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Disclosure Statement COMPLEMENTARY AND ALTERNATIVE MEDICINE: SAFETY, EFFICACY, AND AUTHORITATIVE SOURCES OF INFORMATION

I have no relevant financial relationships to disclose with respect to this presentation.

Christopher Owens, PharmD, MPH Idaho State University College of Pharmacy Spring 2014

Learning Objectives for Pharmacists, Nurses, and Prescribers

Learning Objectives for Technicians

• Define the term “complementary and alternative medicine” and describe its growing role in medical and pharmacy practice • Describe the function of the Food and Drug Administration (FDA), the National Center for Complementary and Alternative Medicine (NCCAM), and the Office of Dietary Supplements (ODS) in regulation, research, and dissemination of information related to CAM therapies • Classify commonly used natural products according to the level of safety and efficacy information and describe the place in therapy of for specific clinical conditions

• Define the term “complementary and alternative medicine” and describe its growing role in medical and pharmacy practice • Describe the function of the Food and Drug Administration (FDA), the National Center for Complementary and Alternative Medicine (NCCAM), and the Office of Dietary Supplements (ODS) in regulation, research, and dissemination of information related to CAM therapies • Cite commonly used CAM therapies and important safety considerations

“Alternative” Medicine

Alternative vs. Conventional

• The phrase “complementary and alternative medicine” (or CAM) describes a wide array of treatments, health practices, and practitioner disciplines with historical roots OUTSIDE conventional medicine • Examples include:

• Conventional Medicine

• Meditation, yoga, massage • Chiropractic, homeopathy, acupuncture • Herbal products and dietary supplements

• The terms “complementary” or “integrative” are preferred because they underscore the importance of a combined approach for optimal care that also respects the values of individual patients

• Utilizes drugs, surgery, and other medical procedures to diagnose, treat, and prevent disease • Based on the scientific method which became central to Western thinking since the 1600’s

• Alternative Medicine • Utilizes vast array of physical, spiritual, or energybased therapies to maintain or promote wellness and treat disease • Understands an individual to be comprised of body, mind, and spirit with complex interactions

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CAM Popularity •Data from the 2007 National Health Interview Survey indicated that approximately 40% of US adult residents (83 million) reported use of at least 1 CAM therapy as part their personal healthcare • Excluding vitamins, “folk remedies,” and faith-based practices

•Most common therapies were herbal products, deep breathing, & meditation •About $22 billion spent on self-care products

Have YOU used a natural product or dietary supplement for yourself for a health-related reason in the past 12 months?

A. Yes B. No C. Unsure

Concerns about CAM • Conventional medical practitioners have identified several concerns with CAM: • Scientific implausibility of many therapies • Unjustified claims of benefit, accompanied by hype and paranoia • Possible adverse effects and/or interactions with conventional treatments • Lack of standardization of products or practices; adulteration of products • Possibility that vulnerable patients with serious diseases may be misled and forgo conventional treatments with proven benefits

Why do people use CAM? • Widespread use of CAM is perplexing to many conventional healthcare professionals • Oft-cited reasons for CAM utilization on the part of patients includes: • Some medical conditions are not taken seriously or not able to be treated with conventional therapies • Individual values, autonomy, and a desire to be “more in control” of their own health • Issues with the US healthcare system • Belief that centuries-old therapies are safer and/or more effective

The Spectrum of Attitude Toward CAM Practices In the CAM world, individuals usually fall at different levels on a continuum

The Cautious

The Enthusiast

The Skeptic

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Kevin Trudeau

THE ENTHUSIAST

• TV personality who was featured in many Infomercials that condemn the medical establishment • Claims are made regarding drugs, the drug industry, and the availability of cures for many diseases

Image available at: www.amazon.com

Dr. Mehmet Oz • A cardiothoracic surgeon, author, and television personality • He first appeared on the The Oprah Winfrey Show in 2004 • Now has a daily program that discusses CAM issues

The Skeptical Side • Opposite the enthusiast is the skeptic • Many are conventional medical practitioners who report negative CAM experiences with their patients • Skeptics hold that the scientific method and use of evidence must guide the use of any medical therapy • Are more likely to use the term “quackery” when describing many (most) CAM therapies

THE SKEPTIC

Dr. Steven Novella • An neurologist and assistant professor at Yale University School of Medicine • Well known for his involvement in the skeptical movement • New England Skeptical Society (NESS)

• Is often a guest on talk shows and news programs when CAM is discussed

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Indictments of CAM

Quackwatch • A non-profit organization whose purpose is to combat health-related frauds, myths, fads, and fallacies • Founded by Dr. Stephen Barrett in 1969

• Website: http://www.quackwatch. org

A Cautious Approach to CAM • In this presentation I will advocate a cautious, evidence-based approached to CAM

THE CAUTIOUS

• Concerns regarding scientific plausibility, magnitude of clinical efficacy, and patient safety issues are valid • The placebo effect is a well-described phenomenon

• The National Institutes of Health (NIH) has led efforts to address these concerns since the 1990s, seeking to fill the gap in scientific evidence regarding efficacy and safety of CAM products and practices

NIH and NCCAM • Because of the growing use of CAM practices, the Office of Alternative Medicine (OAM) was formed in 1992

• To promote evidence-based CAM the National Center for Complementary and Alternative Medicine (NCCAM) was formed

• Operating budget of $2 million • Senators Harkin (D-Iowa) and Hatch (R-Utah) were instrumental in its establishment • PBS Frontline special: “The Alternative Fix” (2004)

• In 1998, the National Institutes of Health (NIH) established a center to replace the OAM

• One of the 27 institutes, centers, and offices that makes up the NIH • Operating budget has grown from $50 million to over $125 million Senators Harkin, Specter, and Hatch Image available at: www.the-scientist.com

• Dedicated to conducting research on CAM therapies and disseminating findings • Official website: http://nccam.nih.gov

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NCCAM Mission •The NCCAM is dedicated to: •

• • •

Exploring complementary and alternative healing practices in the context of rigorous science Training complementary and alternative medicine researchers Disseminating authoritative information to the public and health professionals Integrating CAM practices into conventional medicine

Which of the following are cited as difficulties in studying CAM therapies using randomized, controlled trials? 1. Placebo control is not always possible or practical 2. Lack of standardization with natural products 3. Difficult to recruit patients 4. Lack of expertise on the part of researchers 5. All of the above

TYPES OF CAM According to the NCCAM

NCCAM Investments • A major focus has been on rigorous, appropriately powered, placebo-controlled trials of widely used herbal products and dietary supplements • St. John’s wort • Glucosamine • Saw palmetto

• The results of many of these large studies failed to confirm the benefits reported in earlier studies • Research has also revealed important safety information regarding potential toxicity and interactions

NATURAL PRODUCTS: HERBALS & DIETARY SUPPLEMENTS

• Increased awareness that “natural does not mean safe”

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Natural Products •Popular form of CAM utilized by nearly 1 in 5 adults in the past 12 months • Widely marketed and readily accessible without a prescription in pharmacies, drug stores, and other retail outlets and online • Often used for self-diagnosed conditions ranging from arthritis and GERD to depression and cancer

•Referred to as “non-vitamin, non-mineral natural products” to differentiate from vitamins

DSHEA • Legal compromise was reached with the Dietary Supplement Health & Education Act (DSHEA) of 1994 • Established criteria for marketing and labeling herbals and other products taken for health reasons • Established the term, “dietary supplement;” separate and distinct from “food” and “drug” • Provided a scope of FDA authority in regulation

The FDA must validate the safety and efficacy of a dietary supplement prior to marketing. A. True B. False C. Depends on the type of supplement

Natural Product Regulation • Prior to 1993, most natural products were regulated as foods • In the early 1990’s the FDA proposed more stringent regulation as these products were being viewed less as foods and more as drugs • This was opposed by industry and consumer groups • Opposition was manifested in numerous letters to legislators and public campaigns (including TV and radio spots) defending the rights of US citizens to purchase and use these products without restriction

Dietary Supplement •To be considered a dietary supplement, must meet the following criteria: • Taken by mouth • Contain at least one identified dietary ingredient • Intended to supplement the diet • Not intended to diagnose, treat, prevent, or cure any disease • Examples: herbals, vitamins, enzymes, others (glucosamine, probiotics, coenzyme Q10)

Scope of FDA Authority • May not require efficacy and safety testing prior to marketing • May establish good manufacturing practices and periodically inspect facilities • May take action if a product is suspected to be unsafe (via MedWatch or other reports) • May take action if a product’s labeling is misleading or untruthful (working with the Federal Trade Commission or FTC)

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Labeling Requirements • Must be clearly identified as a dietary supplement • Include appropriate directions for use • List name and quantity of each active ingredient and serving size (dosage) • List of excipients • If botanical, must list part of plant used • Name and place of business of manufacturer

Seals of Approval

Standardization • Many products carry a statement regarding standardization • Example: • “St. John’s Wort (300mg), standardized 0.3% hypericin (0.9mg) per capsule”

• Accuracy is not monitored by the FDA • Manufacturers often have their own quality assurance programs in place • Many such programs are rigorous and valid; still, manufacturers must be taken at their word

Structure/Function Claims & Disclaimer • Although a dietary supplement may not claim to diagnose, prevent, treat, or cure a disease, it may make a structure/function claim • All supplements must clearly indicate the following in conjunction with any structure/function claim:

• “This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.”

Which of the following is/are examples of structure/function claim(s)? A. Soy isoflavones may help relieve the symptoms of menopause B. St. John’s wort promotes a healthy mood C. Echinacea supports the immune system D. Only B and C E. None of these

FDA Criteria for Disease Claims • Has an effect on a specific disease or class of diseases • Has an effect, using scientific or lay terms, on one or more signs or symptoms that are recognizable to health care professionals or consumers as being characteristic of a specific disease or of a number of different diseases • Has an effect on an abnormal condition associated with a natural state or process, if the abnormal condition is uncommon or can cause significant or permanent harm • Is a substitute for a product that is a therapy for a disease • Has a role in the body's response to a disease or to a vector of disease • Otherwise suggests an effect on a disease or diseases

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Office of Dietary Supplements • Created in 1995 within the Office of Disease Prevention • Mission is to:

NATURAL PRODUCTS FOR CARDIOVASCULAR HEALTH

• Explore the potential role of dietary supplements as a significant part of the efforts of the US to improve health • Promote scientific study of the benefits of dietary supplements • Conduct and coordinate scientific research within NIH and collect and compile the results of research, including data from foreign sources

Fish Oil (omega-3 fatty acids) Garlic

http://ods.od.nih.gov/

Omega-3 Fatty Acids • Dietary sources include fish oil and certain plant/nut oils • Fish oil contains docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) • Krill is another marine source of DHA & EPA

• Large scale epidemiologic studies have shown that people who consume fish or fish oil as a normal part of their diet have lower risk of many different CV conditions including strokes and heart attacks

Fish Oil: CV Indications • The strongest evidence from clinical trials is for EPA+DHA in lowering triglycerides • Small decreases in LDL and small increases in HDL were also found • May also decrease cardiovascular inflammation • Small decreases in blood pressure also noted

• There is some evidence to suggest that fish oil can decrease the risk of a second heart attack, results are less compelling for preventing a first heart attack • Recent meta-analysis published in 2012 casts doubt on the effectiveness of fish oils for cardiovascular protection

Fish Oil Dosage • Only about 30-50% of the oil in many fish oil supplements is DHA and EPA • The prescription drug Lovaza® is “purified and concentrated” and contains approximately 85% EPA & DHA

• So for a typical fish oil supplement the following is true: • Comes as a 1 gram (1,000 mg) capsule • Of which maybe 50% is EPA and DHA (so 500 mg) • Ratio is usually 300 mg of EPA and 200 mg of DHA

• A recommended dosage of 4 capsules a day would provide a total of 1,200 mg EPA and 800 mg DHA (or 2,000 mg of omega-3 fatty acids)

Fish Oil: Recommendations • Dosage is 2-4 grams/day of EPA+DHA • Adverse effects include fishy breath odor, heartburn, upset stomach, anticoagulant effect • Watch mercury content

• Effective for decreasing TGs (20-50%) • Possibly effective for preventing coronary heart disease (20-30% decreased risk) or for other inflammatory conditions

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Garlic • Used for its beneficial cardiovascular effects including cholesterol and blood pressure lowering • Dosed between 600- 1200 mg/day • Most products are standardized to contain 1.3% alliin which generates 3600 mcg of allicin • Alternative: eating equivalent of about 2 cloves per day

• May act like statin drugs decreasing the liver’s production of LDL; may also have antioxidant effects and decrease CV inflammation

Garlic • Likely safe when used at appropriate dosages • Side-effects include body and breath odor, burning sensation in the mouth, GI upset, anti-platelet activity • Rated as possibly effective for slowing atherosclerosis • May lower blood pressure by 8% • Mixed results in decreasing LDL

American Heart Association’s Stand • “The American Heart Association (AHA) does not recommend using vitamin, mineral or herbal supplements to treat or prevent heart disease and stroke. • To get the nutrients you need, choose foods like vegetables, fruits, whole-grain products and fat-free or low-fat dairy products most often.”

NATURAL PRODUCTS FOR DIABETES MELLITUS Cinnamon Ginseng

• Source: http://www.heart.org/HEARTORG/GettingHealthy/Nutriti onCenter/Dietary-Supplements

Cinnamon (Cassia) • Well-known spice that started receiving attention as a treatment for diabetes in 2004 • Mechanism of action: • May increase phosphorylation of the insulin receptor, which increases insulin sensitivity

• Type bought for culinary purposes is often a mixture of different cinnamons • McCormick’s Ground Cinnamon is cassia

Cinnamon: Dosing & Safety • Dosage: 1-6 grams/day in 3 major studies • (1 tsp=3-5g)

• Usually administered in capsules or mixed with meals in divided doses • Adverse effects: • Orally, cassia cinnamon appears to be well-tolerated • Hepatotoxicity is a concern at very high doses (much higher than doses used in trials) • Contains coumarin components and may affect coagulation

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Cinnamon: Efficacy • Smaller studies have indicated an average glucose lowering effect of 20-40 mg/dL • Meta-analysis of 5 randomized, controlled clinical trials (n=282) published in 2008 • Baker WL, et al. Effect of cinnamon on glucose control and lipid parameters. Diabetes Care. 2008;31:41-43.

• Concluded that: • “Cinnamon does not appear to improve A1c, FBG, or lipid parameters in patients with type 1 or 2 diabetes mellitus”

Ginseng: Efficacy & Safety in Diabetes • Reported effects on blood glucose: • Decrease rate of carbohydrate absorption, increased glucose transport and uptake, modulates insulin secretion • Optimal dosing yet to be determined • 200mg up to 4.5g per day is most common • Some data suggest any dose >3 grams is not more beneficial • Overall fasting blood glucose reduction ~ 20mg/dL • Adverse effects: • Insomnia, tachycardia, hypertension

Ginseng (Panax ginseng or quinquefolius) • Common uses: increase physical/mental stamina, resistance to stress, and promote cognitive function • May also lower blood glucose • Dose: 100 mg to 3g/day in divided doses (higher doses for BG lowering effect) • Standardized to contain 5% ginsenosides/dose • MOA: characterized as an “adaptogen” • Increases resistance to exogenous stress factors

Photo source: www.research.psu.edu

American Diabetes Association’s Stand • The American Diabetes Association (ADA) recognizes patient interest in these therapies • Have no specific recommendations for any product • Suggest a practitioner role in promoting the safe use of CAM therapies • Recommend patients report the use of these products to their healthcare providers

• Reference: • American Diabetes Association. Patient information: a step-by-step approach to complementary therapies. Diabetes Spectrum. 2001;14:225

Bio-identical Hormone Replacement Therapy (BHRT) • The term “bioidentical” has connotations that are not recognized by the FDA

NATURAL PRODUCTS FOR MENOPAUSE Bio-identical hormones Soy isoflavones

• Refers to estrogens (estradiol, estrone, estriol) products customcompounded in specialty pharmacies

• Formulations include topical creams, sublingual tablets, subdermal implants, and suppositories • NOT regulated by the FDA and may vary in dosing, purity, efficacy, and safety • Dosing is customized based on saliva testing of hormone concentrations

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FDA Position on BHRT • Many claims made by marketers of compounded "bioidentical" hormones, also known as "bio-identical hormone replacement therapy" (BHRT) are unproven. FDA is concerned that claims like these mislead women and health care professionals, giving them a false sense of assurance about using potentially dangerous hormone products: • “A natural, safer alternative to dangerous prescription drugs" • "Can slim you down by reducing hormonal imbalances" • "Prevents Alzheimer's disease and senility" • Source: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm04931 1.htm

Phytoestrogen Effects • Epidemiologic studies indicate that Asian women experience fewer and less severe menopausal symptoms when compared to other populations • Asian diet contains much more soy protein than the typical North American diet

• Effects on cancer risk are unclear • Laboratory evidence suggests soy isoflavones can stimulate proliferation of normal human breast tissue and doses of >150 mg/day can stimulate endometrial thickening • Population studies (mostly in Asia) suggest that soy in the diet modestly DECREASES risk of breast cancer

Soy: Efficacy & Safety • Most commonly used source of isoflavones • Products have been compared to conventional therapies in treating hot flashes and appear to be effective (30% reduction in symptoms vs. 50% for conventional treatments) • Also may lower LDL by 10% and increase bone mineral density (fracture data is weakly positive)

• Considered safe for most people when used as a food or when supplements are taken for short periods of time (up to 185mg/day of isoflavones have been taken for up to 16 weeks) • Doses of >150mg taken for longer than 4 years are discouraged (risk of endometrial cancer increased) • Adverse effects: Nausea, bloating, constipation; allergic reactions

Phytoestrogens • Group of natural products sometimes called “plant estrogens” • Three main types: • Isoflavones (in legumes such as soy, chickpeas, red clover, lentils) • Flaxseed (lentils, whole grains, beans, fruits and vegetables) • Coumestans (red clover, sunflower seeds, sprouts)

• Isoflavones are the most potent and common

Isoflavone Dosing • The best-studied dosage range of isoflavones for treating hot flashes is 35 to 120mg/daily • Doses of less than 15mg have inconsistent findings • Available from food sources: • 20 grams of soy protein contains approximately 35 mg of isoflavones • 3 cups of soy milk • 1 cup of tofu • ¾ cup of soybeans • Also sold as concentrated products containing genistein (60mg per tablet is common)

ACOG Recommendations • American College of Obstetricians and Gynecologists (ACOG) published a patient-education pamphlet in 2003: “Herbal Products for Menopause” • Recommendations: • Patients should inform their doctors of herbal use • Soy products may be helpful for menopausal symptoms and to increase BMD, but there are risks • Black cohosh has mixed results and there are risks

• A separate ACOG sub-committee report released in 2012 recommends against the use of compounded bio-identical hormones; favors FDA-approved products

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Echinacea

OTHER COMMONLY USED NATURAL PRODUCTS Echinacea Ginkgo St. John’s Wort Saw Palmetto

Echinacea, continued • Mechanism of action: • May increase phagocytosis and lymphocyte activity • Promotes the release of tumor necrosis factor (TNF), interleukin-1 (IL-1), and interferon • Adverse effects: • Nausea, abdominal pain, diarrhea, allergic reactions, dry mouth, headache, insomnia • Precautions: • Allergies to ragweed or daisy family • Not recommended for children