality discussion above.³⁷ A 2014 meta-analysis concluded that coffee consumption is inversely associated with cardiovascular mortality. Drinking 3 or 4 cups a day appears to be the amount that may decrease one’s risk of death when compared to those who do not drink coffee at all.³⁶

Liver disease. Friedrich et al performed a study involving 379 patients with end stage liver disease, and found that coffee consumption delayed the progression of disease in patients with both alcoholic liver disease and primary sclerosing cholangitis.³⁹ Coffee consumption also increased long-term survival after liver transplantation.³⁹ However, the study found that coffee did not have any effect on patients with chronic viral hepatitis.

In a 2016 meta-analysis, caffeinated coffee consumption reduced hepatic fibrosis of nonalcoholic fatty liver disease, although caffeine consumption did not reduce the prevalence of nonalcoholic fatty liver disease.⁴⁰ Another meta-analysis, including 16 studies, also found caffeine reduced the risk for hepatic fibrosis and cirrhosis.⁴¹

Depression. Based on 2 different systematic reviews and meta-analyses from 2016, coffee consumption appears to have a significant protective effect, decreasing the risk of developing depression.^40,42

Alzheimer’s disease/dementia. Coffee, tea, and caffeine consumption show promise in reducing the risk of cognitive decline and dementia. Individuals who consume one to 2 cups of coffee per day had a decreased incidence of mild cognitive impairment compared to non-drinkers.⁴³ A 2015 Japanese study also found an inverse association between coffee consumption and dementia among women, nonsmokers, and those who do not drink alcohol.⁴⁴ Most recently, a 2016 study, the Women’s Health Initiative Memory Study, looked at incident dementia rates in women >65 years of age with high vs low caffeine intake. Women with higher caffeine intake were less likely to develop dementia or any cognitive impairment compared with those consuming <64 mg/day.⁴⁵

Type 2 diabetes. A 2009 prospective cohort study, which included 40,011 participants followed for more than 10 years, found that drinking at least 3 cups of coffee or tea was associated with a lowered risk of type 2 diabetes.⁴⁶ A 2009 systematic review of 20 cohort studies showed that high intakes of coffee, decaffeinated coffee, and tea are associated with a reduced risk of diabetes.⁴⁷

A meta-analysis of 12 studies involving 832,956 participants found an inverse relationship between cutaneous melanoma and coffee consumption.

Melanoma. A meta-analysis of 12 studies involving 832,956 participants demon­strated an inverse relationship between cutaneous melanoma and coffee consumption.⁴⁷ The risk of melanoma decreased by 3% and 4% for one cup/day of total coffee and caffeinated coffee consumption, respectively. Furthermore, a 2016 meta-analysis found that caffeinated coffee may have greater chemopreventive effects against melanoma than decaffeinated coffee.⁴⁸

Adverse effects

Despite the many potential benefits of coffee, caffeine is a potent drug that should be used with caution.⁴⁹ People with underlying heart problems should avoid caffeine due to concern that it may cause palpitations from tachycardia. It may worsen anxiety problems or depression. Coffee may increase the production of stomach acids, which can worsen acid reflux or stomach ulcers.

Regular coffee intake is associated with a lower risk of mortality, reduced CV events, and a reduction in liver disease progression.

Caffeine is a potent diuretic and may decrease absorption of calcium and cause OA. Caffeine may cause dependence and withdrawal symptoms. Some of the symptoms of withdrawal include drowsiness, headaches, irritability, nausea, and vomiting. It may disrupt sleeping patterns by causing jitters and sleeplessness.⁴⁹ Additionally, large amounts of caffeine may cause overdose and death.

The bottom line

Regular coffee intake is associated with a lower risk of mortality, reduced cardiovascular events, and a reduction in liver disease progression. Coffee may also have some utility for improving cognitive function and reducing the risk of type 2 diabetes. Caffeinated coffee should be limited to no more than 32 oz per day, due to the risk of insomnia, palpitations, anxiety, and gastritis.

Overview

Few natural products have been claimed to successfully treat as many disorders as chocolate. The modern concept of chocolate as food has overshadowed its traditional medicinal use, although recent trials have looked at evidence for some of its traditional uses. Chocolate is processed from the pod of the cacao plant. The earliest evidence for its medical use is in Mayan civilizations, and for most of its approximately 4000-year history, chocolate was consumed as a bitter drink referred to as the “drink of the Gods.” The traditional drink was mixed with water, vanilla, honey, chili peppers, and other spices. Important components in chocolate include flavonoids (antioxidants), cocoa butter, caffeine, theobromine, and phenylethylamine.  

Chocolate has stimulating, anti-inflammatory, neuroprotective, and cardioprotective effects, and improves the bioavailability of nitric oxide, which can improve blood pressure and platelet function.⁵⁰ Epicatechin (an antioxidant) in cocoa is primarily responsible for its favorable impact on vascular endothelium via its effect on both acute and chronic upregulation of nitric oxide production. Other cardiovascular effects are mediated by the anti-inflammatory effects of cocoa polyphenols, and modulated through the activity of NF-kappaB.⁵¹

Multiple studies have shown that chocolate is associated with a reduction in cardiovascular risk.

Dark chocolate appears to have the greatest benefit, as milk binds to antioxidants in chocolate, making them unavailable. Therefore, milk chocolate is not a good antioxidant source. There is no specific amount of chocolate that is known to be ideal, but an average of one to 2 ounces per day is often used in studies.

Cardiovascular effects. Chocolate does contain saturated fat, but a comparative, double-blind study found that short-term use of cocoa powder lowered plasma low-density lipoprotein (LDL) cholesterol, oxidized LDL, and apo B concentrations, and the plasma high-density lipoprotein (HDL) cholesterol concentration increased, relative to baseline in the low-, middle-, and high-cocoa groups.⁵² A small randomized crossover trial without clinical outcomes indicated that chocolate may increase HDL cholesterol without increasing weight.⁵³

A meta-analysis of short-term (2-12 weeks) treatment with dark chocolate/cocoa products showed reductions in LDL and total cholesterol, but no changes in HDL or triglycerides.⁵⁴ Another meta-analysis of RCTs, however, showed no short-term effect of cocoa/chocolate on lipid concentrations.⁵⁵ A randomized, placebo-controlled double-blind study of 62 patients with diabetes and hypertension showed that high polyphenol chocolate improved triglyceride levels.⁵⁶

Chocolate intake was associated with a lower risk of cognitive decline, with the greatest benefit noted in those who averaged more than one chocolate bar per week.

Multiple studies have shown that chocolate is associated with a reduction in cardiovascular risk.^57-59 A best case scenario analysis using a Markov model to predict the long-term effectiveness and cost effectiveness of daily dark chocolate consumption in a population with metabolic syndrome at high risk of cardiovascular disease concluded that daily consumption of dark chocolate can reduce cardiovascular events by 85 per 10,000 population treated over 10 years. The study concluded that $42 could be cost effectively spent per person per year on prevention strategies using dark chocolate.⁵⁹

In addition, a meta-analysis of 7 observational studies showed that high levels of chocolate consumption (any type) were associated with a 29% reduction in stroke compared with the lowest levels of chocolate intake.⁵⁷ Results of a similar meta-analysis from Neurology in 2012 also suggested that moderate chocolate consumption (any type) may lower the risk of stroke.⁶⁰

That said, 2 systematic reviews specifically relating to the risk of coronary heart disease and chocolate intake were inconclusive.^61-62

Blood pressure (BP). An RCT published in JAMA indicates that inclusion of small amounts of polyphenol-rich dark chocolate as part of a usual diet efficiently reduced BP and improved the formation of vasodilative nitric oxide.⁶³ A meta-analysis of 10 RCTs also showed mean BP change in the active cocoa treatment arms across all trials was -4.5 mm Hg (95% confidence interval (CI), -5.9 to -3.2; P<.001) for systolic BP and -2.5 mm Hg (95% CI, -3.9 to -1.2; P<.001) for diastolic BP.⁶⁴

A Cochrane Review meta-analysis of 20 studies revealed a statistically significant BP-reducing effect of flavanol-rich cocoa products compared with control in short-term trials of 2 to 18 weeks' duration.⁶⁵ Because studies have shown improvement in BP with chocolate intake, investigations into a role of chocolate in the prevention of preeclampsia have been undertaken. In some studies, chocolate intake was associated with reduced odds of preeclampsia and gestational hypertension.^66,67

Diabetes. Chocolate may exert significant vascular protection because of its antioxidant properties and possible increase of nitric oxide bioavailability, which can influence glucose uptake. A small trial comparing the effects of either dark or white chocolate bars (which do not contain the polyphenols) showed improved BP and glucose and insulin responses to an oral glucose tolerance test in healthy subjects on dark chocolate, but not white chocolate.⁶⁸ A comparison of chocolate consumption and risk of diabetes in the Physicians’ Health Study showed an inverse relationship between chocolate intake with incident disease, but this association appeared only to apply in younger and normal-body weight men after controlling for comprehensive lifestyles, including total energy consumption.⁶⁹

Fatigue. The effect of chocolate on a person’s energy level has been noted for centuries.⁷⁰ A small randomized trial showed improved energy levels in those treated with higher chocolate intakes. In a double-blind, randomized, clinical pilot crossover study, high cocoa liquor/polyphenol rich chocolate, reduced fatigue in subjects with chronic fatigue syndrome.⁷¹

Anxiety. A small randomized trial showed chocolate decreased anxiety in high-anxiety trait subjects and improved the anxiety level and the energy levels of low-anxiety trait participants.⁷²

Eye effects. The literature presents conflicting evidence regarding the effect of flavonoids on patients with glaucoma and ocular hypertension. However, a meta-analysis showed that flavonoids have a promising role in improving visual function in patients with glaucoma and ocular hypertension, and appear to play a part in both improving and slowing the progression of visual field loss.⁷³

Cognitive decline. Chocolate intake (any type) was associated with a lower risk of cognitive decline (RR = 0.59; 95% CI, 0.38-0.92) with the greatest benefit noted in those who averaged more than one chocolate bar or one tablespoon of cocoa powder per week. This protective effect was observed only among subjects with an average daily consumption of caffeine <75  mg (69% of the participants; RR = 0.50; 95% CI, 0.31-0.82).⁷⁴

The bottom line

Chocolate with high cocoa content (dark chocolate) appears to be safe and beneficial as part of a healthy diet and lifestyle that includes exercise and stress reduction to decrease cardiovascular risk and may improve energy levels.

CORRESPONDENCE
Michael Malone, MD, Family and Community Medicine, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033; [email protected].

Despite universal agreement that antibiotic overprescribing is a problem, the practice continues to vex us. Antibiotic use—whether appropriate or not—has been linked to rising rates of antimicrobial resistance, disruption of the gut microbiome leading to Clostridium difficile infections, allergic reactions, and increased health care costs (TABLE 1^1-6). And yet, physicians continue to overprescribe this class of medication.

A 2016 Centers for Disease Control and Prevention (CDC) report estimates that at least 30% of antibiotics prescribed in US outpatient settings are unnecessary.⁷ Another report cites a slightly higher figure across a variety of health care settings.⁸ Pair these findings with the fact that there are currently few new drugs in development to target resistant bacteria, and you have the potential for a post-antibiotic era in which common infections could become lethal.⁷

In 2003, the CDC launched its “Get Smart: Know When Antibiotics Work” program, focused on decreasing inappropriate antibiotic use in the outpatient setting.⁹ In 2014, the White House released the National Action Plan for Combating Antibiotic-Resistant Bacteria with a goal of decreasing inappropriate outpatient antibiotic use by 50% and inappropriate inpatient use by 20% by 2020.¹⁰ And, on an international level, the World Health Organization (WHO) developed a 5-year strategic framework in 2015 for implementing its Global Action Plan on Antimicrobial Resistance.¹¹

Family practitioners are on the front lines of this battle. Here’s what we can do now.

[polldaddy:9885811]

When and where are antibiotics most often inappropriately prescribed?

The diagnosis leading to the most frequent inappropriate prescribing of antibiotics is acute respiratory tract infection (ARTI), which includes bronchitis, otitis media, pharyngitis, sinusitis, tonsillitis, the common cold, and pneumonia. Up to 40% of antibiotic prescriptions for these conditions are unnecessary.^8,12 Bronchitis is the most common ARTI diagnosis associated with inappropriate antibiotic prescriptions, while sinusitis, suppurative otitis media, and pharyngitis are the diagnoses associated with the lion’s share of all (appropriate and inappropriate) antibiotic prescriptions within the ARTI category.^8,9,12,13 There are national clinical guidelines delineating when antibiotic treatment is appropriate for these conditions.^14-16

With respect to setting, studies have presented conflicting results as to whether there is a difference between antibiotic prescribing in office-based vs emergency department (ED) settings. Here is a sample of some of the literature to date:

• One study found a higher rate of antibiotic prescribing during ED visits (21%) than office visits (9%), despite the fact that between 2007 and 2009, more antibiotic prescriptions were written for adults in primary care offices than in either outpatient hospital clinics or EDs.¹⁷
• A cross-sectional study focused on the frequency with which antibiotics were prescribed for uncomplicated acute rhinosinusitis. Researchers analyzed data from 2005 to 2010 National Ambulatory Medical Care Surveys (NAMCS) and National Hospital Ambulatory Medical Care Surveys (NHAMCS) and found that more than half of the patients received prescriptions for antibiotics, but that there was no overall difference in antibiotic prescriptions between primary care and ED presentation.¹⁸
• A retrospective analysis that examined antibiotic prescribing found that between 2006 and 2010, outpatient hospital practices (56%) and community-practice offices (60%) prescribed more antibiotics for ARTIs than EDs (51%).¹²

Stick to narrow-spectrum agents when possible

Using broad-spectrum antibiotics, such as quinolones or imipenem, first line, contributes more to the problem of antibiotic resistance than does prescribing narrow-spectrum antibiotics such as amoxicillin, cephalexin, or trimethoprim-sulfamethoxazole.⁷ Yet between 2007 and 2009, broad-spectrum agents were prescribed for 61% of outpatient adult visits in which patients received an antibiotic prescription.¹⁷ Quinolones (25%), macrolides (20%), and aminopenicillins (12%) were most commonly prescribed, and antibiotic prescriptions were most often written for respiratory conditions, such as bronchitis, for which we now know antibiotics are rarely indicated.¹⁷

Up to 40% of antibiotic prescriptions for acute respiratory tract infections are unnecessary.

Between 2006 and 2008, pediatric patients who received antibiotic prescriptions were given broad-spectrum agents 50% of the time, of which macrolides were the class most commonly prescribed.¹³

More recently, researchers examined the frequency with which physicians prescribe narrow-spectrum, first-line antibiotics for otitis media, sinusitis, and pharyngitis using 2010 to 2011 NAMCS/NHAMCS data. They found that physicians used first-line agents recommended by professional guidelines 52% of the time, although it was estimated that they would have been appropriate in 80% of cases; pediatric patients were more likely to receive appropriate first-line antibiotics than adult patients.¹⁹ Macrolides, especially azithromycin, were the most common non–first-line antibiotics prescribed.^19,20 The bottom line is that when antibiotics are indicated for upper respiratory infections (otitis media, sinusitis, and pharyngitis), physicians should prescribe a narrow-spectrum antibiotic first.

Antibiotic overprescribing affects the gut and beyond

The human intestinal microbiome is composed of a diverse array of bacteria, viruses, and parasites.²¹ The main functions of the gut microbiome include interacting with the immune system and participating in biochemical reactions in the gut, such as absorption of fat-soluble vitamins and the production of vitamin K.

As we know, antibiotics decrease the diversity of gut bacteria, which, in turn, can cause less efficient nutrient extraction, as well as a vulnerability to enteric infections.²¹ It is well known, for example, that the bacterial gut microbiome can either inhibit or promote diarrheal illnesses such as those caused by C. difficile. C. difficile infection (CDI) is now the most common health care-related infection, accounting for approximately a half million health care facility infections a year.²² CDI extends hospital stays an average of almost 10 days and is estimated to cost the health care system $6.3 billion annually.²³

We should pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

Antibiotics can also eliminate antibiotic-susceptible organisms, allowing resistant organisms to proliferate.⁴ They also promote the transmission of genes for antibiotic resistance between gut bacteria.⁴

Beyond the gut

Less well known is that gut bacteria can promote or inhibit extraintestinal infections.

Gut bacteria and HIV. In early human immunodeficiency virus (HIV) infections, for example, gut populations of Lactobacillus and Bifidobacteria are reduced, and the gut barrier becomes compromised.²⁴ Increasing translocation of bacterial products is associated with HIV disease progression. Preservation of Lactobacillus populations in the gut is associated with markers predictive of better HIV outcomes, including a higher CD4 count, a lower viral load, and less evidence of gut microbial translocation.²⁴ This underscores the importance of maintaining a healthy gut flora in patients with HIV, using such steps as avoiding unnecessary antibiotics.

Gut bacteria and stress, depression. Antibiotics directly induce the expression of key genes that affect the stress response.²⁵ While causative studies are lacking, there is a growing body of evidence suggesting that the gut microbiome is involved in 2-way communication with the brain and can affect, and be affected by, stress and depression.^21,26-30 Diseases and conditions that seem to have a putative connection to a disordered microbiome (dysbiosis) include depression, anxiety, Crohn’s disease, type 2 diabetes, and obesity.

Gut bacteria and childhood obesity. Repeated use of broader-spectrum antibiotics in children <24 months of age increases the risk of developing childhood obesity.^1,6 One theory for the association is that the effects of broad-spectrum antibiotics on the intestinal flora of young children may alter long-term energy homeostasis resulting in a higher risk for obesity.¹

Gut bacteria and asthma. Studies demonstrate differences in the gut microbiome of asthmatic and nonasthmatic patients. These differences affect the activities of helper T-cell subsets (Th1 and Th2), which in turn affect the development of immune tolerance.³¹

Although additional studies are needed to confirm these findings, the evidence collected thus far should make us all pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

What can we do right now?

The issues created by the inappropriate prescribing of antibiotics have been known for decades, and multiple attempts have been made to find solutions and implement change. Although some small successes have occurred, little overall progress has been made in reducing antibiotic prescribing in the general population. A historical review of why physicians prescribe antibiotics inappropriately and the interventions that have successfully reduced this prescribing may prove valuable as we continue to look for new, effective answers.

Why do we overprescribe antibiotics? A 2015 systematic literature review found that patient demand, pharmaceutical company marketing activities, limited up-to-date information sources, and physician fear of losing their patients are major reasons physicians cite for prescribing antibiotics.³²

Monthly emails to physicians comparing their prescribing habits to peers and top performers reduced inappropriate antibiotic prescribing for acute respiratory tract infections.

In a separate study that explored antibiotic prescribing habits for acute bronchitis,³³ clinicians cited “patient demand” as the major reason for prescribing antibiotics. Respondents also reported that “other physicians were responsible for inappropriate antibiotic prescribing.”³³

Strategies that work

Some early intervention programs directed at reducing antibiotic prescribing demonstrated success (TABLE 2).^34-36 One example comes from a 1996 to 1998 study of 4 primary care practices.³⁴ Researchers evaluated the impact of a multidimensional intervention effort targeted at clinicians and patients and aimed at lowering the use of antimicrobial agents for acute uncomplicated bronchitis in adults. It incorporated a number of elements, including office-based and household patient educational materials, and a clinician intervention involving education, practice profiling, and academic detailing. Physicians in this program reduced their rates of antibiotic prescribing for uncomplicated bronchitis from 74% to 48%.³⁴

Employing EMRs. A more recent study focused on using electronic medical records (EMRs) and communications to modify physician antibiotic prescribing.³⁵ By sending physicians monthly emails comparing their prescribing patterns to peers and “typical top performers,” inappropriate antibiotic prescriptions for ARTIs went from 19.9% to 3.7%.³⁵

Patients and parents reported higher satisfaction with physicians who explained why antibiotics were not indicated vs physicians who simply prescribed them.

In another effort, the same researchers modified physicians’ EMRs to detect when potentially inappropriate antibiotics were prescribed. The system then prompted the physician to provide an “antibiotic justification note,” which remained visible in the patient’s chart. This approach, which encouraged physicians to follow prescribing guidelines by taking advantage of their concerns about their reputations, produced a 77% reduction in antibiotic prescribing.³⁵

Focusing on the public. Studies have also examined the effectiveness of educating the public about when antibiotics are not likely to be helpful and of the harms of unnecessary antibiotics. Studies conducted in Tennessee and Wisconsin that combined prescriber and community education about unnecessary antibiotics for children found that the intervention reduced antibiotic prescribing in both locations by about 19% compared with about a 9% reduction in the control groups.^36,37

Does prescribing antibiotics affect patient satisfaction?

The results are mixed as to whether prescribing antibiotics affects patient satisfaction. Two studies in the early 2000s found that both patients and parents reported higher satisfaction with physicians who explained why antibiotics were not indicated vs physicians who simply prescribed them, and that such explanations do not need to take a lot of time.^37,38 (See TABLE 3^9,37,38 for patient care tips.)

A more recent study found that higher antibiotic prescribing practices in Britain were associated with modestly higher patient satisfaction ratings.³⁹ The authors of this study noted, however, that reduced antibiotic prescribing may be a proxy for other practice patterns that affected satisfaction ratings.

Reducing antibiotic prescribing reduces resistance

There is also strong evidence that when physicians decrease antibiotic prescribing, antimicrobial resistance follows suit. One of the earlier landmark studies to demonstrate this was a Finnish study published in 1997.⁴⁰ The authors found that a reduction of macrolide antibiotic consumption in Finland led to a reduction in streptococci macrolide resistance from 16.5% to 8.6%.⁴⁰

There is strong evidence that when physicians decrease antibiotic prescribing, antimicrobial resistance follows suit.

Since then, multiple studies have demonstrated similar results for both respiratory and urinary tract infections.^41,42 A 2017 meta-analysis analyzing 32 studies found that antibiotic stewardship programs reduced the incidence of infections and colonization with multidrug-resistant Gram-negative bacteria (51% reduction), extended-spectrum beta-lactamase–producing Gram-negative bacteria (48%), and methicillin-resistant Staphylococcus aureus (37%). There was also a reduction in the incidence of C. difficile infections (32%).⁴³

CORRESPONDENCE
David C. Fiore, MD, Department of Family and Community Medicine, University of Nevada, Reno School of Medicine, Brigham Bldg, MS 316, Reno, NV 89557; [email protected].

Despite universal agreement that antibiotic overprescribing is a problem, the practice continues to vex us. Antibiotic use—whether appropriate or not—has been linked to rising rates of antimicrobial resistance, disruption of the gut microbiome leading to Clostridium difficile infections, allergic reactions, and increased health care costs (TABLE 1^1-6). And yet, physicians continue to overprescribe this class of medication.

A 2016 Centers for Disease Control and Prevention (CDC) report estimates that at least 30% of antibiotics prescribed in US outpatient settings are unnecessary.⁷ Another report cites a slightly higher figure across a variety of health care settings.⁸ Pair these findings with the fact that there are currently few new drugs in development to target resistant bacteria, and you have the potential for a post-antibiotic era in which common infections could become lethal.⁷

In 2003, the CDC launched its “Get Smart: Know When Antibiotics Work” program, focused on decreasing inappropriate antibiotic use in the outpatient setting.⁹ In 2014, the White House released the National Action Plan for Combating Antibiotic-Resistant Bacteria with a goal of decreasing inappropriate outpatient antibiotic use by 50% and inappropriate inpatient use by 20% by 2020.¹⁰ And, on an international level, the World Health Organization (WHO) developed a 5-year strategic framework in 2015 for implementing its Global Action Plan on Antimicrobial Resistance.¹¹

Family practitioners are on the front lines of this battle. Here’s what we can do now.

[polldaddy:9885811]

When and where are antibiotics most often inappropriately prescribed?

The diagnosis leading to the most frequent inappropriate prescribing of antibiotics is acute respiratory tract infection (ARTI), which includes bronchitis, otitis media, pharyngitis, sinusitis, tonsillitis, the common cold, and pneumonia. Up to 40% of antibiotic prescriptions for these conditions are unnecessary.^8,12 Bronchitis is the most common ARTI diagnosis associated with inappropriate antibiotic prescriptions, while sinusitis, suppurative otitis media, and pharyngitis are the diagnoses associated with the lion’s share of all (appropriate and inappropriate) antibiotic prescriptions within the ARTI category.^8,9,12,13 There are national clinical guidelines delineating when antibiotic treatment is appropriate for these conditions.^14-16

With respect to setting, studies have presented conflicting results as to whether there is a difference between antibiotic prescribing in office-based vs emergency department (ED) settings. Here is a sample of some of the literature to date:

• One study found a higher rate of antibiotic prescribing during ED visits (21%) than office visits (9%), despite the fact that between 2007 and 2009, more antibiotic prescriptions were written for adults in primary care offices than in either outpatient hospital clinics or EDs.¹⁷
• A cross-sectional study focused on the frequency with which antibiotics were prescribed for uncomplicated acute rhinosinusitis. Researchers analyzed data from 2005 to 2010 National Ambulatory Medical Care Surveys (NAMCS) and National Hospital Ambulatory Medical Care Surveys (NHAMCS) and found that more than half of the patients received prescriptions for antibiotics, but that there was no overall difference in antibiotic prescriptions between primary care and ED presentation.¹⁸
• A retrospective analysis that examined antibiotic prescribing found that between 2006 and 2010, outpatient hospital practices (56%) and community-practice offices (60%) prescribed more antibiotics for ARTIs than EDs (51%).¹²

Stick to narrow-spectrum agents when possible

Using broad-spectrum antibiotics, such as quinolones or imipenem, first line, contributes more to the problem of antibiotic resistance than does prescribing narrow-spectrum antibiotics such as amoxicillin, cephalexin, or trimethoprim-sulfamethoxazole.⁷ Yet between 2007 and 2009, broad-spectrum agents were prescribed for 61% of outpatient adult visits in which patients received an antibiotic prescription.¹⁷ Quinolones (25%), macrolides (20%), and aminopenicillins (12%) were most commonly prescribed, and antibiotic prescriptions were most often written for respiratory conditions, such as bronchitis, for which we now know antibiotics are rarely indicated.¹⁷

Up to 40% of antibiotic prescriptions for acute respiratory tract infections are unnecessary.

Between 2006 and 2008, pediatric patients who received antibiotic prescriptions were given broad-spectrum agents 50% of the time, of which macrolides were the class most commonly prescribed.¹³

More recently, researchers examined the frequency with which physicians prescribe narrow-spectrum, first-line antibiotics for otitis media, sinusitis, and pharyngitis using 2010 to 2011 NAMCS/NHAMCS data. They found that physicians used first-line agents recommended by professional guidelines 52% of the time, although it was estimated that they would have been appropriate in 80% of cases; pediatric patients were more likely to receive appropriate first-line antibiotics than adult patients.¹⁹ Macrolides, especially azithromycin, were the most common non–first-line antibiotics prescribed.^19,20 The bottom line is that when antibiotics are indicated for upper respiratory infections (otitis media, sinusitis, and pharyngitis), physicians should prescribe a narrow-spectrum antibiotic first.

Antibiotic overprescribing affects the gut and beyond

The human intestinal microbiome is composed of a diverse array of bacteria, viruses, and parasites.²¹ The main functions of the gut microbiome include interacting with the immune system and participating in biochemical reactions in the gut, such as absorption of fat-soluble vitamins and the production of vitamin K.

As we know, antibiotics decrease the diversity of gut bacteria, which, in turn, can cause less efficient nutrient extraction, as well as a vulnerability to enteric infections.²¹ It is well known, for example, that the bacterial gut microbiome can either inhibit or promote diarrheal illnesses such as those caused by C. difficile. C. difficile infection (CDI) is now the most common health care-related infection, accounting for approximately a half million health care facility infections a year.²² CDI extends hospital stays an average of almost 10 days and is estimated to cost the health care system $6.3 billion annually.²³

We should pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

Antibiotics can also eliminate antibiotic-susceptible organisms, allowing resistant organisms to proliferate.⁴ They also promote the transmission of genes for antibiotic resistance between gut bacteria.⁴

Beyond the gut

Less well known is that gut bacteria can promote or inhibit extraintestinal infections.

Gut bacteria and HIV. In early human immunodeficiency virus (HIV) infections, for example, gut populations of Lactobacillus and Bifidobacteria are reduced, and the gut barrier becomes compromised.²⁴ Increasing translocation of bacterial products is associated with HIV disease progression. Preservation of Lactobacillus populations in the gut is associated with markers predictive of better HIV outcomes, including a higher CD4 count, a lower viral load, and less evidence of gut microbial translocation.²⁴ This underscores the importance of maintaining a healthy gut flora in patients with HIV, using such steps as avoiding unnecessary antibiotics.

Gut bacteria and stress, depression. Antibiotics directly induce the expression of key genes that affect the stress response.²⁵ While causative studies are lacking, there is a growing body of evidence suggesting that the gut microbiome is involved in 2-way communication with the brain and can affect, and be affected by, stress and depression.^21,26-30 Diseases and conditions that seem to have a putative connection to a disordered microbiome (dysbiosis) include depression, anxiety, Crohn’s disease, type 2 diabetes, and obesity.

Gut bacteria and childhood obesity. Repeated use of broader-spectrum antibiotics in children <24 months of age increases the risk of developing childhood obesity.^1,6 One theory for the association is that the effects of broad-spectrum antibiotics on the intestinal flora of young children may alter long-term energy homeostasis resulting in a higher risk for obesity.¹

Gut bacteria and asthma. Studies demonstrate differences in the gut microbiome of asthmatic and nonasthmatic patients. These differences affect the activities of helper T-cell subsets (Th1 and Th2), which in turn affect the development of immune tolerance.³¹

Although additional studies are needed to confirm these findings, the evidence collected thus far should make us all pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

What can we do right now?

The issues created by the inappropriate prescribing of antibiotics have been known for decades, and multiple attempts have been made to find solutions and implement change. Although some small successes have occurred, little overall progress has been made in reducing antibiotic prescribing in the general population. A historical review of why physicians prescribe antibiotics inappropriately and the interventions that have successfully reduced this prescribing may prove valuable as we continue to look for new, effective answers.

Why do we overprescribe antibiotics? A 2015 systematic literature review found that patient demand, pharmaceutical company marketing activities, limited up-to-date information sources, and physician fear of losing their patients are major reasons physicians cite for prescribing antibiotics.³²

Monthly emails to physicians comparing their prescribing habits to peers and top performers reduced inappropriate antibiotic prescribing for acute respiratory tract infections.

In a separate study that explored antibiotic prescribing habits for acute bronchitis,³³ clinicians cited “patient demand” as the major reason for prescribing antibiotics. Respondents also reported that “other physicians were responsible for inappropriate antibiotic prescribing.”³³

Strategies that work

Some early intervention programs directed at reducing antibiotic prescribing demonstrated success (TABLE 2).^34-36 One example comes from a 1996 to 1998 study of 4 primary care practices.³⁴ Researchers evaluated the impact of a multidimensional intervention effort targeted at clinicians and patients and aimed at lowering the use of antimicrobial agents for acute uncomplicated bronchitis in adults. It incorporated a number of elements, including office-based and household patient educational materials, and a clinician intervention involving education, practice profiling, and academic detailing. Physicians in this program reduced their rates of antibiotic prescribing for uncomplicated bronchitis from 74% to 48%.³⁴

Employing EMRs. A more recent study focused on using electronic medical records (EMRs) and communications to modify physician antibiotic prescribing.³⁵ By sending physicians monthly emails comparing their prescribing patterns to peers and “typical top performers,” inappropriate antibiotic prescriptions for ARTIs went from 19.9% to 3.7%.³⁵

Patients and parents reported higher satisfaction with physicians who explained why antibiotics were not indicated vs physicians who simply prescribed them.

In another effort, the same researchers modified physicians’ EMRs to detect when potentially inappropriate antibiotics were prescribed. The system then prompted the physician to provide an “antibiotic justification note,” which remained visible in the patient’s chart. This approach, which encouraged physicians to follow prescribing guidelines by taking advantage of their concerns about their reputations, produced a 77% reduction in antibiotic prescribing.³⁵

Focusing on the public. Studies have also examined the effectiveness of educating the public about when antibiotics are not likely to be helpful and of the harms of unnecessary antibiotics. Studies conducted in Tennessee and Wisconsin that combined prescriber and community education about unnecessary antibiotics for children found that the intervention reduced antibiotic prescribing in both locations by about 19% compared with about a 9% reduction in the control groups.^36,37

Does prescribing antibiotics affect patient satisfaction?

The results are mixed as to whether prescribing antibiotics affects patient satisfaction. Two studies in the early 2000s found that both patients and parents reported higher satisfaction with physicians who explained why antibiotics were not indicated vs physicians who simply prescribed them, and that such explanations do not need to take a lot of time.^37,38 (See TABLE 3^9,37,38 for patient care tips.)

A more recent study found that higher antibiotic prescribing practices in Britain were associated with modestly higher patient satisfaction ratings.³⁹ The authors of this study noted, however, that reduced antibiotic prescribing may be a proxy for other practice patterns that affected satisfaction ratings.

Reducing antibiotic prescribing reduces resistance

There is also strong evidence that when physicians decrease antibiotic prescribing, antimicrobial resistance follows suit. One of the earlier landmark studies to demonstrate this was a Finnish study published in 1997.⁴⁰ The authors found that a reduction of macrolide antibiotic consumption in Finland led to a reduction in streptococci macrolide resistance from 16.5% to 8.6%.⁴⁰

There is strong evidence that when physicians decrease antibiotic prescribing, antimicrobial resistance follows suit.

Since then, multiple studies have demonstrated similar results for both respiratory and urinary tract infections.^41,42 A 2017 meta-analysis analyzing 32 studies found that antibiotic stewardship programs reduced the incidence of infections and colonization with multidrug-resistant Gram-negative bacteria (51% reduction), extended-spectrum beta-lactamase–producing Gram-negative bacteria (48%), and methicillin-resistant Staphylococcus aureus (37%). There was also a reduction in the incidence of C. difficile infections (32%).⁴³

CORRESPONDENCE
David C. Fiore, MD, Department of Family and Community Medicine, University of Nevada, Reno School of Medicine, Brigham Bldg, MS 316, Reno, NV 89557; [email protected].

Despite universal agreement that antibiotic overprescribing is a problem, the practice continues to vex us. Antibiotic use—whether appropriate or not—has been linked to rising rates of antimicrobial resistance, disruption of the gut microbiome leading to Clostridium difficile infections, allergic reactions, and increased health care costs (TABLE 1^1-6). And yet, physicians continue to overprescribe this class of medication.

A 2016 Centers for Disease Control and Prevention (CDC) report estimates that at least 30% of antibiotics prescribed in US outpatient settings are unnecessary.⁷ Another report cites a slightly higher figure across a variety of health care settings.⁸ Pair these findings with the fact that there are currently few new drugs in development to target resistant bacteria, and you have the potential for a post-antibiotic era in which common infections could become lethal.⁷

In 2003, the CDC launched its “Get Smart: Know When Antibiotics Work” program, focused on decreasing inappropriate antibiotic use in the outpatient setting.⁹ In 2014, the White House released the National Action Plan for Combating Antibiotic-Resistant Bacteria with a goal of decreasing inappropriate outpatient antibiotic use by 50% and inappropriate inpatient use by 20% by 2020.¹⁰ And, on an international level, the World Health Organization (WHO) developed a 5-year strategic framework in 2015 for implementing its Global Action Plan on Antimicrobial Resistance.¹¹

Family practitioners are on the front lines of this battle. Here’s what we can do now.

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When and where are antibiotics most often inappropriately prescribed?

The diagnosis leading to the most frequent inappropriate prescribing of antibiotics is acute respiratory tract infection (ARTI), which includes bronchitis, otitis media, pharyngitis, sinusitis, tonsillitis, the common cold, and pneumonia. Up to 40% of antibiotic prescriptions for these conditions are unnecessary.^8,12 Bronchitis is the most common ARTI diagnosis associated with inappropriate antibiotic prescriptions, while sinusitis, suppurative otitis media, and pharyngitis are the diagnoses associated with the lion’s share of all (appropriate and inappropriate) antibiotic prescriptions within the ARTI category.^8,9,12,13 There are national clinical guidelines delineating when antibiotic treatment is appropriate for these conditions.^14-16

With respect to setting, studies have presented conflicting results as to whether there is a difference between antibiotic prescribing in office-based vs emergency department (ED) settings. Here is a sample of some of the literature to date:

• One study found a higher rate of antibiotic prescribing during ED visits (21%) than office visits (9%), despite the fact that between 2007 and 2009, more antibiotic prescriptions were written for adults in primary care offices than in either outpatient hospital clinics or EDs.¹⁷
• A cross-sectional study focused on the frequency with which antibiotics were prescribed for uncomplicated acute rhinosinusitis. Researchers analyzed data from 2005 to 2010 National Ambulatory Medical Care Surveys (NAMCS) and National Hospital Ambulatory Medical Care Surveys (NHAMCS) and found that more than half of the patients received prescriptions for antibiotics, but that there was no overall difference in antibiotic prescriptions between primary care and ED presentation.¹⁸
• A retrospective analysis that examined antibiotic prescribing found that between 2006 and 2010, outpatient hospital practices (56%) and community-practice offices (60%) prescribed more antibiotics for ARTIs than EDs (51%).¹²

Stick to narrow-spectrum agents when possible

Using broad-spectrum antibiotics, such as quinolones or imipenem, first line, contributes more to the problem of antibiotic resistance than does prescribing narrow-spectrum antibiotics such as amoxicillin, cephalexin, or trimethoprim-sulfamethoxazole.⁷ Yet between 2007 and 2009, broad-spectrum agents were prescribed for 61% of outpatient adult visits in which patients received an antibiotic prescription.¹⁷ Quinolones (25%), macrolides (20%), and aminopenicillins (12%) were most commonly prescribed, and antibiotic prescriptions were most often written for respiratory conditions, such as bronchitis, for which we now know antibiotics are rarely indicated.¹⁷

Up to 40% of antibiotic prescriptions for acute respiratory tract infections are unnecessary.

Between 2006 and 2008, pediatric patients who received antibiotic prescriptions were given broad-spectrum agents 50% of the time, of which macrolides were the class most commonly prescribed.¹³

More recently, researchers examined the frequency with which physicians prescribe narrow-spectrum, first-line antibiotics for otitis media, sinusitis, and pharyngitis using 2010 to 2011 NAMCS/NHAMCS data. They found that physicians used first-line agents recommended by professional guidelines 52% of the time, although it was estimated that they would have been appropriate in 80% of cases; pediatric patients were more likely to receive appropriate first-line antibiotics than adult patients.¹⁹ Macrolides, especially azithromycin, were the most common non–first-line antibiotics prescribed.^19,20 The bottom line is that when antibiotics are indicated for upper respiratory infections (otitis media, sinusitis, and pharyngitis), physicians should prescribe a narrow-spectrum antibiotic first.

Antibiotic overprescribing affects the gut and beyond

The human intestinal microbiome is composed of a diverse array of bacteria, viruses, and parasites.²¹ The main functions of the gut microbiome include interacting with the immune system and participating in biochemical reactions in the gut, such as absorption of fat-soluble vitamins and the production of vitamin K.

As we know, antibiotics decrease the diversity of gut bacteria, which, in turn, can cause less efficient nutrient extraction, as well as a vulnerability to enteric infections.²¹ It is well known, for example, that the bacterial gut microbiome can either inhibit or promote diarrheal illnesses such as those caused by C. difficile. C. difficile infection (CDI) is now the most common health care-related infection, accounting for approximately a half million health care facility infections a year.²² CDI extends hospital stays an average of almost 10 days and is estimated to cost the health care system $6.3 billion annually.²³

We should pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

Antibiotics can also eliminate antibiotic-susceptible organisms, allowing resistant organisms to proliferate.⁴ They also promote the transmission of genes for antibiotic resistance between gut bacteria.⁴

Beyond the gut

Less well known is that gut bacteria can promote or inhibit extraintestinal infections.

Gut bacteria and HIV. In early human immunodeficiency virus (HIV) infections, for example, gut populations of Lactobacillus and Bifidobacteria are reduced, and the gut barrier becomes compromised.²⁴ Increasing translocation of bacterial products is associated with HIV disease progression. Preservation of Lactobacillus populations in the gut is associated with markers predictive of better HIV outcomes, including a higher CD4 count, a lower viral load, and less evidence of gut microbial translocation.²⁴ This underscores the importance of maintaining a healthy gut flora in patients with HIV, using such steps as avoiding unnecessary antibiotics.

Gut bacteria and stress, depression. Antibiotics directly induce the expression of key genes that affect the stress response.²⁵ While causative studies are lacking, there is a growing body of evidence suggesting that the gut microbiome is involved in 2-way communication with the brain and can affect, and be affected by, stress and depression.^21,26-30 Diseases and conditions that seem to have a putative connection to a disordered microbiome (dysbiosis) include depression, anxiety, Crohn’s disease, type 2 diabetes, and obesity.

Gut bacteria and childhood obesity. Repeated use of broader-spectrum antibiotics in children <24 months of age increases the risk of developing childhood obesity.^1,6 One theory for the association is that the effects of broad-spectrum antibiotics on the intestinal flora of young children may alter long-term energy homeostasis resulting in a higher risk for obesity.¹

Gut bacteria and asthma. Studies demonstrate differences in the gut microbiome of asthmatic and nonasthmatic patients. These differences affect the activities of helper T-cell subsets (Th1 and Th2), which in turn affect the development of immune tolerance.³¹

Although additional studies are needed to confirm these findings, the evidence collected thus far should make us all pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

What can we do right now?

The issues created by the inappropriate prescribing of antibiotics have been known for decades, and multiple attempts have been made to find solutions and implement change. Although some small successes have occurred, little overall progress has been made in reducing antibiotic prescribing in the general population. A historical review of why physicians prescribe antibiotics inappropriately and the interventions that have successfully reduced this prescribing may prove valuable as we continue to look for new, effective answers.

Why do we overprescribe antibiotics? A 2015 systematic literature review found that patient demand, pharmaceutical company marketing activities, limited up-to-date information sources, and physician fear of losing their patients are major reasons physicians cite for prescribing antibiotics.³²

Monthly emails to physicians comparing their prescribing habits to peers and top performers reduced inappropriate antibiotic prescribing for acute respiratory tract infections.

In a separate study that explored antibiotic prescribing habits for acute bronchitis,³³ clinicians cited “patient demand” as the major reason for prescribing antibiotics. Respondents also reported that “other physicians were responsible for inappropriate antibiotic prescribing.”³³

Strategies that work

Some early intervention programs directed at reducing antibiotic prescribing demonstrated success (TABLE 2).^34-36 One example comes from a 1996 to 1998 study of 4 primary care practices.³⁴ Researchers evaluated the impact of a multidimensional intervention effort targeted at clinicians and patients and aimed at lowering the use of antimicrobial agents for acute uncomplicated bronchitis in adults. It incorporated a number of elements, including office-based and household patient educational materials, and a clinician intervention involving education, practice profiling, and academic detailing. Physicians in this program reduced their rates of antibiotic prescribing for uncomplicated bronchitis from 74% to 48%.³⁴

Employing EMRs. A more recent study focused on using electronic medical records (EMRs) and communications to modify physician antibiotic prescribing.³⁵ By sending physicians monthly emails comparing their prescribing patterns to peers and “typical top performers,” inappropriate antibiotic prescriptions for ARTIs went from 19.9% to 3.7%.³⁵

Patients and parents reported higher satisfaction with physicians who explained why antibiotics were not indicated vs physicians who simply prescribed them.

In another effort, the same researchers modified physicians’ EMRs to detect when potentially inappropriate antibiotics were prescribed. The system then prompted the physician to provide an “antibiotic justification note,” which remained visible in the patient’s chart. This approach, which encouraged physicians to follow prescribing guidelines by taking advantage of their concerns about their reputations, produced a 77% reduction in antibiotic prescribing.³⁵

Focusing on the public. Studies have also examined the effectiveness of educating the public about when antibiotics are not likely to be helpful and of the harms of unnecessary antibiotics. Studies conducted in Tennessee and Wisconsin that combined prescriber and community education about unnecessary antibiotics for children found that the intervention reduced antibiotic prescribing in both locations by about 19% compared with about a 9% reduction in the control groups.^36,37

Does prescribing antibiotics affect patient satisfaction?

The results are mixed as to whether prescribing antibiotics affects patient satisfaction. Two studies in the early 2000s found that both patients and parents reported higher satisfaction with physicians who explained why antibiotics were not indicated vs physicians who simply prescribed them, and that such explanations do not need to take a lot of time.^37,38 (See TABLE 3^9,37,38 for patient care tips.)

A more recent study found that higher antibiotic prescribing practices in Britain were associated with modestly higher patient satisfaction ratings.³⁹ The authors of this study noted, however, that reduced antibiotic prescribing may be a proxy for other practice patterns that affected satisfaction ratings.

Reducing antibiotic prescribing reduces resistance

There is also strong evidence that when physicians decrease antibiotic prescribing, antimicrobial resistance follows suit. One of the earlier landmark studies to demonstrate this was a Finnish study published in 1997.⁴⁰ The authors found that a reduction of macrolide antibiotic consumption in Finland led to a reduction in streptococci macrolide resistance from 16.5% to 8.6%.⁴⁰

There is strong evidence that when physicians decrease antibiotic prescribing, antimicrobial resistance follows suit.

Since then, multiple studies have demonstrated similar results for both respiratory and urinary tract infections.^41,42 A 2017 meta-analysis analyzing 32 studies found that antibiotic stewardship programs reduced the incidence of infections and colonization with multidrug-resistant Gram-negative bacteria (51% reduction), extended-spectrum beta-lactamase–producing Gram-negative bacteria (48%), and methicillin-resistant Staphylococcus aureus (37%). There was also a reduction in the incidence of C. difficile infections (32%).⁴³

CORRESPONDENCE
David C. Fiore, MD, Department of Family and Community Medicine, University of Nevada, Reno School of Medicine, Brigham Bldg, MS 316, Reno, NV 89557; [email protected].

Over the past decade, physician-pharmacist collaborative practices have gained traction in primary care as a way to implement team-based-care models. And there is evidence pointing to the effectiveness of this multidisciplinary heath care team approach, in which pharmacists are typically responsible for such things as obtaining medication histories, identifying barriers to adherence, and adjusting medication regimens.

Several studies have shown the significant impact that physician-pharmacist collaborative management (PPCM) can have on blood pressure (BP) control among patients with hypertension (HTN).^1-8 Additionally, PPCM may have positive effects on HbA1c reduction and diabetes control,^9-11 suggesting that benefits may extend to other chronic diseases, too.

In the review that follows, we’ll detail the impact that PPCM can have on patient care, health-care utilization, and cost effectiveness. (For a look at PPCM “in action,” see the sidebar below.) We’ll also review the challenges of implementing this model that, at present, is mostly found in academically-affiliated clinics and large health systems.

PPCM impacts chronic diseases

The current literature is rife with studies investigating the impact of PPCM on chronic diseases in the primary care setting.^1-12 Although no specific guidelines on implementing PPCM exist, these studies utilized similar interventions that provided pharmacists with the ability to manage medication therapy under the supervision of a physician. A number of these studies incorporated collaborative practice plans to delineate the specific duties performed by physicians and pharmacists.^2,6,8,10,11 Responsibilities for pharmacists often included assessing vital signs, reviewing laboratory parameters and ordering appropriate tests, providing patient education, screening for drug interactions, identifying barriers to medication adherence, and adjusting medication regimens. The TABLE^1-12 provides a summary of studies investigating the impact of PPCM in the primary care setting.

PPCM leads to greater BP reductions, improved BP control

The majority of research surrounding PPCM has focused on uncontrolled HTN.^1-8 Patients in many of these studies saw a pharmacist in a specialized HTN clinic, where the multidisciplinary staff performed a thorough evaluation of the patient’s current hypertensive management. The pharmacists in these PPCM programs closely monitored patients and made adjustments to antihypertensive regimens as necessary. Systolic and diastolic BP reductions in the intervention groups ranged from 14 to 36 mm Hg and 7 to 15 mm Hg, respectively.^1-5,7,8 The percentage of patients with BP control at the end of the studies ranged from 43% to 89%.^1,3,4,6,7

In a prospective, cluster-randomized trial performed at 32 primary care offices in 15 states, researchers assigned 625 patients with uncontrolled HTN to receive physician-pharmacist collaborative care or usual care with primary care provider management.⁷ As part of the PPCM intervention, clinical pharmacists conducted a thorough medical record review and a structured interview of the patients. During the interview, the clinical pharmacists reviewed the patient’s medication history, assessed the patient’s knowledge of BP medications, and addressed any barriers to adherence. In collaboration with the physician, the pharmacists developed a care plan with recommendations for optimizing the drug regimen. After the baseline visit, the pharmacists conducted structured face-to-face interviews with patients at 1, 2, 4, 6, and 8 months, with additional visits scheduled if BP was still uncontrolled.

At 9 months, patients in the PPCM group had significantly greater reductions in BP than those in the control group, and BP control was achieved in 43% of the PPCM group vs 34% of the control group. This study corroborates results from previous (similar) studies investigating the impact of PPCM on patients with uncontrolled HTN.^1-6

PPCM helps patients reduce their HbA1c levels

Researchers have also studied the impact of PPCM strategies on the management of diabetes mellitus.^9-11 In one retrospective study of 157 patients, implementation of a pharmacy-coordinated diabetes (any type) management program significantly improved HbA1c and increased the percentage of patients reaching their HbA1c goal.⁹ Furthermore, researchers observed improvements in low-density lipoprotein cholesterol (LDL-C) levels and an increased number of patients obtaining a microalbumin screening after initiation of the program.

A more recent prospective, multicenter cohort study of 206 patients with uncontrolled type 2 diabetes had similar results.¹⁰ In collaboration with the primary care physician (PCP), clinical pharmacists provided medication therapy management through adjustment of antihyperglycemic, antihypertensive, or lipid-lowering medications. Additional interventions provided by the pharmacists included reviewing blood glucose logs, ordering and monitoring laboratory tests, performing sensory foot examinations, and providing patient education.

Implementation of PPCM reduced the average HbA1c by 1.2% and increased the percentage of patients achieving an HbA1c <7% by about 24%. The researchers also observed improvements in BP and LDL-C levels in this patient population.¹¹

Asthma and beyond

Future studies may well show that the benefits of PPCM extend to the management of other chronic diseases. One prospective, pre-post study of 126 patients with asthma found that the number of emergency department (ED) visits and/or hospitalizations decreased 30% during 9 months with a PPCM intervention and then returned to levels similar to baseline once the intervention ceased.¹² Other potential disease areas that have been studied, or are being studied, include chronic obstructive pulmonary disease, chronic kidney disease, dyslipidemia, and congestive heart failure.¹³

Benefits derive from altered health care utilization

Researchers attribute much of the benefit observed with PPCM to the increased—albeit different—health-care utilization among the patients in the intervention groups. In general, patients participating in PPCM have an increased total number of visits, but more of those visits are with pharmacists and fewer are with physicians; they also are prescribed more medications, but don’t necessarily take more pills per day.^1,2,5 In the end, patients have been found to achieve significantly better disease control without compromising quality of life or satisfaction.²

Some studies have found that continued pharmacist involvement may be necessary to sustain the benefits achieved.⁶ However, other studies have suggested that the benefits are maintained even after discontinuation of the pharmacist intervention.^14,15 Thus, further research is necessary to determine which patients may benefit most from ongoing involvement with a pharmacist.

How cost-effective is the PPCM model?

Implementing a PPCM model in a primary care setting often hinges upon whether the intervention will be cost-effective. Several studies have reported the cost-effectiveness of clinical pharmacists in the management of HTN.^1,16,17

Borenstein and colleagues found significantly lower provider visit costs per patient in the PPCM group ($160) compared with the usual care group ($195), a difference that the authors attributed to a decreased number of visits to PCPs and an increased number of lower cost visits with pharmacists in the PPCM group.¹ However, the difference could have been affected by the arbitrary measurement of physician-pharmacist collaboration time in the study.

Overcoming implementation challenges

Implementation of pharmacist collaboration within primary care medicine may pose a challenge, as the requirements and resources vary widely among primary care settings. Health-system administrators, for example, may need to reorganize the clinic structure and budget resources in order to overcome some of the obstacles to implementing a PPCM model.

Researchers found that patients in a physician-pharmacist collaborative management model had significantly greater reductions in BP than those in the control group.

Experts have reported several strategies that help in establishing PPCM within primary care clinics,¹⁸ including proactively identifying patients who may benefit from pharmacist intervention, requiring appropriate training and credentialing of pharmacists, and establishing a set schedule for pharmacists to interview patients. Clinics would also be well served to model interventions outlined in the studies mentioned in this article and provide adequate time for pharmacists to perform structured activities, including review of medication history, assessment of current disease state control, and adjustment of medication therapy regimens. And, of course, given the diversity of primary care settings, administrators will need to identify the specific PPCM strategies that best complement their respective collaborative practice plans and environments.

The lack of well-defined reimbursement models for pharmacy services has presented a challenge for generating revenue and effectively implementing PPCM within many primary care settings. Currently, the Centers for Medicare and Medicaid Services and third-party payers do not recognize pharmacists as independent providers, creating a barrier for obtaining reimbursement for clinical pharmacy services. Typically, pharmacists have charged for clinic visits under a consultant physician through the “incident to” billing model, with the option to bill at higher levels if the patient was seen jointly with the physician.

Can this model benefit the underserved?

A prospective, cluster-randomized clinic study has shown pharmacist intervention to reduce racial and socioeconomic disparities in the treatment of elevated BP.¹⁹ This study is the first to show that a team-care model can overcome inequalities arising from low income, low patient education status, and little or no insurance to produce the same health care benefit as in those with higher socioeconomic and educational status. This type of collaborative care model may be particularly beneficial when incorporated within a PCMH catering to underserved populations.²⁰

Implementation of a physician-pharmacist collaborative management model reduced the average HbA1c by 1.2%.

However, sparse data currently exist regarding the benefits of the PPCM model within a PCMH, despite the fact that integration of this type of collaborative model is expected to contribute positively to patient care.²¹

Physician acceptance of pharmacist involvement is mixed

While physician acceptance of pharmacist recommendations is generally high, at least one study indicated that some health-care professionals in patient-care teams are reluctant to incorporate pharmacists into a PCMH. Reasons include difficulty in coordination of care with pharmacy services and limited knowledge by other professionals of pharmacists’ training.²²

Centralization can combat a lack of resources

As noted earlier, primary care offices that implement PPCM models are mostly academically affiliated or are part of large health systems. Many private primary care offices lack the resources to employ a pharmacist in their office. As an alternative, prospective clinical trials are looking at a centralized, Web-based cardiovascular risk service managed by pharmacists.^23,24 This service’s primary objective is to improve adherence to metric-based outcomes developed as part of The Guideline Advantage quality improvement program put forth by the American Cancer Society, American Diabetes Association, and the American Heart and Stroke Associations. (See http://www.guidelineadvantage.org/TGA/ for more information.)

Researchers hope to prove that a centralized, pharmacist-run, clinical service can meet metric-driven outcomes that many primary care offices are now being required to meet in order to receive compensation from insurance companies. One of these studies is specifically looking at rural private offices that lack many of the resources that many large academic offices possess.²³ The study is ongoing and results are expected sometime in 2018.

CORRESPONDENCE
John G. Gums, PharmD, College of Pharmacy, University of Florida, 1225 Center Drive, HPNP 4332, Gainesville, FL 32601; [email protected].

Over the past decade, physician-pharmacist collaborative practices have gained traction in primary care as a way to implement team-based-care models. And there is evidence pointing to the effectiveness of this multidisciplinary heath care team approach, in which pharmacists are typically responsible for such things as obtaining medication histories, identifying barriers to adherence, and adjusting medication regimens.

Several studies have shown the significant impact that physician-pharmacist collaborative management (PPCM) can have on blood pressure (BP) control among patients with hypertension (HTN).^1-8 Additionally, PPCM may have positive effects on HbA1c reduction and diabetes control,^9-11 suggesting that benefits may extend to other chronic diseases, too.

In the review that follows, we’ll detail the impact that PPCM can have on patient care, health-care utilization, and cost effectiveness. (For a look at PPCM “in action,” see the sidebar below.) We’ll also review the challenges of implementing this model that, at present, is mostly found in academically-affiliated clinics and large health systems.

PPCM impacts chronic diseases

The current literature is rife with studies investigating the impact of PPCM on chronic diseases in the primary care setting.^1-12 Although no specific guidelines on implementing PPCM exist, these studies utilized similar interventions that provided pharmacists with the ability to manage medication therapy under the supervision of a physician. A number of these studies incorporated collaborative practice plans to delineate the specific duties performed by physicians and pharmacists.^2,6,8,10,11 Responsibilities for pharmacists often included assessing vital signs, reviewing laboratory parameters and ordering appropriate tests, providing patient education, screening for drug interactions, identifying barriers to medication adherence, and adjusting medication regimens. The TABLE^1-12 provides a summary of studies investigating the impact of PPCM in the primary care setting.

PPCM leads to greater BP reductions, improved BP control

The majority of research surrounding PPCM has focused on uncontrolled HTN.^1-8 Patients in many of these studies saw a pharmacist in a specialized HTN clinic, where the multidisciplinary staff performed a thorough evaluation of the patient’s current hypertensive management. The pharmacists in these PPCM programs closely monitored patients and made adjustments to antihypertensive regimens as necessary. Systolic and diastolic BP reductions in the intervention groups ranged from 14 to 36 mm Hg and 7 to 15 mm Hg, respectively.^1-5,7,8 The percentage of patients with BP control at the end of the studies ranged from 43% to 89%.^1,3,4,6,7

In a prospective, cluster-randomized trial performed at 32 primary care offices in 15 states, researchers assigned 625 patients with uncontrolled HTN to receive physician-pharmacist collaborative care or usual care with primary care provider management.⁷ As part of the PPCM intervention, clinical pharmacists conducted a thorough medical record review and a structured interview of the patients. During the interview, the clinical pharmacists reviewed the patient’s medication history, assessed the patient’s knowledge of BP medications, and addressed any barriers to adherence. In collaboration with the physician, the pharmacists developed a care plan with recommendations for optimizing the drug regimen. After the baseline visit, the pharmacists conducted structured face-to-face interviews with patients at 1, 2, 4, 6, and 8 months, with additional visits scheduled if BP was still uncontrolled.

At 9 months, patients in the PPCM group had significantly greater reductions in BP than those in the control group, and BP control was achieved in 43% of the PPCM group vs 34% of the control group. This study corroborates results from previous (similar) studies investigating the impact of PPCM on patients with uncontrolled HTN.^1-6

PPCM helps patients reduce their HbA1c levels

Researchers have also studied the impact of PPCM strategies on the management of diabetes mellitus.^9-11 In one retrospective study of 157 patients, implementation of a pharmacy-coordinated diabetes (any type) management program significantly improved HbA1c and increased the percentage of patients reaching their HbA1c goal.⁹ Furthermore, researchers observed improvements in low-density lipoprotein cholesterol (LDL-C) levels and an increased number of patients obtaining a microalbumin screening after initiation of the program.

A more recent prospective, multicenter cohort study of 206 patients with uncontrolled type 2 diabetes had similar results.¹⁰ In collaboration with the primary care physician (PCP), clinical pharmacists provided medication therapy management through adjustment of antihyperglycemic, antihypertensive, or lipid-lowering medications. Additional interventions provided by the pharmacists included reviewing blood glucose logs, ordering and monitoring laboratory tests, performing sensory foot examinations, and providing patient education.

Implementation of PPCM reduced the average HbA1c by 1.2% and increased the percentage of patients achieving an HbA1c <7% by about 24%. The researchers also observed improvements in BP and LDL-C levels in this patient population.¹¹

Asthma and beyond

Future studies may well show that the benefits of PPCM extend to the management of other chronic diseases. One prospective, pre-post study of 126 patients with asthma found that the number of emergency department (ED) visits and/or hospitalizations decreased 30% during 9 months with a PPCM intervention and then returned to levels similar to baseline once the intervention ceased.¹² Other potential disease areas that have been studied, or are being studied, include chronic obstructive pulmonary disease, chronic kidney disease, dyslipidemia, and congestive heart failure.¹³

Benefits derive from altered health care utilization

Researchers attribute much of the benefit observed with PPCM to the increased—albeit different—health-care utilization among the patients in the intervention groups. In general, patients participating in PPCM have an increased total number of visits, but more of those visits are with pharmacists and fewer are with physicians; they also are prescribed more medications, but don’t necessarily take more pills per day.^1,2,5 In the end, patients have been found to achieve significantly better disease control without compromising quality of life or satisfaction.²

Some studies have found that continued pharmacist involvement may be necessary to sustain the benefits achieved.⁶ However, other studies have suggested that the benefits are maintained even after discontinuation of the pharmacist intervention.^14,15 Thus, further research is necessary to determine which patients may benefit most from ongoing involvement with a pharmacist.

How cost-effective is the PPCM model?

Implementing a PPCM model in a primary care setting often hinges upon whether the intervention will be cost-effective. Several studies have reported the cost-effectiveness of clinical pharmacists in the management of HTN.^1,16,17

Borenstein and colleagues found significantly lower provider visit costs per patient in the PPCM group ($160) compared with the usual care group ($195), a difference that the authors attributed to a decreased number of visits to PCPs and an increased number of lower cost visits with pharmacists in the PPCM group.¹ However, the difference could have been affected by the arbitrary measurement of physician-pharmacist collaboration time in the study.

Overcoming implementation challenges

Implementation of pharmacist collaboration within primary care medicine may pose a challenge, as the requirements and resources vary widely among primary care settings. Health-system administrators, for example, may need to reorganize the clinic structure and budget resources in order to overcome some of the obstacles to implementing a PPCM model.

Researchers found that patients in a physician-pharmacist collaborative management model had significantly greater reductions in BP than those in the control group.

Experts have reported several strategies that help in establishing PPCM within primary care clinics,¹⁸ including proactively identifying patients who may benefit from pharmacist intervention, requiring appropriate training and credentialing of pharmacists, and establishing a set schedule for pharmacists to interview patients. Clinics would also be well served to model interventions outlined in the studies mentioned in this article and provide adequate time for pharmacists to perform structured activities, including review of medication history, assessment of current disease state control, and adjustment of medication therapy regimens. And, of course, given the diversity of primary care settings, administrators will need to identify the specific PPCM strategies that best complement their respective collaborative practice plans and environments.

The lack of well-defined reimbursement models for pharmacy services has presented a challenge for generating revenue and effectively implementing PPCM within many primary care settings. Currently, the Centers for Medicare and Medicaid Services and third-party payers do not recognize pharmacists as independent providers, creating a barrier for obtaining reimbursement for clinical pharmacy services. Typically, pharmacists have charged for clinic visits under a consultant physician through the “incident to” billing model, with the option to bill at higher levels if the patient was seen jointly with the physician.

Can this model benefit the underserved?

A prospective, cluster-randomized clinic study has shown pharmacist intervention to reduce racial and socioeconomic disparities in the treatment of elevated BP.¹⁹ This study is the first to show that a team-care model can overcome inequalities arising from low income, low patient education status, and little or no insurance to produce the same health care benefit as in those with higher socioeconomic and educational status. This type of collaborative care model may be particularly beneficial when incorporated within a PCMH catering to underserved populations.²⁰

Implementation of a physician-pharmacist collaborative management model reduced the average HbA1c by 1.2%.

However, sparse data currently exist regarding the benefits of the PPCM model within a PCMH, despite the fact that integration of this type of collaborative model is expected to contribute positively to patient care.²¹

Physician acceptance of pharmacist involvement is mixed

While physician acceptance of pharmacist recommendations is generally high, at least one study indicated that some health-care professionals in patient-care teams are reluctant to incorporate pharmacists into a PCMH. Reasons include difficulty in coordination of care with pharmacy services and limited knowledge by other professionals of pharmacists’ training.²²

Centralization can combat a lack of resources

As noted earlier, primary care offices that implement PPCM models are mostly academically affiliated or are part of large health systems. Many private primary care offices lack the resources to employ a pharmacist in their office. As an alternative, prospective clinical trials are looking at a centralized, Web-based cardiovascular risk service managed by pharmacists.^23,24 This service’s primary objective is to improve adherence to metric-based outcomes developed as part of The Guideline Advantage quality improvement program put forth by the American Cancer Society, American Diabetes Association, and the American Heart and Stroke Associations. (See http://www.guidelineadvantage.org/TGA/ for more information.)

Researchers hope to prove that a centralized, pharmacist-run, clinical service can meet metric-driven outcomes that many primary care offices are now being required to meet in order to receive compensation from insurance companies. One of these studies is specifically looking at rural private offices that lack many of the resources that many large academic offices possess.²³ The study is ongoing and results are expected sometime in 2018.

CORRESPONDENCE
John G. Gums, PharmD, College of Pharmacy, University of Florida, 1225 Center Drive, HPNP 4332, Gainesville, FL 32601; [email protected].

Over the past decade, physician-pharmacist collaborative practices have gained traction in primary care as a way to implement team-based-care models. And there is evidence pointing to the effectiveness of this multidisciplinary heath care team approach, in which pharmacists are typically responsible for such things as obtaining medication histories, identifying barriers to adherence, and adjusting medication regimens.

Several studies have shown the significant impact that physician-pharmacist collaborative management (PPCM) can have on blood pressure (BP) control among patients with hypertension (HTN).^1-8 Additionally, PPCM may have positive effects on HbA1c reduction and diabetes control,^9-11 suggesting that benefits may extend to other chronic diseases, too.

In the review that follows, we’ll detail the impact that PPCM can have on patient care, health-care utilization, and cost effectiveness. (For a look at PPCM “in action,” see the sidebar below.) We’ll also review the challenges of implementing this model that, at present, is mostly found in academically-affiliated clinics and large health systems.

PPCM impacts chronic diseases

The current literature is rife with studies investigating the impact of PPCM on chronic diseases in the primary care setting.^1-12 Although no specific guidelines on implementing PPCM exist, these studies utilized similar interventions that provided pharmacists with the ability to manage medication therapy under the supervision of a physician. A number of these studies incorporated collaborative practice plans to delineate the specific duties performed by physicians and pharmacists.^2,6,8,10,11 Responsibilities for pharmacists often included assessing vital signs, reviewing laboratory parameters and ordering appropriate tests, providing patient education, screening for drug interactions, identifying barriers to medication adherence, and adjusting medication regimens. The TABLE^1-12 provides a summary of studies investigating the impact of PPCM in the primary care setting.

PPCM leads to greater BP reductions, improved BP control

The majority of research surrounding PPCM has focused on uncontrolled HTN.^1-8 Patients in many of these studies saw a pharmacist in a specialized HTN clinic, where the multidisciplinary staff performed a thorough evaluation of the patient’s current hypertensive management. The pharmacists in these PPCM programs closely monitored patients and made adjustments to antihypertensive regimens as necessary. Systolic and diastolic BP reductions in the intervention groups ranged from 14 to 36 mm Hg and 7 to 15 mm Hg, respectively.^1-5,7,8 The percentage of patients with BP control at the end of the studies ranged from 43% to 89%.^1,3,4,6,7

In a prospective, cluster-randomized trial performed at 32 primary care offices in 15 states, researchers assigned 625 patients with uncontrolled HTN to receive physician-pharmacist collaborative care or usual care with primary care provider management.⁷ As part of the PPCM intervention, clinical pharmacists conducted a thorough medical record review and a structured interview of the patients. During the interview, the clinical pharmacists reviewed the patient’s medication history, assessed the patient’s knowledge of BP medications, and addressed any barriers to adherence. In collaboration with the physician, the pharmacists developed a care plan with recommendations for optimizing the drug regimen. After the baseline visit, the pharmacists conducted structured face-to-face interviews with patients at 1, 2, 4, 6, and 8 months, with additional visits scheduled if BP was still uncontrolled.

At 9 months, patients in the PPCM group had significantly greater reductions in BP than those in the control group, and BP control was achieved in 43% of the PPCM group vs 34% of the control group. This study corroborates results from previous (similar) studies investigating the impact of PPCM on patients with uncontrolled HTN.^1-6

PPCM helps patients reduce their HbA1c levels

Researchers have also studied the impact of PPCM strategies on the management of diabetes mellitus.^9-11 In one retrospective study of 157 patients, implementation of a pharmacy-coordinated diabetes (any type) management program significantly improved HbA1c and increased the percentage of patients reaching their HbA1c goal.⁹ Furthermore, researchers observed improvements in low-density lipoprotein cholesterol (LDL-C) levels and an increased number of patients obtaining a microalbumin screening after initiation of the program.

A more recent prospective, multicenter cohort study of 206 patients with uncontrolled type 2 diabetes had similar results.¹⁰ In collaboration with the primary care physician (PCP), clinical pharmacists provided medication therapy management through adjustment of antihyperglycemic, antihypertensive, or lipid-lowering medications. Additional interventions provided by the pharmacists included reviewing blood glucose logs, ordering and monitoring laboratory tests, performing sensory foot examinations, and providing patient education.

Implementation of PPCM reduced the average HbA1c by 1.2% and increased the percentage of patients achieving an HbA1c <7% by about 24%. The researchers also observed improvements in BP and LDL-C levels in this patient population.¹¹

Asthma and beyond

Future studies may well show that the benefits of PPCM extend to the management of other chronic diseases. One prospective, pre-post study of 126 patients with asthma found that the number of emergency department (ED) visits and/or hospitalizations decreased 30% during 9 months with a PPCM intervention and then returned to levels similar to baseline once the intervention ceased.¹² Other potential disease areas that have been studied, or are being studied, include chronic obstructive pulmonary disease, chronic kidney disease, dyslipidemia, and congestive heart failure.¹³

Benefits derive from altered health care utilization

Researchers attribute much of the benefit observed with PPCM to the increased—albeit different—health-care utilization among the patients in the intervention groups. In general, patients participating in PPCM have an increased total number of visits, but more of those visits are with pharmacists and fewer are with physicians; they also are prescribed more medications, but don’t necessarily take more pills per day.^1,2,5 In the end, patients have been found to achieve significantly better disease control without compromising quality of life or satisfaction.²

Some studies have found that continued pharmacist involvement may be necessary to sustain the benefits achieved.⁶ However, other studies have suggested that the benefits are maintained even after discontinuation of the pharmacist intervention.^14,15 Thus, further research is necessary to determine which patients may benefit most from ongoing involvement with a pharmacist.

How cost-effective is the PPCM model?

Implementing a PPCM model in a primary care setting often hinges upon whether the intervention will be cost-effective. Several studies have reported the cost-effectiveness of clinical pharmacists in the management of HTN.^1,16,17

Borenstein and colleagues found significantly lower provider visit costs per patient in the PPCM group ($160) compared with the usual care group ($195), a difference that the authors attributed to a decreased number of visits to PCPs and an increased number of lower cost visits with pharmacists in the PPCM group.¹ However, the difference could have been affected by the arbitrary measurement of physician-pharmacist collaboration time in the study.

Overcoming implementation challenges

Implementation of pharmacist collaboration within primary care medicine may pose a challenge, as the requirements and resources vary widely among primary care settings. Health-system administrators, for example, may need to reorganize the clinic structure and budget resources in order to overcome some of the obstacles to implementing a PPCM model.

Researchers found that patients in a physician-pharmacist collaborative management model had significantly greater reductions in BP than those in the control group.

Experts have reported several strategies that help in establishing PPCM within primary care clinics,¹⁸ including proactively identifying patients who may benefit from pharmacist intervention, requiring appropriate training and credentialing of pharmacists, and establishing a set schedule for pharmacists to interview patients. Clinics would also be well served to model interventions outlined in the studies mentioned in this article and provide adequate time for pharmacists to perform structured activities, including review of medication history, assessment of current disease state control, and adjustment of medication therapy regimens. And, of course, given the diversity of primary care settings, administrators will need to identify the specific PPCM strategies that best complement their respective collaborative practice plans and environments.

The lack of well-defined reimbursement models for pharmacy services has presented a challenge for generating revenue and effectively implementing PPCM within many primary care settings. Currently, the Centers for Medicare and Medicaid Services and third-party payers do not recognize pharmacists as independent providers, creating a barrier for obtaining reimbursement for clinical pharmacy services. Typically, pharmacists have charged for clinic visits under a consultant physician through the “incident to” billing model, with the option to bill at higher levels if the patient was seen jointly with the physician.

Can this model benefit the underserved?

A prospective, cluster-randomized clinic study has shown pharmacist intervention to reduce racial and socioeconomic disparities in the treatment of elevated BP.¹⁹ This study is the first to show that a team-care model can overcome inequalities arising from low income, low patient education status, and little or no insurance to produce the same health care benefit as in those with higher socioeconomic and educational status. This type of collaborative care model may be particularly beneficial when incorporated within a PCMH catering to underserved populations.²⁰

Implementation of a physician-pharmacist collaborative management model reduced the average HbA1c by 1.2%.

However, sparse data currently exist regarding the benefits of the PPCM model within a PCMH, despite the fact that integration of this type of collaborative model is expected to contribute positively to patient care.²¹

Physician acceptance of pharmacist involvement is mixed

While physician acceptance of pharmacist recommendations is generally high, at least one study indicated that some health-care professionals in patient-care teams are reluctant to incorporate pharmacists into a PCMH. Reasons include difficulty in coordination of care with pharmacy services and limited knowledge by other professionals of pharmacists’ training.²²

Centralization can combat a lack of resources

As noted earlier, primary care offices that implement PPCM models are mostly academically affiliated or are part of large health systems. Many private primary care offices lack the resources to employ a pharmacist in their office. As an alternative, prospective clinical trials are looking at a centralized, Web-based cardiovascular risk service managed by pharmacists.^23,24 This service’s primary objective is to improve adherence to metric-based outcomes developed as part of The Guideline Advantage quality improvement program put forth by the American Cancer Society, American Diabetes Association, and the American Heart and Stroke Associations. (See http://www.guidelineadvantage.org/TGA/ for more information.)

Researchers hope to prove that a centralized, pharmacist-run, clinical service can meet metric-driven outcomes that many primary care offices are now being required to meet in order to receive compensation from insurance companies. One of these studies is specifically looking at rural private offices that lack many of the resources that many large academic offices possess.²³ The study is ongoing and results are expected sometime in 2018.

CORRESPONDENCE
John G. Gums, PharmD, College of Pharmacy, University of Florida, 1225 Center Drive, HPNP 4332, Gainesville, FL 32601; [email protected].

Interest in osteopathy continues to rise in this country. Currently, more than 20% of medical students in the United States are training to be osteopathic physicians.¹ In addition, the 2007 National Health Interview Survey found that spinal manipulation was among the most common complementary and alternative medicine (CAM) therapies used; with 8.6% of US adults reporting that they used it within the previous 12 months.²

With the growing number of DOs and the high utilization of osteopathic manipulative treatment (OMT), it is important for all physicians to understand the role OMT can play in the treatment of conditions ranging from low back pain to irritable bowel syndrome so that patients may be offered, or referred for, the treatment when appropriate.

To clarify when OMT may be most beneficial, we performed a literature review. Our findings are summarized here. But first, a word about osteopathic medicine and what OMT entails.

Osteopathic physicians view the body as a whole

According to the American Osteopathic Association, “the osteopathic philosophy of medicine sees an interrelated unity in all systems of the body, with each working with the other to heal in times of illness."³ This “whole-person approach to medicine” focuses on looking beyond symptoms alone to understand how lifestyle and environmental factors impact well-being.

As part of their education, DOs receive special training in the musculoskeletal system and in OMT. OMT is the process by which DOs use their hands to diagnose illness and injury and then mobilize a patient’s joints and soft tissues using techniques that include muscle activation, stretching, joint articulation, and gentle pressure to encourage the body’s natural tendency to heal itself.

These patients with low back pain will likely benefit

In the past, studies with small sample sizes, blinding issues, differing controls, and subjective outcome measurements have marred research efforts to demonstrate the effectiveness of OMT. More recently, researchers have attempted to minimize these issues, particularly when evaluating the efficacy of OMT for low back pain.

Meta-analyses show decreased pain and improved function in patients who received osteopathic manipulative treatment for low back pain.

In addition to increasing sample size, studies have compared OMT to usual care, to sham manipulation, and more recently to other manual modalities including ultrasound to equalize the subjective effects of interventions.⁴ With improved study designs, there has been increased awareness of the effectiveness of spinal manipulation by organizations that develop guidelines for the care of patients with low back pain. The most recent clinical practice guideline from the American College of Physicians includes spinal manipulation as a treatment modality that should be considered by clinicians for patients who have acute, subacute, or chronic low back pain.⁵

Chronic nonspecific low back pain. Looking at OMT vs other interventions for chronic nonspecific low back pain, a 2014 meta-analysis found moderate quality evidence for clinically relevant effects of OMT on low back pain and function. In 6 studies that evaluated 769 patients with chronic nonspecific low back pain, there was a significant difference in pain—equivalent to a 1.5-point improvement (mean difference [MD]= -14.93; 95% confidence interval [CI], -25.18 to -4.68)—in favor of OMT compared with controls, as measured on a 10-point visual analogue scale (VAS).⁶ In all of the studies in this meta-analysis, the treating examiner used clinical judgment to determine which manipulation techniques would be most appropriate for each patient—an approach that best represents "real-world" osteopathic practice.⁶

Acute and chronic nonspecific low back pain. Similarly, in the same 2014 meta-analysis, 1141 participants with acute and chronic nonspecific low back pain in 10 studies had the equivalent of 1.3 points more pain relief with OMT compared with controls (MD= -12.91; 95% CI, -20.00 to -5.82). The authors used the standardized mean difference (SMD), which is the difference in means divided by the standard deviation, to interpret the magnitude of difference in function between participants who received OMT and those in the control groups. Further, 1046 participants with acute and chronic nonspecific low back pain in 9 studies had a small improvement in functional status using the Roland-Morris Disability Questionnaire (RMDQ) or Oswestry-Disability Index (SMD= -0.36; 95% CI, -0.58 to -0.14).⁶

A 2005 meta-analysis that evaluated 6 randomized controlled trials (RCTs) involving 549 patients with low back pain found that 318 patients who received OMT had significantly less low back pain compared with 231 controls (effect size= -0.30; 95% CI, -0.47 to -0.13; P=.001).⁷ Although significant, an effect size of this magnitude is characterized as small.⁸

Other benefits of OMT include increased patient satisfaction, fewer meds

A randomized double-blind, sham-controlled study involving 455 patients with chronic low back pain compared outcomes of OMT to sham OMT applied in 6 treatment sessions over 8 weeks.⁹ Intention-to-treat analysis was performed to measure moderate and substantial improvements in low back pain at Week 12 (≥30% and ≥50% pain reductions from baseline, respectively). Based on the Cochrane Back Review Group criteria for effect sizes, response ratios were calculated to determine if the differences seen were considered clinically relevant.¹⁰

Patients receiving OMT were more likely to achieve moderate (response ratio=1.38; 95% CI, 1.16-1.64; P<.001) and substantial (response ratio=1.41; 95% CI, 1.13-1.76; P=.002) improvements in low back pain at Week 12. The calculated number needed to treat (NNT) for moderate and significant improvement in pain at 12 weeks was 6 and 7, respectively. In addition, patients in the OMT group were more likely to be very satisfied with their care (P<.001) with an NNT of 5, and used fewer medications than did patients in the sham group during the 12 weeks of the study (use ratio=0.66; 95% CI, 0.43-1.00; P=.048; NNT=15).⁹

Pregnant women may benefit from OMT in the third trimester

A 2013 RCT involving 144 patients randomized to OMT, sham ultrasound, or usual obstetric care found that 68 patients (47%) experienced back-specific dysfunction during their third trimester of pregnancy (defined by a ≥2-point increase in the RMDQ).¹¹

OMT reduced the risk of back-specific dysfunction by 40% vs the ultrasound group (relative risk [RR]=0.6; 95% CI, 0.3-1; P=.046) and 60% vs the usual obstetric care group (RR=0.4; 95% CI, 0.2-0.7; P<.001). The corresponding NNTs were 5.1 (95% CI, 2.7-282.2) for the OMT group vs the ultrasound group and 2.5 (95% CI, 1.8-4.9) vs the usual care group. The outcomes of this study were not conclusive because the initial RMDQ score was 1.8 points worse for the OMT group than for the usual care group.¹¹

Subsequently, the PROMOTE (Pregnancy Research on Osteopathic Manipulation Optimizing Treatment Effects) study involving 400 patients demonstrated that a standard OMT protocol was effective for decreasing pain and function deterioration compared with usual obstetric care.¹² However, results from the OMT group did not differ significantly from those of the ultrasound group, which were labeled as subtherapeutic in the study.¹²

The most recent Cochrane Review on low back pain in pregnancy noted that there was moderate quality evidence (due to study design limitations or imprecision) that OMT significantly reduced low back pain and function disability.¹³

OMT for other conditions? The evidence is limited

To date, studies on conditions other than low back pain have not demonstrated the same robust improvements in design as have those concerning low back pain (ie, larger sample sizes, comparisons to usual care and other treatments, etc.), and available data are not sufficiently significant to compel a change in clinical practice. Despite this, patients seek out, and receive, OMT as an alternative or adjunctive treatment for many conditions other than low back pain,² and family physicians should be aware of the current evidence for OMT in those conditions.

OMT for acute neck pain: A comparison with ketorolac

Researchers randomized 58 patients presenting to 3 emergency departments with neck pain of less than 3 weeks’ duration to receive either OMT or 30 mg IM ketorolac.¹⁴ OMT techniques were provided at the discretion of the physician based on patient needs. Patients rated their pain intensity on an 11-point numerical scale at the time of presentation and one hour after treatment. Patients receiving ketorolac or OMT had significant reductions in pain intensity with improvements of 1.7 +/- 1.6 (95% CI, 1.1-2.3; P<.001) and 2.8 +/- 1.7 (95% CI, 2.1-3.4; P<.001), respectively.

Patients who received osteopathic manipulative treatment for low back pain used fewer medications.

Although the pain reduction changes were statistically significant in both groups, the improvements were small enough to question if they were functionally significant. Compared to those receiving ketorolac, those receiving OMT reported a significantly greater decrease in their pain intensity (2.8 vs 1.7; 95% CI, 0.2-1.9; P=.02), but it’s worth noting that the dose of ketorolac was half the recommended dose for moderate or severe pain.¹⁴

Patients may have more headache-free days with OMT

To assess the use of OMT to treat chronic migraine, researchers conducted a prospective, single-blind RCT in which 105 chronic migraine sufferers (average of 22.5 migraine days/month) were split into 3 treatment groups: OMT plus medications, sham OMT plus medications, and medications alone.¹⁵

OMT led to fewer days with migraines compared with the medication group (MD= -21.06; 95% CI, -23.19 to -18.92; P<.001) and sham OMT group (MD= -17.43; 95% CI, -19.57 to -15.29; P<.001), resulting in less functional disability (P<.001).¹⁵ Caution should be taken in interpreting the results of this small trial, however, as an effect of this size has not been replicated in other studies.

A small (N=29) single-blind RCT looked at progressive muscular relaxation with and without OMT for the treatment of tension headache. Patients who completed relaxation exercises plus 3 sessions of OMT experienced significantly more headache-free days (1.79 vs 0.21; P=.016).¹⁶ Despite this finding, headache intensity and headache diary ratings were not different between the 2 groups in this study.

Postoperative OMT may decrease length of stay

In a retrospective study evaluating the effect of OMT on postoperative outcomes in 55 patients who underwent gastrointestinal surgery, a total of 17 patients who received a single OMT session within 48 hours of surgery had a mean time to flatus of 3.1 days compared with 4.7 days in the usual care control group (P=.035).¹⁷ The mean length of stay was 6.1 days in the OMT group and 11.5 days in the non-OMT group (P=.006).

Major limitations of this study include that it was retrospective in design and that only 17 of 55 patients had OMT performed, indicating a possible selection bias.

Pneumonia: OMT may reduce LOS and duration of antibiotic usage

The Multicenter Osteopathic Pneumonia Study in the Elderly (MOPSE), a double-blind RCT, looked at 406 patients ≥50 years hospitalized with pneumonia. Researchers randomized the group to receive either conventional care (CC; antibiotic treatment only), OMT and antibiotic therapy, or light-touch sham therapy with antibiotics.¹⁸ The researchers found no significant differences between the groups for any outcomes in the intention-to-treat analysis.

Patients who received osteopathic manipulative treatment for acute neck pain had greater pain relief than those who received a small dose of IM ketorolac.

In results obtained from the per protocol analysis, however, the median length of stay for those in the OMT group was 3.5 days, compared with 4.5 days for those in the CC group (95% CI, 3.2-4.0; P=.01). Multiple comparisons also indicated a reduction in mean duration of intravenous antibiotic use of 3 days in the OMT group (95% CI, 2.7-3.5) vs 3.5 days in the CC group (95% CI, 3.2-3.9). The treatment end-points of either death or respiratory failure occurred significantly less frequently in the OMT group compared with the CC group (P=.006).¹⁸

A Cochrane review of RCTs assessing the efficacy of adjunctive techniques compared with conventional therapy for patients with pneumonia revealed a reduction in hospital stay of 2 days (95% CI, -3.5 to -0.6) for patients who received OMT and positive expiratory pressure vs those who received neither intervention.¹⁹ Additionally, the duration of IV antibiotics and total duration of all (IV and oral) antibiotic treatment required in those treated adjunctively with OMT was shorter (MD for IV antibiotics= -2.1 days; 95% CI, -3.4 to -0.9 and MD for all antibiotics= -1.9 days; 95% CI, -3.1 to -0.7).¹⁹ The review was notable for a small sample size, with only 79 patients assessed.

OMT may improve IBS symptoms

A crossover study of 31 patients that compared visceral manipulation and sacral articulation OMT with sham therapy for the treatment of irritable bowel syndrome (IBS) demonstrated that OMT significantly decreased self-reported diarrhea (P=.016), abdominal distention (P=.043), abdominal pain (P=.013), and rectal sensitivity (P<.001), but did not significantly affect constipation.²⁰

In another study, researchers randomized 30 patients with IBS in a 2:1 distribution to OMT vs sham treatment.²¹ OMT included abdominal visceral techniques and direct and indirect spine techniques. All of the patients received 2 treatment sessions, and the researchers evaluated them at 7 and 28 days. At 7 days, both groups demonstrated a significant reduction in IBS symptoms, although the OMT group had significantly greater improvement (P=.01). At 28 days, however, neither group showed a significant reduction in symptoms.²¹

The lack of a control group (in the first study due to the crossover design), small sample sizes, and self-reported symptoms are major limitations to applying these studies to IBS treatment recommendations.

CORRESPONDENCE
Andrew H. Slattengren, DO, Broadway Family Medicine Clinic, 1020 West Broadway Avenue, Minneapolis, MN 55411; [email protected].

Interest in osteopathy continues to rise in this country. Currently, more than 20% of medical students in the United States are training to be osteopathic physicians.¹ In addition, the 2007 National Health Interview Survey found that spinal manipulation was among the most common complementary and alternative medicine (CAM) therapies used; with 8.6% of US adults reporting that they used it within the previous 12 months.²

With the growing number of DOs and the high utilization of osteopathic manipulative treatment (OMT), it is important for all physicians to understand the role OMT can play in the treatment of conditions ranging from low back pain to irritable bowel syndrome so that patients may be offered, or referred for, the treatment when appropriate.

To clarify when OMT may be most beneficial, we performed a literature review. Our findings are summarized here. But first, a word about osteopathic medicine and what OMT entails.

Osteopathic physicians view the body as a whole

According to the American Osteopathic Association, “the osteopathic philosophy of medicine sees an interrelated unity in all systems of the body, with each working with the other to heal in times of illness."³ This “whole-person approach to medicine” focuses on looking beyond symptoms alone to understand how lifestyle and environmental factors impact well-being.

As part of their education, DOs receive special training in the musculoskeletal system and in OMT. OMT is the process by which DOs use their hands to diagnose illness and injury and then mobilize a patient’s joints and soft tissues using techniques that include muscle activation, stretching, joint articulation, and gentle pressure to encourage the body’s natural tendency to heal itself.

These patients with low back pain will likely benefit

In the past, studies with small sample sizes, blinding issues, differing controls, and subjective outcome measurements have marred research efforts to demonstrate the effectiveness of OMT. More recently, researchers have attempted to minimize these issues, particularly when evaluating the efficacy of OMT for low back pain.

Meta-analyses show decreased pain and improved function in patients who received osteopathic manipulative treatment for low back pain.

In addition to increasing sample size, studies have compared OMT to usual care, to sham manipulation, and more recently to other manual modalities including ultrasound to equalize the subjective effects of interventions.⁴ With improved study designs, there has been increased awareness of the effectiveness of spinal manipulation by organizations that develop guidelines for the care of patients with low back pain. The most recent clinical practice guideline from the American College of Physicians includes spinal manipulation as a treatment modality that should be considered by clinicians for patients who have acute, subacute, or chronic low back pain.⁵

Chronic nonspecific low back pain. Looking at OMT vs other interventions for chronic nonspecific low back pain, a 2014 meta-analysis found moderate quality evidence for clinically relevant effects of OMT on low back pain and function. In 6 studies that evaluated 769 patients with chronic nonspecific low back pain, there was a significant difference in pain—equivalent to a 1.5-point improvement (mean difference [MD]= -14.93; 95% confidence interval [CI], -25.18 to -4.68)—in favor of OMT compared with controls, as measured on a 10-point visual analogue scale (VAS).⁶ In all of the studies in this meta-analysis, the treating examiner used clinical judgment to determine which manipulation techniques would be most appropriate for each patient—an approach that best represents "real-world" osteopathic practice.⁶

Acute and chronic nonspecific low back pain. Similarly, in the same 2014 meta-analysis, 1141 participants with acute and chronic nonspecific low back pain in 10 studies had the equivalent of 1.3 points more pain relief with OMT compared with controls (MD= -12.91; 95% CI, -20.00 to -5.82). The authors used the standardized mean difference (SMD), which is the difference in means divided by the standard deviation, to interpret the magnitude of difference in function between participants who received OMT and those in the control groups. Further, 1046 participants with acute and chronic nonspecific low back pain in 9 studies had a small improvement in functional status using the Roland-Morris Disability Questionnaire (RMDQ) or Oswestry-Disability Index (SMD= -0.36; 95% CI, -0.58 to -0.14).⁶

A 2005 meta-analysis that evaluated 6 randomized controlled trials (RCTs) involving 549 patients with low back pain found that 318 patients who received OMT had significantly less low back pain compared with 231 controls (effect size= -0.30; 95% CI, -0.47 to -0.13; P=.001).⁷ Although significant, an effect size of this magnitude is characterized as small.⁸

Other benefits of OMT include increased patient satisfaction, fewer meds

A randomized double-blind, sham-controlled study involving 455 patients with chronic low back pain compared outcomes of OMT to sham OMT applied in 6 treatment sessions over 8 weeks.⁹ Intention-to-treat analysis was performed to measure moderate and substantial improvements in low back pain at Week 12 (≥30% and ≥50% pain reductions from baseline, respectively). Based on the Cochrane Back Review Group criteria for effect sizes, response ratios were calculated to determine if the differences seen were considered clinically relevant.¹⁰

Patients receiving OMT were more likely to achieve moderate (response ratio=1.38; 95% CI, 1.16-1.64; P<.001) and substantial (response ratio=1.41; 95% CI, 1.13-1.76; P=.002) improvements in low back pain at Week 12. The calculated number needed to treat (NNT) for moderate and significant improvement in pain at 12 weeks was 6 and 7, respectively. In addition, patients in the OMT group were more likely to be very satisfied with their care (P<.001) with an NNT of 5, and used fewer medications than did patients in the sham group during the 12 weeks of the study (use ratio=0.66; 95% CI, 0.43-1.00; P=.048; NNT=15).⁹

Pregnant women may benefit from OMT in the third trimester

A 2013 RCT involving 144 patients randomized to OMT, sham ultrasound, or usual obstetric care found that 68 patients (47%) experienced back-specific dysfunction during their third trimester of pregnancy (defined by a ≥2-point increase in the RMDQ).¹¹

OMT reduced the risk of back-specific dysfunction by 40% vs the ultrasound group (relative risk [RR]=0.6; 95% CI, 0.3-1; P=.046) and 60% vs the usual obstetric care group (RR=0.4; 95% CI, 0.2-0.7; P<.001). The corresponding NNTs were 5.1 (95% CI, 2.7-282.2) for the OMT group vs the ultrasound group and 2.5 (95% CI, 1.8-4.9) vs the usual care group. The outcomes of this study were not conclusive because the initial RMDQ score was 1.8 points worse for the OMT group than for the usual care group.¹¹

Subsequently, the PROMOTE (Pregnancy Research on Osteopathic Manipulation Optimizing Treatment Effects) study involving 400 patients demonstrated that a standard OMT protocol was effective for decreasing pain and function deterioration compared with usual obstetric care.¹² However, results from the OMT group did not differ significantly from those of the ultrasound group, which were labeled as subtherapeutic in the study.¹²

The most recent Cochrane Review on low back pain in pregnancy noted that there was moderate quality evidence (due to study design limitations or imprecision) that OMT significantly reduced low back pain and function disability.¹³

OMT for other conditions? The evidence is limited

To date, studies on conditions other than low back pain have not demonstrated the same robust improvements in design as have those concerning low back pain (ie, larger sample sizes, comparisons to usual care and other treatments, etc.), and available data are not sufficiently significant to compel a change in clinical practice. Despite this, patients seek out, and receive, OMT as an alternative or adjunctive treatment for many conditions other than low back pain,² and family physicians should be aware of the current evidence for OMT in those conditions.

OMT for acute neck pain: A comparison with ketorolac

Researchers randomized 58 patients presenting to 3 emergency departments with neck pain of less than 3 weeks’ duration to receive either OMT or 30 mg IM ketorolac.¹⁴ OMT techniques were provided at the discretion of the physician based on patient needs. Patients rated their pain intensity on an 11-point numerical scale at the time of presentation and one hour after treatment. Patients receiving ketorolac or OMT had significant reductions in pain intensity with improvements of 1.7 +/- 1.6 (95% CI, 1.1-2.3; P<.001) and 2.8 +/- 1.7 (95% CI, 2.1-3.4; P<.001), respectively.

Patients who received osteopathic manipulative treatment for low back pain used fewer medications.

Although the pain reduction changes were statistically significant in both groups, the improvements were small enough to question if they were functionally significant. Compared to those receiving ketorolac, those receiving OMT reported a significantly greater decrease in their pain intensity (2.8 vs 1.7; 95% CI, 0.2-1.9; P=.02), but it’s worth noting that the dose of ketorolac was half the recommended dose for moderate or severe pain.¹⁴

Patients may have more headache-free days with OMT

To assess the use of OMT to treat chronic migraine, researchers conducted a prospective, single-blind RCT in which 105 chronic migraine sufferers (average of 22.5 migraine days/month) were split into 3 treatment groups: OMT plus medications, sham OMT plus medications, and medications alone.¹⁵

OMT led to fewer days with migraines compared with the medication group (MD= -21.06; 95% CI, -23.19 to -18.92; P<.001) and sham OMT group (MD= -17.43; 95% CI, -19.57 to -15.29; P<.001), resulting in less functional disability (P<.001).¹⁵ Caution should be taken in interpreting the results of this small trial, however, as an effect of this size has not been replicated in other studies.

A small (N=29) single-blind RCT looked at progressive muscular relaxation with and without OMT for the treatment of tension headache. Patients who completed relaxation exercises plus 3 sessions of OMT experienced significantly more headache-free days (1.79 vs 0.21; P=.016).¹⁶ Despite this finding, headache intensity and headache diary ratings were not different between the 2 groups in this study.

Postoperative OMT may decrease length of stay

In a retrospective study evaluating the effect of OMT on postoperative outcomes in 55 patients who underwent gastrointestinal surgery, a total of 17 patients who received a single OMT session within 48 hours of surgery had a mean time to flatus of 3.1 days compared with 4.7 days in the usual care control group (P=.035).¹⁷ The mean length of stay was 6.1 days in the OMT group and 11.5 days in the non-OMT group (P=.006).

Major limitations of this study include that it was retrospective in design and that only 17 of 55 patients had OMT performed, indicating a possible selection bias.

Pneumonia: OMT may reduce LOS and duration of antibiotic usage

The Multicenter Osteopathic Pneumonia Study in the Elderly (MOPSE), a double-blind RCT, looked at 406 patients ≥50 years hospitalized with pneumonia. Researchers randomized the group to receive either conventional care (CC; antibiotic treatment only), OMT and antibiotic therapy, or light-touch sham therapy with antibiotics.¹⁸ The researchers found no significant differences between the groups for any outcomes in the intention-to-treat analysis.

Patients who received osteopathic manipulative treatment for acute neck pain had greater pain relief than those who received a small dose of IM ketorolac.

In results obtained from the per protocol analysis, however, the median length of stay for those in the OMT group was 3.5 days, compared with 4.5 days for those in the CC group (95% CI, 3.2-4.0; P=.01). Multiple comparisons also indicated a reduction in mean duration of intravenous antibiotic use of 3 days in the OMT group (95% CI, 2.7-3.5) vs 3.5 days in the CC group (95% CI, 3.2-3.9). The treatment end-points of either death or respiratory failure occurred significantly less frequently in the OMT group compared with the CC group (P=.006).¹⁸

A Cochrane review of RCTs assessing the efficacy of adjunctive techniques compared with conventional therapy for patients with pneumonia revealed a reduction in hospital stay of 2 days (95% CI, -3.5 to -0.6) for patients who received OMT and positive expiratory pressure vs those who received neither intervention.¹⁹ Additionally, the duration of IV antibiotics and total duration of all (IV and oral) antibiotic treatment required in those treated adjunctively with OMT was shorter (MD for IV antibiotics= -2.1 days; 95% CI, -3.4 to -0.9 and MD for all antibiotics= -1.9 days; 95% CI, -3.1 to -0.7).¹⁹ The review was notable for a small sample size, with only 79 patients assessed.

OMT may improve IBS symptoms

A crossover study of 31 patients that compared visceral manipulation and sacral articulation OMT with sham therapy for the treatment of irritable bowel syndrome (IBS) demonstrated that OMT significantly decreased self-reported diarrhea (P=.016), abdominal distention (P=.043), abdominal pain (P=.013), and rectal sensitivity (P<.001), but did not significantly affect constipation.²⁰

In another study, researchers randomized 30 patients with IBS in a 2:1 distribution to OMT vs sham treatment.²¹ OMT included abdominal visceral techniques and direct and indirect spine techniques. All of the patients received 2 treatment sessions, and the researchers evaluated them at 7 and 28 days. At 7 days, both groups demonstrated a significant reduction in IBS symptoms, although the OMT group had significantly greater improvement (P=.01). At 28 days, however, neither group showed a significant reduction in symptoms.²¹

The lack of a control group (in the first study due to the crossover design), small sample sizes, and self-reported symptoms are major limitations to applying these studies to IBS treatment recommendations.

CORRESPONDENCE
Andrew H. Slattengren, DO, Broadway Family Medicine Clinic, 1020 West Broadway Avenue, Minneapolis, MN 55411; [email protected].

Interest in osteopathy continues to rise in this country. Currently, more than 20% of medical students in the United States are training to be osteopathic physicians.¹ In addition, the 2007 National Health Interview Survey found that spinal manipulation was among the most common complementary and alternative medicine (CAM) therapies used; with 8.6% of US adults reporting that they used it within the previous 12 months.²

With the growing number of DOs and the high utilization of osteopathic manipulative treatment (OMT), it is important for all physicians to understand the role OMT can play in the treatment of conditions ranging from low back pain to irritable bowel syndrome so that patients may be offered, or referred for, the treatment when appropriate.

To clarify when OMT may be most beneficial, we performed a literature review. Our findings are summarized here. But first, a word about osteopathic medicine and what OMT entails.

Osteopathic physicians view the body as a whole

According to the American Osteopathic Association, “the osteopathic philosophy of medicine sees an interrelated unity in all systems of the body, with each working with the other to heal in times of illness."³ This “whole-person approach to medicine” focuses on looking beyond symptoms alone to understand how lifestyle and environmental factors impact well-being.

As part of their education, DOs receive special training in the musculoskeletal system and in OMT. OMT is the process by which DOs use their hands to diagnose illness and injury and then mobilize a patient’s joints and soft tissues using techniques that include muscle activation, stretching, joint articulation, and gentle pressure to encourage the body’s natural tendency to heal itself.

These patients with low back pain will likely benefit

In the past, studies with small sample sizes, blinding issues, differing controls, and subjective outcome measurements have marred research efforts to demonstrate the effectiveness of OMT. More recently, researchers have attempted to minimize these issues, particularly when evaluating the efficacy of OMT for low back pain.

Meta-analyses show decreased pain and improved function in patients who received osteopathic manipulative treatment for low back pain.

In addition to increasing sample size, studies have compared OMT to usual care, to sham manipulation, and more recently to other manual modalities including ultrasound to equalize the subjective effects of interventions.⁴ With improved study designs, there has been increased awareness of the effectiveness of spinal manipulation by organizations that develop guidelines for the care of patients with low back pain. The most recent clinical practice guideline from the American College of Physicians includes spinal manipulation as a treatment modality that should be considered by clinicians for patients who have acute, subacute, or chronic low back pain.⁵

Chronic nonspecific low back pain. Looking at OMT vs other interventions for chronic nonspecific low back pain, a 2014 meta-analysis found moderate quality evidence for clinically relevant effects of OMT on low back pain and function. In 6 studies that evaluated 769 patients with chronic nonspecific low back pain, there was a significant difference in pain—equivalent to a 1.5-point improvement (mean difference [MD]= -14.93; 95% confidence interval [CI], -25.18 to -4.68)—in favor of OMT compared with controls, as measured on a 10-point visual analogue scale (VAS).⁶ In all of the studies in this meta-analysis, the treating examiner used clinical judgment to determine which manipulation techniques would be most appropriate for each patient—an approach that best represents "real-world" osteopathic practice.⁶

Acute and chronic nonspecific low back pain. Similarly, in the same 2014 meta-analysis, 1141 participants with acute and chronic nonspecific low back pain in 10 studies had the equivalent of 1.3 points more pain relief with OMT compared with controls (MD= -12.91; 95% CI, -20.00 to -5.82). The authors used the standardized mean difference (SMD), which is the difference in means divided by the standard deviation, to interpret the magnitude of difference in function between participants who received OMT and those in the control groups. Further, 1046 participants with acute and chronic nonspecific low back pain in 9 studies had a small improvement in functional status using the Roland-Morris Disability Questionnaire (RMDQ) or Oswestry-Disability Index (SMD= -0.36; 95% CI, -0.58 to -0.14).⁶

A 2005 meta-analysis that evaluated 6 randomized controlled trials (RCTs) involving 549 patients with low back pain found that 318 patients who received OMT had significantly less low back pain compared with 231 controls (effect size= -0.30; 95% CI, -0.47 to -0.13; P=.001).⁷ Although significant, an effect size of this magnitude is characterized as small.⁸

Other benefits of OMT include increased patient satisfaction, fewer meds

A randomized double-blind, sham-controlled study involving 455 patients with chronic low back pain compared outcomes of OMT to sham OMT applied in 6 treatment sessions over 8 weeks.⁹ Intention-to-treat analysis was performed to measure moderate and substantial improvements in low back pain at Week 12 (≥30% and ≥50% pain reductions from baseline, respectively). Based on the Cochrane Back Review Group criteria for effect sizes, response ratios were calculated to determine if the differences seen were considered clinically relevant.¹⁰

Patients receiving OMT were more likely to achieve moderate (response ratio=1.38; 95% CI, 1.16-1.64; P<.001) and substantial (response ratio=1.41; 95% CI, 1.13-1.76; P=.002) improvements in low back pain at Week 12. The calculated number needed to treat (NNT) for moderate and significant improvement in pain at 12 weeks was 6 and 7, respectively. In addition, patients in the OMT group were more likely to be very satisfied with their care (P<.001) with an NNT of 5, and used fewer medications than did patients in the sham group during the 12 weeks of the study (use ratio=0.66; 95% CI, 0.43-1.00; P=.048; NNT=15).⁹

Pregnant women may benefit from OMT in the third trimester

A 2013 RCT involving 144 patients randomized to OMT, sham ultrasound, or usual obstetric care found that 68 patients (47%) experienced back-specific dysfunction during their third trimester of pregnancy (defined by a ≥2-point increase in the RMDQ).¹¹

OMT reduced the risk of back-specific dysfunction by 40% vs the ultrasound group (relative risk [RR]=0.6; 95% CI, 0.3-1; P=.046) and 60% vs the usual obstetric care group (RR=0.4; 95% CI, 0.2-0.7; P<.001). The corresponding NNTs were 5.1 (95% CI, 2.7-282.2) for the OMT group vs the ultrasound group and 2.5 (95% CI, 1.8-4.9) vs the usual care group. The outcomes of this study were not conclusive because the initial RMDQ score was 1.8 points worse for the OMT group than for the usual care group.¹¹

Subsequently, the PROMOTE (Pregnancy Research on Osteopathic Manipulation Optimizing Treatment Effects) study involving 400 patients demonstrated that a standard OMT protocol was effective for decreasing pain and function deterioration compared with usual obstetric care.¹² However, results from the OMT group did not differ significantly from those of the ultrasound group, which were labeled as subtherapeutic in the study.¹²

The most recent Cochrane Review on low back pain in pregnancy noted that there was moderate quality evidence (due to study design limitations or imprecision) that OMT significantly reduced low back pain and function disability.¹³

OMT for other conditions? The evidence is limited

To date, studies on conditions other than low back pain have not demonstrated the same robust improvements in design as have those concerning low back pain (ie, larger sample sizes, comparisons to usual care and other treatments, etc.), and available data are not sufficiently significant to compel a change in clinical practice. Despite this, patients seek out, and receive, OMT as an alternative or adjunctive treatment for many conditions other than low back pain,² and family physicians should be aware of the current evidence for OMT in those conditions.

OMT for acute neck pain: A comparison with ketorolac

Researchers randomized 58 patients presenting to 3 emergency departments with neck pain of less than 3 weeks’ duration to receive either OMT or 30 mg IM ketorolac.¹⁴ OMT techniques were provided at the discretion of the physician based on patient needs. Patients rated their pain intensity on an 11-point numerical scale at the time of presentation and one hour after treatment. Patients receiving ketorolac or OMT had significant reductions in pain intensity with improvements of 1.7 +/- 1.6 (95% CI, 1.1-2.3; P<.001) and 2.8 +/- 1.7 (95% CI, 2.1-3.4; P<.001), respectively.

Patients who received osteopathic manipulative treatment for low back pain used fewer medications.

Although the pain reduction changes were statistically significant in both groups, the improvements were small enough to question if they were functionally significant. Compared to those receiving ketorolac, those receiving OMT reported a significantly greater decrease in their pain intensity (2.8 vs 1.7; 95% CI, 0.2-1.9; P=.02), but it’s worth noting that the dose of ketorolac was half the recommended dose for moderate or severe pain.¹⁴

Patients may have more headache-free days with OMT

To assess the use of OMT to treat chronic migraine, researchers conducted a prospective, single-blind RCT in which 105 chronic migraine sufferers (average of 22.5 migraine days/month) were split into 3 treatment groups: OMT plus medications, sham OMT plus medications, and medications alone.¹⁵

OMT led to fewer days with migraines compared with the medication group (MD= -21.06; 95% CI, -23.19 to -18.92; P<.001) and sham OMT group (MD= -17.43; 95% CI, -19.57 to -15.29; P<.001), resulting in less functional disability (P<.001).¹⁵ Caution should be taken in interpreting the results of this small trial, however, as an effect of this size has not been replicated in other studies.

A small (N=29) single-blind RCT looked at progressive muscular relaxation with and without OMT for the treatment of tension headache. Patients who completed relaxation exercises plus 3 sessions of OMT experienced significantly more headache-free days (1.79 vs 0.21; P=.016).¹⁶ Despite this finding, headache intensity and headache diary ratings were not different between the 2 groups in this study.

Postoperative OMT may decrease length of stay

In a retrospective study evaluating the effect of OMT on postoperative outcomes in 55 patients who underwent gastrointestinal surgery, a total of 17 patients who received a single OMT session within 48 hours of surgery had a mean time to flatus of 3.1 days compared with 4.7 days in the usual care control group (P=.035).¹⁷ The mean length of stay was 6.1 days in the OMT group and 11.5 days in the non-OMT group (P=.006).

Major limitations of this study include that it was retrospective in design and that only 17 of 55 patients had OMT performed, indicating a possible selection bias.

Pneumonia: OMT may reduce LOS and duration of antibiotic usage

The Multicenter Osteopathic Pneumonia Study in the Elderly (MOPSE), a double-blind RCT, looked at 406 patients ≥50 years hospitalized with pneumonia. Researchers randomized the group to receive either conventional care (CC; antibiotic treatment only), OMT and antibiotic therapy, or light-touch sham therapy with antibiotics.¹⁸ The researchers found no significant differences between the groups for any outcomes in the intention-to-treat analysis.

Patients who received osteopathic manipulative treatment for acute neck pain had greater pain relief than those who received a small dose of IM ketorolac.

In results obtained from the per protocol analysis, however, the median length of stay for those in the OMT group was 3.5 days, compared with 4.5 days for those in the CC group (95% CI, 3.2-4.0; P=.01). Multiple comparisons also indicated a reduction in mean duration of intravenous antibiotic use of 3 days in the OMT group (95% CI, 2.7-3.5) vs 3.5 days in the CC group (95% CI, 3.2-3.9). The treatment end-points of either death or respiratory failure occurred significantly less frequently in the OMT group compared with the CC group (P=.006).¹⁸

A Cochrane review of RCTs assessing the efficacy of adjunctive techniques compared with conventional therapy for patients with pneumonia revealed a reduction in hospital stay of 2 days (95% CI, -3.5 to -0.6) for patients who received OMT and positive expiratory pressure vs those who received neither intervention.¹⁹ Additionally, the duration of IV antibiotics and total duration of all (IV and oral) antibiotic treatment required in those treated adjunctively with OMT was shorter (MD for IV antibiotics= -2.1 days; 95% CI, -3.4 to -0.9 and MD for all antibiotics= -1.9 days; 95% CI, -3.1 to -0.7).¹⁹ The review was notable for a small sample size, with only 79 patients assessed.

OMT may improve IBS symptoms

A crossover study of 31 patients that compared visceral manipulation and sacral articulation OMT with sham therapy for the treatment of irritable bowel syndrome (IBS) demonstrated that OMT significantly decreased self-reported diarrhea (P=.016), abdominal distention (P=.043), abdominal pain (P=.013), and rectal sensitivity (P<.001), but did not significantly affect constipation.²⁰

In another study, researchers randomized 30 patients with IBS in a 2:1 distribution to OMT vs sham treatment.²¹ OMT included abdominal visceral techniques and direct and indirect spine techniques. All of the patients received 2 treatment sessions, and the researchers evaluated them at 7 and 28 days. At 7 days, both groups demonstrated a significant reduction in IBS symptoms, although the OMT group had significantly greater improvement (P=.01). At 28 days, however, neither group showed a significant reduction in symptoms.²¹

The lack of a control group (in the first study due to the crossover design), small sample sizes, and self-reported symptoms are major limitations to applying these studies to IBS treatment recommendations.

CORRESPONDENCE
Andrew H. Slattengren, DO, Broadway Family Medicine Clinic, 1020 West Broadway Avenue, Minneapolis, MN 55411; [email protected].

The care of women with female sexual disorders has made great strides since Masters and Johnson first began their study in 1957. In 2000, the Sexual Function Health Council of the American Foundation for Urologic Disease defined the classification system for female sexual dysfunction, which was eventually published and officially defined in the Diagnostic and Statistical Manual of Mental Disorders-IV-TR.¹ There are now definitions for sexual desire disorders, sexual arousal disorders, orgasmic disorder, and sexual pain disorders.

Female sexual dysfunction (FSD) has complex physiologic and psychological components that require a detailed screening, history, and physical examination. Our goal in this review is to provide family physicians with insights and practical advice to help screen, diagnose, and treat female sexual dysfunction, which can have a profound impact on patients’ most intimate relationships.

Understanding the types of female sexual dysfunction

Most women consider sexual health an important part of their overall health.² Factors that can disrupt normal sexual function include aging, socioeconomics, and other medical comorbidities. FSD is common in women throughout their lives and refers to various sexual dysfunctions including diminished arousal, problems achieving orgasm, dyspareunia, and low desire. Its prevalence is reported as high as 20% to 43%.^3,4

The World Health Organization and the US Surgeon General have released statements encouraging health care providers to address sexual health during a patient’s annual visits.⁵ Unfortunately, despite this call to action, many patients and providers are initially hesitant to discuss these problems.⁶

The Diagnostic and Statistical Manual of Mental Disorders, Fifth edition (DSM-5) provides the definition and diagnostic guidelines for the different components of FSD. Its classification of sexual disorders was simplified and published in May 2013.⁷ There are now only 3 female dysfunctions as opposed to 5 in DSM-IV.

• Female hypoactive desire dysfunction and female arousal dysfunction were merged into a single syndrome labeled female sexual interest/arousal disorder.
• The formerly separate dyspareunia (painful intercourse) and vaginismus are now called genitopelvic pain/penetration disorder.
• Female orgasmic disorder remains as a category and is unchanged.

To qualify as a dysfunction, the problem must be present more than 75% of the time, for more than 6 months, causing significant distress, and must not be explained by a nonsexual mental disorder, relationship distress, substance abuse, or a medical condition.

Substance- or medication-induced sexual dysfunction falls under “Other Dysfunctions” and is defined as a clinically significant disturbance in sexual function that is predominant in the clinical picture. The criteria for substance- and medication-induced sexual dysfunction are unchanged and include neither the 75% nor the 6-month requirement. The diagnosis of sexual dysfunction due to a general medical condition and sexual aversion disorder are absent from the DSM-5.⁷

A common symptom. Female sexual disorders can be caused by several complex physiologic and psychological factors. A common symptom among many women is dyspareunia. It is seen more often in postmenopausal women, and its prevalence ranges from 8% to 22%.⁸ Pain on vaginal entry usually indicates vaginal atrophy, vaginal dermatitis, or provoked vestibulodynia. Pain on deep penetration could be caused by endometriosis, interstitial cystitis, or uterine leiomyomas.⁹

The physical examination will reproduce the pain when the vulva or vagina is touched with a cotton swab or when you insert a finger into the vagina. The differential diagnosis is listed in the TABLE.^9-11

Evaluating the patient

Initially, many patients and providers may hesitate to discuss sexual dysfunction, but the annual exam is a good opportunity to broach the topic of sexual health.

Screening and history

Clinicians can screen all patients, regardless of age, with the help of a validated sex questionnaire or during a routine review of systems. There are many validated screening tools available. A simple, integrated screening tool to use is the Brief Sexual Symptom Checklist for Women (BSSC-W), created by the International Consultation in Sexual Medicine.¹² Although recommended by the American Congress of Obstetricians and Gynecologists,⁹ the BSSC-W is not validated. The questionnaire includes 4 questions that ascertain personal information regarding an individual’s overall sexual function satisfaction, the problem causing dysfunction, how bothersome the symptoms are, and if the patient is interested in discussing it with her provider.¹²

The prevalence of female sexual dysfunction is as high as 43%.

It’s important to obtain a detailed obstetric and gynecologic history that includes any sexually transmitted diseases, sexual abuse, urinary and bowel complaints, or surgeries. In addition, you’ll want to differentiate between various types of dysfunctions. A thorough physical examination, including an external and internal pelvic exam, can help to rule out other causes of sexual dysfunction.

General examination: What to look for

The external pelvic examination begins with visual inspection of the vulva, labia majora, and labia minora. Often, this is best accomplished gently with a gloved hand and a cotton swab. This inspection may reveal changes in pubic hair distribution, vulvar skin disorders, lesions, masses, cracks, or fissures. Inspection may also reveal redness and pain typical of vestibulitis, a flattening and pallor of the labia that suggests estrogen deficiency, or pelvic organ prolapse.

The internal pelvic examination begins with a manual evaluation of the muscles of the pelvic floor, uterus, bladder, urethra, anus, and adnexa. Make careful note of any unusual tenderness or pelvic masses. Pelvic floor muscles (PFMs) should voluntarily contract and relax and are not normally tender to palpation. Pelvic organ prolapse and/or hypermobility of the bladder may indicate a weakening of the endopelvic fascia and may cause sexual pain. The size and flexion of the uterus, tenderness in the vaginal fornix possibly indicating endometriosis, and adnexal fullness and/or masses should be identified and evaluated.

Neurologic exam of the pelvis will involve evaluation of sensory and motor function of both lower extremities and include a screening lumbosacral neurologic examination. Lumbosacral examination includes assessment of PFM strength, anal sphincter resting tone, voluntary anal contraction, and perineal sensation. If abnormalities are noted in the screening assessment, a complete comprehensive neurologic examination should be performed.

It’s important to assess pelvic floor muscle strength

Sexual function is associated with normal PFM function.^13,14 The PFMs, particularly the pubococcygeus and iliococcygeus, are responsible for involuntary contractions during orgasm.¹³ Orgasm has been considered a reflex, which is preceded by increased blood flow to the genital organs, tumescence of the vulva and vagina, increased secretions during sexual arousal, and increased tension and contractions of the PFMs.¹⁵

Systemic estrogen in oral form, transdermal preparations, and topical formulations may increase sexual arousal and decrease dyspareunia.

Lowenstein et al found that women with strong or moderate PFM contractions scored significantly higher on both orgasm and arousal domains of the female sexual function index (FSFI) compared with women with weak PFM contractions.¹⁶ Orgasm and arousal functions may be associated with PFM strength, with a positive association between pelvic floor strength and sexual activity and function.^17,18

The function and dysfunction of the PFMs have been characterized as normal, overactive (high tone), underactive (low tone), and non-functioning.

• Normal PFMs are those that can voluntarily and involuntary contract and relax.^19,20
• Overactive (high-tone) muscles are those that do not relax and possibly contract during times of relaxation for micturition or defecation. This type of dysfunction can lead to voiding dysfunction, defecatory dysfunction, and dyspareunia.¹⁹
• Underactive, or low-tone, PFMs cannot contract voluntarily. This can be associated with urinary and anal incontinence and pelvic organ prolapse.
• Nonfunctioning muscles are completely inactive.¹⁹

How to assess. There are several ways to assess PFM tone and strength.²⁰ The first is intravaginal or intrarectal digital palpation, which can be performed when the patient is in a supine or standing position. This examination evaluates PFM tone, squeeze pressure during contraction, symmetry, and relaxation. However, there is no validated scale to quantify PFM strength. Contractions can be further divided into voluntary and involuntary.¹⁹

During the examination, the physician should ask the patient to contract as much as she can to evaluate the maximum strength and sustained contraction for endurance. This measurement can be done with digital palpation or with pressure manometry or dynamometry.

Examination can be focused on the levator ani, piriformis, and internal obturator muscles bilaterally and rated by the patient’s reactions. Pelvic muscle tenderness, which can be highly prevalent in women with chronic pelvic pain, is associated with higher degrees of dyspareunia.²¹ Digital evaluation of the pelvic floor musculature varies in scale, number of fingers used, and parameters evaluated. Lukban et al has described a zero to 4 numbered scale that evaluates tenderness in the pelvic floor.²² The scale denotes “1” as comfortable pressure associated with the exam, “2” as uncomfortable pressure associated with the exam, “3” as moderate pain associated with the exam and that intensifies with contraction, and “4” indicating severe pain with the exam and inability to perform the contraction maneuver due to pain.

Effective treatment includes multiple options

Lifestyle modifications can help

Lifestyle changes may help improve sexual function. These modifications include physical activity, healthy diet, nutrition counseling, and adequate sleep.^23,24

Identifying medical conditions such as depression and anxiety will help delineate differential diagnoses of sexual dysfunction. Cardiovascular diseases may contribute to arousal disorder as a result of atherosclerosis of the vessels supplying the vagina and clitoris. Neurologic diseases such as multiple sclerosis and diabetes can affect sexual dysfunction by impairing arousal and orgasm. Identification of concurrent comorbidities and implementation of lifestyle changes will help improve overall health and may improve sexual function.²⁵

Manual therapies, including transvaginal technique, may relieve female sexual dysfunction that results from a variety of causes.

In addition, Herati et al²⁶ found food sensitivities to grapefruit juice, spicy foods, alcohol, and caffeine were more prevalent in patients with interstitial cystitis and chronic pelvic pain. Avoiding irritants such as soap and other detergents in the perineal region may help decrease dysfunction.²⁷ Finally, foods high in oxalate and other acidic items may cause bladder pain and worsening symptoms of vulvodynia.²⁸

Topical therapies worth considering

Lubricants and moisturizers may help women with dyspareunia or symptoms of vaginal atrophy.

Zestra, for instance, which is applied to the vulva prior to sexual activity, has been proven more effective than placebo for improving desire and arousal.²⁹

Neogyn is a non-hormonal cream containing cutaneous lysate and has been shown to improve vulvar pain in women with vulvodynia. A double-blind placebo-controlled randomized crossover trial followed 30 patients over 3 months and found a significant reduction in pain during sexual activity and a significant reduction in erythema.³⁰

Alprostadil is a prostaglandin E1 analogue that increases genital vasodilation when applied topically and is currently undergoing investigational trials.^31,32 Patients can also choose from many over-the-counter lubricants that contain water-based, oil-based, or silicone-based ingredients.

Don’t overlook physical therapy

Manual therapies, including the transvaginal technique, are used for female sexual dysfunction that results from a variety of causes, including high-tone pelvic floor dysfunction. The transvaginal technique can identify myofascial pain; treatment involves internal release of the PFMs and external trigger point identification and alleviation.

One pilot study, which involved transvaginal Thiele massage twice a week for 5 weeks on 21 symptomatic women with IC and high-tone pelvic floor dysfunction found it decreased hyptertonicity of the pelvic floor and generated statistically significant improvement in the Symptom and Problem Indexes of the O’Leary-Sant Questionnaire, Likert Visual Analogue Scales for urgency and pain, and the Physical and Mental Component Summary from the SF-12 Quality-of-Life Scale.³³ Transvaginal physical therapy is also an effective treatment for myofascial pelvic pain.³⁴

Biofeedback, which can be used in combination with pelvic floor physical therapy, teaches the patient to control the PFMs by visualizing the activity to achieve conscious control over contraction of the pelvic floor and ceasing the cycle of spasm.³⁵ Ger et al³⁶ investigated patients with levator spasm and found biofeedback decreased pain; relief was rated as good or excellent at 15-month follow-up in 6 out of 14 patients (43%).

Home devices such as Eros Therapy, an FDA-approved, nonpharmacologic battery-operated device, provide vacuum suction to the clitoris with vibratory sensation. Eros Therapy has been shown to increase blood flow to the clitoris, vagina, and pelvic floor and increase sensation, orgasm, lubrication, and satisfaction.³⁷

The treatment of female sexual dysfunction may require a multimodal systematic approach targeting genitopelvic pain.

Vaginal dilators allow increasing lengths and girths designed to treat vaginal and pelvic floor pain.³⁸ In our practice, we encourage pelvic muscle strengthening tools in the form of kegal trainers and other insertion devices that may improve PFM coordination and strength.

Pharmacotherapy has its place

The treatment of FSD may require a multimodal systematic approach targeting genito-pelvic pain. But before the best options can be found, it is important to first establish the cause of the pain. Several drug formulations have been effectively used including hormonal and non-hormonal options.

Conjugated estrogens are FDA approved for the treatment of dyspareunia, which can contribute to decreased desire. Systemic estrogen in oral form, transdermal preparations, and topical formulations may increase sexual desire and arousal and decrease dyspareunia.³⁹ Even synthetic steroid compounds such as tibolone may improve sexual function, although it is not FDA approved for that purpose.⁴⁰

Ospemifene (Osphena) is a selective estrogen receptor modulator that acts as an estrogen agonist in select tissues, including vaginal epithelium. It is FDA approved for dyspareunia in postmenopausal women.^41,42 A daily dose of 60 mg is effective and safe with minimal adverse effects.⁴² Studies suggest that testosterone, although not FDA approved in the United States for this purpose, improves sexual desire, pleasure, orgasm, and arousal satisfaction.³⁹ The hormone has not gained FDA approval because of concerns about long-term safety and efficacy.⁴²

Non-hormonal drugs including flibanserin (Addyi), a well-tolerated serotonin receptor 1A agonist, 2A antagonist shown to improve sexual desire, increase the number of satisfying sexual events, and reduce distress associated with low sexual desire when compared with placebo.⁴³ The FDA has approved flibanserin as the first treatment targeted for women with hypoactive sexual desire disorder (HSDD). It can, however, cause severe hypotension and syncope, is not well tolerated with alcohol, and is contraindicated in patients who take strong CYP3A4 inhibitors, such as fluconazole, verapamil, and erythromycin, or who have liver impairment.

Buproprion, a mild dopamine and norepinephrine reuptake inhibitor and acetylcholine receptor antagonist, has been shown to improve desire in women with and without depression. Although it is FDA approved for major depressive disorder, it is not approved for female sexual dysfunction and is still under investigation.

Tricyclic antidepressants such as nortriptyline and amitriptyline may be effective in treating neuropathic pain. Starting doses of both amitriptyline and nortriptyline are 10 mg/d and can be increased to a maximum of 100 mg/d.⁴⁴ Tricyclic antidepressants are still under investigation for the treatment of FSD.

Muscle relaxants in oral and topical compounded form are used to treat increased pelvic floor tension and spasticity. Cyclobenzaprine and tizanidine are FDA-approved muscle relaxants indicated for muscle spasticity.

Cyclobenzaprine, at a starting dose of 10 mg, can be taken up to 3 times a day for pelvic floor tension. Tizanidine is a centrally active alpha 2 agonist that’s superior to placebo in treating high-tone pelvic floor dysfunction.⁴⁴

Other medications include benzodiazepines such as oral clonazepam and intra-vaginal diazepam, although they are not FDA approved for high-tone pelvic floor dysfunction. Rogalski et al reviewed 26 patients who received vaginal diazepam for bladder pain, sexual pain, and levator hypertonus.⁴⁵ They found subjective and sexual pain improvement assessed on FSFI and the visual analog pain scale. PFM tone significantly improved during resting, squeezing, and relaxation phases. Multimodal therapy can be used for muscle spasticity and high-tone pelvic floor dysfunction.

Trigger point and Botox injections

Although drug therapy has its place in the management of sexual dysfunction, other modalities that involve trigger point injections or botulinum toxin injections to the PFMs may prove helpful for patients with high-tone pelvic floor dysfunction.

A prospective study investigated the role of trigger point injections in 18 women with levator ani muscle spasm with a mixture of 0.25% bupivacaine in 10 mL, 2% lidocaine in 10 mL, and 40 mg of triamcinolone in 1 mL combined and used for injection of 5 mL per trigger point.⁴⁶ Three months after injections, 13 of the 18 women improved, resulting in a success rate of 72%. Trigger point injections can be applied externally or transvaginally.

OnabotulinumtoxinA (Botox) has also been tested for relief of levator ani muscle spasm. Botox is FDA approved for upper and lower limb spasticity but is not approved for pelvic floor spasticity or tension. It may reduce pressure in the PFMs and may be useful in women with high-tone pelvic floor dysfunction.⁴⁷

In a prospective 6-month pilot study, 28 patients with pelvic pain who failed conservative treatment received up to 300 U Botox into the pelvic floor.¹¹ The study, which used needle electromyography guidance and a transperineal approach, found that the dyspareunia visual analog scale improved significantly at Weeks 12 and 24. Keep in mind, however, that onabotulinumtoxinA should be reserved for patients who fail conventional treatments.^47,48

Addressing psychological issues

Sex therapy is a traditional approach that aims to improve individual or couples’ sexual experiences and help reduce anxiety related to sex.⁴² Cognitive behavioral sex therapy includes traditional sex therapy components but puts greater emphasis on modifying thought patterns that interfere with intimacy and sex.⁴²

Three months after trigger point injections, 13 of 18 women improved, resulting in a success rate of 72%.

Mindfulness-based cognitive-behavioral treatments have shown promise for sexual desire problems. It is an ancient eastern practice with Buddhist roots. This therapy is a nonjudgmental, present-moment awareness comprised of self-regulation of attention and accepting orientation to the present.⁴⁹ Although there is little evidence from prospective studies, it may benefit women with sexual dysfunction after intervention with sex therapy and cognitive behavioral therapy.

Female sexual dysfunction is common and affects women of all ages. It can negatively impact a women’s quality of life and overall well-being. The etiology of FSD is complex, and treatments are based on the causes of the dysfunction. Difficult cases warrant referral to a specialist in sexual health and female pelvic medicine. Future prospective trials, randomized controlled trials, the use of validated questionnaires, and meta-analyses will continue to move us forward as we find better ways to understand, identify, and treat female sexual dysfunction.

CORRESPONDENCE
Melissa L. Dawson, DO, MS, Department of OB/GYN, Drexel University College of Medicine, 207 N Broad St. 4th Floor, Philadelphia, PA 19107; [email protected].