HERBAL MEDICINE

Spicing Up Litigation

By Cindy Pordon, DO, and Erin Rooney, RD, Litigation Management, Inc.

Despite signs of slowing sales and recent negative media coverage of the 18-billion-dollar (1)dietary supplement industry, it is expected that consumer demand for supplements will continue and the industry will likely grow. (2) The Food and Drug Administration estimates that there are currently more than 29,000 varieties of herbal and dietary supplements available to consumers, with more than 1,000 new products introduced each year.( 3) Health professionals need to keep this in mind when evaluating and treating patients. In addition, attorneys need to consider this when reviewing cases to determine if supplements may have been a factor in an alleged injury.

A survey published in The Journal of the American Medical Association in January of 2002 showed that there was a significant overlap in the use of prescription medications and herbals/supplements by adults in the United States.(4) Health experts are realizing that Americans love to self-medicate. David W. Kaufman, ScD, lead author of the study, noted that health care providers need to be aware that a substantial number of people are taking herbal preparations as well as prescription drugs, and the possible interactions of these products have not been well studied.( 4) Herbal supplements appeal to consumers for a wide variety of reasons. They expect that these products will make them feel better, prevent illness, prolong life, build strength and muscle, and aid weight management; consumers may also be using supplements on the advice of a physician.( 5) The heaviest users of supplements are baby-boomers age 46 and older, hoping to alleviate or avoid the effects of aging. Despite the widespread use of supplements, many Americans may not be well equipped to make informed choices about their responsible use. More information is needed by consumers regarding how supplements work in the body, what dosages are recommended, and warnings of potential adverse reactions. Consumers may not be careful about dosages, often assuming that more is better. In addition, while 92% of consumers said they consult their doctors about prescriptions, only 49% discuss supplement use with their doctors, and consumers over age 65 are the least likely group to discuss supplement use with their doctor.( 6)

In illustration, consider the following hypothetical case study as reviewed by a medical/legal analyst who suspected that a patient might have been combining herbal remedies and prescription drugs. The discussion also focuses on Food and Drug Administration actions in regard to dietary supplements.

CASE STUDY: MEDICAL ISSUES

Jane Smith, age 54, alleges that she suffered a stroke as the result of taking a common prescription medication. As one of her treating physicians attested, she presented quite a challenge with respect to managing her multiple medical problems. She was a smoker, despite multiple recommendations to quit. Her medical history included adult-onset diabetes, hypertension, and paroxysmal atrial fibrillation [heart rhythm abnormality that can result in blood clots]. She had been non-compliant with traditional therapies that had been prescribed in the past. In reviewing records from other physicians, the medical analyst noticed that she seemed to prefer a "natural" approach. She took many supplements, frequently following the advice of friends who would recommend various remedies that "worked for them." The names of these supplements were not specified in the physician office notes. The anticoagulant warfarin had been prescribed because of the potential risk of stroke due to her atrial fibrillation. Adjusting the warfarin dosage was difficult, and marked fluctuations in the Prothrombin Time [PT] levels persisted.

Approximately 8 months after starting warfarin, Ms. Smith was admitted with a hemorrhagic stroke. She had a prolonged hospitalization, and was left with impaired right arm function, difficulty swallowing, and memory loss, all of which contributed in her inability to return to her previous occupation as a computer programmer. Her treatment included intensive physical and occupational rehabilitation. A nutrition consultation was also obtained to help identify any dietary indiscretion that may have been contributing to the PT level fluctuations.

CASE STUDY: REVIEW OF THE RECORDS

All references to traditional forms of treatment, as well as all references to complementary or alternative therapies were scrutinized in Mrs. Smith's records. Information is often "hidden" in records other than physician notes. Patients frequently do not report the use of supplements to their physicians and physicians do not always ask specifically for this information, erroneously assuming that patients will include these products when questioned about their current medications. The general public often does not view supplements as medications. Therefore, this information may not be readily identified in review of physician records. Information regarding the use of supplements can often be found in dietary, physical and occupational therapy, chiropractic, nursing, social service, and psychiatric records. Dietary records may also indicate the use of some food products, such as tea, which may contain herbal additives. Key phrases may include references to nutritional supplements, vitamins, or natural products. It is also important to note if the patient engages in alternative practices [such as acupuncture], participates heavily in sports or weight loss, or belongs to a fitness facility as these may indicate an interest in or use of supplements. It is important to remember that laymen may refer to supplements with different nomenclature. Physicians and attorneys should phrase an inquiry about supplements using descriptive terms such as herbal products, nonprescription medications, dietary aids, home remedies, and over-the-counter preparations.

In Ms. Smith's case, the nutrition assessment revealed that in addition to enjoying a salad almost every day, she was taking vitamins and supplements. Further questioning revealed that she was taking vitamins A, C, and E, ginkgo biloba, and another herbal remedy to enhance well-being. The dietician requested that her family members provide the actual supplement bottles in order to assess the ingredients. Upon review, it was noted that one product contained multiple herbs, including ginseng. The label directions for this herbal supplement recommended taking two pills per day with food. Ms. Smith admitted to taking four to six pills daily, since her neighbor "felt so much better at that dose."

Reviews of laboratory records that may be beneficial in the analysis of Ms. Smith's case include coagulation and liver function studies [Tables 1a and 1b]. Trending of these test results, especially noting abnormalities prior to the use of the medication in question, may give insight into alternative causation. PT and INR levels may be difficult to "adjust" in patients taking warfarin. It is important to note that dietary changes [Table 2] and many traditional medications, as well as supplements [Table 4], may affect the action of warfarin. These may either potentiate or "inactivate" warfarin, resulting in either prolongation or normalization of the PT and INR. Abnormalities in liver function tests may indicate prior or current underlying liver disease. Other prescription or over-the-counter medications may alter liver function. Elevations of liver function tests, in conjunction with the use of warfarin, may result in prolongation of the PT and elevation of the INR, thus predisposing the patient to increased bleeding problems, either spontaneously or as the result of injury.

CASE STUDY ANALYSIS

There are multiple inherent difficulties in warfarin management. Often, dietary changes such as periodic increased consumption of salads will affect PT levels and may require changes in warfarin dosing. Hemorrhagic stroke may be caused by the potentiation of warfarin's blood thinning properties by the use of ginkgo and ginseng. Although not specific to Ms. Smith's case, head injuries, accelerated hypertension, and congenital abnormalities such as arteriovenous malformation would also warrant consideration as possible etiologies for hemorrhagic strokes. In the case of Ms. Smith, it was identified that outpatient records alluded to the use of supplements. Further investigation of hospital records, including all nursing and ancillary notes, identified the self-administration of ginkgo biloba for memory enhancement, and a product that contained ginseng to improve her "energy level." This information was identified in the nutrition consult.

GENERAL ISSUES

The use of herbal supplements is a time-honored, worldwide practice. Recently, the general public's interest in complementary and alternative medicine [CAM] has been increasing. People are drawn to herbal supplements for many reasons. Some individuals feel they are "safer," because they consider them to be "natural." Many people are unaware of the potential side effects that may occur with their use. The National Center for Complementary and Alternative Medicine [NCCAM] was established in 1998 at the National Institutes of Health. NCCAM defines CAM as including a diverse group of medical and health care practices and products that are not currently considered conventional medicine. Complementary medicine is practiced in conjunction with conventional medicine; alternative medicine is practiced in place of conventional medicine. Integrative medicine combines mainstream medical therapies and CAM therapies for which some scientific evidence exists regarding safety and effectiveness. Dietary supplements are considered to be a type of CAM therapy.( 7) The Dietary Supplement Health and Education Act of 1994 has defined this wide of array of products.( 8)

Although approximately 30% of traditional medicines are derived from botanicals, we know little about the true benefits and risks of herbal therapies. Most physicians are unfamiliar with supplements.( 9) This may be another reason why many medical records lack documentation of supplement use. Although specific guidelines have not been provided, it is generally believed that it is safest for preoperative patients to avoid use of supplements known to affect the coagulation system for 1-2 weeks before scheduled surgery.( 10)

After passage of the Dietary Supplement Health and Education Act [DSHEA] in 1994, a new regulatory system was created for the safety and labeling of dietary supplements, as well as establishing a formal definition. Instead of receiving pre-market approval by the FDA as with prescription medications, the responsibility falls to the manufacturer to ensure that a dietary or herbal product is safe and that advertising claims are correct.( 11) But product quality and safety have become continuing concerns for the supplement industry, (12) whether it involves herbal products or vitamin and mineral supplements.

Sometimes supplements are marketed for purposes other than their traditional uses. For instance, ephedra was traditionally used in China as a short-term treatment for a respiratory condition, but in the United States, ephedra is sold as a stimulant and used for extended periods for weight loss.

The potential for interaction with prescription medications is another concern. According to an advisory issued by the FDA in February of 2000, the popular herbal supplement St. John's Wort may reduce the effectiveness of common medications used for birth control, heart disease, and depression. St. John's Wort has also been found to interfere with traditional cancer treatments, and may endanger organ transplant success by decreasing cyclosporin levels.( 13)

The side effects of supplements range from the known to the unknown. They can be relatively benign, such as valerian causing mild stomach upset (14) to previously unknown serious side effects with significant medical implications. For instance, saw palmetto is generally regarded as safe and nearly free of side effects, but one recent case report indicated that saw palmetto caused excessive bleeding during surgery. Although it was only a single incident, this may be important information for individuals planning to undergo surgery, or for those taking a medication that has a blood-thinning effect, such as aspirin or warfarin.( 15)

Product impurities or batch-to-batch variability may also result in adverse effects and interactions with conventional medications. Another problem encountered is the potential for contamination, which can occur either in growing the plants or manufacturing the product. Microbiological, pesticide, and heavy metal contamination have led to recalls of some dietary supplements.( 16) A study by the independent company, Consumerlab.com, revealed that 8 of 21 brands of ginseng contained unacceptable levels of pesticide residues, and two brands contained high levels of lead. A consumer warning and recall was issued by the California State Health Director in February 2002 for "PC SPES" and "SPES" capsules after an investigation revealed that these products contained the undeclared prescription drug ingredients warfarin and Xanax (anti-anxiolytic), with the potential for serious health effects if not taken under medical supervision.( 17) Inaccurate labeling has also been discovered. One firm had to recall its product because the actual folic acid content was only 35% of the amount claimed on the label. Another recall involved a product that was inadvertently ten times higher in niacin than what may be considered safe.( 18) These examples illustrate the quality problems associated with a few of the more familiar supplements. Looking at the broader range of supplements, the FDA has received approximately 7,000 voluntary adverse event reports regarding dietary supplements since 1993, many of which they believe may be related to product mislabeling or adulteration.( 16)

Recently, the Department of Health and Human Services issued a report following the evaluation of 100 labels for content and presentation with the following findings: 1) The safety information was usually incomplete or inconsistent regarding adverse reactions or side effects; potential interactions with other supplements, over-the-counter, or prescription drugs; maximum recommended dose; and contraindications, such as use during pregnancy. 2) Ingredient information was often incomplete and insufficient for consumers to understand what they were taking. The majority failed to identify the active ingredients or the ingredient amounts, and ingredient names were inconsistent across supplement labels, especially for botanicals, creating the potential for unaware consumers to take multiple doses of the same botanical, resulting in an overdose. 3) Information about benefits and risks was often unbalanced.( 19)

There is some hope, however, for consumers such as hypothetical Jane Smith. In an attempt to address some of these quality problems, on March 7, 2003, the FDA proposed regulations to establish Current Good Manufacturing Practices [CGMPs] for manufacturers to follow. The proposed rules would help to ensure that dietary supplements and dietary ingredients are not adulterated with contaminants or impurities, and are labeled accurately to reflect the active ingredients and other ingredients in the product.( 16) [see Table 4] It is anticipated that the implementation process for the new regulations may take three years for large firms, with smaller firms having until 2007 to comply. The proposed guidelines will also provide requirements for the design and construction of physical plants, quality control procedures, testing of the final product, handling consumer complaints, and maintaining records to demonstrate compliance with the regulations.( 16)

Proposed CGMP rules would prevent: Potentially harmful extra ingredients not listed on the label. Missing or reduced active ingredients compared to the label. Inclusion of incorrect ingredients in formulation. Drug contamination of product. Other contamination (bacteria, pesticide, glass, lead). Foreign material in product container. Improper packaging. Mislabeling

Table 4.

Ms. Smith is not yet out of the woods, however. Although the proposal will require manufacturers to evaluate the identity, purity, quality, strength, and composition of all dietary supplements, the new CGMPs do not address the efficacy of dietary supplements. They will not ensure that supplements perform as expected, and safety issues will continue to exist in regard to the active ingredient itself causing adverse reactions.( 20)

Very few controlled trials involving supplements have been undertaken. However, this FDA action may also encourage more research on dietary supplements to improve the scientific evidence regarding their safety and effectiveness.( 18) One limiting factor is the cost of research. Many herbal remedies cannot be patented, and manufacturers believe they would be unable to recoup the expenditures required for such studies. NCCAM was mandated to conduct research into complementary medicines and techniques, but only a few therapies could be evaluated on the limited budget of $68.7 million for 2000.( 21)

Manufacturers must ensure that claims made about dietary supplements are substantiated by evidence to show they are not false or misleading. Unlike prescription drugs, these products do not need approval by the FDA before being marketed. Manufacturers are not permitted to promote the product as a treatment, prevention, or cure for a specific disease or condition.( 11) The FDA does allow manufacturers to use three types of claims on their labels. The first type represents health claims categorized as authorized health claims, health claims based on authoritative statements, and qualified health claims. The second type is a structure-function claim accompanied by a disclaimer that the FDA has not evaluated the claim. The third permissible type is a nutrient content claim, such as "good source of " or "high in" a particular nutrient which usually has an established daily value.( 22)

( 11) Recently, the FTC cited the marketers of a coral calcium supplement for making false and unsubstantiated claims about their product's health benefit by claiming that it can treat or cure cancer and other diseases. The FDA and FTC also sent strong warning letters to Web site operators marketing coral calcium to remove false or deceptive claims from their sites immediately.( 23) The FTC also brought three enforcement actions against direct marketers of weight loss products containing ephedra in July 2003. The complaints and stipulated final judgments are available at http://www.ftc.gov.

WHAT'S NEW ON THE HORIZON?

The National Institutes of Health's Office of Dietary Supplements has developed an evidence-based review program to assess the available scientific evidence on dietary supplements' efficacy and safety. These reviews will help the NIH establish research agendas for dietary supplements.( 24) Resources for consumers and professionals are available on the NIH web site, including information on a supplement's indications for use, its known interactions with medications, and references to published scientific data.

Recent government actions could ultimately be a positive factor for the industry, by signaling to consumers that someone is looking out for their safety. (25) In the past few years, the perception that the natural health business is an unregulated industry has affected the dietary supplement business financially. Slowdowns in sales of some products have caused investors to take a wait-and-see attitude toward the industry. Rebecca Madley-Wright, editor of Nutraceuticals World, has reported there is $300 million waiting on the sidelines to be invested in this area. Tighter regulation may well improve the prospects of the industry by driving out unethical practitioners. (2)

CONCLUSION

Consumer education is paramount. More information is becoming available to consumers and professionals to help them make informed decisions. There are numerous government web sites, professional association resources such as the American Dietetic Association, and various private or nonprofit organizations that provide data regarding safety, quality, and research on dietary supplements. Identifying reputable sources continues to be a problem, as consumers often believe advertisements appearing in newspapers, television or the internet. Medical professionals need to be aware that their patients may be listening to other sources of information, and be prepared to offer sound medical advice in regard to dietary supplements and herbal products.

Upon discharge from the hospital, the hypothetical Jane Smith received instructions from a dietician to avoid sudden increases in foods that are high in vitamin K, such as broccoli, cabbage, green tea, spinach, and liver, as well as to avoid certain supplements and herbal teas containing coumarin. In addition, the dietitian provided some guidance through the tangle of information that surrounds any dietary supplements she may wish to take in the future. This review material was also made available to the physicians who will continue to care for Ms. Smith, so that they may help reinforce the instructions. Ms. Smith will need to raise her level of awareness about the safety issues surrounding these herbal products, as they are subject to looser standards of labeling, purity, safety, dose, and efficacy than those required for medications.( 26)

In spite of negative press and decreased consumer confidence, consumers continue to buy dietary supplements. This was evidenced by the recent boost in multivitamin sales after JAMA published an article indicating that all Americans should take a multivitamin daily. Furthermore, following the news that hormone replacement therapy may increase a woman's risk for heart disease and breast cancer, sales of natural estrogen alternatives, such as black cohosh and soy, grew by 32.5% and 7.6% respectively.( 25) Consumers want these products, and it is expected that the dietary supplement industry will continue to grow despite occasional reports of side effects. This should be kept in mind when reviewing and interpreting medical records, as it may be another risk factor to investigate.

Prothrombin Time (PT). Normal 10-13 seconds. Evaluates the extrinsic coagulation system; aids in screening for some congenital factor deficiencies; assess warfarin effect; liver failure, vitamin K deficiency screen; disseminated intravascular coagulation (DIC). Partial Thromboplastin Time (PTT). Normal 25-29 seconds. Evaluates intrinsic coagulation system; monitor heparin therapy; aids in screening for some congenital factor deficiencies; vitamin K deficiency, liver failure, DIC. Activated Clotting Time (ACT). Normal varies between labs. Monitors heparin effect during cardiopulmonary bypass surgery; screen for coagulation deficiencies.

Coagulation Factor Assay. Tests for specific clotting factors. Avoid warfarin therapy for 2 weeks and heparin for 2 days prior to testing. D-Dimer. Screening test for detection of deep vein thrombosis, acute myocardial infarction, and disseminated intravascular coagulation (DIC). Fibrinogen. Coagulation protein and acute phase reactant. Interpretation difficult since multiple factors may affect level. Platelet Count. Used in evaluation of bleeding disorders. Further evaluation may include platelet antibody, aggregation, and adhesion testing.

Table 1a. Common Coagulation Laboratory Studies (30)

Alanine Aminotransferase (ALT, SGPT). Liver test; more specific for liver injury than AST (SGOT). Aspartate Aminotransferase (AST, SGOT). Primarily used to evaluate function; may be elevated in wide range of disease entities. Bilirubin. Elevated in various liver and other diseases; large number of drugs may cause jaundice. Can be fractionated into direct and indirect components.

Gamma Glutamyl Transferase (GGT). Biliary enzyme useful in diagnosis of obstructive jaundice, intrahepatic cholestasis, and pancreatitis. Hepatitis Profile. May include screening for hepatitis A, B, C, and/or D; antibodies and antigens may be evaluated; aids in detection of the stage of hepatitis.

Table 1b. Common Liver Function Laboratory Studies (30)

Algae, purple laver, konbu, hijiki Apple, green peel Broccoli Brussels sprouts Chive, raw Chrysanthemum, garland Green leafy vegetables Green tea leaf, dry Oils (salad, soybean, canola) Onion, green scallion, raw

Table 2. Common foods that interact with warfarin

Agrimony Alfalfa Aloe gel Angelica (Dong Quai) Aniseed Arnica Asa foetida Aspen Black cohosh Black haw Bladder wrack Bogbean Boldo Bromelains Buchu Capsicum Cassia Celery Chamomile (German and Roman)

Clove Dandelion Danshen Fenugreek Feverfew Fish oil Garlic German sarsaparilla Ginger Ginkgo biloba Ginseng Goldenseal Horse chestnut Horseradish Inositol nicotinate Kava Licorice Meadowsweet Mistletoe Nettle

Onion Parsley Pau d'arco Passion flower Policosanol Poplar Prickly ash (northern) Quassia Red clover Senega Sweet clover Sweet woodruff Tamarind Tonka beans Wild carrot Wild lettuce Willow Wintergreen

Table 3. Supplements affecting coagulation. (10, 27, 28, 29)

OTHER RESOURCES ON HERBAL MEDICINES

Government Resources:

A. US Food & Drug Administration Center for Food Safety & Applied Nutrition, http://www.cfsan.fda.gov

B. MEDLINE Plus Health Information, http://www.nlm.nih.gov/medlineplus

C. The International Bibliographic Information on Dietary Supplements (IBIDS) NIH-Office of Dietary Supplements, http://ods.od.nih.gov

D. Food and Nutrition Information Center Dietary Supplements Resource List, http://www.nal.usda.gov/fnic

E. The National Center for Complementary and Alternative Medicine (NCCAM) of the National Institutes of Health, http://nccam.nih.gov/health

F. Office of Dietary Supplements (ODS) of the National Institutes of Health, (provides Fact Sheets on Dietary Supplements) http://dietary-supplements.info.nih.gov

Other Resources:

A. Quackwatch, http://www.quackwatch.org

B. SupplementWatch, Inc, http://supplementwatch.com

C. The Dietary Supplement LLC, http://www.TheDietarySupplement.com

D. Consumerlab, http://www.consumerlab.com

E. US Pharmacopeia, http://www.uspdsvp.org

REFERENCES

1. Fessenden, F. Studies of Dietary Supplements Come Under Growing Scrutiny. The New York Times; 2003.

2. Ephedra Fallout Could Shake Up an Industry. NJBIZ. 2003;16(15):6.

3. Mitchell, M. Self-Medication is Widespread, Study Says. Fort Worth Star Telegram. 2002.

4. Kaufman, D. Recent Patterns of Medication Use in the Ambulatory Adult Population of the United States. JAMA 2002;287(3).

5. Exploring Consumer Attitudes About Dietary Supplement Barometer Survey. http://www.supplementinfo.org/latest_news/survey_results.htm

6. Dietary Supplement Education Alliance. The Key to Consumer Confidence in Dietary Supplements. Update. 2001:6. http://ww.fdli.org

7. http://nccam.nih.gov/health/whatiscam

8. http://dietary-supplements.info.nih.gov/health.aspx

9. Kaye, SR. Perioperative considerations for the patient taking herbal medicines. Heart Dis 2001;3(2):87-96.

10. Mercado, DL, Petty, BG. Perioperative medication management. Medical Clinics of North America. 2003;87(1).

11. Overview of Dietary Supplements. USFDA Center for Food Safety and Applied Nutrition. January 3, 2001. http://www.cfsan.fda.gov/~dms/ds-oview.html

12. Silverglade, BC. Is the Food and Drug Administration Over Regulating the Dietary-Supplement Industry? Insight on the News. 2002.

13. Ernst, E. St. John's Wort supplements endanger the success of organ transplantation. Arch Surg. 2002;137(3):316-9.

14. Busch, F. The New Nutrition From Antioxidants to Zucchini. John Wiley & Sons, Inc. 2000; 186.

15. Saw Palmetto. http://www.consumerlab.com/results/sawpalmetto.asp. 2003.

16. FDA Proposes Manufacturing and Labeling Standards for All Dietary Supplements. http://www.fda.gov. 2003.

17. State Health Director Warns Consumers About Prescription Drugs in Herbal Products. California Dept. of Health Services. http://www.dhs.cahwnet.gov. 2002.

18. Complementary and Alternative Medicine: FDA Proposes Labeling and Manufacturing Standards for All Dietary Supplements. Medical Letter on the CDC & FDA. 2003.

19. Dietary Supplement Labels are Found Wanting; Rx News. Center for Medical Consumers, Inc., HealthFacts. 2003;6(28):5.

20. Johnsen, M. GMPs Could Boost OTC Credibility, But Do Proposals Go Far Enough? Drug Store News. 2003;5(25):13.

21. Nahin RL, Straus SE. Research into complementary and alternative medicine: Problems and potential. BMJ 2001;322:161-4.

22. Claims That Can Be Made For Conventional Foods and Dietary Supplements. USFDA, Center for Food Safety and Applied Nutrition. September 2003. http://www.cfsan.fda.gov/~dms/hclaims.html.

23. FTC Charges Marketers of Coral Calcium Supreme Dietary Supplement and a Pain-Relief Product With Making False and Unsubstantiated Claims. Federal Trade Commission. 2003.

24. Evidence-Based Review Program. NIH Office of Dietary Supplements. http://www.ods.od.nih.gov/showpage.aspx?pageid=92.

25. AMA's Nod To Vitamins Props Up Natural Health. Drug Store News. 2003;8(25):44.

26. Busch, F. The New Nutrition From Antioxidants to Zucchini. John Wiley & Sons, Inc. 2000.

27. Valli, G, Giardina, EV. Benefits, adverse effects and drug interactions of herbal therapies with cardiovascular effects. JACC 2002;39(7):1083-1095.

28. Miller, LG, Murray, WJ. Herbal Medicinals: A Clinician's Guide. Pharmaceutical Products Press. 1998.

29. Physician's Desk Reference. 2003.

30. Laboratory Test Handbook, 3rd edition.

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