The interferon-gamma release assay (IGRA) was significantly more sensitive than a tuberculin skin test as an adjunct tuberculosis diagnosis of children aged 5 years and older, according to data from a population-based study of 778 cases.

IGRAs have shown greater specificity than tuberculin skin tests (TSTs), but data on their sensitivity to TB in children are limited, wrote Alexander W. Kay, MD, of the California Department of Public Health and his colleagues in a study published in Pediatrics.

CDC/James Archer

SOURCE: Kay A et al. Pediatrics. 2018 May 4. doi: 10.1542/peds.2017-3918.

The interferon-gamma release assay (IGRA) was significantly more sensitive than a tuberculin skin test as an adjunct tuberculosis diagnosis of children aged 5 years and older, according to data from a population-based study of 778 cases.

IGRAs have shown greater specificity than tuberculin skin tests (TSTs), but data on their sensitivity to TB in children are limited, wrote Alexander W. Kay, MD, of the California Department of Public Health and his colleagues in a study published in Pediatrics.

CDC/James Archer

SOURCE: Kay A et al. Pediatrics. 2018 May 4. doi: 10.1542/peds.2017-3918.

The interferon-gamma release assay (IGRA) was significantly more sensitive than a tuberculin skin test as an adjunct tuberculosis diagnosis of children aged 5 years and older, according to data from a population-based study of 778 cases.

IGRAs have shown greater specificity than tuberculin skin tests (TSTs), but data on their sensitivity to TB in children are limited, wrote Alexander W. Kay, MD, of the California Department of Public Health and his colleagues in a study published in Pediatrics.

CDC/James Archer

SOURCE: Kay A et al. Pediatrics. 2018 May 4. doi: 10.1542/peds.2017-3918.

Murthy, S.K., et al, Endoscopy 49(12):1228, December 2017

BACKGROUND: Repeat colonoscopy is recommended ten years after a negative screening for colorectal cancer (CRC) in low-risk persons, but the real-world benefit of this recommendation is uncertain.

METHODS: These Canadian authors, coordinated at the University of Ottawa, performed a retrospective cohort study to determine the utility of ten-year repeat screening colonoscopy using population-level data from Ontario adults aged 50-74 years with a low to moderate risk of CRC (no relevant gastrointestinal disorders) who had a negative colonoscopy in 1996-2001 and a repeat negative screening within eight to twelve years, excluding those with intervening events (CRC detection, colectomy, or lower endoscopy). The primary outcome was early incident CRC in the group having repeat screening within twelve years compared with an unexposed control group matched by age, sex and year of baseline colonoscopy. 

RESULTS: A total of 13,350 matched pairs (median age 68 years; 56% female) were analyzed for CRC incidence over a median follow-up of 4.5 years.  The cumulative probability of CRC over three, five and eight years following a negative baseline colonoscopy was 0.16%, 0.30%, and 0.54%, respectively. Among patients having repeat colonoscopy, 46 developed CRC, compared with 52 in unexposed controls, for cumulative probabilities of 0.70% and 0.77%, respectively, and a hazard ratio of 0.91 (95% CI 0.68-1.22) after adjusting for competing risks and comorbidity burden. CRC-related mortality was also similar between groups (8 and 9 patients). Short follow-up was a study limitation. 

CONCLUSIONS: Repeat colonoscopy within eight to twelve years of a negative screen was not associated with subsequent CRC incidence, which raises questions about the utility of ten-year repeat screening.  21 references ([email protected] – no reprints)
 

Murthy, S.K., et al, Endoscopy 49(12):1228, December 2017

BACKGROUND: Repeat colonoscopy is recommended ten years after a negative screening for colorectal cancer (CRC) in low-risk persons, but the real-world benefit of this recommendation is uncertain.

METHODS: These Canadian authors, coordinated at the University of Ottawa, performed a retrospective cohort study to determine the utility of ten-year repeat screening colonoscopy using population-level data from Ontario adults aged 50-74 years with a low to moderate risk of CRC (no relevant gastrointestinal disorders) who had a negative colonoscopy in 1996-2001 and a repeat negative screening within eight to twelve years, excluding those with intervening events (CRC detection, colectomy, or lower endoscopy). The primary outcome was early incident CRC in the group having repeat screening within twelve years compared with an unexposed control group matched by age, sex and year of baseline colonoscopy. 

RESULTS: A total of 13,350 matched pairs (median age 68 years; 56% female) were analyzed for CRC incidence over a median follow-up of 4.5 years.  The cumulative probability of CRC over three, five and eight years following a negative baseline colonoscopy was 0.16%, 0.30%, and 0.54%, respectively. Among patients having repeat colonoscopy, 46 developed CRC, compared with 52 in unexposed controls, for cumulative probabilities of 0.70% and 0.77%, respectively, and a hazard ratio of 0.91 (95% CI 0.68-1.22) after adjusting for competing risks and comorbidity burden. CRC-related mortality was also similar between groups (8 and 9 patients). Short follow-up was a study limitation. 

CONCLUSIONS: Repeat colonoscopy within eight to twelve years of a negative screen was not associated with subsequent CRC incidence, which raises questions about the utility of ten-year repeat screening.  21 references ([email protected] – no reprints)
 

Murthy, S.K., et al, Endoscopy 49(12):1228, December 2017

BACKGROUND: Repeat colonoscopy is recommended ten years after a negative screening for colorectal cancer (CRC) in low-risk persons, but the real-world benefit of this recommendation is uncertain.

METHODS: These Canadian authors, coordinated at the University of Ottawa, performed a retrospective cohort study to determine the utility of ten-year repeat screening colonoscopy using population-level data from Ontario adults aged 50-74 years with a low to moderate risk of CRC (no relevant gastrointestinal disorders) who had a negative colonoscopy in 1996-2001 and a repeat negative screening within eight to twelve years, excluding those with intervening events (CRC detection, colectomy, or lower endoscopy). The primary outcome was early incident CRC in the group having repeat screening within twelve years compared with an unexposed control group matched by age, sex and year of baseline colonoscopy. 

RESULTS: A total of 13,350 matched pairs (median age 68 years; 56% female) were analyzed for CRC incidence over a median follow-up of 4.5 years.  The cumulative probability of CRC over three, five and eight years following a negative baseline colonoscopy was 0.16%, 0.30%, and 0.54%, respectively. Among patients having repeat colonoscopy, 46 developed CRC, compared with 52 in unexposed controls, for cumulative probabilities of 0.70% and 0.77%, respectively, and a hazard ratio of 0.91 (95% CI 0.68-1.22) after adjusting for competing risks and comorbidity burden. CRC-related mortality was also similar between groups (8 and 9 patients). Short follow-up was a study limitation. 

CONCLUSIONS: Repeat colonoscopy within eight to twelve years of a negative screen was not associated with subsequent CRC incidence, which raises questions about the utility of ten-year repeat screening.  21 references ([email protected] – no reprints)
 

The National Center for Complementary and Integrative Health, a division of the National Institutes of Medicine, estimates that 38% of American adults use complementary and alternative medicine (including 17.7% who say they use “natural products”).¹ Despite the popularity of these products, many providers remain skeptical—and for good reason. Enthusiasts may offer dramatic anecdotes to “prove” their supplements’ worth, but little scientific support is available for most herbal remedies. There are, however, exceptions—capsaicin, butterbur, green tea, and peppermint—as this review of the medical literature reveals.

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 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.

CAPSAICIN

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 Topical 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

Meta-analyses and systematic reviews have shown capsaicin is effective for various painful conditions, including peripheral diabetic neuropathy, osteoarthritis (OA), low back pain (LBP), and postherpetic neuralgia (PHN).

Peripheral neuropathy. A Cochrane review of six randomized, double-blind, placebo-controlled studies of at least six weeks’ duration using topical 8% capsaicin to treat PHN and HIV-associated neuropathy concluded that high-concentration topical capsaicin provided more relief in patients with high pain levels than control patients who received 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. In randomized trials, capsaicin provided mild-to-moderate efficacy 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 and resulted in a significant number of adverse events.⁹

LBP. Based on a 2014 Cochrane review of three 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 placebo.¹⁰

PHN. Topical 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 The cost of the capsaicin patch was similar to a topical lidocaine patch and oral products for PHN.¹¹ A meta-analysis of seven RCTs indicated that 8% topical capsaicin was superior to the low-dose capsaicin patch for relieving pain associated with PHN.¹²

Continue to: 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 was reported 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 three 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

Continue to: BUTTERBUR

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 hyperexcitation 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 butterbur 75 mg bid significantly reduced migraine frequency by 48%, compared with 26% for the placebo group.¹⁶ Butterbur 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.

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 four months.¹⁷

In their 2012 guidelines for migraine prevention, the American Academy of Neurology (AAN) and American Headache Society gave butterbur a Level A recommendation, concluding that butterbur should be offered to patients with migraine to reduce the frequency and severity of migraine attacks.¹⁸ However, the AAN changed its position in 2015, redacting the recommendation due to serious safety concerns.¹⁹

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

Continue to: 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 PA 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 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.

Continue to: GREEN TEA

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 Of the many types of tea, 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 ß-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 five-year period found that frequent green tea consumption (> 5 cups per day) was associated with a lower risk for dementia.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 LDL 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 for coronary heart disease, cardiac death, stroke, and total mortality.³⁰

Cancer. Many studies have shown that green tea may reduce the risk for cancer, 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 mechanism by which tea interacts with cancerous cells is unknown.²³

Several population-based studies have been performed, mostly in Japan, which showed green tea consumption reduced the risk for 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.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 for diabetes concluded that three or more cups of tea per day was associated with a lower risk for diabetes.³⁶ Another meta-analysis of 17 RCTs focused on green tea concluded that green tea improves glucose control and A1C values.³⁷

Continue to: 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

Consuming green tea in the diet may lower the risk for 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, dementia, and risk for diabetes, cancer, and cardiovascular disease. Patients may want to consider drinking green tea as part of a healthy diet, in combination with exercise.

Continue to: PEPPERMINT

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. 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 is used both orally and topically, and has been studied in the treatment of multiple conditions.

Irritable bowel syndrome (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 nine 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 eight 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 two 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. In a randomized, placebo-controlled, double-blind crossover study, 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

Continue to: Musculoskeletal pain

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 RCT concluded that topical menthol acutely reduced pain intensity in slaughterhouse workers with CTS, and it should be considered as an effective nonsystemic 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.

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 CTS.^54,55

The National Center for Complementary and Integrative Health, a division of the National Institutes of Medicine, estimates that 38% of American adults use complementary and alternative medicine (including 17.7% who say they use “natural products”).¹ Despite the popularity of these products, many providers remain skeptical—and for good reason. Enthusiasts may offer dramatic anecdotes to “prove” their supplements’ worth, but little scientific support is available for most herbal remedies. There are, however, exceptions—capsaicin, butterbur, green tea, and peppermint—as this review of the medical literature reveals.

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 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.

CAPSAICIN

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 Topical 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

Meta-analyses and systematic reviews have shown capsaicin is effective for various painful conditions, including peripheral diabetic neuropathy, osteoarthritis (OA), low back pain (LBP), and postherpetic neuralgia (PHN).

Peripheral neuropathy. A Cochrane review of six randomized, double-blind, placebo-controlled studies of at least six weeks’ duration using topical 8% capsaicin to treat PHN and HIV-associated neuropathy concluded that high-concentration topical capsaicin provided more relief in patients with high pain levels than control patients who received 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. In randomized trials, capsaicin provided mild-to-moderate efficacy 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 and resulted in a significant number of adverse events.⁹

LBP. Based on a 2014 Cochrane review of three 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 placebo.¹⁰

PHN. Topical 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 The cost of the capsaicin patch was similar to a topical lidocaine patch and oral products for PHN.¹¹ A meta-analysis of seven RCTs indicated that 8% topical capsaicin was superior to the low-dose capsaicin patch for relieving pain associated with PHN.¹²

Continue to: 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 was reported 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 three 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

Continue to: BUTTERBUR

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 hyperexcitation 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 butterbur 75 mg bid significantly reduced migraine frequency by 48%, compared with 26% for the placebo group.¹⁶ Butterbur 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.

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 four months.¹⁷

In their 2012 guidelines for migraine prevention, the American Academy of Neurology (AAN) and American Headache Society gave butterbur a Level A recommendation, concluding that butterbur should be offered to patients with migraine to reduce the frequency and severity of migraine attacks.¹⁸ However, the AAN changed its position in 2015, redacting the recommendation due to serious safety concerns.¹⁹

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

Continue to: 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 PA 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 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.

Continue to: GREEN TEA

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 Of the many types of tea, 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 ß-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 five-year period found that frequent green tea consumption (> 5 cups per day) was associated with a lower risk for dementia.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 LDL 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 for coronary heart disease, cardiac death, stroke, and total mortality.³⁰

Cancer. Many studies have shown that green tea may reduce the risk for cancer, 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 mechanism by which tea interacts with cancerous cells is unknown.²³

Several population-based studies have been performed, mostly in Japan, which showed green tea consumption reduced the risk for 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.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 for diabetes concluded that three or more cups of tea per day was associated with a lower risk for diabetes.³⁶ Another meta-analysis of 17 RCTs focused on green tea concluded that green tea improves glucose control and A1C values.³⁷

Continue to: 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

Consuming green tea in the diet may lower the risk for 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, dementia, and risk for diabetes, cancer, and cardiovascular disease. Patients may want to consider drinking green tea as part of a healthy diet, in combination with exercise.

Continue to: PEPPERMINT

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. 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 is used both orally and topically, and has been studied in the treatment of multiple conditions.

Irritable bowel syndrome (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 nine 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 eight 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 two 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. In a randomized, placebo-controlled, double-blind crossover study, 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

Continue to: Musculoskeletal pain

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 RCT concluded that topical menthol acutely reduced pain intensity in slaughterhouse workers with CTS, and it should be considered as an effective nonsystemic 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.

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 CTS.^54,55

The National Center for Complementary and Integrative Health, a division of the National Institutes of Medicine, estimates that 38% of American adults use complementary and alternative medicine (including 17.7% who say they use “natural products”).¹ Despite the popularity of these products, many providers remain skeptical—and for good reason. Enthusiasts may offer dramatic anecdotes to “prove” their supplements’ worth, but little scientific support is available for most herbal remedies. There are, however, exceptions—capsaicin, butterbur, green tea, and peppermint—as this review of the medical literature reveals.

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 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.

CAPSAICIN

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 Topical 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

Meta-analyses and systematic reviews have shown capsaicin is effective for various painful conditions, including peripheral diabetic neuropathy, osteoarthritis (OA), low back pain (LBP), and postherpetic neuralgia (PHN).

Peripheral neuropathy. A Cochrane review of six randomized, double-blind, placebo-controlled studies of at least six weeks’ duration using topical 8% capsaicin to treat PHN and HIV-associated neuropathy concluded that high-concentration topical capsaicin provided more relief in patients with high pain levels than control patients who received 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. In randomized trials, capsaicin provided mild-to-moderate efficacy 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 and resulted in a significant number of adverse events.⁹

LBP. Based on a 2014 Cochrane review of three 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 placebo.¹⁰

PHN. Topical 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 The cost of the capsaicin patch was similar to a topical lidocaine patch and oral products for PHN.¹¹ A meta-analysis of seven RCTs indicated that 8% topical capsaicin was superior to the low-dose capsaicin patch for relieving pain associated with PHN.¹²

Continue to: 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 was reported 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 three 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

Continue to: BUTTERBUR

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 hyperexcitation 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 butterbur 75 mg bid significantly reduced migraine frequency by 48%, compared with 26% for the placebo group.¹⁶ Butterbur 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.

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 four months.¹⁷

In their 2012 guidelines for migraine prevention, the American Academy of Neurology (AAN) and American Headache Society gave butterbur a Level A recommendation, concluding that butterbur should be offered to patients with migraine to reduce the frequency and severity of migraine attacks.¹⁸ However, the AAN changed its position in 2015, redacting the recommendation due to serious safety concerns.¹⁹

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

Continue to: 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 PA 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 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.

Continue to: GREEN TEA

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 Of the many types of tea, 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 ß-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 five-year period found that frequent green tea consumption (> 5 cups per day) was associated with a lower risk for dementia.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 LDL 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 for coronary heart disease, cardiac death, stroke, and total mortality.³⁰

Cancer. Many studies have shown that green tea may reduce the risk for cancer, 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 mechanism by which tea interacts with cancerous cells is unknown.²³

Several population-based studies have been performed, mostly in Japan, which showed green tea consumption reduced the risk for 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.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 for diabetes concluded that three or more cups of tea per day was associated with a lower risk for diabetes.³⁶ Another meta-analysis of 17 RCTs focused on green tea concluded that green tea improves glucose control and A1C values.³⁷

Continue to: 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

Consuming green tea in the diet may lower the risk for 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, dementia, and risk for diabetes, cancer, and cardiovascular disease. Patients may want to consider drinking green tea as part of a healthy diet, in combination with exercise.

Continue to: PEPPERMINT

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. 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 is used both orally and topically, and has been studied in the treatment of multiple conditions.

Irritable bowel syndrome (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 nine 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 eight 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 two 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. In a randomized, placebo-controlled, double-blind crossover study, 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

Continue to: Musculoskeletal pain

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 RCT concluded that topical menthol acutely reduced pain intensity in slaughterhouse workers with CTS, and it should be considered as an effective nonsystemic 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.

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 CTS.^54,55

Both obesity and weight loss are associated with worsening disability from rheumatoid arthritis, new research suggests.

An analysis of data from two long-term clinical registries involving a total of 25,020 patients with rheumatoid arthritis and 62,484 person-years of follow-up revealed that severely obese individuals with RA had significantly higher Health Assessment Questionnaire or Multi-Dimensional-HAQ scores at enrollment, compared with overweight participants, even after adjusting for confounders such as age, sex, race, smoking, disease duration, and comorbidity.

SOURCE: Baker J et al. Arthritis Care Res. 2018 Apr 30. doi: 10.1002/acr.23579.

Both obesity and weight loss are associated with worsening disability from rheumatoid arthritis, new research suggests.

An analysis of data from two long-term clinical registries involving a total of 25,020 patients with rheumatoid arthritis and 62,484 person-years of follow-up revealed that severely obese individuals with RA had significantly higher Health Assessment Questionnaire or Multi-Dimensional-HAQ scores at enrollment, compared with overweight participants, even after adjusting for confounders such as age, sex, race, smoking, disease duration, and comorbidity.

SOURCE: Baker J et al. Arthritis Care Res. 2018 Apr 30. doi: 10.1002/acr.23579.

Both obesity and weight loss are associated with worsening disability from rheumatoid arthritis, new research suggests.

An analysis of data from two long-term clinical registries involving a total of 25,020 patients with rheumatoid arthritis and 62,484 person-years of follow-up revealed that severely obese individuals with RA had significantly higher Health Assessment Questionnaire or Multi-Dimensional-HAQ scores at enrollment, compared with overweight participants, even after adjusting for confounders such as age, sex, race, smoking, disease duration, and comorbidity.

SOURCE: Baker J et al. Arthritis Care Res. 2018 Apr 30. doi: 10.1002/acr.23579.

Tai chi appears to be an appropriate substitute for pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD) and seems to confer better long-term improvement, suggests a study published online in the journal CHEST^®.

Willie B. Thomas/iStockphoto

[email protected]

SOURCE: Polkey MI et al. CHEST. 2018 May;153[5]:1116-24.

Tai chi appears to be an appropriate substitute for pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD) and seems to confer better long-term improvement, suggests a study published online in the journal CHEST^®.

Willie B. Thomas/iStockphoto

[email protected]

SOURCE: Polkey MI et al. CHEST. 2018 May;153[5]:1116-24.

Tai chi appears to be an appropriate substitute for pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD) and seems to confer better long-term improvement, suggests a study published online in the journal CHEST^®.

Willie B. Thomas/iStockphoto

[email protected]

SOURCE: Polkey MI et al. CHEST. 2018 May;153[5]:1116-24.

LOS ANGELES—Adding a rapid-response team member into the emergency department process to coordinate care for patients eligible for IV t-PA significantly reduces door-to-admission times, according to research presented at the International Stroke Conference 2018. This improvement may be attributed to faster placement and prioritized processing of admission orders.

In this study, the rapid-response team “acted as a control center, relaying vital information to the admission office and the acute stroke unit charge nurse,” said Tarun Girotra, MD, a neurologist at the Henry Ford Hospital in Detroit, and colleagues. “The emergency department registered nurse (RN) was relieved of some of the administrative responsibilities and was able to focus solely on patient care, which resulted in decreased misses in the vital sign documentations.”

The American Heart Association (AHA) recommends a door-to-admission time of less than three hours for patients eligible for IV t-PA. In large tertiary hospitals, administrative complexity and the coordination required often cause delays in admissions, said the researchers. Few studies have examined methods for streamlining the process of admitting patients for treatment with IV t-PA and for increasing compliance with the AHA Get With the Guidelines initiative’s quality measures.

Examining a Policy’s Effect on Time to Admission

Dr. Girotra and colleagues conducted a study to assess whether having a dedicated rapid-response team RN available to respond to the emergency department to coordinate care of patients receiving IV t-PA reduces door-to-admission times. A rapid-response team comprises nurses trained for intensive care units who coordinate care within hospitals and actively participate in inpatient emergencies that require resuscitation.

For this study, the emergency department at the authors’ hospital implemented a policy of notifying the rapid-response team RN of all patients eligible for IV t-PA. The role of the rapid-response team was defined as facilitating admissions through the coordination of care between neurology residents, emergency department physicians, the emergency department RN, the stroke unit charge RN, and the admissions office.

The study’s primary end point was door-to-admission times, which were collected prospectively for three months before and after the intervention (ie, the new policy). Secondary end points included the number of missed neurologic checks and vital sign checks, which AHA guidelines recommend recording. Researchers used the Wilcoxon two-sample test to analyze time variables and compliance rates.

Policy Did Not Affect Neurologic Checks

In all, 13 patients were admitted to receive IV t-PA before the intervention, and 16 were admitted after the intervention. Thirty-eight percent of patients in the preintervention group were female, and 56% of patients in the postintervention group were female. The mean age of participants in the preintervention group was 62.7, and the mean age of participants in the postintervention group was 67. The study lasted six months, with three months of preintervention and three months of postintervention.

Overall, the intervention decreased the mean door-to-admission time from 242.7 minutes to 167.9 minutes. In addition, significantly fewer patients had more than one miss in their documented vital signs after the intervention, compared with before the intervention. No significant difference was observed in the documented neurologic checks per the AHA protocol. There was a higher-than-expected number of misses in neurologic exams by the emergency department RN, however, said the authors. Other centers could use similar interventions to help decrease door-to-admission times, the investigators concluded.

—Erica Tricarico

LOS ANGELES—Adding a rapid-response team member into the emergency department process to coordinate care for patients eligible for IV t-PA significantly reduces door-to-admission times, according to research presented at the International Stroke Conference 2018. This improvement may be attributed to faster placement and prioritized processing of admission orders.

In this study, the rapid-response team “acted as a control center, relaying vital information to the admission office and the acute stroke unit charge nurse,” said Tarun Girotra, MD, a neurologist at the Henry Ford Hospital in Detroit, and colleagues. “The emergency department registered nurse (RN) was relieved of some of the administrative responsibilities and was able to focus solely on patient care, which resulted in decreased misses in the vital sign documentations.”

The American Heart Association (AHA) recommends a door-to-admission time of less than three hours for patients eligible for IV t-PA. In large tertiary hospitals, administrative complexity and the coordination required often cause delays in admissions, said the researchers. Few studies have examined methods for streamlining the process of admitting patients for treatment with IV t-PA and for increasing compliance with the AHA Get With the Guidelines initiative’s quality measures.

Examining a Policy’s Effect on Time to Admission

Dr. Girotra and colleagues conducted a study to assess whether having a dedicated rapid-response team RN available to respond to the emergency department to coordinate care of patients receiving IV t-PA reduces door-to-admission times. A rapid-response team comprises nurses trained for intensive care units who coordinate care within hospitals and actively participate in inpatient emergencies that require resuscitation.

For this study, the emergency department at the authors’ hospital implemented a policy of notifying the rapid-response team RN of all patients eligible for IV t-PA. The role of the rapid-response team was defined as facilitating admissions through the coordination of care between neurology residents, emergency department physicians, the emergency department RN, the stroke unit charge RN, and the admissions office.

The study’s primary end point was door-to-admission times, which were collected prospectively for three months before and after the intervention (ie, the new policy). Secondary end points included the number of missed neurologic checks and vital sign checks, which AHA guidelines recommend recording. Researchers used the Wilcoxon two-sample test to analyze time variables and compliance rates.

Policy Did Not Affect Neurologic Checks

In all, 13 patients were admitted to receive IV t-PA before the intervention, and 16 were admitted after the intervention. Thirty-eight percent of patients in the preintervention group were female, and 56% of patients in the postintervention group were female. The mean age of participants in the preintervention group was 62.7, and the mean age of participants in the postintervention group was 67. The study lasted six months, with three months of preintervention and three months of postintervention.

Overall, the intervention decreased the mean door-to-admission time from 242.7 minutes to 167.9 minutes. In addition, significantly fewer patients had more than one miss in their documented vital signs after the intervention, compared with before the intervention. No significant difference was observed in the documented neurologic checks per the AHA protocol. There was a higher-than-expected number of misses in neurologic exams by the emergency department RN, however, said the authors. Other centers could use similar interventions to help decrease door-to-admission times, the investigators concluded.

—Erica Tricarico

LOS ANGELES—Adding a rapid-response team member into the emergency department process to coordinate care for patients eligible for IV t-PA significantly reduces door-to-admission times, according to research presented at the International Stroke Conference 2018. This improvement may be attributed to faster placement and prioritized processing of admission orders.

In this study, the rapid-response team “acted as a control center, relaying vital information to the admission office and the acute stroke unit charge nurse,” said Tarun Girotra, MD, a neurologist at the Henry Ford Hospital in Detroit, and colleagues. “The emergency department registered nurse (RN) was relieved of some of the administrative responsibilities and was able to focus solely on patient care, which resulted in decreased misses in the vital sign documentations.”

The American Heart Association (AHA) recommends a door-to-admission time of less than three hours for patients eligible for IV t-PA. In large tertiary hospitals, administrative complexity and the coordination required often cause delays in admissions, said the researchers. Few studies have examined methods for streamlining the process of admitting patients for treatment with IV t-PA and for increasing compliance with the AHA Get With the Guidelines initiative’s quality measures.

Examining a Policy’s Effect on Time to Admission

Dr. Girotra and colleagues conducted a study to assess whether having a dedicated rapid-response team RN available to respond to the emergency department to coordinate care of patients receiving IV t-PA reduces door-to-admission times. A rapid-response team comprises nurses trained for intensive care units who coordinate care within hospitals and actively participate in inpatient emergencies that require resuscitation.

For this study, the emergency department at the authors’ hospital implemented a policy of notifying the rapid-response team RN of all patients eligible for IV t-PA. The role of the rapid-response team was defined as facilitating admissions through the coordination of care between neurology residents, emergency department physicians, the emergency department RN, the stroke unit charge RN, and the admissions office.

The study’s primary end point was door-to-admission times, which were collected prospectively for three months before and after the intervention (ie, the new policy). Secondary end points included the number of missed neurologic checks and vital sign checks, which AHA guidelines recommend recording. Researchers used the Wilcoxon two-sample test to analyze time variables and compliance rates.

Policy Did Not Affect Neurologic Checks

In all, 13 patients were admitted to receive IV t-PA before the intervention, and 16 were admitted after the intervention. Thirty-eight percent of patients in the preintervention group were female, and 56% of patients in the postintervention group were female. The mean age of participants in the preintervention group was 62.7, and the mean age of participants in the postintervention group was 67. The study lasted six months, with three months of preintervention and three months of postintervention.

Overall, the intervention decreased the mean door-to-admission time from 242.7 minutes to 167.9 minutes. In addition, significantly fewer patients had more than one miss in their documented vital signs after the intervention, compared with before the intervention. No significant difference was observed in the documented neurologic checks per the AHA protocol. There was a higher-than-expected number of misses in neurologic exams by the emergency department RN, however, said the authors. Other centers could use similar interventions to help decrease door-to-admission times, the investigators concluded.

—Erica Tricarico

AUSTIN, TEX. – Transgender patients face many barriers to care, including a lack of necessary expertise among providers, but a large majority of those surveyed in a study in which they were asked whether they would want to go to a transgender-only clinic said they would not.

Lauren Abern, MD, of Atrius Health, Cambridge, Mass., discussed the aims and results of her survey at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

The anonymous online survey consisted of 120 individuals, aged 18-64 years: 100 transgender men and 20 transgender women. Of these, 83 reported experiencing barriers to care. The most common problem cited was cost (68, 82%), and other barriers were access to care (47, 57%), stigma (33, 40%), and discrimination (23, 26%). Cost was a factor even though a large majority of the respondents had health insurance; a majority of respondents had an income of less than $24,000 per year.

The most common way respondents found transgender-competent health care was through word of mouth (79, 77%).

When asked whether they would want to go to a transgender-only clinic, a majority of both transgender women and transgender men respondents either answered, “no,” or that they were unsure (86, 77%). Some respondents cited a desire not to out themselves as transgender, and others considered the separate clinic medically unnecessary. One wrote: “You wouldn’t need a broken foot–only clinic.”

“Basic preventative services can be provided without specific expertise in transgender health. If providers are uncomfortable, they should refer [transgender patients] elsewhere.” said Dr. Abern.

The survey project was conducted in collaboration with the University of Miami and the YES Institute in Miami.

Dr. Abern also spoke about wider transgender health considerations for the ob.gyn. in a separate presentation at the meeting and in a video interview.

For example, transgender men on testosterone may have persistent bleeding and may be uncomfortable with pelvic exams.

Making more inclusive intake forms and fostering a respectful office environment (for example, having a nondiscrimination policy displayed in the waiting area) are measures beneficial to all patients, she said.

“My dream or goal would be that transgender people can be seen and accepted at any office and feel comfortable and not avoid seeking health care.”

[email protected]

AUSTIN, TEX. – Transgender patients face many barriers to care, including a lack of necessary expertise among providers, but a large majority of those surveyed in a study in which they were asked whether they would want to go to a transgender-only clinic said they would not.

Lauren Abern, MD, of Atrius Health, Cambridge, Mass., discussed the aims and results of her survey at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

The anonymous online survey consisted of 120 individuals, aged 18-64 years: 100 transgender men and 20 transgender women. Of these, 83 reported experiencing barriers to care. The most common problem cited was cost (68, 82%), and other barriers were access to care (47, 57%), stigma (33, 40%), and discrimination (23, 26%). Cost was a factor even though a large majority of the respondents had health insurance; a majority of respondents had an income of less than $24,000 per year.

The most common way respondents found transgender-competent health care was through word of mouth (79, 77%).

When asked whether they would want to go to a transgender-only clinic, a majority of both transgender women and transgender men respondents either answered, “no,” or that they were unsure (86, 77%). Some respondents cited a desire not to out themselves as transgender, and others considered the separate clinic medically unnecessary. One wrote: “You wouldn’t need a broken foot–only clinic.”

“Basic preventative services can be provided without specific expertise in transgender health. If providers are uncomfortable, they should refer [transgender patients] elsewhere.” said Dr. Abern.

The survey project was conducted in collaboration with the University of Miami and the YES Institute in Miami.

Dr. Abern also spoke about wider transgender health considerations for the ob.gyn. in a separate presentation at the meeting and in a video interview.

For example, transgender men on testosterone may have persistent bleeding and may be uncomfortable with pelvic exams.

Making more inclusive intake forms and fostering a respectful office environment (for example, having a nondiscrimination policy displayed in the waiting area) are measures beneficial to all patients, she said.

“My dream or goal would be that transgender people can be seen and accepted at any office and feel comfortable and not avoid seeking health care.”

[email protected]

AUSTIN, TEX. – Transgender patients face many barriers to care, including a lack of necessary expertise among providers, but a large majority of those surveyed in a study in which they were asked whether they would want to go to a transgender-only clinic said they would not.

Lauren Abern, MD, of Atrius Health, Cambridge, Mass., discussed the aims and results of her survey at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

The anonymous online survey consisted of 120 individuals, aged 18-64 years: 100 transgender men and 20 transgender women. Of these, 83 reported experiencing barriers to care. The most common problem cited was cost (68, 82%), and other barriers were access to care (47, 57%), stigma (33, 40%), and discrimination (23, 26%). Cost was a factor even though a large majority of the respondents had health insurance; a majority of respondents had an income of less than $24,000 per year.

The most common way respondents found transgender-competent health care was through word of mouth (79, 77%).

When asked whether they would want to go to a transgender-only clinic, a majority of both transgender women and transgender men respondents either answered, “no,” or that they were unsure (86, 77%). Some respondents cited a desire not to out themselves as transgender, and others considered the separate clinic medically unnecessary. One wrote: “You wouldn’t need a broken foot–only clinic.”

“Basic preventative services can be provided without specific expertise in transgender health. If providers are uncomfortable, they should refer [transgender patients] elsewhere.” said Dr. Abern.

The survey project was conducted in collaboration with the University of Miami and the YES Institute in Miami.

Dr. Abern also spoke about wider transgender health considerations for the ob.gyn. in a separate presentation at the meeting and in a video interview.

For example, transgender men on testosterone may have persistent bleeding and may be uncomfortable with pelvic exams.

Making more inclusive intake forms and fostering a respectful office environment (for example, having a nondiscrimination policy displayed in the waiting area) are measures beneficial to all patients, she said.

“My dream or goal would be that transgender people can be seen and accepted at any office and feel comfortable and not avoid seeking health care.”

[email protected]

In cutaneous field cancerization, focal treatments such as cryotherapy are impractical, thus necessitating the use of field-directed therapies over the lesion and the surrounding skin field. Although evidence-based guidelines do not exist, field-directed therapy has been proposed in cases of 3 or more actinic keratoses (AKs) in a 25-cm² area or larger.¹ It can be further speculated that patients who are vulnerable to aggressive phenotypes of cutaneous malignancies, such as those with a genodermatosis or who are immunocompromised, necessitate a higher index of suspicion for field effect with even 1 or 2 AKs.

Current field-directed therapies include topical agents (imiquimod, fluorouracil, ingenol mebutate, and diclo-fenac), photodynamic therapy (PDT), and resurfacing procedures (lasers, chemical peels, dermabrasion). Although topical agents and PDT currently are gold standards in field treatment, the use of energy-based devices (ie, ablative and nonablative lasers) are attractive options as monotherapy or as part of a combination therapy. These devices are attractive options for field-directed therapy because they offer defined, customizable control of settings, allowing for optimal cosmesis and precision of therapy.

Principally, lasers function by damaging skin tissue to induce resurfacing, neocollagenesis, and vascular restructuring. Fractional versions of ablative and nonablative systems are available to target a fraction of the treatment area in evenly spaced microthermal zones and to minimize overall thermal damage.²

Given recent advances in laser systems and numerous investigations reported in the literature, a review of ablative and nonablative lasers that have been studied as treatment options for cutaneous field cancerization is provided, with a focus on treatment efficacy.

Ablative Lasers

Ablative lasers operate at higher wavelengths than nonablative lasers to destroy epidermal and dermal tissue. The 10,600-nm carbon dioxide (CO₂) and 2940-nm Er:YAG lasers have been heavily investigated for field therapy for multiple AKs, both as monotherapies (Table 1) and in combination with PDT (Table 2).

Monotherapy
One randomized trial with 5-year follow-up compared the efficacy of full-face pulsed CO₂ laser therapy, full-face trichloroacetic acid (TCA) peel 30%, and fluorouracil cream 5% (twice daily for 3 weeks) on AKs on the face and head.³ Thirty-one participants were randomized to the 3 treatment arms and a negative control arm. The mean AK counts at baseline for the CO₂, TCA, and fluorouracil treatment groups were 78.0, 83.7, and 61.8, respectively. At 3-month follow-up, all treatment groups had significant reductions in the mean AK count from baseline (CO₂ group, 92% [P=.03]; TCA group, 89% [P=.004]; fluorouracil group, 83% [P=.008]). No significant differences in efficacy among the treatment groups were noted. All 3 treatment groups had a demonstrably lower incidence of nonmelanoma skin cancer over 5-year follow-up compared to the control group (P<.001).³

In contrast to these promising results, the pulsed CO₂ laser showed only short-term efficacy in a split-face study of 12 participants with at least 5 facial or scalp AKs on each of 2 symmetric facial sides who were randomized to 1 treatment side.⁴ At 1-month follow-up, the treatment side exhibited significantly fewer AKs compared to the control side (47% vs 71% at baseline; P=.01), but the improvement was not sustained at 3-month follow-up (49% vs 57%; P=.47).⁴

In another study, the CO₂ laser was found to be inferior to 5-aminolevulinic acid PDT.⁵ Twenty-one participants who had at least 4 AKs in each symmetric half of a body region (head, hands, forearms) were randomized to PDT on 1 side and CO₂ laser therapy on the other. Median baseline AK counts for the PDT and CO₂ laser groups were 6 and 8, respectively. Both treatment groups exhibited significant median AK reduction from baseline 4 weeks posttreatment (PDT group, 82.1% [P<.05], CO₂ laser group, 100% [P<.05]); however. at 3 months posttreatment the PDT group had significantly higher absolute (P=.0155) and relative (P=.0362) reductions in AK count compared to the CO₂ laser group. One participant received a topical antibiotic for superficial infection on the PDT treatment side.⁵

Many questions remain regarding the practical application of laser ablation monotherapy for multiple AKs. More studies are needed to determine the practicality and long-term clinical efficacy of these devices.

PDT Combination Therapy
Laser ablation may be combined with PDT to increase efficacy and prolong remission rates. In fact, laser ablation may be thought of as a physical drug-delivery system to boost uptake of topical agents—in this case, aminolevulinic acid and methyl aminolevulinate (MAL)—given that it disrupts the skin barrier.

In a comparative study of ablative fractional laser (AFXL)–assisted PDT and AFXL alone in 10 organ transplant recipients on immunosuppression with at least 5 AKs on each dorsal hand, participants were randomized to AFXL-PDT on one treatment side and PDT on the other side.⁶ Participants received AFXL in an initial lesion-directed pass and then a second field-directed pass of a fractional CO₂ laser. After AFXL exposure, methyl aminolevulinate was applied to the AFXL-PDT treatment side, with 3-hour occlusion. A total of 680 AKs were treated (335 in the AFXL-PDT group, 345 in the PDT group); results were stratified by the clinical grade of the lesion (1, slightly palpable; 2, moderately thick; 3, very thick or obvious). At 4-month follow-up, the AFXL-PDT group had a significantly higher median complete response rate of 73% compared to 31% in the AFXL group (P=.002). Interestingly, AFXL-PDT was also significantly more efficacious compared to AFXL for grades 1 (80% vs 37%; P=.02) and 2 (53% vs 7%, P=.009) AKs but not grade 3 AKs (4% vs 0%, P=.17).⁶

The combination of fractional CO₂ laser and PDT also demonstrated superiority to PDT.⁷ In a split-face investigation, 15 participants with bilateral symmetric areas of 2 to 10 AKs on the face or scalp were randomized to receive fractional CO₂ laser and MAL-PDT combination therapy on 1 treatment side and conventional MAL-PDT on the other side.⁷ The AFXL-PDT treatment side received laser ablation with immediate subsequent application of MAL to both treatment sides under 3-hour occlusion. At baseline, 103 AKs were treated by AFXL-PDT and 109 AKs were treated with conventional PDT. At 3-month follow-up, the AFXL-PDT treatment group exhibited a significantly higher rate of complete response (90%) compared to the conventional PDT group (67%)(P=.0002).⁷

Like the CO₂ laser, the Er:YAG laser has demonstrated superior results when used in combination with PDT to treat field cancerization compared to either treatment alone. In a comparison study, 93 patients with 2 to 10 AK lesions on the face or scalp were randomized to treatment with AFXL (Er:YAG laser) and MAL-PDT with 3-hour occlusion, AFXL (Er:YAG laser) and MAL-PDT with 2-hour occlusion, and MAL-PDT with 3-hour occlusion.⁸ A total of 440 baseline AK lesions on the face or scalp were treated. At 3-month follow-up, the AFXL-PDT (3-hour occlusion) group had the highest rate of complete response (91.7%), compared to 76.8% (P=.001) in the AFXL-PDT (2-hour occlusion) and 65.6% (P=.001) in the PDT groups, regardless of the grade of AK lesion. The AFXL-PDT (2-hour occlusion) treatment was also superior to PDT alone (P=.038). These findings were sustained at 12-month follow-up (84.8% in the AFXL-PDT [3-hour occlusion] group [P<.001, compared to others]; 67.5% in the AFXL-PDT [2-hour occlusion] group [P<.001, compared to 3-hour PDT]; 51.1% in the PDT group). Importantly, the AK lesion recurrence rate was also lowest in the AFL-PDT (3-hour occlusion) group (7.5% vs 12.1% and 22.1% in the AFXL-PDT [2-hour occlusion] and PDT groups, respectively; P=.007).⁸

Combination therapy with AFXL and daylight PDT (dPDT) may improve the tolerability of PDT and the efficacy rate of field therapy in organ transplant recipients. One study demonstrated the superiority of this combination therapy in a population of 16 organ transplant recipients on immunosuppressants with at least 2 moderate to severely thick AKs in each of 4 comparable areas in the same anatomic region.⁹ The 4 areas were randomized to a single session of AFXL-dPDT, dPDT alone, conventional PDT, or AFXL alone. Ablation was performed with a fractional Er:YAG laser. The AFXL-dPDT and dPDT alone groups received MAL for 2.5 hours without occlusion, and the conventional PDT group received MAL for 3 hours with occlusion. Daylight exposure in dPDT groups was initiated 30 minutes after MAL application for 2 hours total. A baseline total of 542 AKs were treated. At 3-month follow-up, the complete response rate was highest for the AFXL-dPDT group (74%) compared to dPDT alone (46%; P=.0262), conventional PDT (50%; P=.042), and AFXL alone (5%; P=.004). Pain scores for AFXL–dPDT and dPDT alone were significantly lower than for conventional PDT and AFXL alone (P<.001).⁹

Nonablative Lasers

By heating the dermis to induce neogenesis without destruction, nonablative lasers offer superior healing times compared to their ablative counterparts. Multiple treatments with nonablative lasers may be necessary for maximal effect. Four nonablative laser devices have demonstrated efficacy in the treatment of multiple AKs^10-14: (1) the Q-switched 1064-nm Nd:YAG laser, with or without a 532-nm potassium titanyl phosphate (KTP) laser; (2) the 1540-nm fractional erbium glass laser; (3) the 1550-nm fractional erbium-doped fiber laser; and (4) the 1927-nm fractional thulium laser (Table 3).

In a proof-of-concept study of the Q-switched Nd:YAG laser with the 532-nm KTP laser, 1 treatment session induced full remission of AKs in 10 patients at follow-up day 20, although the investigator did not grade improvement on a numerical scale.¹⁰ In a study of the fractional Q-switched 1064-nm Nd:YAG laser alone, 6 patients with trace or mild AKs received 4 treatment sessions at approximately 2-week intervals.¹⁴ All but 1 patient (who had trace AKs) had no AKs at 3-month follow-up.

The efficacy of the 1540-nm fractional erbium glass laser was examined in 17 participants with investigator-rated moderate-to-severe AK involvement of the scalp and face.¹² Participants were given 2 or 3 treatment sessions at 3- to 4-week intervals and were graded by blinded dermatologists on a quartile scale of 0 (no improvement), 1 (1%–25% improvement), 2 (26%–50% improvement), 3 (51%–75% improvement), or 4 (76%–100% improvement). At 3 months posttreatment, the average grade of improvement was 3.4.¹²

The 1550-nm fractional erbium-doped fiber laser was tested in 14 men with multiple facial AKs (range, 9–44 AKs [mean, 22.1 AKs]).¹¹ Participants received 5 treatment sessions at 2- to 4-week intervals, with majority energies used at 70 MJ and treatment level 11. The mean AK count was reduced significantly by 73.1%, 66.2%, and 55.6% at 1-, 3-, and 6-month follow-up, respectively (P<.001).¹¹

The 1927-nm fractional thulium laser showed promising results in 24 participants with facial AKs.¹³ Participants received up to 4 treatment sessions at intervals from 2 to 6 weeks at the investigators’ discretion. At baseline, patients had an average of 14.04 facial AKs. At 1-, 3-, and 6-month follow-up, participants exhibited 91.3%, 87.3%, and 86.6% reduction in AK counts, respectively. The mean AK count at 3-month follow-up was 1.88.¹³

Due to limited sample sizes and/or lack of quantifiable results and controls in these studies, more studies are needed to fully elucidate the role of nonablative lasers in the treatment of AK.

Future Directions

Iontophoresis involves the noninvasive induction of an electrical current to facilitate ion movement through the skin and may be a novel method to boost the efficacy of current field therapies. In the first known study of its kisnd, iontophoresis-assisted AFXL-PDT was found to be noninferior to conventional AFXL-PDT¹⁵; however, additional studies demonstrating its superiority are needed before more widespread clinical use is considered.

Pretreatment with AFXL prior to topical field-directed therapies also has been proposed.¹⁶ In a case series of 13 patients, combination therapy with AFXL and ingenol mebutate was shown to be superior to ingenol mebutate alone (AK clearance rate, 89.2% vs 72.1%, respectively; P<.001).¹⁶ Randomized studies with longer follow-up time are needed.

Conclusion

Ablative and nonablative laser systems have yielded limited data about their potential as monotherapies for treatment of multiple AKs and are unlikely to replace topical agents and PDT as a first-line modality in field-directed treatment at this time. More studies with a larger number of participants and long-term follow-up are needed for further clarification of efficacy, safety, and clinical feasibility. Nevertheless, fractional ablative lasers in combination with PDT have shown robust efficacy and a favorable safety profile for treatment of multiple AKs.^6-9 Further, this combination therapy exhibited a superior clearance rate and lower lesion recurrence in organ transplant recipients—a demographic that classically is difficult to treat.^6-9

With continued rapid evolution of laser systems and more widespread use in dermatology, monotherapy and combination therapy may offer a dynamic new option in field cancerization that can decrease disease burden and treatment frequency.

In cutaneous field cancerization, focal treatments such as cryotherapy are impractical, thus necessitating the use of field-directed therapies over the lesion and the surrounding skin field. Although evidence-based guidelines do not exist, field-directed therapy has been proposed in cases of 3 or more actinic keratoses (AKs) in a 25-cm² area or larger.¹ It can be further speculated that patients who are vulnerable to aggressive phenotypes of cutaneous malignancies, such as those with a genodermatosis or who are immunocompromised, necessitate a higher index of suspicion for field effect with even 1 or 2 AKs.

Current field-directed therapies include topical agents (imiquimod, fluorouracil, ingenol mebutate, and diclo-fenac), photodynamic therapy (PDT), and resurfacing procedures (lasers, chemical peels, dermabrasion). Although topical agents and PDT currently are gold standards in field treatment, the use of energy-based devices (ie, ablative and nonablative lasers) are attractive options as monotherapy or as part of a combination therapy. These devices are attractive options for field-directed therapy because they offer defined, customizable control of settings, allowing for optimal cosmesis and precision of therapy.

Principally, lasers function by damaging skin tissue to induce resurfacing, neocollagenesis, and vascular restructuring. Fractional versions of ablative and nonablative systems are available to target a fraction of the treatment area in evenly spaced microthermal zones and to minimize overall thermal damage.²

Given recent advances in laser systems and numerous investigations reported in the literature, a review of ablative and nonablative lasers that have been studied as treatment options for cutaneous field cancerization is provided, with a focus on treatment efficacy.

Ablative Lasers

Ablative lasers operate at higher wavelengths than nonablative lasers to destroy epidermal and dermal tissue. The 10,600-nm carbon dioxide (CO₂) and 2940-nm Er:YAG lasers have been heavily investigated for field therapy for multiple AKs, both as monotherapies (Table 1) and in combination with PDT (Table 2).

Monotherapy
One randomized trial with 5-year follow-up compared the efficacy of full-face pulsed CO₂ laser therapy, full-face trichloroacetic acid (TCA) peel 30%, and fluorouracil cream 5% (twice daily for 3 weeks) on AKs on the face and head.³ Thirty-one participants were randomized to the 3 treatment arms and a negative control arm. The mean AK counts at baseline for the CO₂, TCA, and fluorouracil treatment groups were 78.0, 83.7, and 61.8, respectively. At 3-month follow-up, all treatment groups had significant reductions in the mean AK count from baseline (CO₂ group, 92% [P=.03]; TCA group, 89% [P=.004]; fluorouracil group, 83% [P=.008]). No significant differences in efficacy among the treatment groups were noted. All 3 treatment groups had a demonstrably lower incidence of nonmelanoma skin cancer over 5-year follow-up compared to the control group (P<.001).³

In contrast to these promising results, the pulsed CO₂ laser showed only short-term efficacy in a split-face study of 12 participants with at least 5 facial or scalp AKs on each of 2 symmetric facial sides who were randomized to 1 treatment side.⁴ At 1-month follow-up, the treatment side exhibited significantly fewer AKs compared to the control side (47% vs 71% at baseline; P=.01), but the improvement was not sustained at 3-month follow-up (49% vs 57%; P=.47).⁴

In another study, the CO₂ laser was found to be inferior to 5-aminolevulinic acid PDT.⁵ Twenty-one participants who had at least 4 AKs in each symmetric half of a body region (head, hands, forearms) were randomized to PDT on 1 side and CO₂ laser therapy on the other. Median baseline AK counts for the PDT and CO₂ laser groups were 6 and 8, respectively. Both treatment groups exhibited significant median AK reduction from baseline 4 weeks posttreatment (PDT group, 82.1% [P<.05], CO₂ laser group, 100% [P<.05]); however. at 3 months posttreatment the PDT group had significantly higher absolute (P=.0155) and relative (P=.0362) reductions in AK count compared to the CO₂ laser group. One participant received a topical antibiotic for superficial infection on the PDT treatment side.⁵

Many questions remain regarding the practical application of laser ablation monotherapy for multiple AKs. More studies are needed to determine the practicality and long-term clinical efficacy of these devices.

PDT Combination Therapy
Laser ablation may be combined with PDT to increase efficacy and prolong remission rates. In fact, laser ablation may be thought of as a physical drug-delivery system to boost uptake of topical agents—in this case, aminolevulinic acid and methyl aminolevulinate (MAL)—given that it disrupts the skin barrier.

In a comparative study of ablative fractional laser (AFXL)–assisted PDT and AFXL alone in 10 organ transplant recipients on immunosuppression with at least 5 AKs on each dorsal hand, participants were randomized to AFXL-PDT on one treatment side and PDT on the other side.⁶ Participants received AFXL in an initial lesion-directed pass and then a second field-directed pass of a fractional CO₂ laser. After AFXL exposure, methyl aminolevulinate was applied to the AFXL-PDT treatment side, with 3-hour occlusion. A total of 680 AKs were treated (335 in the AFXL-PDT group, 345 in the PDT group); results were stratified by the clinical grade of the lesion (1, slightly palpable; 2, moderately thick; 3, very thick or obvious). At 4-month follow-up, the AFXL-PDT group had a significantly higher median complete response rate of 73% compared to 31% in the AFXL group (P=.002). Interestingly, AFXL-PDT was also significantly more efficacious compared to AFXL for grades 1 (80% vs 37%; P=.02) and 2 (53% vs 7%, P=.009) AKs but not grade 3 AKs (4% vs 0%, P=.17).⁶

The combination of fractional CO₂ laser and PDT also demonstrated superiority to PDT.⁷ In a split-face investigation, 15 participants with bilateral symmetric areas of 2 to 10 AKs on the face or scalp were randomized to receive fractional CO₂ laser and MAL-PDT combination therapy on 1 treatment side and conventional MAL-PDT on the other side.⁷ The AFXL-PDT treatment side received laser ablation with immediate subsequent application of MAL to both treatment sides under 3-hour occlusion. At baseline, 103 AKs were treated by AFXL-PDT and 109 AKs were treated with conventional PDT. At 3-month follow-up, the AFXL-PDT treatment group exhibited a significantly higher rate of complete response (90%) compared to the conventional PDT group (67%)(P=.0002).⁷

Like the CO₂ laser, the Er:YAG laser has demonstrated superior results when used in combination with PDT to treat field cancerization compared to either treatment alone. In a comparison study, 93 patients with 2 to 10 AK lesions on the face or scalp were randomized to treatment with AFXL (Er:YAG laser) and MAL-PDT with 3-hour occlusion, AFXL (Er:YAG laser) and MAL-PDT with 2-hour occlusion, and MAL-PDT with 3-hour occlusion.⁸ A total of 440 baseline AK lesions on the face or scalp were treated. At 3-month follow-up, the AFXL-PDT (3-hour occlusion) group had the highest rate of complete response (91.7%), compared to 76.8% (P=.001) in the AFXL-PDT (2-hour occlusion) and 65.6% (P=.001) in the PDT groups, regardless of the grade of AK lesion. The AFXL-PDT (2-hour occlusion) treatment was also superior to PDT alone (P=.038). These findings were sustained at 12-month follow-up (84.8% in the AFXL-PDT [3-hour occlusion] group [P<.001, compared to others]; 67.5% in the AFXL-PDT [2-hour occlusion] group [P<.001, compared to 3-hour PDT]; 51.1% in the PDT group). Importantly, the AK lesion recurrence rate was also lowest in the AFL-PDT (3-hour occlusion) group (7.5% vs 12.1% and 22.1% in the AFXL-PDT [2-hour occlusion] and PDT groups, respectively; P=.007).⁸

Combination therapy with AFXL and daylight PDT (dPDT) may improve the tolerability of PDT and the efficacy rate of field therapy in organ transplant recipients. One study demonstrated the superiority of this combination therapy in a population of 16 organ transplant recipients on immunosuppressants with at least 2 moderate to severely thick AKs in each of 4 comparable areas in the same anatomic region.⁹ The 4 areas were randomized to a single session of AFXL-dPDT, dPDT alone, conventional PDT, or AFXL alone. Ablation was performed with a fractional Er:YAG laser. The AFXL-dPDT and dPDT alone groups received MAL for 2.5 hours without occlusion, and the conventional PDT group received MAL for 3 hours with occlusion. Daylight exposure in dPDT groups was initiated 30 minutes after MAL application for 2 hours total. A baseline total of 542 AKs were treated. At 3-month follow-up, the complete response rate was highest for the AFXL-dPDT group (74%) compared to dPDT alone (46%; P=.0262), conventional PDT (50%; P=.042), and AFXL alone (5%; P=.004). Pain scores for AFXL–dPDT and dPDT alone were significantly lower than for conventional PDT and AFXL alone (P<.001).⁹

Nonablative Lasers

By heating the dermis to induce neogenesis without destruction, nonablative lasers offer superior healing times compared to their ablative counterparts. Multiple treatments with nonablative lasers may be necessary for maximal effect. Four nonablative laser devices have demonstrated efficacy in the treatment of multiple AKs^10-14: (1) the Q-switched 1064-nm Nd:YAG laser, with or without a 532-nm potassium titanyl phosphate (KTP) laser; (2) the 1540-nm fractional erbium glass laser; (3) the 1550-nm fractional erbium-doped fiber laser; and (4) the 1927-nm fractional thulium laser (Table 3).

In a proof-of-concept study of the Q-switched Nd:YAG laser with the 532-nm KTP laser, 1 treatment session induced full remission of AKs in 10 patients at follow-up day 20, although the investigator did not grade improvement on a numerical scale.¹⁰ In a study of the fractional Q-switched 1064-nm Nd:YAG laser alone, 6 patients with trace or mild AKs received 4 treatment sessions at approximately 2-week intervals.¹⁴ All but 1 patient (who had trace AKs) had no AKs at 3-month follow-up.

The efficacy of the 1540-nm fractional erbium glass laser was examined in 17 participants with investigator-rated moderate-to-severe AK involvement of the scalp and face.¹² Participants were given 2 or 3 treatment sessions at 3- to 4-week intervals and were graded by blinded dermatologists on a quartile scale of 0 (no improvement), 1 (1%–25% improvement), 2 (26%–50% improvement), 3 (51%–75% improvement), or 4 (76%–100% improvement). At 3 months posttreatment, the average grade of improvement was 3.4.¹²

The 1550-nm fractional erbium-doped fiber laser was tested in 14 men with multiple facial AKs (range, 9–44 AKs [mean, 22.1 AKs]).¹¹ Participants received 5 treatment sessions at 2- to 4-week intervals, with majority energies used at 70 MJ and treatment level 11. The mean AK count was reduced significantly by 73.1%, 66.2%, and 55.6% at 1-, 3-, and 6-month follow-up, respectively (P<.001).¹¹

The 1927-nm fractional thulium laser showed promising results in 24 participants with facial AKs.¹³ Participants received up to 4 treatment sessions at intervals from 2 to 6 weeks at the investigators’ discretion. At baseline, patients had an average of 14.04 facial AKs. At 1-, 3-, and 6-month follow-up, participants exhibited 91.3%, 87.3%, and 86.6% reduction in AK counts, respectively. The mean AK count at 3-month follow-up was 1.88.¹³

Due to limited sample sizes and/or lack of quantifiable results and controls in these studies, more studies are needed to fully elucidate the role of nonablative lasers in the treatment of AK.

Future Directions

Iontophoresis involves the noninvasive induction of an electrical current to facilitate ion movement through the skin and may be a novel method to boost the efficacy of current field therapies. In the first known study of its kisnd, iontophoresis-assisted AFXL-PDT was found to be noninferior to conventional AFXL-PDT¹⁵; however, additional studies demonstrating its superiority are needed before more widespread clinical use is considered.

Pretreatment with AFXL prior to topical field-directed therapies also has been proposed.¹⁶ In a case series of 13 patients, combination therapy with AFXL and ingenol mebutate was shown to be superior to ingenol mebutate alone (AK clearance rate, 89.2% vs 72.1%, respectively; P<.001).¹⁶ Randomized studies with longer follow-up time are needed.

Conclusion

Ablative and nonablative laser systems have yielded limited data about their potential as monotherapies for treatment of multiple AKs and are unlikely to replace topical agents and PDT as a first-line modality in field-directed treatment at this time. More studies with a larger number of participants and long-term follow-up are needed for further clarification of efficacy, safety, and clinical feasibility. Nevertheless, fractional ablative lasers in combination with PDT have shown robust efficacy and a favorable safety profile for treatment of multiple AKs.^6-9 Further, this combination therapy exhibited a superior clearance rate and lower lesion recurrence in organ transplant recipients—a demographic that classically is difficult to treat.^6-9

With continued rapid evolution of laser systems and more widespread use in dermatology, monotherapy and combination therapy may offer a dynamic new option in field cancerization that can decrease disease burden and treatment frequency.

In cutaneous field cancerization, focal treatments such as cryotherapy are impractical, thus necessitating the use of field-directed therapies over the lesion and the surrounding skin field. Although evidence-based guidelines do not exist, field-directed therapy has been proposed in cases of 3 or more actinic keratoses (AKs) in a 25-cm² area or larger.¹ It can be further speculated that patients who are vulnerable to aggressive phenotypes of cutaneous malignancies, such as those with a genodermatosis or who are immunocompromised, necessitate a higher index of suspicion for field effect with even 1 or 2 AKs.

Current field-directed therapies include topical agents (imiquimod, fluorouracil, ingenol mebutate, and diclo-fenac), photodynamic therapy (PDT), and resurfacing procedures (lasers, chemical peels, dermabrasion). Although topical agents and PDT currently are gold standards in field treatment, the use of energy-based devices (ie, ablative and nonablative lasers) are attractive options as monotherapy or as part of a combination therapy. These devices are attractive options for field-directed therapy because they offer defined, customizable control of settings, allowing for optimal cosmesis and precision of therapy.

Principally, lasers function by damaging skin tissue to induce resurfacing, neocollagenesis, and vascular restructuring. Fractional versions of ablative and nonablative systems are available to target a fraction of the treatment area in evenly spaced microthermal zones and to minimize overall thermal damage.²

Given recent advances in laser systems and numerous investigations reported in the literature, a review of ablative and nonablative lasers that have been studied as treatment options for cutaneous field cancerization is provided, with a focus on treatment efficacy.

Ablative Lasers

Ablative lasers operate at higher wavelengths than nonablative lasers to destroy epidermal and dermal tissue. The 10,600-nm carbon dioxide (CO₂) and 2940-nm Er:YAG lasers have been heavily investigated for field therapy for multiple AKs, both as monotherapies (Table 1) and in combination with PDT (Table 2).

Monotherapy
One randomized trial with 5-year follow-up compared the efficacy of full-face pulsed CO₂ laser therapy, full-face trichloroacetic acid (TCA) peel 30%, and fluorouracil cream 5% (twice daily for 3 weeks) on AKs on the face and head.³ Thirty-one participants were randomized to the 3 treatment arms and a negative control arm. The mean AK counts at baseline for the CO₂, TCA, and fluorouracil treatment groups were 78.0, 83.7, and 61.8, respectively. At 3-month follow-up, all treatment groups had significant reductions in the mean AK count from baseline (CO₂ group, 92% [P=.03]; TCA group, 89% [P=.004]; fluorouracil group, 83% [P=.008]). No significant differences in efficacy among the treatment groups were noted. All 3 treatment groups had a demonstrably lower incidence of nonmelanoma skin cancer over 5-year follow-up compared to the control group (P<.001).³

In contrast to these promising results, the pulsed CO₂ laser showed only short-term efficacy in a split-face study of 12 participants with at least 5 facial or scalp AKs on each of 2 symmetric facial sides who were randomized to 1 treatment side.⁴ At 1-month follow-up, the treatment side exhibited significantly fewer AKs compared to the control side (47% vs 71% at baseline; P=.01), but the improvement was not sustained at 3-month follow-up (49% vs 57%; P=.47).⁴

In another study, the CO₂ laser was found to be inferior to 5-aminolevulinic acid PDT.⁵ Twenty-one participants who had at least 4 AKs in each symmetric half of a body region (head, hands, forearms) were randomized to PDT on 1 side and CO₂ laser therapy on the other. Median baseline AK counts for the PDT and CO₂ laser groups were 6 and 8, respectively. Both treatment groups exhibited significant median AK reduction from baseline 4 weeks posttreatment (PDT group, 82.1% [P<.05], CO₂ laser group, 100% [P<.05]); however. at 3 months posttreatment the PDT group had significantly higher absolute (P=.0155) and relative (P=.0362) reductions in AK count compared to the CO₂ laser group. One participant received a topical antibiotic for superficial infection on the PDT treatment side.⁵

Many questions remain regarding the practical application of laser ablation monotherapy for multiple AKs. More studies are needed to determine the practicality and long-term clinical efficacy of these devices.

PDT Combination Therapy
Laser ablation may be combined with PDT to increase efficacy and prolong remission rates. In fact, laser ablation may be thought of as a physical drug-delivery system to boost uptake of topical agents—in this case, aminolevulinic acid and methyl aminolevulinate (MAL)—given that it disrupts the skin barrier.

In a comparative study of ablative fractional laser (AFXL)–assisted PDT and AFXL alone in 10 organ transplant recipients on immunosuppression with at least 5 AKs on each dorsal hand, participants were randomized to AFXL-PDT on one treatment side and PDT on the other side.⁶ Participants received AFXL in an initial lesion-directed pass and then a second field-directed pass of a fractional CO₂ laser. After AFXL exposure, methyl aminolevulinate was applied to the AFXL-PDT treatment side, with 3-hour occlusion. A total of 680 AKs were treated (335 in the AFXL-PDT group, 345 in the PDT group); results were stratified by the clinical grade of the lesion (1, slightly palpable; 2, moderately thick; 3, very thick or obvious). At 4-month follow-up, the AFXL-PDT group had a significantly higher median complete response rate of 73% compared to 31% in the AFXL group (P=.002). Interestingly, AFXL-PDT was also significantly more efficacious compared to AFXL for grades 1 (80% vs 37%; P=.02) and 2 (53% vs 7%, P=.009) AKs but not grade 3 AKs (4% vs 0%, P=.17).⁶

The combination of fractional CO₂ laser and PDT also demonstrated superiority to PDT.⁷ In a split-face investigation, 15 participants with bilateral symmetric areas of 2 to 10 AKs on the face or scalp were randomized to receive fractional CO₂ laser and MAL-PDT combination therapy on 1 treatment side and conventional MAL-PDT on the other side.⁷ The AFXL-PDT treatment side received laser ablation with immediate subsequent application of MAL to both treatment sides under 3-hour occlusion. At baseline, 103 AKs were treated by AFXL-PDT and 109 AKs were treated with conventional PDT. At 3-month follow-up, the AFXL-PDT treatment group exhibited a significantly higher rate of complete response (90%) compared to the conventional PDT group (67%)(P=.0002).⁷

Like the CO₂ laser, the Er:YAG laser has demonstrated superior results when used in combination with PDT to treat field cancerization compared to either treatment alone. In a comparison study, 93 patients with 2 to 10 AK lesions on the face or scalp were randomized to treatment with AFXL (Er:YAG laser) and MAL-PDT with 3-hour occlusion, AFXL (Er:YAG laser) and MAL-PDT with 2-hour occlusion, and MAL-PDT with 3-hour occlusion.⁸ A total of 440 baseline AK lesions on the face or scalp were treated. At 3-month follow-up, the AFXL-PDT (3-hour occlusion) group had the highest rate of complete response (91.7%), compared to 76.8% (P=.001) in the AFXL-PDT (2-hour occlusion) and 65.6% (P=.001) in the PDT groups, regardless of the grade of AK lesion. The AFXL-PDT (2-hour occlusion) treatment was also superior to PDT alone (P=.038). These findings were sustained at 12-month follow-up (84.8% in the AFXL-PDT [3-hour occlusion] group [P<.001, compared to others]; 67.5% in the AFXL-PDT [2-hour occlusion] group [P<.001, compared to 3-hour PDT]; 51.1% in the PDT group). Importantly, the AK lesion recurrence rate was also lowest in the AFL-PDT (3-hour occlusion) group (7.5% vs 12.1% and 22.1% in the AFXL-PDT [2-hour occlusion] and PDT groups, respectively; P=.007).⁸

Combination therapy with AFXL and daylight PDT (dPDT) may improve the tolerability of PDT and the efficacy rate of field therapy in organ transplant recipients. One study demonstrated the superiority of this combination therapy in a population of 16 organ transplant recipients on immunosuppressants with at least 2 moderate to severely thick AKs in each of 4 comparable areas in the same anatomic region.⁹ The 4 areas were randomized to a single session of AFXL-dPDT, dPDT alone, conventional PDT, or AFXL alone. Ablation was performed with a fractional Er:YAG laser. The AFXL-dPDT and dPDT alone groups received MAL for 2.5 hours without occlusion, and the conventional PDT group received MAL for 3 hours with occlusion. Daylight exposure in dPDT groups was initiated 30 minutes after MAL application for 2 hours total. A baseline total of 542 AKs were treated. At 3-month follow-up, the complete response rate was highest for the AFXL-dPDT group (74%) compared to dPDT alone (46%; P=.0262), conventional PDT (50%; P=.042), and AFXL alone (5%; P=.004). Pain scores for AFXL–dPDT and dPDT alone were significantly lower than for conventional PDT and AFXL alone (P<.001).⁹

Nonablative Lasers

By heating the dermis to induce neogenesis without destruction, nonablative lasers offer superior healing times compared to their ablative counterparts. Multiple treatments with nonablative lasers may be necessary for maximal effect. Four nonablative laser devices have demonstrated efficacy in the treatment of multiple AKs^10-14: (1) the Q-switched 1064-nm Nd:YAG laser, with or without a 532-nm potassium titanyl phosphate (KTP) laser; (2) the 1540-nm fractional erbium glass laser; (3) the 1550-nm fractional erbium-doped fiber laser; and (4) the 1927-nm fractional thulium laser (Table 3).

In a proof-of-concept study of the Q-switched Nd:YAG laser with the 532-nm KTP laser, 1 treatment session induced full remission of AKs in 10 patients at follow-up day 20, although the investigator did not grade improvement on a numerical scale.¹⁰ In a study of the fractional Q-switched 1064-nm Nd:YAG laser alone, 6 patients with trace or mild AKs received 4 treatment sessions at approximately 2-week intervals.¹⁴ All but 1 patient (who had trace AKs) had no AKs at 3-month follow-up.

The efficacy of the 1540-nm fractional erbium glass laser was examined in 17 participants with investigator-rated moderate-to-severe AK involvement of the scalp and face.¹² Participants were given 2 or 3 treatment sessions at 3- to 4-week intervals and were graded by blinded dermatologists on a quartile scale of 0 (no improvement), 1 (1%–25% improvement), 2 (26%–50% improvement), 3 (51%–75% improvement), or 4 (76%–100% improvement). At 3 months posttreatment, the average grade of improvement was 3.4.¹²

The 1550-nm fractional erbium-doped fiber laser was tested in 14 men with multiple facial AKs (range, 9–44 AKs [mean, 22.1 AKs]).¹¹ Participants received 5 treatment sessions at 2- to 4-week intervals, with majority energies used at 70 MJ and treatment level 11. The mean AK count was reduced significantly by 73.1%, 66.2%, and 55.6% at 1-, 3-, and 6-month follow-up, respectively (P<.001).¹¹

The 1927-nm fractional thulium laser showed promising results in 24 participants with facial AKs.¹³ Participants received up to 4 treatment sessions at intervals from 2 to 6 weeks at the investigators’ discretion. At baseline, patients had an average of 14.04 facial AKs. At 1-, 3-, and 6-month follow-up, participants exhibited 91.3%, 87.3%, and 86.6% reduction in AK counts, respectively. The mean AK count at 3-month follow-up was 1.88.¹³

Due to limited sample sizes and/or lack of quantifiable results and controls in these studies, more studies are needed to fully elucidate the role of nonablative lasers in the treatment of AK.

Future Directions

Iontophoresis involves the noninvasive induction of an electrical current to facilitate ion movement through the skin and may be a novel method to boost the efficacy of current field therapies. In the first known study of its kisnd, iontophoresis-assisted AFXL-PDT was found to be noninferior to conventional AFXL-PDT¹⁵; however, additional studies demonstrating its superiority are needed before more widespread clinical use is considered.

Pretreatment with AFXL prior to topical field-directed therapies also has been proposed.¹⁶ In a case series of 13 patients, combination therapy with AFXL and ingenol mebutate was shown to be superior to ingenol mebutate alone (AK clearance rate, 89.2% vs 72.1%, respectively; P<.001).¹⁶ Randomized studies with longer follow-up time are needed.

Conclusion

Ablative and nonablative laser systems have yielded limited data about their potential as monotherapies for treatment of multiple AKs and are unlikely to replace topical agents and PDT as a first-line modality in field-directed treatment at this time. More studies with a larger number of participants and long-term follow-up are needed for further clarification of efficacy, safety, and clinical feasibility. Nevertheless, fractional ablative lasers in combination with PDT have shown robust efficacy and a favorable safety profile for treatment of multiple AKs.^6-9 Further, this combination therapy exhibited a superior clearance rate and lower lesion recurrence in organ transplant recipients—a demographic that classically is difficult to treat.^6-9

With continued rapid evolution of laser systems and more widespread use in dermatology, monotherapy and combination therapy may offer a dynamic new option in field cancerization that can decrease disease burden and treatment frequency.

DALLAS – One year after patients underwent treatment of basal cell carcinoma (BCC) with the 1064-nm Nd:YAG laser, no recurrences have occurred, according to early results from a study being conducted at two centers.

“The 1064-nm Nd:YAG laser is a promising noninvasive treatment approach for treating basal cell carcinoma,” Arisa E. Ortiz, MD, said at the annual conference of the American Society for Laser Medicine and Surgery. “Clearance rates are comparable to or better than other topical modalities such as electrodesiccation and curettage and topical imiquimod. It’s a reasonable alternative for treatment patients with multiple tumors or those who are poor surgical candidates.”

“Laser surgery also provides precision that ordinary surgical techniques cannot match. Despite the obvious obstacles, there is no reason such surgical techniques cannot be expanded someday to other internal cutaneous tumors, including GI tumors. To some extent this is happening already. Vascular lasers are being used to treat a bleeding disorder of the colon known as angiodysplasia. Cautious exploration of laser- and light-based treatments should be further explored as a means of sparing tissue and surgical morbidity.”

Dr. Ortiz disclosed that she has received grant funding from Sienna and Revance, as well as equipment from BTL, Invasix, and Sciton. She has received consulting fees from Alastin, Merz, and Sciton; honoraria from Alastin, Cutera, Invasix, and Sciton; and she holds ownership interest with Allergan. She also has served on the advisory boards for Alastin, Allergan, Invasix, Rodan + Fields, Sciton, Sienna, and Merz.

Dr. Avram disclosed that he serves on the medical advisory board of Sciton and on the scientific advisory boards of Sienna Biopharmaceuticals, Cytrellis, and Allergan. He is also a consultant for Merz Aesthetics, Allergan, Soliton, Invasix, and Revance and has intellectual property with Cytrellis. He also holds stock options with Cytrellis, Invasix, and Zalea.

[email protected]

DALLAS – One year after patients underwent treatment of basal cell carcinoma (BCC) with the 1064-nm Nd:YAG laser, no recurrences have occurred, according to early results from a study being conducted at two centers.

“The 1064-nm Nd:YAG laser is a promising noninvasive treatment approach for treating basal cell carcinoma,” Arisa E. Ortiz, MD, said at the annual conference of the American Society for Laser Medicine and Surgery. “Clearance rates are comparable to or better than other topical modalities such as electrodesiccation and curettage and topical imiquimod. It’s a reasonable alternative for treatment patients with multiple tumors or those who are poor surgical candidates.”

“Laser surgery also provides precision that ordinary surgical techniques cannot match. Despite the obvious obstacles, there is no reason such surgical techniques cannot be expanded someday to other internal cutaneous tumors, including GI tumors. To some extent this is happening already. Vascular lasers are being used to treat a bleeding disorder of the colon known as angiodysplasia. Cautious exploration of laser- and light-based treatments should be further explored as a means of sparing tissue and surgical morbidity.”

Dr. Ortiz disclosed that she has received grant funding from Sienna and Revance, as well as equipment from BTL, Invasix, and Sciton. She has received consulting fees from Alastin, Merz, and Sciton; honoraria from Alastin, Cutera, Invasix, and Sciton; and she holds ownership interest with Allergan. She also has served on the advisory boards for Alastin, Allergan, Invasix, Rodan + Fields, Sciton, Sienna, and Merz.

Dr. Avram disclosed that he serves on the medical advisory board of Sciton and on the scientific advisory boards of Sienna Biopharmaceuticals, Cytrellis, and Allergan. He is also a consultant for Merz Aesthetics, Allergan, Soliton, Invasix, and Revance and has intellectual property with Cytrellis. He also holds stock options with Cytrellis, Invasix, and Zalea.

[email protected]

DALLAS – One year after patients underwent treatment of basal cell carcinoma (BCC) with the 1064-nm Nd:YAG laser, no recurrences have occurred, according to early results from a study being conducted at two centers.

“The 1064-nm Nd:YAG laser is a promising noninvasive treatment approach for treating basal cell carcinoma,” Arisa E. Ortiz, MD, said at the annual conference of the American Society for Laser Medicine and Surgery. “Clearance rates are comparable to or better than other topical modalities such as electrodesiccation and curettage and topical imiquimod. It’s a reasonable alternative for treatment patients with multiple tumors or those who are poor surgical candidates.”

“Laser surgery also provides precision that ordinary surgical techniques cannot match. Despite the obvious obstacles, there is no reason such surgical techniques cannot be expanded someday to other internal cutaneous tumors, including GI tumors. To some extent this is happening already. Vascular lasers are being used to treat a bleeding disorder of the colon known as angiodysplasia. Cautious exploration of laser- and light-based treatments should be further explored as a means of sparing tissue and surgical morbidity.”

Dr. Ortiz disclosed that she has received grant funding from Sienna and Revance, as well as equipment from BTL, Invasix, and Sciton. She has received consulting fees from Alastin, Merz, and Sciton; honoraria from Alastin, Cutera, Invasix, and Sciton; and she holds ownership interest with Allergan. She also has served on the advisory boards for Alastin, Allergan, Invasix, Rodan + Fields, Sciton, Sienna, and Merz.

Dr. Avram disclosed that he serves on the medical advisory board of Sciton and on the scientific advisory boards of Sienna Biopharmaceuticals, Cytrellis, and Allergan. He is also a consultant for Merz Aesthetics, Allergan, Soliton, Invasix, and Revance and has intellectual property with Cytrellis. He also holds stock options with Cytrellis, Invasix, and Zalea.

[email protected]

LAS VEGAS – For women with larger hepatic adenomas, current guidelines suggest reassessment at 6 months after oral contraceptive withdrawal to determine whether resection is warranted.

However, emerging data show reassessing at that time point may lead to overtreatment, according to Laura M. Kulik, MD, professor of medicine (gastroenterology and hepatology), radiology and surgery (organ transplantation), Northwestern University, Chicago.

“There’s been some controversy that 6 months may be too short,” Dr. Kulik said at the inaugural Perspectives in Digestive Diseases meeting held by Global Academy for Medical Education.

Unlike other benign liver lesions, hepatic adenomas can hemorrhage and transform to hepatocellular carcinoma. Current guidelines from the European Association for the Study of the Liver state that larger lesions (i.e., 5 cm or greater on baseline imaging) are associated with a higher risk of complications. According to one systematic review cited in the document, almost all cases of hemorrhage or spontaneous rupture occur in lesions 5 cm or larger.

Oral contraceptive use has been associated with a 30- to 40-fold increase in hepatic adenoma incidence, according to the guidelines.

All men with hepatic adenomas should undergo resection or curative treatment, the guidelines say, since they have a significantly higher risk of hepatocellular carcinoma.

By contrast, women with hepatic adenomas larger than 5 cm should discontinue oral contraceptives – which may lead to tumor regression in some cases – and should be reassessed 6 months later with contrast-enhanced MRI; if the lesion is still greater than 5 cm at that time, they should be considered for resection or curative treatment, the guidelines say.

However, authors of a retrospective cohort study have challenged that advice, suggesting that a 6-month follow-up may not always be long enough to see adequate tumor regression (HPB 2017 Apr;19[Suppl 1]:S3).

LAS VEGAS – For women with larger hepatic adenomas, current guidelines suggest reassessment at 6 months after oral contraceptive withdrawal to determine whether resection is warranted.

However, emerging data show reassessing at that time point may lead to overtreatment, according to Laura M. Kulik, MD, professor of medicine (gastroenterology and hepatology), radiology and surgery (organ transplantation), Northwestern University, Chicago.

“There’s been some controversy that 6 months may be too short,” Dr. Kulik said at the inaugural Perspectives in Digestive Diseases meeting held by Global Academy for Medical Education.

Unlike other benign liver lesions, hepatic adenomas can hemorrhage and transform to hepatocellular carcinoma. Current guidelines from the European Association for the Study of the Liver state that larger lesions (i.e., 5 cm or greater on baseline imaging) are associated with a higher risk of complications. According to one systematic review cited in the document, almost all cases of hemorrhage or spontaneous rupture occur in lesions 5 cm or larger.

Oral contraceptive use has been associated with a 30- to 40-fold increase in hepatic adenoma incidence, according to the guidelines.

All men with hepatic adenomas should undergo resection or curative treatment, the guidelines say, since they have a significantly higher risk of hepatocellular carcinoma.

By contrast, women with hepatic adenomas larger than 5 cm should discontinue oral contraceptives – which may lead to tumor regression in some cases – and should be reassessed 6 months later with contrast-enhanced MRI; if the lesion is still greater than 5 cm at that time, they should be considered for resection or curative treatment, the guidelines say.

However, authors of a retrospective cohort study have challenged that advice, suggesting that a 6-month follow-up may not always be long enough to see adequate tumor regression (HPB 2017 Apr;19[Suppl 1]:S3).

LAS VEGAS – For women with larger hepatic adenomas, current guidelines suggest reassessment at 6 months after oral contraceptive withdrawal to determine whether resection is warranted.

However, emerging data show reassessing at that time point may lead to overtreatment, according to Laura M. Kulik, MD, professor of medicine (gastroenterology and hepatology), radiology and surgery (organ transplantation), Northwestern University, Chicago.

“There’s been some controversy that 6 months may be too short,” Dr. Kulik said at the inaugural Perspectives in Digestive Diseases meeting held by Global Academy for Medical Education.

Unlike other benign liver lesions, hepatic adenomas can hemorrhage and transform to hepatocellular carcinoma. Current guidelines from the European Association for the Study of the Liver state that larger lesions (i.e., 5 cm or greater on baseline imaging) are associated with a higher risk of complications. According to one systematic review cited in the document, almost all cases of hemorrhage or spontaneous rupture occur in lesions 5 cm or larger.

Oral contraceptive use has been associated with a 30- to 40-fold increase in hepatic adenoma incidence, according to the guidelines.

All men with hepatic adenomas should undergo resection or curative treatment, the guidelines say, since they have a significantly higher risk of hepatocellular carcinoma.

By contrast, women with hepatic adenomas larger than 5 cm should discontinue oral contraceptives – which may lead to tumor regression in some cases – and should be reassessed 6 months later with contrast-enhanced MRI; if the lesion is still greater than 5 cm at that time, they should be considered for resection or curative treatment, the guidelines say.

However, authors of a retrospective cohort study have challenged that advice, suggesting that a 6-month follow-up may not always be long enough to see adequate tumor regression (HPB 2017 Apr;19[Suppl 1]:S3).