Thank you for your tribute to David Warfield Stires, The Journal of Family Practice’s founding publisher (J Fam Pract. 2017;66:654-655). The real hero of the story, however, is Dr. John Geyman, who had the vision to found a research journal at the birth of our specialty. This was no easy task, as John faced a challenging chicken-and-egg problem: how to establish a research journal when academic family medicine was just getting underway and had no track record of generating a steady stream of quality research. The latter problem was due, in part, to the lack of a research journal devoted to promoting and publishing research in the field.

Yet, John did it, putting family medicine research on the publishing map. His groundbreaking work set the stage for future journals, including the Journal of the American Board of Family Medicine, the American Medical Association’s now-defunct Archives of Family Medicine, and the American Academy of Family Physicians’ Annals of Family Medicine.

As a family medicine resident in the 1970s, I remember coveting JFP so much that I managed to collect every issue from Volume 1, Issue 1, through the turn of the century. And as a young faculty member at Georgetown University Medical Center in the 1980s, I painstakingly created an annotated bibliography of the then-published content of JFP to use for teaching, research, and administration.

When I became editor of American Family Physician in 1988, I made a pilgrimage to the University of Washington School of Medicine in Seattle, where John was chairman of the Department of Family Medicine. I wanted to seek his advice, learn from his vast experience, and pay tribute to all that he’d done for our specialty. Over the past 30 years, John has continued to leave his mark. (See http://www.johngeymanmd.org/bio.html.)

A tribute to David Warfield Stires is incomplete without a corresponding acknowledgement and celebration of John’s decades-long visionary leadership in family medicine.

Jay Siwek, MD
Washington, DC

Thank you for your tribute to David Warfield Stires, The Journal of Family Practice’s founding publisher (J Fam Pract. 2017;66:654-655). The real hero of the story, however, is Dr. John Geyman, who had the vision to found a research journal at the birth of our specialty. This was no easy task, as John faced a challenging chicken-and-egg problem: how to establish a research journal when academic family medicine was just getting underway and had no track record of generating a steady stream of quality research. The latter problem was due, in part, to the lack of a research journal devoted to promoting and publishing research in the field.

Yet, John did it, putting family medicine research on the publishing map. His groundbreaking work set the stage for future journals, including the Journal of the American Board of Family Medicine, the American Medical Association’s now-defunct Archives of Family Medicine, and the American Academy of Family Physicians’ Annals of Family Medicine.

As a family medicine resident in the 1970s, I remember coveting JFP so much that I managed to collect every issue from Volume 1, Issue 1, through the turn of the century. And as a young faculty member at Georgetown University Medical Center in the 1980s, I painstakingly created an annotated bibliography of the then-published content of JFP to use for teaching, research, and administration.

When I became editor of American Family Physician in 1988, I made a pilgrimage to the University of Washington School of Medicine in Seattle, where John was chairman of the Department of Family Medicine. I wanted to seek his advice, learn from his vast experience, and pay tribute to all that he’d done for our specialty. Over the past 30 years, John has continued to leave his mark. (See http://www.johngeymanmd.org/bio.html.)

A tribute to David Warfield Stires is incomplete without a corresponding acknowledgement and celebration of John’s decades-long visionary leadership in family medicine.

Jay Siwek, MD
Washington, DC

Thank you for your tribute to David Warfield Stires, The Journal of Family Practice’s founding publisher (J Fam Pract. 2017;66:654-655). The real hero of the story, however, is Dr. John Geyman, who had the vision to found a research journal at the birth of our specialty. This was no easy task, as John faced a challenging chicken-and-egg problem: how to establish a research journal when academic family medicine was just getting underway and had no track record of generating a steady stream of quality research. The latter problem was due, in part, to the lack of a research journal devoted to promoting and publishing research in the field.

Yet, John did it, putting family medicine research on the publishing map. His groundbreaking work set the stage for future journals, including the Journal of the American Board of Family Medicine, the American Medical Association’s now-defunct Archives of Family Medicine, and the American Academy of Family Physicians’ Annals of Family Medicine.

As a family medicine resident in the 1970s, I remember coveting JFP so much that I managed to collect every issue from Volume 1, Issue 1, through the turn of the century. And as a young faculty member at Georgetown University Medical Center in the 1980s, I painstakingly created an annotated bibliography of the then-published content of JFP to use for teaching, research, and administration.

When I became editor of American Family Physician in 1988, I made a pilgrimage to the University of Washington School of Medicine in Seattle, where John was chairman of the Department of Family Medicine. I wanted to seek his advice, learn from his vast experience, and pay tribute to all that he’d done for our specialty. Over the past 30 years, John has continued to leave his mark. (See http://www.johngeymanmd.org/bio.html.)

A tribute to David Warfield Stires is incomplete without a corresponding acknowledgement and celebration of John’s decades-long visionary leadership in family medicine.

Jay Siwek, MD
Washington, DC

In the article, “Hypertension treatment strategies for older adults” (J Fam Pract. 2017;66:546-554), Hansell et al recommend a systolic blood pressure (SBP) treatment target of <120 mm Hg for community-dwelling, nondiabetic patients ≥75 years of age. This recommendation is not supported by the authors’ cited guidelines, and we have serious concerns about the risk of harm from such overly stringent BP control in this population.

While Hansell et al acknowledge that no consensus exists regarding an optimal BP target for older patients, the authors cite the Eighth Joint National Committee (JNC 8), the American College of Physicians (ACP), the Systolic Blood Pressure Intervention Trial (SPRINT) subgroup analysis, and the BP arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial to justify their recommendation. But as the authors mention, JNC 8 conducted a comprehensive review of the available evidence and determined that a BP target of <150/90 mm Hg for hypertensive patients ≥60 years of age is appropriate.¹

While it is tempting to make generalizations about BP treatment targets, we owe it to our patients to understand the nuances of applicable guidelines.

The authors also state that ACP recommends an SBP target of <140 mm Hg, while, in fact, the recommendations from ACP (which are joint guidelines published with the American Academy of Family Physicians) say that high-quality evidence strongly supports an SBP target of <150 mm Hg to reduce the risk for mortality, stroke, and cardiac events in adults ≥60 years of age.²

SPRINT does support Hansell et al’s recommended SBP target of <120 mm Hg, but this trial provided only composite data of adults ≥75 years of age and did not differentiate between the outcomes in otherwise healthy adults ≥75 years of age vs those with cardiovascular conditions.³ As Hansell et al point out, the SPRINT trial was halted prematurely, which compromises the validity of their findings.

Lastly, the ACCORD trial did not find benefit to treating SBP <120 mm Hg compared with <140 mm Hg in adults with diabetes, but it did find substantial harms in the <120 mm Hg group, including an increased risk of renal impairment and hypokalemia.⁴

Hansel et al’s overreliance on the SPRINT subgroup analysis represents a significant flaw in the assertion that an SBP target <120 mm Hg is reasonable for all community-dwelling, non-diabetic adults ≥75 years of age. While the authors made the allowance that a higher target (<140 mm Hg) is acceptable if a target of <120 mm Hg places undue burden on the patient, the guidelines they cited, when considered together, suggest that starting at a higher target is not only sufficient to prevent complications, but also reduces overtreatment.

Adults ≥75 years of age are a diverse group regarding disease conditions, life expectancy, and personal priorities. While it is tempting to make generalizations about BP treatment targets, we owe it to our patients to understand the nuances of applicable guidelines so that we can tailor BP treatment targets to each patient’s unique clinical situation and personal priorities. Applying a blanket recommendation to this heterogeneous population may result in significant harms from overtreatment.

Jennifer L. Middleton, MD, MPH, FAAFP; Miriam Chan, PharmD, CDE
Columbus, Ohio

1. James PA, Oparil S, Carter BL, et al. 2014 Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507-520.

2. Qaseem A, Wilt TJ, Rich R, et al. Pharmacological treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2017;166:430-437.

3. Williamson JD, Suplano MA, Applegate WB, et al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥75 years: a randomized clinical trial. JAMA. 2016;315:2673-2682.

4. ACCORD Study Group, Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575-1585.

We agree with the title of this letter, “Utilize guidelines, but customize BP treatment in older patients.” Our recommendations are not limited to targeting a systolic BP <120 mm Hg for community-dwelling, nondiabetic adults ≥75 years of age, but include consideration for “undue burden.” Our third practice recommendation, which recommends that one consider cognitive function, polypharmacy, multimorbidity, and frailty, is an equally—if not more—important recommendation.

With regard to the specific concerns about the current guidelines:

1. The American College of Physicians and American Academy of Family Physicians’ “Recommendation 1” advocates a systolic BP goal <150 mm Hg for adults ≥60 years of age. However, “Recommendation 3” endorses intensifying treatment in adults ≥60 years of age at high cardiovascular (CV) risk. Based on Framingham criteria, all adults ≥75 years of age are considered at high risk for CV disease, as stated in our article. Therefore, “Recommendation 3” for a target of <140 mm Hg is applicable for the population addressed in our article.¹
2. The Eighth Joint National Committee (JNC 8) does recommend a BP target <150 mm Hg for adults ≥60 years of age, but does not take into account recent data, which is why we wanted to highlight that data for physicians.²
3. Since submission of our article, The American College of Cardiology/American Heart Association (ACC/AHA) has published its first set of guidelines since 2003, which lowered BP target to <130 mm Hg in patients with high CV risk. Those guidelines outline the validity of SPRINT and the consistency of the existing evidence, including the linear relationship of BP and mortality.³
4. SPRINT was halted early specifically because of the mortality benefit in the intensive treatment group, which is ethically appropriate.⁴ It is unclear to us how this compromises the validity of the trial. There is often concern for bias from early cessation in small trials, but this was a large, well-powered trial.
5. The ACC/AHA guidelines also address some of the nuances of ACCORD, which is specific to patients with diabetes (whom we excluded from our first Practice Recommendation). Although no overall mortality benefit was found, there was stroke reduction in this group and additional benefit in the standard glycemia group.^3,5 A meta-analysis of SPRINT and ACCORD showed CV disease reduction with a BP target <120 mm Hg.⁶

Although we do believe that SPRINT is a landmark trial, we strongly emphasized that comorbidities, frailty, and dementia greatly impact treatment decisions.

Although we do believe that SPRINT is a landmark trial contributing a great deal to our recommendations, we strongly emphasized that comorbidities, frailty, and dementia greatly impact treatment decisions. We stressed that prescribers use caution and slow titration because of adverse effects. Geriatric medicine is a complex art, and one of the goals of our article was to highlight this complexity and emphasize the importance of considering goals of care, comorbidity, frailty, and cognitive function when choosing optimal BP targets.

Maggie W. Hansell, MD; Emily M. Mann, MD; Julienne K. Kirk, PharmD
Winston-Salem, NC

1. Qaseem A, Wilt TJ, Rich R, et al. Pharmacological treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2017;166:430-437.

2. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507-520.

3. Whelton PK, Carey RM, Aronow WS, et al. ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Available at: http://hyper.ahajournals.org/content/hypertensionaha/early/2017/11/10/HYP.0000000000000066.full.pdf. Accessed December 12, 2017.

4. SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103-2106.

5. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive blood-pressure control in type 2 diabetes. N Engl J Med. 2010;362:1575-1585.

6. Perkovic V, Rodgers A. Redefining blood-pressure targets—SPRINT starts the marathon. N Engl Med. 2015;373:2175-2178.

In the article, “Hypertension treatment strategies for older adults” (J Fam Pract. 2017;66:546-554), Hansell et al recommend a systolic blood pressure (SBP) treatment target of <120 mm Hg for community-dwelling, nondiabetic patients ≥75 years of age. This recommendation is not supported by the authors’ cited guidelines, and we have serious concerns about the risk of harm from such overly stringent BP control in this population.

While Hansell et al acknowledge that no consensus exists regarding an optimal BP target for older patients, the authors cite the Eighth Joint National Committee (JNC 8), the American College of Physicians (ACP), the Systolic Blood Pressure Intervention Trial (SPRINT) subgroup analysis, and the BP arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial to justify their recommendation. But as the authors mention, JNC 8 conducted a comprehensive review of the available evidence and determined that a BP target of <150/90 mm Hg for hypertensive patients ≥60 years of age is appropriate.¹

While it is tempting to make generalizations about BP treatment targets, we owe it to our patients to understand the nuances of applicable guidelines.

The authors also state that ACP recommends an SBP target of <140 mm Hg, while, in fact, the recommendations from ACP (which are joint guidelines published with the American Academy of Family Physicians) say that high-quality evidence strongly supports an SBP target of <150 mm Hg to reduce the risk for mortality, stroke, and cardiac events in adults ≥60 years of age.²

SPRINT does support Hansell et al’s recommended SBP target of <120 mm Hg, but this trial provided only composite data of adults ≥75 years of age and did not differentiate between the outcomes in otherwise healthy adults ≥75 years of age vs those with cardiovascular conditions.³ As Hansell et al point out, the SPRINT trial was halted prematurely, which compromises the validity of their findings.

Lastly, the ACCORD trial did not find benefit to treating SBP <120 mm Hg compared with <140 mm Hg in adults with diabetes, but it did find substantial harms in the <120 mm Hg group, including an increased risk of renal impairment and hypokalemia.⁴

Hansel et al’s overreliance on the SPRINT subgroup analysis represents a significant flaw in the assertion that an SBP target <120 mm Hg is reasonable for all community-dwelling, non-diabetic adults ≥75 years of age. While the authors made the allowance that a higher target (<140 mm Hg) is acceptable if a target of <120 mm Hg places undue burden on the patient, the guidelines they cited, when considered together, suggest that starting at a higher target is not only sufficient to prevent complications, but also reduces overtreatment.

Adults ≥75 years of age are a diverse group regarding disease conditions, life expectancy, and personal priorities. While it is tempting to make generalizations about BP treatment targets, we owe it to our patients to understand the nuances of applicable guidelines so that we can tailor BP treatment targets to each patient’s unique clinical situation and personal priorities. Applying a blanket recommendation to this heterogeneous population may result in significant harms from overtreatment.

Jennifer L. Middleton, MD, MPH, FAAFP; Miriam Chan, PharmD, CDE
Columbus, Ohio

1. James PA, Oparil S, Carter BL, et al. 2014 Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507-520.

2. Qaseem A, Wilt TJ, Rich R, et al. Pharmacological treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2017;166:430-437.

3. Williamson JD, Suplano MA, Applegate WB, et al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥75 years: a randomized clinical trial. JAMA. 2016;315:2673-2682.

4. ACCORD Study Group, Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575-1585.

We agree with the title of this letter, “Utilize guidelines, but customize BP treatment in older patients.” Our recommendations are not limited to targeting a systolic BP <120 mm Hg for community-dwelling, nondiabetic adults ≥75 years of age, but include consideration for “undue burden.” Our third practice recommendation, which recommends that one consider cognitive function, polypharmacy, multimorbidity, and frailty, is an equally—if not more—important recommendation.

With regard to the specific concerns about the current guidelines:

1. The American College of Physicians and American Academy of Family Physicians’ “Recommendation 1” advocates a systolic BP goal <150 mm Hg for adults ≥60 years of age. However, “Recommendation 3” endorses intensifying treatment in adults ≥60 years of age at high cardiovascular (CV) risk. Based on Framingham criteria, all adults ≥75 years of age are considered at high risk for CV disease, as stated in our article. Therefore, “Recommendation 3” for a target of <140 mm Hg is applicable for the population addressed in our article.¹
2. The Eighth Joint National Committee (JNC 8) does recommend a BP target <150 mm Hg for adults ≥60 years of age, but does not take into account recent data, which is why we wanted to highlight that data for physicians.²
3. Since submission of our article, The American College of Cardiology/American Heart Association (ACC/AHA) has published its first set of guidelines since 2003, which lowered BP target to <130 mm Hg in patients with high CV risk. Those guidelines outline the validity of SPRINT and the consistency of the existing evidence, including the linear relationship of BP and mortality.³
4. SPRINT was halted early specifically because of the mortality benefit in the intensive treatment group, which is ethically appropriate.⁴ It is unclear to us how this compromises the validity of the trial. There is often concern for bias from early cessation in small trials, but this was a large, well-powered trial.
5. The ACC/AHA guidelines also address some of the nuances of ACCORD, which is specific to patients with diabetes (whom we excluded from our first Practice Recommendation). Although no overall mortality benefit was found, there was stroke reduction in this group and additional benefit in the standard glycemia group.^3,5 A meta-analysis of SPRINT and ACCORD showed CV disease reduction with a BP target <120 mm Hg.⁶

Although we do believe that SPRINT is a landmark trial, we strongly emphasized that comorbidities, frailty, and dementia greatly impact treatment decisions.

Although we do believe that SPRINT is a landmark trial contributing a great deal to our recommendations, we strongly emphasized that comorbidities, frailty, and dementia greatly impact treatment decisions. We stressed that prescribers use caution and slow titration because of adverse effects. Geriatric medicine is a complex art, and one of the goals of our article was to highlight this complexity and emphasize the importance of considering goals of care, comorbidity, frailty, and cognitive function when choosing optimal BP targets.

Maggie W. Hansell, MD; Emily M. Mann, MD; Julienne K. Kirk, PharmD
Winston-Salem, NC

1. Qaseem A, Wilt TJ, Rich R, et al. Pharmacological treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2017;166:430-437.

2. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507-520.

3. Whelton PK, Carey RM, Aronow WS, et al. ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Available at: http://hyper.ahajournals.org/content/hypertensionaha/early/2017/11/10/HYP.0000000000000066.full.pdf. Accessed December 12, 2017.

4. SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103-2106.

5. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive blood-pressure control in type 2 diabetes. N Engl J Med. 2010;362:1575-1585.

6. Perkovic V, Rodgers A. Redefining blood-pressure targets—SPRINT starts the marathon. N Engl Med. 2015;373:2175-2178.

In the article, “Hypertension treatment strategies for older adults” (J Fam Pract. 2017;66:546-554), Hansell et al recommend a systolic blood pressure (SBP) treatment target of <120 mm Hg for community-dwelling, nondiabetic patients ≥75 years of age. This recommendation is not supported by the authors’ cited guidelines, and we have serious concerns about the risk of harm from such overly stringent BP control in this population.

While Hansell et al acknowledge that no consensus exists regarding an optimal BP target for older patients, the authors cite the Eighth Joint National Committee (JNC 8), the American College of Physicians (ACP), the Systolic Blood Pressure Intervention Trial (SPRINT) subgroup analysis, and the BP arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial to justify their recommendation. But as the authors mention, JNC 8 conducted a comprehensive review of the available evidence and determined that a BP target of <150/90 mm Hg for hypertensive patients ≥60 years of age is appropriate.¹

While it is tempting to make generalizations about BP treatment targets, we owe it to our patients to understand the nuances of applicable guidelines.

The authors also state that ACP recommends an SBP target of <140 mm Hg, while, in fact, the recommendations from ACP (which are joint guidelines published with the American Academy of Family Physicians) say that high-quality evidence strongly supports an SBP target of <150 mm Hg to reduce the risk for mortality, stroke, and cardiac events in adults ≥60 years of age.²

SPRINT does support Hansell et al’s recommended SBP target of <120 mm Hg, but this trial provided only composite data of adults ≥75 years of age and did not differentiate between the outcomes in otherwise healthy adults ≥75 years of age vs those with cardiovascular conditions.³ As Hansell et al point out, the SPRINT trial was halted prematurely, which compromises the validity of their findings.

Lastly, the ACCORD trial did not find benefit to treating SBP <120 mm Hg compared with <140 mm Hg in adults with diabetes, but it did find substantial harms in the <120 mm Hg group, including an increased risk of renal impairment and hypokalemia.⁴

Hansel et al’s overreliance on the SPRINT subgroup analysis represents a significant flaw in the assertion that an SBP target <120 mm Hg is reasonable for all community-dwelling, non-diabetic adults ≥75 years of age. While the authors made the allowance that a higher target (<140 mm Hg) is acceptable if a target of <120 mm Hg places undue burden on the patient, the guidelines they cited, when considered together, suggest that starting at a higher target is not only sufficient to prevent complications, but also reduces overtreatment.

Adults ≥75 years of age are a diverse group regarding disease conditions, life expectancy, and personal priorities. While it is tempting to make generalizations about BP treatment targets, we owe it to our patients to understand the nuances of applicable guidelines so that we can tailor BP treatment targets to each patient’s unique clinical situation and personal priorities. Applying a blanket recommendation to this heterogeneous population may result in significant harms from overtreatment.

Jennifer L. Middleton, MD, MPH, FAAFP; Miriam Chan, PharmD, CDE
Columbus, Ohio

1. James PA, Oparil S, Carter BL, et al. 2014 Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507-520.

2. Qaseem A, Wilt TJ, Rich R, et al. Pharmacological treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2017;166:430-437.

3. Williamson JD, Suplano MA, Applegate WB, et al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥75 years: a randomized clinical trial. JAMA. 2016;315:2673-2682.

4. ACCORD Study Group, Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575-1585.

We agree with the title of this letter, “Utilize guidelines, but customize BP treatment in older patients.” Our recommendations are not limited to targeting a systolic BP <120 mm Hg for community-dwelling, nondiabetic adults ≥75 years of age, but include consideration for “undue burden.” Our third practice recommendation, which recommends that one consider cognitive function, polypharmacy, multimorbidity, and frailty, is an equally—if not more—important recommendation.

With regard to the specific concerns about the current guidelines:

1. The American College of Physicians and American Academy of Family Physicians’ “Recommendation 1” advocates a systolic BP goal <150 mm Hg for adults ≥60 years of age. However, “Recommendation 3” endorses intensifying treatment in adults ≥60 years of age at high cardiovascular (CV) risk. Based on Framingham criteria, all adults ≥75 years of age are considered at high risk for CV disease, as stated in our article. Therefore, “Recommendation 3” for a target of <140 mm Hg is applicable for the population addressed in our article.¹
2. The Eighth Joint National Committee (JNC 8) does recommend a BP target <150 mm Hg for adults ≥60 years of age, but does not take into account recent data, which is why we wanted to highlight that data for physicians.²
3. Since submission of our article, The American College of Cardiology/American Heart Association (ACC/AHA) has published its first set of guidelines since 2003, which lowered BP target to <130 mm Hg in patients with high CV risk. Those guidelines outline the validity of SPRINT and the consistency of the existing evidence, including the linear relationship of BP and mortality.³
4. SPRINT was halted early specifically because of the mortality benefit in the intensive treatment group, which is ethically appropriate.⁴ It is unclear to us how this compromises the validity of the trial. There is often concern for bias from early cessation in small trials, but this was a large, well-powered trial.
5. The ACC/AHA guidelines also address some of the nuances of ACCORD, which is specific to patients with diabetes (whom we excluded from our first Practice Recommendation). Although no overall mortality benefit was found, there was stroke reduction in this group and additional benefit in the standard glycemia group.^3,5 A meta-analysis of SPRINT and ACCORD showed CV disease reduction with a BP target <120 mm Hg.⁶

Although we do believe that SPRINT is a landmark trial, we strongly emphasized that comorbidities, frailty, and dementia greatly impact treatment decisions.

Although we do believe that SPRINT is a landmark trial contributing a great deal to our recommendations, we strongly emphasized that comorbidities, frailty, and dementia greatly impact treatment decisions. We stressed that prescribers use caution and slow titration because of adverse effects. Geriatric medicine is a complex art, and one of the goals of our article was to highlight this complexity and emphasize the importance of considering goals of care, comorbidity, frailty, and cognitive function when choosing optimal BP targets.

Maggie W. Hansell, MD; Emily M. Mann, MD; Julienne K. Kirk, PharmD
Winston-Salem, NC

1. Qaseem A, Wilt TJ, Rich R, et al. Pharmacological treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2017;166:430-437.

2. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507-520.

3. Whelton PK, Carey RM, Aronow WS, et al. ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Available at: http://hyper.ahajournals.org/content/hypertensionaha/early/2017/11/10/HYP.0000000000000066.full.pdf. Accessed December 12, 2017.

4. SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103-2106.

5. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive blood-pressure control in type 2 diabetes. N Engl J Med. 2010;362:1575-1585.

6. Perkovic V, Rodgers A. Redefining blood-pressure targets—SPRINT starts the marathon. N Engl Med. 2015;373:2175-2178.

THE CASE

A 41-year-old, right-hand dominant man sought care at our facility one day after trying to pull his boat out of the water. He’d tried to lift the boat with his hands while his forearms were fully supinated and his elbows were flexed to about 90°. He then felt a sharp burning sensation in his left anterior shoulder and was unable to lift the boat. The patient denied feeling a popping sensation at the time of the injury. He had mild pain at night, but was able to sleep. He said that he had mild diminished strength with elbow flexion, but denied having any numbness, tingling, or discoloration of his skin.

The patient said he did weightlifting and strength training of his upper and lower extremities 4 times/week. He was in good general health, was not taking any medications or supplements, and denied smoking or using illicit drugs. His surgical history was significant for a Bankart repair 8 years ago.

On physical examination, the patient had a scar from the previous surgery, a hollow area in his left anterior shoulder, and a prominent biceps muscle belly (FIGURE). His shoulder range of motion was normal. Left shoulder Neer, Hawkins-Kennedy, drop-arm, cross-arm, empty can, and apprehension tests were negative. A left Speed’s test (resisted elbow flexion when elbow is flexed 20° to 30° with the forearm in supination and the arm in about 60° of flexion) was positive for mild anterior shoulder pain. So, too, was a Yergason’s test (resisted forearm supination and elbow flexion when forearm is pronated and elbow is flexed to 90°). The patient’s elbow flexion strength was 4 out of 5, and his supination strength was 5 out of 5. Neurovascular and sensory examinations of his upper extremities, including radial and ulnar pulses, were normal.

THE DIAGNOSIS

A diagnostic musculoskeletal ultrasound revealed an empty tendon sheath of the long head of the biceps in the bicipital groove and a retracted echogenic stump with associated hematoma at the proximal musculotendinous junction. Based on the patient’s history, physical examination, and ultrasound, a diagnosis of an acute rupture of the left long head of the biceps brachii tendon was made.

DISCUSSION

Diagnosis of acute rupture is often made clinically based on a visually apparent defect proximally and a bulbous mass distally (“Popeye deformity”).¹ Ultrasound and magnetic resonance imaging (MRI) may aid in the diagnosis by demonstrating an absence of the long head in the bicipital groove or at its insertion.

The biceps brachii tendon functions in flexion and supination of the forearm. The long head of the biceps also plays a stabilizing role in the glenohumeral joint during elbow flexion and supination.² Injury to the biceps most often occurs in middle-aged men following a traumatic sudden eccentric bicipital contraction event, during which most patients describe a snapping or popping sensation.^3,4

Rupture of the proximal biceps tendon represents about 90% of all biceps ruptures, which almost exclusively involve the long head of the biceps.^3,5,6 Risk factors for tendon rupture include obesity, smoking, steroid injection in or around the tendon, and previous tendinopathy.^7-10

Functional limitations. It is generally thought that functional limitations following a proximal biceps rupture are relatively minimal, due to the work of other flexors and supinators, including the brachialis and brachioradialis. However, because strength and endurance of the muscle can decrease by about 25%, physical laborers and high-demand athletes may notice a degree of residual weakness with supination and elbow flexion.^11,12

Surgical repair is recommended for acute ruptures in patients with high physical demands and for whom a slight loss of flexion and su­pination strength would not be well tolerated.¹³ Tenotomy and tenodesis are the main techniques used to surgically repair a rupture of the long head of the biceps brachii tendon. Although there is no consensus on which technique is superior, it seems that there is less cosmetic deformity and better post-surgery biomechanical strength with tenodesis compared with tenotomy.¹⁴ However, tenodesis is associated with a higher likelihood of bicipital pain,¹⁴ and recent case reports have suggested it is associated with an increased risk of humeral fracture.¹⁵ Therefore, each patient should be treated on an individual case basis, taking into account age, activity level, and physical demand.¹⁴

For most patients, treatment remains conservative with typically excellent outcomes. Nonoperative management includes gentle range-of-motion exercises for the prevention of contractures of the elbow and shoulder. Such exercises can be started almost immediately after injury. In one study, nonoperative management was recommended for patients with sedentary work, injury in the non-dominant arm, and acceptable cosmetic deformity. Researchers noted that patients who opt for a nonsurgical treatment generally do well with a home exercise program and rarely have stiffness.¹

Nonoperative management includes gentle range-of-motion exercises for the prevention of contractures of the elbow and shoulder.

If the patient is a young athlete, if cosmetic deformity is unacceptable, or if the injury is in the dominant arm of a laborer, then the patient may want to consider tenodesis.¹ Tangari et al found that in high-demand athletes, biceps tenodesis resulted in excellent functional and cosmetic results with no clinically significant decrease in strength after an average follow-up of 7.6 years.¹³ In a case series of 5 patients who chose nonoperative treatment, Geaney and Mazzocca reported that patients experienced a 15% loss of supination strength at 4.5 years follow-up compared with the uninjured side.¹

Our patient elected to proceed with a tenodesis procedure. Two months after the surgery, he had fully recovered.

THE TAKEAWAY

Rupture of the biceps brachii tendon is relatively uncommon. In the vast majority of cases, it happens in the long head of the dominant arm of middle-aged men. Diagnosis is mainly clinical; however, ultrasound and MRI can confirm the diagnosis when there is doubt. Nonoperative management is appropriate for the majority of patients. Young athletes, patients who are concerned with cosmetic appearance, and labor workers with injury to their dominant arm should be referred to an orthopedic surgeon for possible surgery.

THE CASE

A 41-year-old, right-hand dominant man sought care at our facility one day after trying to pull his boat out of the water. He’d tried to lift the boat with his hands while his forearms were fully supinated and his elbows were flexed to about 90°. He then felt a sharp burning sensation in his left anterior shoulder and was unable to lift the boat. The patient denied feeling a popping sensation at the time of the injury. He had mild pain at night, but was able to sleep. He said that he had mild diminished strength with elbow flexion, but denied having any numbness, tingling, or discoloration of his skin.

The patient said he did weightlifting and strength training of his upper and lower extremities 4 times/week. He was in good general health, was not taking any medications or supplements, and denied smoking or using illicit drugs. His surgical history was significant for a Bankart repair 8 years ago.

On physical examination, the patient had a scar from the previous surgery, a hollow area in his left anterior shoulder, and a prominent biceps muscle belly (FIGURE). His shoulder range of motion was normal. Left shoulder Neer, Hawkins-Kennedy, drop-arm, cross-arm, empty can, and apprehension tests were negative. A left Speed’s test (resisted elbow flexion when elbow is flexed 20° to 30° with the forearm in supination and the arm in about 60° of flexion) was positive for mild anterior shoulder pain. So, too, was a Yergason’s test (resisted forearm supination and elbow flexion when forearm is pronated and elbow is flexed to 90°). The patient’s elbow flexion strength was 4 out of 5, and his supination strength was 5 out of 5. Neurovascular and sensory examinations of his upper extremities, including radial and ulnar pulses, were normal.

THE DIAGNOSIS

A diagnostic musculoskeletal ultrasound revealed an empty tendon sheath of the long head of the biceps in the bicipital groove and a retracted echogenic stump with associated hematoma at the proximal musculotendinous junction. Based on the patient’s history, physical examination, and ultrasound, a diagnosis of an acute rupture of the left long head of the biceps brachii tendon was made.

DISCUSSION

Diagnosis of acute rupture is often made clinically based on a visually apparent defect proximally and a bulbous mass distally (“Popeye deformity”).¹ Ultrasound and magnetic resonance imaging (MRI) may aid in the diagnosis by demonstrating an absence of the long head in the bicipital groove or at its insertion.

The biceps brachii tendon functions in flexion and supination of the forearm. The long head of the biceps also plays a stabilizing role in the glenohumeral joint during elbow flexion and supination.² Injury to the biceps most often occurs in middle-aged men following a traumatic sudden eccentric bicipital contraction event, during which most patients describe a snapping or popping sensation.^3,4

Rupture of the proximal biceps tendon represents about 90% of all biceps ruptures, which almost exclusively involve the long head of the biceps.^3,5,6 Risk factors for tendon rupture include obesity, smoking, steroid injection in or around the tendon, and previous tendinopathy.^7-10

Functional limitations. It is generally thought that functional limitations following a proximal biceps rupture are relatively minimal, due to the work of other flexors and supinators, including the brachialis and brachioradialis. However, because strength and endurance of the muscle can decrease by about 25%, physical laborers and high-demand athletes may notice a degree of residual weakness with supination and elbow flexion.^11,12

Surgical repair is recommended for acute ruptures in patients with high physical demands and for whom a slight loss of flexion and su­pination strength would not be well tolerated.¹³ Tenotomy and tenodesis are the main techniques used to surgically repair a rupture of the long head of the biceps brachii tendon. Although there is no consensus on which technique is superior, it seems that there is less cosmetic deformity and better post-surgery biomechanical strength with tenodesis compared with tenotomy.¹⁴ However, tenodesis is associated with a higher likelihood of bicipital pain,¹⁴ and recent case reports have suggested it is associated with an increased risk of humeral fracture.¹⁵ Therefore, each patient should be treated on an individual case basis, taking into account age, activity level, and physical demand.¹⁴

For most patients, treatment remains conservative with typically excellent outcomes. Nonoperative management includes gentle range-of-motion exercises for the prevention of contractures of the elbow and shoulder. Such exercises can be started almost immediately after injury. In one study, nonoperative management was recommended for patients with sedentary work, injury in the non-dominant arm, and acceptable cosmetic deformity. Researchers noted that patients who opt for a nonsurgical treatment generally do well with a home exercise program and rarely have stiffness.¹

Nonoperative management includes gentle range-of-motion exercises for the prevention of contractures of the elbow and shoulder.

If the patient is a young athlete, if cosmetic deformity is unacceptable, or if the injury is in the dominant arm of a laborer, then the patient may want to consider tenodesis.¹ Tangari et al found that in high-demand athletes, biceps tenodesis resulted in excellent functional and cosmetic results with no clinically significant decrease in strength after an average follow-up of 7.6 years.¹³ In a case series of 5 patients who chose nonoperative treatment, Geaney and Mazzocca reported that patients experienced a 15% loss of supination strength at 4.5 years follow-up compared with the uninjured side.¹

Our patient elected to proceed with a tenodesis procedure. Two months after the surgery, he had fully recovered.

THE TAKEAWAY

Rupture of the biceps brachii tendon is relatively uncommon. In the vast majority of cases, it happens in the long head of the dominant arm of middle-aged men. Diagnosis is mainly clinical; however, ultrasound and MRI can confirm the diagnosis when there is doubt. Nonoperative management is appropriate for the majority of patients. Young athletes, patients who are concerned with cosmetic appearance, and labor workers with injury to their dominant arm should be referred to an orthopedic surgeon for possible surgery.

THE CASE

A 41-year-old, right-hand dominant man sought care at our facility one day after trying to pull his boat out of the water. He’d tried to lift the boat with his hands while his forearms were fully supinated and his elbows were flexed to about 90°. He then felt a sharp burning sensation in his left anterior shoulder and was unable to lift the boat. The patient denied feeling a popping sensation at the time of the injury. He had mild pain at night, but was able to sleep. He said that he had mild diminished strength with elbow flexion, but denied having any numbness, tingling, or discoloration of his skin.

The patient said he did weightlifting and strength training of his upper and lower extremities 4 times/week. He was in good general health, was not taking any medications or supplements, and denied smoking or using illicit drugs. His surgical history was significant for a Bankart repair 8 years ago.

On physical examination, the patient had a scar from the previous surgery, a hollow area in his left anterior shoulder, and a prominent biceps muscle belly (FIGURE). His shoulder range of motion was normal. Left shoulder Neer, Hawkins-Kennedy, drop-arm, cross-arm, empty can, and apprehension tests were negative. A left Speed’s test (resisted elbow flexion when elbow is flexed 20° to 30° with the forearm in supination and the arm in about 60° of flexion) was positive for mild anterior shoulder pain. So, too, was a Yergason’s test (resisted forearm supination and elbow flexion when forearm is pronated and elbow is flexed to 90°). The patient’s elbow flexion strength was 4 out of 5, and his supination strength was 5 out of 5. Neurovascular and sensory examinations of his upper extremities, including radial and ulnar pulses, were normal.

THE DIAGNOSIS

A diagnostic musculoskeletal ultrasound revealed an empty tendon sheath of the long head of the biceps in the bicipital groove and a retracted echogenic stump with associated hematoma at the proximal musculotendinous junction. Based on the patient’s history, physical examination, and ultrasound, a diagnosis of an acute rupture of the left long head of the biceps brachii tendon was made.

DISCUSSION

Diagnosis of acute rupture is often made clinically based on a visually apparent defect proximally and a bulbous mass distally (“Popeye deformity”).¹ Ultrasound and magnetic resonance imaging (MRI) may aid in the diagnosis by demonstrating an absence of the long head in the bicipital groove or at its insertion.

The biceps brachii tendon functions in flexion and supination of the forearm. The long head of the biceps also plays a stabilizing role in the glenohumeral joint during elbow flexion and supination.² Injury to the biceps most often occurs in middle-aged men following a traumatic sudden eccentric bicipital contraction event, during which most patients describe a snapping or popping sensation.^3,4

Rupture of the proximal biceps tendon represents about 90% of all biceps ruptures, which almost exclusively involve the long head of the biceps.^3,5,6 Risk factors for tendon rupture include obesity, smoking, steroid injection in or around the tendon, and previous tendinopathy.^7-10

Functional limitations. It is generally thought that functional limitations following a proximal biceps rupture are relatively minimal, due to the work of other flexors and supinators, including the brachialis and brachioradialis. However, because strength and endurance of the muscle can decrease by about 25%, physical laborers and high-demand athletes may notice a degree of residual weakness with supination and elbow flexion.^11,12

Surgical repair is recommended for acute ruptures in patients with high physical demands and for whom a slight loss of flexion and su­pination strength would not be well tolerated.¹³ Tenotomy and tenodesis are the main techniques used to surgically repair a rupture of the long head of the biceps brachii tendon. Although there is no consensus on which technique is superior, it seems that there is less cosmetic deformity and better post-surgery biomechanical strength with tenodesis compared with tenotomy.¹⁴ However, tenodesis is associated with a higher likelihood of bicipital pain,¹⁴ and recent case reports have suggested it is associated with an increased risk of humeral fracture.¹⁵ Therefore, each patient should be treated on an individual case basis, taking into account age, activity level, and physical demand.¹⁴

For most patients, treatment remains conservative with typically excellent outcomes. Nonoperative management includes gentle range-of-motion exercises for the prevention of contractures of the elbow and shoulder. Such exercises can be started almost immediately after injury. In one study, nonoperative management was recommended for patients with sedentary work, injury in the non-dominant arm, and acceptable cosmetic deformity. Researchers noted that patients who opt for a nonsurgical treatment generally do well with a home exercise program and rarely have stiffness.¹

Nonoperative management includes gentle range-of-motion exercises for the prevention of contractures of the elbow and shoulder.

If the patient is a young athlete, if cosmetic deformity is unacceptable, or if the injury is in the dominant arm of a laborer, then the patient may want to consider tenodesis.¹ Tangari et al found that in high-demand athletes, biceps tenodesis resulted in excellent functional and cosmetic results with no clinically significant decrease in strength after an average follow-up of 7.6 years.¹³ In a case series of 5 patients who chose nonoperative treatment, Geaney and Mazzocca reported that patients experienced a 15% loss of supination strength at 4.5 years follow-up compared with the uninjured side.¹

Our patient elected to proceed with a tenodesis procedure. Two months after the surgery, he had fully recovered.

THE TAKEAWAY

Rupture of the biceps brachii tendon is relatively uncommon. In the vast majority of cases, it happens in the long head of the dominant arm of middle-aged men. Diagnosis is mainly clinical; however, ultrasound and MRI can confirm the diagnosis when there is doubt. Nonoperative management is appropriate for the majority of patients. Young athletes, patients who are concerned with cosmetic appearance, and labor workers with injury to their dominant arm should be referred to an orthopedic surgeon for possible surgery.

A 48-year-old Chinese woman was referred to our center with a 7-month history of a painful lesion on her left jaw that had been gradually increasing in size. The patient noted occasional purulent and bloody discharge from the lesion. She denied having a toothache.

An examination revealed an erythematous nodule with perilesional puckering superior to the left body of the mandible, measuring 7 × 8 mm, with no discharge or surrounding inflammation (FIGURE 1). There was no cervical lymphadenopathy.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Further examination on the inside of the patient’s mouth revealed root stumps of the left inferior molars (FIGURE 2). Based on the appearance of the lesion and molar involvement, we diagnosed odontogenic sinus tract (OST). OST, also known as odontogenic fistula or dental sinus, is a clinical diagnosis.

Symptoms such as odontalgia may be present in only 50% of patients with OST; thus, patients often initially consult their physician, rather than their dentist.¹ If OST is suspected, evaluation should begin with a thorough history focusing on any recent facial trauma or past dental diseases. Dental panoramic or periapical radiography can be performed to confirm the extent of dental disease, and pulp vitality testing can determine if a diseased tooth is restorable.

Odontogenic sinus tract begins with dental caries, which progress to degeneration of the dental pulp and formation of periapical abscesses.

A biopsy of the sinus tract is not required, as it would only reveal granulation tissue. Bimanual palpation of the oral cavity may reveal a cord-like structure from the cutaneous sinus to the underlying alveolar bone. (This structure was palpated in our patient.)

The pathogenesis of OST begins with dental caries, which progress to degeneration of the pulp and formation of periapical abscesses and root stumps. Progressive suppuration causes local destruction and subsequent tract formation through the alveolar bone and mandible. The build-up in pressure within this tract results in an eruption through the skin, manifesting as a sinus with extrusion of pus. The most common site of OST is at the angle of the mandible.²

The differential Dx is limited

There are a small number of other cutaneous conditions that may arise in the region of the mandible, but they have clinical features that distinguish them from OST.

Pyogenic granuloma presents as an erythematous papule that bleeds on contact. It usually develops rapidly following antecedent trauma.

Actinomycosis usually appears as an indolent plaque, with draining sinuses that extrude yellow grains on pressure. It may result from an underlying dental infection.

Squamous cell carcinoma of the skin often presents as a scaly plaque or non-healing ulcer with irregular margins and everted edges.

A furuncle is a tender, erythematous papule or nodule centered on a hair follicle. It is commonly associated with Staphylococcus aureus infection.

Treating OST

Treatment requires endodontic referral for root canal therapy, after which most cases resolve within a few weeks. OST can heal with post-inflammatory hyper- or hypopigmentation as a result of melanocyte damage. Systemic antibiotic administration is not necessary.³

We referred our patient to a dentist, who removed the root stumps and provided root canal treatment. The OST healed within several weeks. The patient had residual hypopigmentation after the OST healed, but was satisfied with the outcome.

CORRESPONDENCE
Hua-Liang Joel Lim, MBBS, MMed, National Skin Centre, 1 Mandalay Rd, Singapore 308205; [email protected].

A 48-year-old Chinese woman was referred to our center with a 7-month history of a painful lesion on her left jaw that had been gradually increasing in size. The patient noted occasional purulent and bloody discharge from the lesion. She denied having a toothache.

An examination revealed an erythematous nodule with perilesional puckering superior to the left body of the mandible, measuring 7 × 8 mm, with no discharge or surrounding inflammation (FIGURE 1). There was no cervical lymphadenopathy.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Further examination on the inside of the patient’s mouth revealed root stumps of the left inferior molars (FIGURE 2). Based on the appearance of the lesion and molar involvement, we diagnosed odontogenic sinus tract (OST). OST, also known as odontogenic fistula or dental sinus, is a clinical diagnosis.

Symptoms such as odontalgia may be present in only 50% of patients with OST; thus, patients often initially consult their physician, rather than their dentist.¹ If OST is suspected, evaluation should begin with a thorough history focusing on any recent facial trauma or past dental diseases. Dental panoramic or periapical radiography can be performed to confirm the extent of dental disease, and pulp vitality testing can determine if a diseased tooth is restorable.

Odontogenic sinus tract begins with dental caries, which progress to degeneration of the dental pulp and formation of periapical abscesses.

A biopsy of the sinus tract is not required, as it would only reveal granulation tissue. Bimanual palpation of the oral cavity may reveal a cord-like structure from the cutaneous sinus to the underlying alveolar bone. (This structure was palpated in our patient.)

The pathogenesis of OST begins with dental caries, which progress to degeneration of the pulp and formation of periapical abscesses and root stumps. Progressive suppuration causes local destruction and subsequent tract formation through the alveolar bone and mandible. The build-up in pressure within this tract results in an eruption through the skin, manifesting as a sinus with extrusion of pus. The most common site of OST is at the angle of the mandible.²

The differential Dx is limited

There are a small number of other cutaneous conditions that may arise in the region of the mandible, but they have clinical features that distinguish them from OST.

Pyogenic granuloma presents as an erythematous papule that bleeds on contact. It usually develops rapidly following antecedent trauma.

Actinomycosis usually appears as an indolent plaque, with draining sinuses that extrude yellow grains on pressure. It may result from an underlying dental infection.

Squamous cell carcinoma of the skin often presents as a scaly plaque or non-healing ulcer with irregular margins and everted edges.

A furuncle is a tender, erythematous papule or nodule centered on a hair follicle. It is commonly associated with Staphylococcus aureus infection.

Treating OST

Treatment requires endodontic referral for root canal therapy, after which most cases resolve within a few weeks. OST can heal with post-inflammatory hyper- or hypopigmentation as a result of melanocyte damage. Systemic antibiotic administration is not necessary.³

We referred our patient to a dentist, who removed the root stumps and provided root canal treatment. The OST healed within several weeks. The patient had residual hypopigmentation after the OST healed, but was satisfied with the outcome.

CORRESPONDENCE
Hua-Liang Joel Lim, MBBS, MMed, National Skin Centre, 1 Mandalay Rd, Singapore 308205; [email protected].

A 48-year-old Chinese woman was referred to our center with a 7-month history of a painful lesion on her left jaw that had been gradually increasing in size. The patient noted occasional purulent and bloody discharge from the lesion. She denied having a toothache.

An examination revealed an erythematous nodule with perilesional puckering superior to the left body of the mandible, measuring 7 × 8 mm, with no discharge or surrounding inflammation (FIGURE 1). There was no cervical lymphadenopathy.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Further examination on the inside of the patient’s mouth revealed root stumps of the left inferior molars (FIGURE 2). Based on the appearance of the lesion and molar involvement, we diagnosed odontogenic sinus tract (OST). OST, also known as odontogenic fistula or dental sinus, is a clinical diagnosis.

Symptoms such as odontalgia may be present in only 50% of patients with OST; thus, patients often initially consult their physician, rather than their dentist.¹ If OST is suspected, evaluation should begin with a thorough history focusing on any recent facial trauma or past dental diseases. Dental panoramic or periapical radiography can be performed to confirm the extent of dental disease, and pulp vitality testing can determine if a diseased tooth is restorable.

Odontogenic sinus tract begins with dental caries, which progress to degeneration of the dental pulp and formation of periapical abscesses.

A biopsy of the sinus tract is not required, as it would only reveal granulation tissue. Bimanual palpation of the oral cavity may reveal a cord-like structure from the cutaneous sinus to the underlying alveolar bone. (This structure was palpated in our patient.)

The pathogenesis of OST begins with dental caries, which progress to degeneration of the pulp and formation of periapical abscesses and root stumps. Progressive suppuration causes local destruction and subsequent tract formation through the alveolar bone and mandible. The build-up in pressure within this tract results in an eruption through the skin, manifesting as a sinus with extrusion of pus. The most common site of OST is at the angle of the mandible.²

The differential Dx is limited

There are a small number of other cutaneous conditions that may arise in the region of the mandible, but they have clinical features that distinguish them from OST.

Pyogenic granuloma presents as an erythematous papule that bleeds on contact. It usually develops rapidly following antecedent trauma.

Actinomycosis usually appears as an indolent plaque, with draining sinuses that extrude yellow grains on pressure. It may result from an underlying dental infection.

Squamous cell carcinoma of the skin often presents as a scaly plaque or non-healing ulcer with irregular margins and everted edges.

A furuncle is a tender, erythematous papule or nodule centered on a hair follicle. It is commonly associated with Staphylococcus aureus infection.

Treating OST

Treatment requires endodontic referral for root canal therapy, after which most cases resolve within a few weeks. OST can heal with post-inflammatory hyper- or hypopigmentation as a result of melanocyte damage. Systemic antibiotic administration is not necessary.³

We referred our patient to a dentist, who removed the root stumps and provided root canal treatment. The OST healed within several weeks. The patient had residual hypopigmentation after the OST healed, but was satisfied with the outcome.

CORRESPONDENCE
Hua-Liang Joel Lim, MBBS, MMed, National Skin Centre, 1 Mandalay Rd, Singapore 308205; [email protected].

A 62-year-old woman presented with a 2- to 3-week history of fatigue, nonproductive cough, dyspnea on exertion, and intermittent fever/chills. Her past medical history was significant for rheumatoid arthritis (RA) that had been treated with methotrexate and prednisone for the past 6 years. The patient was currently smoking half a pack a day with a 40-pack year history. The patient was a lifelong resident of Arizona and had previously worked in a stone mine.

On physical examination she appeared comfortable without any increased work of breathing. Her vital signs included a temperature of 36.6° C, a blood pressure of 110/54 mm Hg, a pulse of 90 beats/min, respirations of 16/min, and room-air oxygen saturation of 87%. Pulmonary examination revealed scattered wheezes with fine bibasilar crackles. The remainder of her physical exam was normal. Because she was hypoxic, she was admitted to the hospital.

At the hospital, a chest x-ray showed diffuse, bilateral interstitial changes (FIGURE 1). Laboratory tests revealed a white blood cell count of 13,800/mcL (normal: 4500-10,500/mcL) with 73% neutrophils (normal: 40%-60%), 3% bands (normal: 0-3%), 14% monocytes (normal: 2%-8%), 6% eosinophils (normal: 1%-4%), and 3% lymphocytes (normal: 20%-30%). Community-acquired pneumonia was suspected, and the patient was started on levofloxacin. Over the next 2 days, her dyspnea worsened. She became tachycardic, and her oxygen requirement increased to 15 L/min via a non-rebreather mask. She was transferred to the intensive care unit.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Given the patient’s worsening respiratory status, a computed tomography (CT) scan was ordered (FIGURE 2). Review of the CT scan showed ground-glass opacification, mild subpleural honeycombing, reticularity, and traction bronchiectasis bilaterally at the lung bases. Bronchoscopy with lavage was performed to rule out infectious etiologies and was negative. These findings, along with the patient’s medical history of RA and use of methotrexate, led us to diagnose interstitial lung disease (ILD) in this patient.

A chest x-ray has low sensitivity and specificity for interstitial lung disease and can frequently be misinterpreted, as occurred with our patient.

ILD refers to a group of disorders that primarily affects the pulmonary interstitium, rather than the alveolar spaces or pleura.¹ The most common causes of ILD seen in primary care are idiopathic pulmonary fibrosis, connective tissue disease, and hypersensitivity pneumonitis secondary to drugs (such as methotrexate, citalopram, fluoxetine, nitrofurantoin, and cephalosporins), radiation, or occupational exposures. (Textile, metal, and plastic workers are at a heightened risk, as are painters and individuals who work with animals.)¹ In 2010, idiopathic pulmonary fibrosis had a prevalence of 18.2 cases per 100,000 people.² Determining the underlying cause of ILD is important, as it may influence prognosis and treatment decisions.

The most common presenting symptoms of ILD are exertional dyspnea, cough with insidious onset, fatigue, and weakness.^1,3 Bear in mind, however, that patients with ILD associated with a connective tissue disease may have more subtle manifestations of exertional dyspnea, such as a change in activity level or low resting oxygen saturations. The pulmonary exam can be normal or can reveal fine end-inspiratory crackles, and may include high-pitched, inspiratory rhonchi, or “squeaks.”¹

When a diagnosis of ILD is suspected, investigation should begin with high-resolution CT (HRCT).^1.3-5 In patients for whom a potential cause of ILD is not identified or who have more than one potential cause, specific patterns seen on the HRCT can help determine the most likely etiology.⁵ Chest x-ray has low sensitivity and specificity for ILD and can frequently be misinterpreted, as occurred with our patient.¹

Rule out other causes of dyspnea

The differential diagnosis for dyspnea includes:

Heart failure. Congestive heart failure can present with acutely worsening dyspnea and cough, but is also commonly associated with orthopnea and/or paroxysmal nocturnal dyspnea. On physical examination, findings of volume overload such as pulmonary crackles, lower extremity edema, and elevated jugular venous pressure are additional signs that heart failure is present.

Pulmonary embolism (PE). Patients with PE commonly present with acute dyspnea, chest pain, and may also have a cough. Additional risk factors for PE (prolonged immobility, fracture, recent hospitalization) may also be present. A Wells score and a D-dimer test can be used to determine the probability of a patient having PE.

Asthma/chronic obstructive pulmonary disease. COPD exacerbations commonly present with a productive cough and worsening dyspnea. Pulmonary exam findings include wheezing, tachypnea, increased respiratory effort, and poor air movement.

Infection (including coccidioidomycosis in the desert southwest, where this patient lived). Our patient was initially treated for pneumonia because she had reported fevers associated with dyspnea and cough along with an elevated white blood cell count. Chest x-ray findings in patients with pneumonia can reveal either lobar consolidation or interstitial infiltrates.

Patients with interstitial lung disease have a life expectancy that averages 2 to 4 years from diagnosis.

Failure to respond to treatment of the more common causes of dyspnea, as occurred with our patient, should prompt consideration of ILD, particularly in those who have a history of connective tissue disease. Once a diagnosis of ILD is made, referral to a pulmonary specialist is advised.^1,3

A poor prognosis and a focus on quality of life

Immunosuppressive therapy is currently the standard treatment for ILD, although there is little evidence to support this practice.^1,3,4 Therapy usually includes corticosteroids with or without the addition of a second immunosuppressive agent such as azathioprine, mycophenolate mofetil, or cyclophosphamide.^1,4

In addition to drug therapy, the American College of Chest Physicians recommends routine assessment of quality-of-life (QOL) concerns in patients with ILD (TABLE).^6,7 Additional QOL tools available to physicians include the Medical Outcomes Study Short-Form 36-Item Instrument⁸ and the St. George’s Respiratory Questionnaire.⁹

The prognosis is poor, even with treatment. Patients with ILD have a life expectancy that averages 2 to 4 years from diagnosis.⁶ Patients with ILD are frequently distressed about worsening control of dyspnea and becoming a burden to family members; they also have anxiety about dying.⁶ It’s important to allocate sufficient time for end-of-life discussions, as studies have shown that patients would like their physicians to address the issue more thoroughly.¹⁰

Our patient was started on high-flow oxygen and high-dose steroids. Azathioprine was later added. The patient’s methotrexate was stopped, in light of its association with ILD. Unfortunately, the treatments were not successful and the patient’s respiratory status continued to deteriorate. A family meeting was held with the patient to discuss end-of-life wishes, and the patient expressed a preference for hospice care. She died a few days after hospice enrollment.

CORRESPONDENCE
Karyn B. Kolman, MD, University of Arizona College of Medicine at South Campus Family Medicine Residency, 2800 E Ajo Way, Room 3006, Tucson, AZ 85713; [email protected].

A 62-year-old woman presented with a 2- to 3-week history of fatigue, nonproductive cough, dyspnea on exertion, and intermittent fever/chills. Her past medical history was significant for rheumatoid arthritis (RA) that had been treated with methotrexate and prednisone for the past 6 years. The patient was currently smoking half a pack a day with a 40-pack year history. The patient was a lifelong resident of Arizona and had previously worked in a stone mine.

On physical examination she appeared comfortable without any increased work of breathing. Her vital signs included a temperature of 36.6° C, a blood pressure of 110/54 mm Hg, a pulse of 90 beats/min, respirations of 16/min, and room-air oxygen saturation of 87%. Pulmonary examination revealed scattered wheezes with fine bibasilar crackles. The remainder of her physical exam was normal. Because she was hypoxic, she was admitted to the hospital.

At the hospital, a chest x-ray showed diffuse, bilateral interstitial changes (FIGURE 1). Laboratory tests revealed a white blood cell count of 13,800/mcL (normal: 4500-10,500/mcL) with 73% neutrophils (normal: 40%-60%), 3% bands (normal: 0-3%), 14% monocytes (normal: 2%-8%), 6% eosinophils (normal: 1%-4%), and 3% lymphocytes (normal: 20%-30%). Community-acquired pneumonia was suspected, and the patient was started on levofloxacin. Over the next 2 days, her dyspnea worsened. She became tachycardic, and her oxygen requirement increased to 15 L/min via a non-rebreather mask. She was transferred to the intensive care unit.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Given the patient’s worsening respiratory status, a computed tomography (CT) scan was ordered (FIGURE 2). Review of the CT scan showed ground-glass opacification, mild subpleural honeycombing, reticularity, and traction bronchiectasis bilaterally at the lung bases. Bronchoscopy with lavage was performed to rule out infectious etiologies and was negative. These findings, along with the patient’s medical history of RA and use of methotrexate, led us to diagnose interstitial lung disease (ILD) in this patient.

A chest x-ray has low sensitivity and specificity for interstitial lung disease and can frequently be misinterpreted, as occurred with our patient.

ILD refers to a group of disorders that primarily affects the pulmonary interstitium, rather than the alveolar spaces or pleura.¹ The most common causes of ILD seen in primary care are idiopathic pulmonary fibrosis, connective tissue disease, and hypersensitivity pneumonitis secondary to drugs (such as methotrexate, citalopram, fluoxetine, nitrofurantoin, and cephalosporins), radiation, or occupational exposures. (Textile, metal, and plastic workers are at a heightened risk, as are painters and individuals who work with animals.)¹ In 2010, idiopathic pulmonary fibrosis had a prevalence of 18.2 cases per 100,000 people.² Determining the underlying cause of ILD is important, as it may influence prognosis and treatment decisions.

The most common presenting symptoms of ILD are exertional dyspnea, cough with insidious onset, fatigue, and weakness.^1,3 Bear in mind, however, that patients with ILD associated with a connective tissue disease may have more subtle manifestations of exertional dyspnea, such as a change in activity level or low resting oxygen saturations. The pulmonary exam can be normal or can reveal fine end-inspiratory crackles, and may include high-pitched, inspiratory rhonchi, or “squeaks.”¹

When a diagnosis of ILD is suspected, investigation should begin with high-resolution CT (HRCT).^1.3-5 In patients for whom a potential cause of ILD is not identified or who have more than one potential cause, specific patterns seen on the HRCT can help determine the most likely etiology.⁵ Chest x-ray has low sensitivity and specificity for ILD and can frequently be misinterpreted, as occurred with our patient.¹

Rule out other causes of dyspnea

The differential diagnosis for dyspnea includes:

Heart failure. Congestive heart failure can present with acutely worsening dyspnea and cough, but is also commonly associated with orthopnea and/or paroxysmal nocturnal dyspnea. On physical examination, findings of volume overload such as pulmonary crackles, lower extremity edema, and elevated jugular venous pressure are additional signs that heart failure is present.

Pulmonary embolism (PE). Patients with PE commonly present with acute dyspnea, chest pain, and may also have a cough. Additional risk factors for PE (prolonged immobility, fracture, recent hospitalization) may also be present. A Wells score and a D-dimer test can be used to determine the probability of a patient having PE.

Asthma/chronic obstructive pulmonary disease. COPD exacerbations commonly present with a productive cough and worsening dyspnea. Pulmonary exam findings include wheezing, tachypnea, increased respiratory effort, and poor air movement.

Infection (including coccidioidomycosis in the desert southwest, where this patient lived). Our patient was initially treated for pneumonia because she had reported fevers associated with dyspnea and cough along with an elevated white blood cell count. Chest x-ray findings in patients with pneumonia can reveal either lobar consolidation or interstitial infiltrates.

Patients with interstitial lung disease have a life expectancy that averages 2 to 4 years from diagnosis.

Failure to respond to treatment of the more common causes of dyspnea, as occurred with our patient, should prompt consideration of ILD, particularly in those who have a history of connective tissue disease. Once a diagnosis of ILD is made, referral to a pulmonary specialist is advised.^1,3

A poor prognosis and a focus on quality of life

Immunosuppressive therapy is currently the standard treatment for ILD, although there is little evidence to support this practice.^1,3,4 Therapy usually includes corticosteroids with or without the addition of a second immunosuppressive agent such as azathioprine, mycophenolate mofetil, or cyclophosphamide.^1,4

In addition to drug therapy, the American College of Chest Physicians recommends routine assessment of quality-of-life (QOL) concerns in patients with ILD (TABLE).^6,7 Additional QOL tools available to physicians include the Medical Outcomes Study Short-Form 36-Item Instrument⁸ and the St. George’s Respiratory Questionnaire.⁹

The prognosis is poor, even with treatment. Patients with ILD have a life expectancy that averages 2 to 4 years from diagnosis.⁶ Patients with ILD are frequently distressed about worsening control of dyspnea and becoming a burden to family members; they also have anxiety about dying.⁶ It’s important to allocate sufficient time for end-of-life discussions, as studies have shown that patients would like their physicians to address the issue more thoroughly.¹⁰

Our patient was started on high-flow oxygen and high-dose steroids. Azathioprine was later added. The patient’s methotrexate was stopped, in light of its association with ILD. Unfortunately, the treatments were not successful and the patient’s respiratory status continued to deteriorate. A family meeting was held with the patient to discuss end-of-life wishes, and the patient expressed a preference for hospice care. She died a few days after hospice enrollment.

CORRESPONDENCE
Karyn B. Kolman, MD, University of Arizona College of Medicine at South Campus Family Medicine Residency, 2800 E Ajo Way, Room 3006, Tucson, AZ 85713; [email protected].

A 62-year-old woman presented with a 2- to 3-week history of fatigue, nonproductive cough, dyspnea on exertion, and intermittent fever/chills. Her past medical history was significant for rheumatoid arthritis (RA) that had been treated with methotrexate and prednisone for the past 6 years. The patient was currently smoking half a pack a day with a 40-pack year history. The patient was a lifelong resident of Arizona and had previously worked in a stone mine.

On physical examination she appeared comfortable without any increased work of breathing. Her vital signs included a temperature of 36.6° C, a blood pressure of 110/54 mm Hg, a pulse of 90 beats/min, respirations of 16/min, and room-air oxygen saturation of 87%. Pulmonary examination revealed scattered wheezes with fine bibasilar crackles. The remainder of her physical exam was normal. Because she was hypoxic, she was admitted to the hospital.

At the hospital, a chest x-ray showed diffuse, bilateral interstitial changes (FIGURE 1). Laboratory tests revealed a white blood cell count of 13,800/mcL (normal: 4500-10,500/mcL) with 73% neutrophils (normal: 40%-60%), 3% bands (normal: 0-3%), 14% monocytes (normal: 2%-8%), 6% eosinophils (normal: 1%-4%), and 3% lymphocytes (normal: 20%-30%). Community-acquired pneumonia was suspected, and the patient was started on levofloxacin. Over the next 2 days, her dyspnea worsened. She became tachycardic, and her oxygen requirement increased to 15 L/min via a non-rebreather mask. She was transferred to the intensive care unit.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Given the patient’s worsening respiratory status, a computed tomography (CT) scan was ordered (FIGURE 2). Review of the CT scan showed ground-glass opacification, mild subpleural honeycombing, reticularity, and traction bronchiectasis bilaterally at the lung bases. Bronchoscopy with lavage was performed to rule out infectious etiologies and was negative. These findings, along with the patient’s medical history of RA and use of methotrexate, led us to diagnose interstitial lung disease (ILD) in this patient.

A chest x-ray has low sensitivity and specificity for interstitial lung disease and can frequently be misinterpreted, as occurred with our patient.

ILD refers to a group of disorders that primarily affects the pulmonary interstitium, rather than the alveolar spaces or pleura.¹ The most common causes of ILD seen in primary care are idiopathic pulmonary fibrosis, connective tissue disease, and hypersensitivity pneumonitis secondary to drugs (such as methotrexate, citalopram, fluoxetine, nitrofurantoin, and cephalosporins), radiation, or occupational exposures. (Textile, metal, and plastic workers are at a heightened risk, as are painters and individuals who work with animals.)¹ In 2010, idiopathic pulmonary fibrosis had a prevalence of 18.2 cases per 100,000 people.² Determining the underlying cause of ILD is important, as it may influence prognosis and treatment decisions.

The most common presenting symptoms of ILD are exertional dyspnea, cough with insidious onset, fatigue, and weakness.^1,3 Bear in mind, however, that patients with ILD associated with a connective tissue disease may have more subtle manifestations of exertional dyspnea, such as a change in activity level or low resting oxygen saturations. The pulmonary exam can be normal or can reveal fine end-inspiratory crackles, and may include high-pitched, inspiratory rhonchi, or “squeaks.”¹

When a diagnosis of ILD is suspected, investigation should begin with high-resolution CT (HRCT).^1.3-5 In patients for whom a potential cause of ILD is not identified or who have more than one potential cause, specific patterns seen on the HRCT can help determine the most likely etiology.⁵ Chest x-ray has low sensitivity and specificity for ILD and can frequently be misinterpreted, as occurred with our patient.¹

Rule out other causes of dyspnea

The differential diagnosis for dyspnea includes:

Heart failure. Congestive heart failure can present with acutely worsening dyspnea and cough, but is also commonly associated with orthopnea and/or paroxysmal nocturnal dyspnea. On physical examination, findings of volume overload such as pulmonary crackles, lower extremity edema, and elevated jugular venous pressure are additional signs that heart failure is present.

Pulmonary embolism (PE). Patients with PE commonly present with acute dyspnea, chest pain, and may also have a cough. Additional risk factors for PE (prolonged immobility, fracture, recent hospitalization) may also be present. A Wells score and a D-dimer test can be used to determine the probability of a patient having PE.

Asthma/chronic obstructive pulmonary disease. COPD exacerbations commonly present with a productive cough and worsening dyspnea. Pulmonary exam findings include wheezing, tachypnea, increased respiratory effort, and poor air movement.

Infection (including coccidioidomycosis in the desert southwest, where this patient lived). Our patient was initially treated for pneumonia because she had reported fevers associated with dyspnea and cough along with an elevated white blood cell count. Chest x-ray findings in patients with pneumonia can reveal either lobar consolidation or interstitial infiltrates.

Patients with interstitial lung disease have a life expectancy that averages 2 to 4 years from diagnosis.

Failure to respond to treatment of the more common causes of dyspnea, as occurred with our patient, should prompt consideration of ILD, particularly in those who have a history of connective tissue disease. Once a diagnosis of ILD is made, referral to a pulmonary specialist is advised.^1,3

A poor prognosis and a focus on quality of life

Immunosuppressive therapy is currently the standard treatment for ILD, although there is little evidence to support this practice.^1,3,4 Therapy usually includes corticosteroids with or without the addition of a second immunosuppressive agent such as azathioprine, mycophenolate mofetil, or cyclophosphamide.^1,4

In addition to drug therapy, the American College of Chest Physicians recommends routine assessment of quality-of-life (QOL) concerns in patients with ILD (TABLE).^6,7 Additional QOL tools available to physicians include the Medical Outcomes Study Short-Form 36-Item Instrument⁸ and the St. George’s Respiratory Questionnaire.⁹

The prognosis is poor, even with treatment. Patients with ILD have a life expectancy that averages 2 to 4 years from diagnosis.⁶ Patients with ILD are frequently distressed about worsening control of dyspnea and becoming a burden to family members; they also have anxiety about dying.⁶ It’s important to allocate sufficient time for end-of-life discussions, as studies have shown that patients would like their physicians to address the issue more thoroughly.¹⁰

Our patient was started on high-flow oxygen and high-dose steroids. Azathioprine was later added. The patient’s methotrexate was stopped, in light of its association with ILD. Unfortunately, the treatments were not successful and the patient’s respiratory status continued to deteriorate. A family meeting was held with the patient to discuss end-of-life wishes, and the patient expressed a preference for hospice care. She died a few days after hospice enrollment.

CORRESPONDENCE
Karyn B. Kolman, MD, University of Arizona College of Medicine at South Campus Family Medicine Residency, 2800 E Ajo Way, Room 3006, Tucson, AZ 85713; [email protected].

ILLUSTRATIVE CASE

A 54-year-old man presents to the emergency department (ED) with acute onset left flank pain that radiates to the groin. A computed tomography (CT) scan of the abdomen/pelvis without contrast reveals a 7-mm distal ureteral stone. He is deemed appropriate for outpatient management. In addition to pain medications, should you prescribe tamsulosin?

According to the most recent National Health and Nutrition Examination Survey, the population prevalence of kidney stones is 8.8% with a self-reported prevalence in men of 10.6% and a self-reported prevalence in women of 7.1%.² Most ureteral stones can be treated in the outpatient setting with oral hydration, antiemetics, and pain control with nonsteroidal anti-inflammatory medications as first-line treatment and opioids as a second-line option.³ In addition, alpha-blockers are used for medical expulsive therapy (MET). In fact, the European Association of Urology guideline on urolithiasis states that MET may accelerate passage of ureteral stones.³

Recently, however, uncertainty has surrounded the effectiveness of the alpha-blocker tamsulosin. Two systematic reviews, limited by heterogeneity because some of the studies lacked a placebo control and blinding, concluded that alpha-blockers increased stone passage within one to 6 weeks when compared with placebo or no additional therapy.^4,5 However, a recent large multicenter, randomized controlled trial (RCT) revealed no difference between tamsulosin and nifedipine or either one compared with placebo at decreasing the need for further treatment to achieve stone passage within 4 weeks.⁶

[polldaddy:9906038]

STUDY SUMMARY

New meta-analysis breaks down results by stone size

This meta-analysis by Wang et al, consisting of 8 randomized, double-blind, placebo-controlled trials of adult patients (N=1384), examined the effect of oral tamsulosin 0.4 mg/d (average of a 28-day course) on distal ureteral stone passage.¹ A subgroup analysis comparing stone size (<5 mm and 5-10 mm) was also conducted to determine if stone size modified the effect of tamsulosin.

This review went one step further by examining passage rates by stone size and revealed that passage of larger stones (5-10 mm) increased with tamsulosin.

Although the initial search included studies published between 1966 and 2015, the 8 that were eventually analyzed were published between 2009 and 2015, were conducted in multiple countries (and included regardless of language), and were conducted in ED and outpatient urology settings. The main outcome measure was the risk difference in stone passage between the tamsulosin group and placebo group after follow-up imaging at 3 weeks with CT or plain film radiographs.

Tamsulosin helps some, but not all. The pooled risk of stone passage was higher in the tamsulosin group than in the placebo group (85% vs 66%; risk difference [RD]=17%; 95% confidence interval [CI], 6%-27%), but significant heterogeneity existed across the trials (I²=80.2%). After subgroup analysis by stone size, the researchers found that tamsulosin was beneficial for larger stones, 5 to 10 mm in size (6 trials, N=514; RD=22%; 95% CI, 12%-33%; number needed to treat=5), compared with placebo, but not for smaller stones, <5 mm in size (4 trials, N=533; RD=-0.3%; 95% CI, -4% to 3%). The measure of heterogeneity in the 5- to 10-mm subgroup demonstrated a less heterogeneous population of studies (I²=33%) than that for the <5-mm subgroup (I²=0%).

In terms of adverse events, tamsulosin did not increase the risk of dizziness (RD=.2%; 95% CI, -2.1% to 2.5%) or postural hypotension (RD=.1%; 95% CI, -0.4% to 0.5%) compared with placebo.

Passage of larger stones increases with tamsulosin

This meta-analysis included only randomized, double-blind, placebo-controlled trials. Prior meta-analyses did not. Also, this review included the SUSPEND (Spontaneous Urinary Stone Passage Enabled by Drugs) trial, an RCT discussed in a previous PURL (Kidney stones? It’s time to rethink those meds. J Fam Pract. 2016;65:118-120.) that recommended against the alpha-blockers tamsulosin and nifedipine for ureteral stones measuring <10 mm.^6,7

But the subgroup analysis in this more recent review went one step further in the investigation of tamsulosin’s effect by examining passage rates by stone size (<5 mm vs 5-10 mm) and revealing that passage of larger stones (5-10 mm) increased with tamsulosin. The different results based on stone size may explain the recent uncertainty as to whether tamsulosin improves the rate of stone passage.

CAVEATS

Study doesn’t address proximal, or extra-large stones

Only distal stones were included in 7 of the 8 trials. Thus, this meta-analysis was unable to determine the effect on more proximal stones. Also, it’s unclear if the drug provides any benefit with stones >10 mm in size.

CHALLENGES TO IMPLEMENTATION

None worth mentioning

We see no challenges to implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 54-year-old man presents to the emergency department (ED) with acute onset left flank pain that radiates to the groin. A computed tomography (CT) scan of the abdomen/pelvis without contrast reveals a 7-mm distal ureteral stone. He is deemed appropriate for outpatient management. In addition to pain medications, should you prescribe tamsulosin?

According to the most recent National Health and Nutrition Examination Survey, the population prevalence of kidney stones is 8.8% with a self-reported prevalence in men of 10.6% and a self-reported prevalence in women of 7.1%.² Most ureteral stones can be treated in the outpatient setting with oral hydration, antiemetics, and pain control with nonsteroidal anti-inflammatory medications as first-line treatment and opioids as a second-line option.³ In addition, alpha-blockers are used for medical expulsive therapy (MET). In fact, the European Association of Urology guideline on urolithiasis states that MET may accelerate passage of ureteral stones.³

Recently, however, uncertainty has surrounded the effectiveness of the alpha-blocker tamsulosin. Two systematic reviews, limited by heterogeneity because some of the studies lacked a placebo control and blinding, concluded that alpha-blockers increased stone passage within one to 6 weeks when compared with placebo or no additional therapy.^4,5 However, a recent large multicenter, randomized controlled trial (RCT) revealed no difference between tamsulosin and nifedipine or either one compared with placebo at decreasing the need for further treatment to achieve stone passage within 4 weeks.⁶

[polldaddy:9906038]

STUDY SUMMARY

New meta-analysis breaks down results by stone size

This meta-analysis by Wang et al, consisting of 8 randomized, double-blind, placebo-controlled trials of adult patients (N=1384), examined the effect of oral tamsulosin 0.4 mg/d (average of a 28-day course) on distal ureteral stone passage.¹ A subgroup analysis comparing stone size (<5 mm and 5-10 mm) was also conducted to determine if stone size modified the effect of tamsulosin.

This review went one step further by examining passage rates by stone size and revealed that passage of larger stones (5-10 mm) increased with tamsulosin.

Although the initial search included studies published between 1966 and 2015, the 8 that were eventually analyzed were published between 2009 and 2015, were conducted in multiple countries (and included regardless of language), and were conducted in ED and outpatient urology settings. The main outcome measure was the risk difference in stone passage between the tamsulosin group and placebo group after follow-up imaging at 3 weeks with CT or plain film radiographs.

Tamsulosin helps some, but not all. The pooled risk of stone passage was higher in the tamsulosin group than in the placebo group (85% vs 66%; risk difference [RD]=17%; 95% confidence interval [CI], 6%-27%), but significant heterogeneity existed across the trials (I²=80.2%). After subgroup analysis by stone size, the researchers found that tamsulosin was beneficial for larger stones, 5 to 10 mm in size (6 trials, N=514; RD=22%; 95% CI, 12%-33%; number needed to treat=5), compared with placebo, but not for smaller stones, <5 mm in size (4 trials, N=533; RD=-0.3%; 95% CI, -4% to 3%). The measure of heterogeneity in the 5- to 10-mm subgroup demonstrated a less heterogeneous population of studies (I²=33%) than that for the <5-mm subgroup (I²=0%).

In terms of adverse events, tamsulosin did not increase the risk of dizziness (RD=.2%; 95% CI, -2.1% to 2.5%) or postural hypotension (RD=.1%; 95% CI, -0.4% to 0.5%) compared with placebo.

Passage of larger stones increases with tamsulosin

This meta-analysis included only randomized, double-blind, placebo-controlled trials. Prior meta-analyses did not. Also, this review included the SUSPEND (Spontaneous Urinary Stone Passage Enabled by Drugs) trial, an RCT discussed in a previous PURL (Kidney stones? It’s time to rethink those meds. J Fam Pract. 2016;65:118-120.) that recommended against the alpha-blockers tamsulosin and nifedipine for ureteral stones measuring <10 mm.^6,7

But the subgroup analysis in this more recent review went one step further in the investigation of tamsulosin’s effect by examining passage rates by stone size (<5 mm vs 5-10 mm) and revealing that passage of larger stones (5-10 mm) increased with tamsulosin. The different results based on stone size may explain the recent uncertainty as to whether tamsulosin improves the rate of stone passage.

CAVEATS

Study doesn’t address proximal, or extra-large stones

Only distal stones were included in 7 of the 8 trials. Thus, this meta-analysis was unable to determine the effect on more proximal stones. Also, it’s unclear if the drug provides any benefit with stones >10 mm in size.

CHALLENGES TO IMPLEMENTATION

None worth mentioning

We see no challenges to implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 54-year-old man presents to the emergency department (ED) with acute onset left flank pain that radiates to the groin. A computed tomography (CT) scan of the abdomen/pelvis without contrast reveals a 7-mm distal ureteral stone. He is deemed appropriate for outpatient management. In addition to pain medications, should you prescribe tamsulosin?

According to the most recent National Health and Nutrition Examination Survey, the population prevalence of kidney stones is 8.8% with a self-reported prevalence in men of 10.6% and a self-reported prevalence in women of 7.1%.² Most ureteral stones can be treated in the outpatient setting with oral hydration, antiemetics, and pain control with nonsteroidal anti-inflammatory medications as first-line treatment and opioids as a second-line option.³ In addition, alpha-blockers are used for medical expulsive therapy (MET). In fact, the European Association of Urology guideline on urolithiasis states that MET may accelerate passage of ureteral stones.³

Recently, however, uncertainty has surrounded the effectiveness of the alpha-blocker tamsulosin. Two systematic reviews, limited by heterogeneity because some of the studies lacked a placebo control and blinding, concluded that alpha-blockers increased stone passage within one to 6 weeks when compared with placebo or no additional therapy.^4,5 However, a recent large multicenter, randomized controlled trial (RCT) revealed no difference between tamsulosin and nifedipine or either one compared with placebo at decreasing the need for further treatment to achieve stone passage within 4 weeks.⁶

[polldaddy:9906038]

STUDY SUMMARY

New meta-analysis breaks down results by stone size

This meta-analysis by Wang et al, consisting of 8 randomized, double-blind, placebo-controlled trials of adult patients (N=1384), examined the effect of oral tamsulosin 0.4 mg/d (average of a 28-day course) on distal ureteral stone passage.¹ A subgroup analysis comparing stone size (<5 mm and 5-10 mm) was also conducted to determine if stone size modified the effect of tamsulosin.

This review went one step further by examining passage rates by stone size and revealed that passage of larger stones (5-10 mm) increased with tamsulosin.

Although the initial search included studies published between 1966 and 2015, the 8 that were eventually analyzed were published between 2009 and 2015, were conducted in multiple countries (and included regardless of language), and were conducted in ED and outpatient urology settings. The main outcome measure was the risk difference in stone passage between the tamsulosin group and placebo group after follow-up imaging at 3 weeks with CT or plain film radiographs.

Tamsulosin helps some, but not all. The pooled risk of stone passage was higher in the tamsulosin group than in the placebo group (85% vs 66%; risk difference [RD]=17%; 95% confidence interval [CI], 6%-27%), but significant heterogeneity existed across the trials (I²=80.2%). After subgroup analysis by stone size, the researchers found that tamsulosin was beneficial for larger stones, 5 to 10 mm in size (6 trials, N=514; RD=22%; 95% CI, 12%-33%; number needed to treat=5), compared with placebo, but not for smaller stones, <5 mm in size (4 trials, N=533; RD=-0.3%; 95% CI, -4% to 3%). The measure of heterogeneity in the 5- to 10-mm subgroup demonstrated a less heterogeneous population of studies (I²=33%) than that for the <5-mm subgroup (I²=0%).

In terms of adverse events, tamsulosin did not increase the risk of dizziness (RD=.2%; 95% CI, -2.1% to 2.5%) or postural hypotension (RD=.1%; 95% CI, -0.4% to 0.5%) compared with placebo.

Passage of larger stones increases with tamsulosin

This meta-analysis included only randomized, double-blind, placebo-controlled trials. Prior meta-analyses did not. Also, this review included the SUSPEND (Spontaneous Urinary Stone Passage Enabled by Drugs) trial, an RCT discussed in a previous PURL (Kidney stones? It’s time to rethink those meds. J Fam Pract. 2016;65:118-120.) that recommended against the alpha-blockers tamsulosin and nifedipine for ureteral stones measuring <10 mm.^6,7

But the subgroup analysis in this more recent review went one step further in the investigation of tamsulosin’s effect by examining passage rates by stone size (<5 mm vs 5-10 mm) and revealing that passage of larger stones (5-10 mm) increased with tamsulosin. The different results based on stone size may explain the recent uncertainty as to whether tamsulosin improves the rate of stone passage.

CAVEATS

Study doesn’t address proximal, or extra-large stones

Only distal stones were included in 7 of the 8 trials. Thus, this meta-analysis was unable to determine the effect on more proximal stones. Also, it’s unclear if the drug provides any benefit with stones >10 mm in size.

CHALLENGES TO IMPLEMENTATION

None worth mentioning

We see no challenges to implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

The epidemiology of hepatitis A virus (HAV) disease has changed. Since July 2016, there have been 5 large outbreaks of infection involving more than 1600 cases,¹ with affected states requiring assistance from the Centers for Disease Control and Prevention (CDC). Two of these outbreaks were foodborne, and 3 involved person-to-person transmission.¹

Before 2016, the number of outbreaks had been very low, and were predominantly associated with contaminated food, infected food handlers, and other food service-related exposures. Total annual cases of HAV infection had been declining steadily in all age groups since 1995 when HAV vaccine became available, from an estimated 271,000 cases resulting in 100 deaths² to an estimated 2800 cases (with 1390 reported) resulting in 67 deaths in 2015 (FIGURE).³

Extent of the outbreaks

The largest hepatitis A outbreak involving person-to-person transmission in the United States in the past 20 years is occurring now in California. Predominantly affected are the homeless and users of illicit drugs, whose risk of infection is compounded by exposure to fecally-contaminated environments. As of December 1, the largest number of cases were recorded in San Diego (567), Santa Cruz (76), and Los Angeles (11).⁴ Adding 18 cases from other locations, the total has reached 672, resulting in 430 hospitalizations (64%) and 21 deaths (3%).⁴ In San Diego, 20% of those infected also had chronic hepatitis C and 5% had chronic hepatitis B.¹

In southeastern Michigan, 555 cases have been reported, with 457 hospitalizations (82%) and 20 deaths (4%).⁵ In Utah, 91 cases and 53 hospitalizations (58%) have been documented.⁶ In these regions, the predominant risk factors have been homelessness and illicit drug use. And many of those infected have had chronic hepatitis C (27.5%), hepatitis B (13.2%), or both (9.9%).⁶ In 2 of the 3 states just described, the outbreaks have involved HAV genotype 1B.¹

In New York City, an outbreak starting in January 2017 resulted in 51 cases. The epidemiology of this outbreak has been different from the others, involving men who have sex with men (MSM) and the HAV genotype 1A that matches a strain circulating among MSM in Europe.⁷

Low adult immunity is behind the outbreaks

These outbreaks have occurred in an adult US population that has low levels of immunity to HAV. In 2012 only 12.2% of adults ages 19 to 49 years had received 2 doses of HAV vaccine⁸ and only 24.2% of adults had antibodies to HAV,⁹ showing that most adults had never been infected with the virus or vaccinated. The reduction in HAV incidence previously described is due to the introduction of targeted, and then universal, child HAV vaccination recommendations by the Advisory Committee on Immunization Practices.

As the incidence of HAV disease declined, fewer individuals became infected as children, leading later to a susceptible pool of adults who had not been infected as children and who did not receive the vaccine in adulthood. Most of these adults will not be exposed to HAV due to decreased rates of infection in children, which, historically, has been the predominant means of adult exposure. The high hospitalization and death rates encountered in the recent and ongoing large outbreaks are explained by the multiple comorbidities of those infected.

Who should be vaccinated against HAV

The CDC recommends giving HAV vaccine to all children at age one year, and to the following groups:^2,10,11

• residents of a community that has a high rate of hepatitis A infection
• household members or other close personal contacts (eg, regular babysitters) of adopted children newly arrived from countries with high or intermediate hepatitis A endemicity
• men who have sex with other men
• users of illicit injection and noninjection drugs
• workers in, or travelers to, countries with high rates of hepatitis A infection
• individuals with chronic liver disease
• individuals who work with HAV-infected animals or with HAV in a research setting.

Outbreak-specific vaccine recommendations

The CDC has additionally recommended that, during outbreaks, health care providers should consider taking the following 4 steps:^12,13

1. Increase the availability of HAV vaccine to the homeless and to those who use illicit drugs; to anyone who has ongoing, close contact with people who are homeless or who use injection and non-injection drugs; and as post-exposure prophylaxis for unvaccinated people who have been exposed to HAV in the previous 2 weeks.
2. Defer the second dose of HAV vaccine if it is in short supply.
3. Perform pre-vaccination serologic testing to identify those who are immune, thereby preserving vaccine and reducing costs.
4. Use TWINRIX if other HAV vaccines are unavailable, keeping in mind that a single dose of TWINRIX achieves 94% protection against HAV but only 31% against hepatitis B virus (HBV). Three doses of TWINRIX are needed for full protection against HBV.

Available vaccines

Three vaccines are available for protection against HAV (TABLE^2,14). Post-exposure prevention of HAV can be achieved with HAV vaccine or immune globulin.¹⁵ Vaccine is preferred for individuals up to age 40 years and can be used for older individuals if immune globulin is unavailable.

The CDC reports that the supply of adult HAV vaccine is being strained by these large outbreaks.¹⁶ Physicians will need to stay in touch with their local public health departments regarding vaccine availability in the community and any local recommendations being made regarding vaccine administration, as well as to the status of any local HAV outbreaks.

The epidemiology of hepatitis A virus (HAV) disease has changed. Since July 2016, there have been 5 large outbreaks of infection involving more than 1600 cases,¹ with affected states requiring assistance from the Centers for Disease Control and Prevention (CDC). Two of these outbreaks were foodborne, and 3 involved person-to-person transmission.¹

Before 2016, the number of outbreaks had been very low, and were predominantly associated with contaminated food, infected food handlers, and other food service-related exposures. Total annual cases of HAV infection had been declining steadily in all age groups since 1995 when HAV vaccine became available, from an estimated 271,000 cases resulting in 100 deaths² to an estimated 2800 cases (with 1390 reported) resulting in 67 deaths in 2015 (FIGURE).³

Extent of the outbreaks

The largest hepatitis A outbreak involving person-to-person transmission in the United States in the past 20 years is occurring now in California. Predominantly affected are the homeless and users of illicit drugs, whose risk of infection is compounded by exposure to fecally-contaminated environments. As of December 1, the largest number of cases were recorded in San Diego (567), Santa Cruz (76), and Los Angeles (11).⁴ Adding 18 cases from other locations, the total has reached 672, resulting in 430 hospitalizations (64%) and 21 deaths (3%).⁴ In San Diego, 20% of those infected also had chronic hepatitis C and 5% had chronic hepatitis B.¹

In southeastern Michigan, 555 cases have been reported, with 457 hospitalizations (82%) and 20 deaths (4%).⁵ In Utah, 91 cases and 53 hospitalizations (58%) have been documented.⁶ In these regions, the predominant risk factors have been homelessness and illicit drug use. And many of those infected have had chronic hepatitis C (27.5%), hepatitis B (13.2%), or both (9.9%).⁶ In 2 of the 3 states just described, the outbreaks have involved HAV genotype 1B.¹

In New York City, an outbreak starting in January 2017 resulted in 51 cases. The epidemiology of this outbreak has been different from the others, involving men who have sex with men (MSM) and the HAV genotype 1A that matches a strain circulating among MSM in Europe.⁷

Low adult immunity is behind the outbreaks

These outbreaks have occurred in an adult US population that has low levels of immunity to HAV. In 2012 only 12.2% of adults ages 19 to 49 years had received 2 doses of HAV vaccine⁸ and only 24.2% of adults had antibodies to HAV,⁹ showing that most adults had never been infected with the virus or vaccinated. The reduction in HAV incidence previously described is due to the introduction of targeted, and then universal, child HAV vaccination recommendations by the Advisory Committee on Immunization Practices.

As the incidence of HAV disease declined, fewer individuals became infected as children, leading later to a susceptible pool of adults who had not been infected as children and who did not receive the vaccine in adulthood. Most of these adults will not be exposed to HAV due to decreased rates of infection in children, which, historically, has been the predominant means of adult exposure. The high hospitalization and death rates encountered in the recent and ongoing large outbreaks are explained by the multiple comorbidities of those infected.

Who should be vaccinated against HAV

The CDC recommends giving HAV vaccine to all children at age one year, and to the following groups:^2,10,11

• residents of a community that has a high rate of hepatitis A infection
• household members or other close personal contacts (eg, regular babysitters) of adopted children newly arrived from countries with high or intermediate hepatitis A endemicity
• men who have sex with other men
• users of illicit injection and noninjection drugs
• workers in, or travelers to, countries with high rates of hepatitis A infection
• individuals with chronic liver disease
• individuals who work with HAV-infected animals or with HAV in a research setting.

Outbreak-specific vaccine recommendations

The CDC has additionally recommended that, during outbreaks, health care providers should consider taking the following 4 steps:^12,13

1. Increase the availability of HAV vaccine to the homeless and to those who use illicit drugs; to anyone who has ongoing, close contact with people who are homeless or who use injection and non-injection drugs; and as post-exposure prophylaxis for unvaccinated people who have been exposed to HAV in the previous 2 weeks.
2. Defer the second dose of HAV vaccine if it is in short supply.
3. Perform pre-vaccination serologic testing to identify those who are immune, thereby preserving vaccine and reducing costs.
4. Use TWINRIX if other HAV vaccines are unavailable, keeping in mind that a single dose of TWINRIX achieves 94% protection against HAV but only 31% against hepatitis B virus (HBV). Three doses of TWINRIX are needed for full protection against HBV.

Available vaccines

Three vaccines are available for protection against HAV (TABLE^2,14). Post-exposure prevention of HAV can be achieved with HAV vaccine or immune globulin.¹⁵ Vaccine is preferred for individuals up to age 40 years and can be used for older individuals if immune globulin is unavailable.

The CDC reports that the supply of adult HAV vaccine is being strained by these large outbreaks.¹⁶ Physicians will need to stay in touch with their local public health departments regarding vaccine availability in the community and any local recommendations being made regarding vaccine administration, as well as to the status of any local HAV outbreaks.

The epidemiology of hepatitis A virus (HAV) disease has changed. Since July 2016, there have been 5 large outbreaks of infection involving more than 1600 cases,¹ with affected states requiring assistance from the Centers for Disease Control and Prevention (CDC). Two of these outbreaks were foodborne, and 3 involved person-to-person transmission.¹

Before 2016, the number of outbreaks had been very low, and were predominantly associated with contaminated food, infected food handlers, and other food service-related exposures. Total annual cases of HAV infection had been declining steadily in all age groups since 1995 when HAV vaccine became available, from an estimated 271,000 cases resulting in 100 deaths² to an estimated 2800 cases (with 1390 reported) resulting in 67 deaths in 2015 (FIGURE).³

Extent of the outbreaks

The largest hepatitis A outbreak involving person-to-person transmission in the United States in the past 20 years is occurring now in California. Predominantly affected are the homeless and users of illicit drugs, whose risk of infection is compounded by exposure to fecally-contaminated environments. As of December 1, the largest number of cases were recorded in San Diego (567), Santa Cruz (76), and Los Angeles (11).⁴ Adding 18 cases from other locations, the total has reached 672, resulting in 430 hospitalizations (64%) and 21 deaths (3%).⁴ In San Diego, 20% of those infected also had chronic hepatitis C and 5% had chronic hepatitis B.¹

In southeastern Michigan, 555 cases have been reported, with 457 hospitalizations (82%) and 20 deaths (4%).⁵ In Utah, 91 cases and 53 hospitalizations (58%) have been documented.⁶ In these regions, the predominant risk factors have been homelessness and illicit drug use. And many of those infected have had chronic hepatitis C (27.5%), hepatitis B (13.2%), or both (9.9%).⁶ In 2 of the 3 states just described, the outbreaks have involved HAV genotype 1B.¹

In New York City, an outbreak starting in January 2017 resulted in 51 cases. The epidemiology of this outbreak has been different from the others, involving men who have sex with men (MSM) and the HAV genotype 1A that matches a strain circulating among MSM in Europe.⁷

Low adult immunity is behind the outbreaks

These outbreaks have occurred in an adult US population that has low levels of immunity to HAV. In 2012 only 12.2% of adults ages 19 to 49 years had received 2 doses of HAV vaccine⁸ and only 24.2% of adults had antibodies to HAV,⁹ showing that most adults had never been infected with the virus or vaccinated. The reduction in HAV incidence previously described is due to the introduction of targeted, and then universal, child HAV vaccination recommendations by the Advisory Committee on Immunization Practices.

As the incidence of HAV disease declined, fewer individuals became infected as children, leading later to a susceptible pool of adults who had not been infected as children and who did not receive the vaccine in adulthood. Most of these adults will not be exposed to HAV due to decreased rates of infection in children, which, historically, has been the predominant means of adult exposure. The high hospitalization and death rates encountered in the recent and ongoing large outbreaks are explained by the multiple comorbidities of those infected.

Who should be vaccinated against HAV

The CDC recommends giving HAV vaccine to all children at age one year, and to the following groups:^2,10,11

• residents of a community that has a high rate of hepatitis A infection
• household members or other close personal contacts (eg, regular babysitters) of adopted children newly arrived from countries with high or intermediate hepatitis A endemicity
• men who have sex with other men
• users of illicit injection and noninjection drugs
• workers in, or travelers to, countries with high rates of hepatitis A infection
• individuals with chronic liver disease
• individuals who work with HAV-infected animals or with HAV in a research setting.

Outbreak-specific vaccine recommendations

The CDC has additionally recommended that, during outbreaks, health care providers should consider taking the following 4 steps:^12,13

1. Increase the availability of HAV vaccine to the homeless and to those who use illicit drugs; to anyone who has ongoing, close contact with people who are homeless or who use injection and non-injection drugs; and as post-exposure prophylaxis for unvaccinated people who have been exposed to HAV in the previous 2 weeks.
2. Defer the second dose of HAV vaccine if it is in short supply.
3. Perform pre-vaccination serologic testing to identify those who are immune, thereby preserving vaccine and reducing costs.
4. Use TWINRIX if other HAV vaccines are unavailable, keeping in mind that a single dose of TWINRIX achieves 94% protection against HAV but only 31% against hepatitis B virus (HBV). Three doses of TWINRIX are needed for full protection against HBV.

Available vaccines

Three vaccines are available for protection against HAV (TABLE^2,14). Post-exposure prevention of HAV can be achieved with HAV vaccine or immune globulin.¹⁵ Vaccine is preferred for individuals up to age 40 years and can be used for older individuals if immune globulin is unavailable.

The CDC reports that the supply of adult HAV vaccine is being strained by these large outbreaks.¹⁶ Physicians will need to stay in touch with their local public health departments regarding vaccine availability in the community and any local recommendations being made regarding vaccine administration, as well as to the status of any local HAV outbreaks.

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].

ANSWER

The radiograph shows an oblique fracture through the radial styloid process. The patient was placed in a splint and referred to outpatient orthopedics for follow-up.

ANSWER

The radiograph shows an oblique fracture through the radial styloid process. The patient was placed in a splint and referred to outpatient orthopedics for follow-up.

ANSWER

The radiograph shows an oblique fracture through the radial styloid process. The patient was placed in a splint and referred to outpatient orthopedics for follow-up.

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].