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39 - Poisoning

Editors: McPhee, Stephen J.; Papadakis, Maxine A.; Tierney, Lawrence M.

Title: Current Medical Diagnosis & Treatment, 46th Edition

> Table of Contents > 42 - Complementary & Alternative Medicine

Complementary & Alternative Medicine

Ellen F. Hughes MD, PhD

Bradly P. Jacobs MD, MPH

Brian M. Berman MD

The use of complementary and alternative medicine (CAM) has become common in the United States. To maintain effective clinician-patient communication and ensure responsible clinical practice, it is important that clinicians learn the theory, practice, and scientific evidence associated with these therapies. This chapter provides an overview of four alternative medicine therapies: herbal medicine, nonherbal dietary supplements, acupuncture, and homeopathy.

Background

CAM is defined by the National Institutes of Health (NIH) as a group of diverse health care systems, practices, and products that are not presently considered to be part of conventional medicine. CAM therapies may be used alone as an alternative to conventional therapies or in addition to conventional, mainstream medicine to treat conditions and promote well being.

CAM modalities have been classified by NIH into five major categories:

Biologically based practices use substances found in nature, such as herbs, special diets, or vitamins (in doses outside those used in conventional medicine).
Energy medicine involves the use of energy fields, such as magnetic fields or biofields (energy fields that some believe surround and penetrate the human body). Examples include Reiki, external qigong, and therapeutic touch.
Manipulative and body-based practices use manipulation or movement of one or more body parts (massage, chiropractic, Feldenkrais method and other body work systems).
Mind-body medicine uses a variety of techniques designed to enhance the mind's ability to affect bodily function and symptoms, such as meditation, prayer, art and music healing, and imagery.
Whole medical systems are built on complete systems of theory and practice that have evolved apart from ”and often earlier than ”the conventional medical approach used in the United States. Systems such as traditional Oriental medicine, acupuncture, homeopathy, naturopathy, Ayurveda, and Tibetan medicine often use one or more of the methods listed above.

The Centers for Disease Control and Prevention conducted the National Health Interview Survey (NHIS) in 2002; 31,000 American adults from diverse populations were asked about their use of CAM. Thirty-eight percent reported using some form of CAM in the previous 12 months. When prayer (used specifically for health reasons) and megavitamins were included in the definition of CAM, this percentage increased to 62%.

The most commonly reported CAM therapy was prayer. When prayer was excluded from the definition of CAM, biologically based therapies, such as herbs and other dietary supplements, were most popular (22%).

The most common conditions for which adults used CAM were similar to those seen in most primary care offices: musculoskeletal complaints, such as back, neck, and joint pain; colds; anxiety or depression; gastrointestinal disorders; and sleeping problems. Most of the respondents in this survey used CAM on their own, with only 12% seeking care from a licensed CAM practitioner.

Most people who use CAM combine it with conventional medicine because they perceive the combination to be superior to either alone. Half of the NHIS respondents also thought that CAM would be interesting to try. One quarter sought CAM because a conventional medical professional suggested they try it and 13% because they felt that conventional medicine was too expensive. Dissatisfaction with conventional medicine has not previously been found to predict greater CAM use, but more than 25% of US adults said they used CAM because they believed conventional medicine could not help them. No questions on health care spending were asked during NHIS interviews, but a smaller national phone survey conducted in 1997 estimated that the US public paid $36 billion on CAM therapies, much of it out-of-pocket.

In January 2005, the Institute of Medicine of the National Academies released a report on the use of CAM in the United States. They recommended health profession schools incorporate sufficient information about complementary and alternative medicine (CAM) into the standard curriculum at all levels to enable licensed professionals to competently advise their patients about CAM. Indeed, despite the growing numbers of patients

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seeking CAM, less than 40% of alternative therapies used are disclosed to physicians. A lack of communication may be dangerous because some CAM therapies can interact adversely with conventional treatments .

Funding for biomedical research in this field has increased dramatically. The NIH established the Office of Alternative Medicine in 1992 with an annual budget of $2 million; in 1998, its role was expanded as the National Center for Complementary and Alternative Medicine (NCCAM). NCCAM's budget for fiscal year 2005 is $123 million. Although some CAM modalities are not easily evaluated using randomized control trial methodology, the 2005 Institute of Medicine report recommends that conventional and CAM treatments both be held to similar standards of safety and efficacy.

Astin JA: Why patients use alternative medicine: results of a national study. JAMA 1998;279:1548.

Barnes PM et al: Complementary and alternative medicine use among adults: United States, 2002. Adv Data 2004;(343):1.

Eisenberg DM et al: Perceptions about complementary therapies relative to conventional therapies among adults who use both: results from a national survey. Ann Intern Med 2001;135:344.

Eisenberg DM et al: Trends in alternative medicine use in the United States, 1990 “1997: results of a follow-up national survey. JAMA 1998;280:1569.

Institute of Medicine. Complementary and Alternative Medicine in the United States 2005. http://www.nap.edu/books/0309092701/html/

Herbal Medicines

Epidemiology

The use of herbs for medicinal purposes has increased dramatically over the past decade , although sales have leveled off over the past several years . Herbal products are used by one of three Americans at an annual total cost of more than $4 billion, but fewer than half of those individuals discuss the matter with a conventional health care provider. Consumers hold strong views about the efficacy of the supplements they take. Seventy percent state that they would continue to take their favorite supplement even if a government study claimed it was not effective.

In the 1850s, 80% of medicines in the United States Pharmacopeia were derived from plants. Today, approximately 20 “30% of the drugs listed in USP Dictionary are plant-derived ”important examples include atropine, colchicine, digoxin, and many antineoplastic agents .

Herbal medicines have been dispensed for centuries by traditional herbalists who have been involved with their cultivation and preparation as well as assessment of their potency. At present, most herbal products are commercially cultivated, processed in unregulated environments, and purchased over-the-counter without the counseling of a qualified health practitioner.

Regulatory Issues

In 1994, the United States Congress passed the Dietary Supplement and Health Education Act (DSHEA). DSHEA classifies vitamins, minerals, herbs, and amino acids as nutritional or dietary supplements. Under DSHEA, supplements can be marketed without proof of safety or efficacy as long as no claim is made for their use in the diagnosis, treatment or cure, or prevention of disease. Manufacturers can, however, make structure and function claims that a product enhances a normal body function or state such as thinking, mood, or immune function. For example, saw palmetto can be marketed to support urinary tract health but not to treat benign prostatic hyperplasia. In contrast to prescription drugs, the US Food and Drug Administration (FDA) must first prove that a herbal preparation is unsafe before it can order that a product be taken off the market.

Quality Assurance

In March 2003, the FDA proposed new labeling and manufacturing standards for all dietary supplements. Prior to this, consumers had no guarantee of the quality of the products they purchased. They could not be certain that the plant was accurately identified; that the product was free of microbial, pesticide, and heavy metal contamination; or that all batches contained the same ingredients in the same strengths. Indeed, a 17-fold difference in the amount of active ingredient was found when six national brands of St. John's wort were tested off the shelf. Only 12 of 81 randomized controlled trials of five popular herbs published between 2000 “2004 performed tests to quantify the actual contents of the products being evaluated.

Such lack of consistency prompted the Institute of Medicine to call on the government to amend DSHEA to implement improved quality-control manufacturing standards for supplements, more accurate labeling requirements, and greater consumer protections .

Patients should be advised to follow certain guidelines when considering whether to use herbal medicines ( Table 42-1 ).

Table 42-1. Advice to patients using herbal medicines.

Communication
  Discuss use of all therapies with your health care provider.
Product Quality
  Manufacturers are not required to submit evidence to the FDA or any regulatory body to demonstrate product safety, effectiveness, or product quality.
  Ask your primary care provider, a pharmacist, or a trained herbalist regarding the specific herbs you are using.
  Use herbs that are standardized to contain a specific quantity of the active ingredients.
  Select formulations that have been studied in clinical trials.
  Select formulations produced by larger companies. They are more likely to ensure product quality in order to protect their reputation.
Labeling
  Look for a seal of approval from an independent testing agency such as NNFA, NSF, or ConsumerLab.
  It should state the common and scientific names of herb(s).
  It should state the concentration or dose of the herb(s) and provide instructions on dose and frequency.
  It should state that the product is standardized to contain a certain amount of the active ingredient(s).
  It should state the methods used to ensure product quality.
  It should state the name and address of the manufacturer.
  It should state the batch or lot number and the expiration date.
  It should list potential side effects and interactions.
Pregnancy
  Few herbs have been studied for safety during pregnancy.
  Seek advice from your primary care provider before using herbs during pregnancy.
Interactions
  Discuss with your health care provider the safety profile and interactions that may occur when combining herbs and when taking herbs plus drugs.
Reporting
  Report any adverse reactions to your state poison control program or the FDA.

Product Formulations & Standardization

Herbal formulations include liquids ( extracts , tinctures, infusions, and decoctions) and fresh, dried , and powdered preparations . The potency of herbs varies widely depending on which part of the plant is used, where it is cultivated, and what variations there may be in growing conditions and methods of preparation.

To ensure a consistent percentage of the primary active ingredients across batches and brand names, standardized extracts have been developed. Since multiple constituents may have pharmacologic activity, determining the active ingredients for standardization purposes can be a difficult task. The European scientific community has played a significant role in producing and investigating high-quality standardized extracts that contain consistent quantities of marker compounds ( ideally , the active

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ingredients). This work has laid the foundation for conducting phase 2 and phase 3 clinical trials. The quality of research in the field is improving, but most herbal remedies have not been evaluated in controlled clinical trials.

Safety of Herbal Medicines

Although many medicinal herbs are relatively safe, some have significant toxicity. Herbs themselves can have unanticipated effects such as hepatotoxicity as seen with chaparral and germander. Ten of twenty patients with fulminant hepatic failure referred to a liver transplant service over a 21-month period were recent or active users of potentially hepatotoxic supplements. Ma-huang contains ephedrine and was sold as a component of many weight loss products and in a banned euphoriant called herbal ecstasy. Over 800 adverse events associated with Ma-huang have been reported, including the widely publicized death of a US major league baseball player in 2003, causing the FDA to ban ephedra-containing products from the market. (See Ephedra in the specific herbs section for details.) Herbal products may also be intentionally adulterated with prescription drugs or contaminated with harmful substances such as pesticides or heavy metals. Prescription drugs such as prednisone, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, and testosterone have been detected in imported Chinese patent medicines. In January 2006, the FDA issued a warning that two weight loss products available over the Internet contained chlordiazepoxide, fluoxetine, and a stimulant that is converted in the body to amphetamines. An estimated 15 million adults in 1997 took herbal medicines concurrently with prescription medications, creating a potential risk for adverse drug-herb or drug-supplement interactions. Patients taking St. John's wort along with the drugs indinavir or cyclosporine have lower blood levels of these prescription medicines. St. John's wort has the capacity to induce the cytochrome P450 system, which can lead to increased metabolism (ie, lower blood levels) of almost 50% of all prescription medicines that are processed by this system such as warfarin, theophylline, and birth control pills. Proving that a side effect experienced by a patient taking a dietary supplement is caused by that supplement is often difficult. Practitioners should take a detailed history from the patient and, if possible, obtain a sample of the product to facilitate further analysis if needed. All suspected adverse events should be reported to the FDA's Medwatch Program (http://www.fda.gov/medwatch), although it is estimated that less than 1% are actually reported.

Basch EM et al: Natural Standard Herb and Supplement Handbook: The Clinical Bottom Line. Elsevier Mosby, 2005.

Bent S et al: Commonly used herbal medicines in the United States: a review. Am J Med 2004;116:478.

Blendon RJ et al: Americans' views on the use and regulation of dietary supplements. Arch Intern Med 2001;161:805.

Bruno JJ et al: Herbal use among US elderly: 2002 National Health Interview Study. Ann Pharmacother 2005;39:643.

Estes JD et al: High prevalence of potentially hepatotoxic herbal supplement use in patients with fulminant hepatic failure. Arch Surg 2003;138:852.

Hu Z et al: Herb-drug interactions: a literature review. Drugs 2005;65:1239.

Kelly JP et al: Recent trends in use of herbal and other natural products. Arch Intern Med 2005;165:281.

Wolsko PM et al: Lack of herbal supplement characterization in published randomized controlled trials. Am J Med 2005;118:1087.

Review of the evidence for Selected Herbal Medicines

Table 42-2 provides an overview of selected herbal medicines.

Table 42-2. Overview of selected herbal medicines.

	Leading Indications	Active Constituents	Mechanism of Action	Standardized Complex	Dosage	Level of Evidence ¹ and Effect Size ²	Safety ³	Interaction; Side Effects	Comments
Echinacea (purple coneflower)	1. Treatment of URIs2. Prevention of URIs	Isobutyl-amides, chicoric acid, polyenes, alkaloids, and alkylamides	Immunostimulant, phagocytosis, cytokines (IL-1, TNF, IFN)	Above-the-ground preparations of E purpurea	300 mg, or 3 mL q3-4h	1. B: small2. C	I	None known: rash, pruritus, nausea	Avoid in immunocompromised patients; avoid use > 4 weeks
Ephedra	1. Weight loss2. Stimulant	Ephedrine alkaloids	Sympathomimetic		Max: 8 mg/dose; 24 mg/d	1. A: small2. B: dose-dependent	V ( especially at high doses)	Agitation, arrhythmias, stroke, MI, death	Banned by FDA
Garlic ( Allium sativum )	1. Cholesterol2. Hypertension3. Coronary artery disease	Allicin	1. HMG CoA-reductase, 14±-demethylase2. Unclear3. Antiplatelet effects	Allicin 0.6-1.3%	600-900 mg qd	1. B: small2. C: small3. C	I	1. Odor, flatulence 2. May have antiplatelet activity
Ginkgo biloba (EGb 761, GBE)	1. Dementia2. Claudication	Flavonoid glycosides, terpenes such as ginkgolide B	PAF inhibition, antioxidant, membrane stabilization	24% flavonoid glycoside	60 mg tid	1. A: small2. A: small	II	May have anticoagulant effect	Do not use in patients on anticoagulants and use caution if allergic to urushiols (mango rind, sumac-poison ivy, cashew nuts)
Asian ginseng ( Panax ginseng )	Stamina, aphrodisiac, fertility, tonic, energy-booster, adaptogen	Ginsenosides	Unclear	> 2% ginsenosides	200-600 mg qd extract; 1-2 g crude drug	C: multiple studies but few for any given indication	I	Previous reports of toxicity have been attributed to adulterants
Kava ( Piper methysticum )	Anxiety	Kava lactones	May modulate GABA binding	30-55% kava lactones in the United States	70 mg bid-tid kava lactones	A: moderate	II-IV (with recent concerns about liver toxicity)	With excess use, possible yellow scaling of skin; sedation	Avoid combining with sedatives and alcohol
St. John's wort ( Hypericum perforatum )	1. Depression: mild to moderate 2. Depression: major	Napthodianthrones (such as hypericum or hyperforin), flavonoids, and xanthones	May modulate neurotransmitters (serotonin, NE, GABA)	Hypericin 0.3% or hyperforin 3%	300 mg tid	1. A: moderate 2. B: no better than placebo	I (but significant drug-herb interaction)	Induces cytochrome P450, leading to lower serum levels of certain drugs	Cyclosporine, protease inhibitors , oral contraceptives, warfarin, digoxin levels reduced
Saw palmetto ( Serenoa repens )	Benign prostatic hyperplasia	Sterols, free fatty acids	5[±]-Reductase inhibition; inhibition of DHT binding to androgen receptor	85-95% sterols and fatty acids	160 mg bid	B: small or none	I	Mild GI upset and headaches (rare)	Does not effect PSA levels or prostate size
¹ Level of evidence: A, good evidence; B, some evidence; C, insufficient evidence. ² Effect size: none, small, moderate, large. ³ Safety: I, generally safe; II, relatively safe; III, insufficient evidence; IV, may be harmful; V, clear evidence of harm. URI = upper respiratory infection; IL = interleukin; TNF = tumor necrosis factor; IFN = interferon; HMG = hydroxymethylglutaric acid; PAF = platelet -activating factor; MI = myocardial infarction; NE = norepinephrine; DHT = dihydrotestosterone; PSA = prostate-specific antigen.

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St. John's Wort ( Hypericum perforatum )

St. John's wort is used in the treatment of mild to moderate depression. Most preparations are standardized to hypericin or hyperforin. The precise mechanisms of action are not known. Irreversible monoamine oxidase inhibitory activity noted in vitro has not been observed in vivo. Other postulated mechanisms include selective inhibition of serotonin, ³-aminobutyrate, norepinephrine, and dopamine reuptake in the central nervous system.

Over the past two decades, St. John's wort has been studied in thousands of patients with mild to moderate depression. Most of the 60-plus randomized controlled clinical trials, systematic reviews, and meta-analyses have shown that it is more effective than placebo and as effective as tricyclic agents for the treatment of mild to moderate depression. Several recent placebo-controlled studies lasting 4 “12 weeks have also shown that St. John's wort has efficacy similar to the selective serotonin reuptake inhibitors (SSRIs) sertraline, fluoxetine, and paroxetine. Pooled analyses of six recent, large trials restricted to patients with major depression, however, showed only minimal effects of St. John's wort compared with placebo. A 4-year NIH study of 300 patients with mild symptoms of depression began in 2003. Patients are being randomized to St. John's wort, placebo, or citalopram for 12 weeks.

St. John's wort is generally well tolerated. Side effects are not common and include mild headache , photosensitivity, gastrointestinal upset, and restlessness. Data from 35 double-blind randomized trials show that drop out and adverse event rates in patients receiving Hypericum extracts were similar to placebo, lower than with older antidepressants, and slightly lower than with SSRIs. Patients are advised to avoid taking St. John's wort in addition to prescription antidepressants, as there have been case reports of serotonin syndrome. St. John's wort also induces the cytochrome P450 system (isozyme CYP3A4), which may lower the blood levels of other drugs that are metabolized by this system (eg, ethinyl estradiol, warfarin, cyclosporine, and indinavir). At least 50% of all medications currently on the market are at least partially metabolized by this isozyme. Several cases of cardiac and renal organ rejection have been reported in patients whose previously stable level of cyclosporine was lowered after initiation of St. John's wort. Of further concern is that this herb-drug interaction may persist even after St. John's wort is discontinued. A 40% decrease in serum levels of the chemotherapeutic agent irinotecan noted in five patients taking concurrent St. John's wort persisted for 3 weeks after St. John's wort was discontinued.

Bjerkenstedt L et al: Hypericum extract LI-160 and fluoxetine in mild to moderate depression: a randomized, placebo-controlled, multicenter study in outpatients. Eur Arch Psychiatry Clin Neurosci 2005;255:40.

Fava M et al: A double-blind, randomized trial of St. John's wort, fluoxetine and placebo in major depressive disorder . J Clin Psychopharmacol 2005;25:441.

Hypericum Depression Trial Study Group: Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trial. JAMA 2002;287:1807.

Knuppel L et al: Adverse effects of St. John's wort: a systematic review. J Clin Psychiatry 2004;65:1470.

Linde K et al: St. John's wort for depression: meta-analysis of randomized controlled trials. Br J Psychiatry 2005;186:99.

Madabushi R et al: Hyperforin in St. John's wort drug interactions. Eur J Clin Pharmacol 2006;14:1.

Szegedi A et al: Acute treatment of moderate to severe depression with hypericum extract WS5570 (St. John's wort): randomized controlled double blind non-inferiority trial versus paroxetine. BMJ 2005;330:503.

Garlic

Garlic was the top-selling herb in 2004 with greater than $27 million in sales. The German Federal Health Agency Commission E and the European Scientific Cooperative on Phytotherapy have approved garlic for the treatment of hyperlipidemia and atherosclerosis. Allicin, the ingredient believed responsible for garlic's therapeutic benefit and odor, is highly unstable. Both heat and acid destroy the enzyme allinase, which is necessary to produce allicin, and for that reason garlic is best ingested raw. Garlic is also available over-the-counter in multiple formulations (dried, powdered, oils). The best-studied form is an enteric-coated capsule of dehydrated garlic. Freeze-drying helps retain most of the active ingredients found in raw garlic. Enteric coating permits allicin to be released in the small intestine, thereby enhancing absorption and reducing the breath odor. Over-the-counter preparations are frequently standardized to yield 0.6% allicin, but allicin yield among powdered preparations varies as much as 230-fold in brands used in trials. This lack of standardization may contribute to inconsistent results in dozens of clinical trials.

Doses of 600 “900 mg of freeze-dried herb (equivalent to one-half to one clove of raw garlic) appear to have small effects on cholesterol (4 “12% reduction when taken for 4 “6 weeks), minimal effect on blood pressure (< 10 mm Hg), and none on glucose levels. A small study of 15 men with coronary artery disease suggests that short- term treatment with an aged garlic extract may improve impaired endothelial function in men taking aspirin and a statin. Numerous observational studies have suggested that regular consumption of garlic might reduce the risk of developing certain malignancies, but no prospective controlled trials have been performed.

Garlic is well tolerated and apparently safe for long-term use. In addition to the well-known breath and body odor, common side effects include gastrointestinal upset, nausea, and flatulence.

A more than 50% reduction in blood levels of saquinavir after garlic supplementation has been reported. Although the induction of the cytochrome P450 system was hypothesized as the mechanism of action of this significant herb-drug interaction, a recent

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study of healthy volunteers did not reveal an effect of garlic on isozymes CYPP2D6 or CYP3A4. Garlic has been shown to have some antiplatelet activation activity, so there is a theoretical risk of increased bleeding, especially if taken with aspirin, anticoagulants, or NSAIDs. Although there is insufficient evidence to determine a causal association, some physicians recommend stopping garlic 1 “2 weeks prior to undergoing elective surgery.

Markowitz JS et al: Effects of garlic ( Allium sativum L .) supplementation on cytochrome P450 2D6 and 3A4 activity in healthy volunteers. Clin Pharmacol Ther 2003;74:170.

Mulrow C et al: Garlic: Effects on cardiovascular risks and disease, protective effects against cancer, and clinical adverse effects. Rockville, MD: Agency for Healthcare Research and Quality; 2003. AHRQ publication 01-E023.

Piscitelli SC et al: The effect of garlic supplements on the pharmacokinetics of saquinavir. Clin Infect Dis 2002;34:234.

Stevinson C et al: Garlic for treating hypercholesterolemia. A meta-analysis of randomized clinical trials. Ann Intern Med 2000;133:420.

Tattelman E: Health effects of garlic. Am Fam Physician 2005;72:103.

Williams MJ et al: Aged garlic extract improves endothelial function in men with coronary artery disease. Phytother Res 2005;19:314.

Ginkgo

The dried leaf of the ginkgo tree has been used medicinally for thousands of years. More than 400 studies over the past 30 years have investigated ginkgo's ability to improve blood flow in a variety of conditions, including memory impairment, dementia, peripheral vascular disease, vertigo, tinnitus, asthma, SSRI-induced sexual dysfunction, and acute mountain sickness. The German Commission E has approved a standardized form of ginkgo leaf extract (EGb 761) for the treatment of cognitive impairment and intermittent claudication. Multiple pharmacologically active compounds have been isolated from ginkgo, including flavonoid glycosides and terpene lactones (ginkgolides). The flavonoids have antioxidant and free radical scavenging ability. The terpene lactones (especially ginkgolide B) have platelet-activating factor antagonist activity. In addition, ginkgo extracts increase the production of nitric oxide and activate certain central neurotransmitters, including the cholinergic system, which may contribute to their beneficial effects on memory and cognition. EGb 761 ”the formulation that has been studied most extensively ”is standardized to contain 24% flavonoid glycosides and 6% terpene lactones.

Early studies that assessed ginkgo's efficacy on cognitive function in the elderly showed a modest improvement when compared to placebo. The longest of these studies (1 year) showed stabilization of cognitive and functional abilities in 309 demented patients treated with EGb 761 compared with placebo, with no differences in adverse outcomes . In contrast, EGb 761 was no more effective than placebo in 214 elderly Dutch patients with dementia or age-associated memory impairment. There is conflicting evidence about ginkgo's ability to enhance memory in healthy individuals. The NIH has funded investigators at the University of Pittsburgh to determine whether ginkgo taken over 5 years can prevent or delay the development of dementia in 3000 patients 75 years of age or older.

In general, ginkgo is well tolerated in healthy adults at recommended doses for up to 6 months. Allergic skin reactions, gastrointestinal disturbances, and headache occur in less than 2% of patients. There are theoretical concerns about a risk of increased bleeding because antiplatelet activating factor activity has been demonstrated in vitro. Nearly 20 cases of increased bleeding in patients taking ginkgo have been reported, but establishing a causal relationship is challenging because many of these patients had other risk factors including age and use of medications, such as warfarin, aspirin, or NSAIDs. Of note, no excess bleeding complications have been reported in clinical trials and no differences in coagulation , platelet function, or pharmacokinetics of warfarin have been noted in healthy male volunteers. Caution should still be exercised in patients with bleeding disorders or who are taking anticoagulants, aspirin, or other herbs that may increase the risk of bleeding.

Gingko has also been evaluated for its effect on intermittent claudication. A meta-analysis of nine randomized, placebo-controlled, double-blinded trials of patients treated with EGb 761 showed a modest treatment effect in the increase of pain-free walking distance in favor of ginkgo over placebo. There is insufficient evidence to support ginkgo's efficacy in treating tinnitus, acute mountain sickness, vertigo, or SSRI-associated sexual dysfunction.

Bent S et al: Spontaneous bleeding associated with Ginkgo biloba. A case report and systematic review of the literature. J Gen Intern Med 2005;20:657.

Birks J: Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2002;(4):CD003120.

Elsabagh S et al: Differential cognitive effects of Ginkgo biloba after acute and chronic treatment in healthy young volunteers. Psychopharmacology (Berl) 2005;179:437.

Jiang X et al: Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol 2005;59:425.

Kohler S et al: Influence of a 7-day treatment with Ginkgo biloba special extract EGb 761 on bleeding time and coagulation: a randomized, placebo-controlled, double-blind study in healthy volunteers. Blood Coagul Fibrinolysis 2004;15:303.

Pittler MH et al: Complementary therapies for peripheral arterial disease: systematic review. Atherosclerosis 2005;181:1.

Soloman PR et al: Ginkgo for memory enhancement: a randomized controlled trial. JAMA 2002;288:835.

van Dongen M et al: Ginkgo for elderly people with dementia and age-associated memory impairment: a randomized clinical trial. J Clin Epidemiol 2003;56:367.

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Echinacea

Echinacea ranks second among the top-selling herbs in the United States, accounting for more than $300 million in sales annually. Three of nine Echinacea species are currently used for the treatment and prevention of upper respiratory infections. Preparations are made from roots ( Echinacea pallida and Echinacea angustifolia ), above-ground parts ( stems , leaves , and flowers of Echinacea purpurea ), or a combination of both. Multiple forms are available over-the-counter, including capsules, fresh pressed juice , tinctures, and teas. Differences in species, growing conditions, plant parts used, and extraction procedures can result in differences in chemical composition and biologic activity. Several active ingredients have been identified, including polysaccharides, glycoproteins, alkaloids, and flavonoids. In vitro, animal, and human studies suggest that these ingredients cause stimulation of the immune system (natural killer cells , macrophages, and cytokine activity) and that they possess anti-inflammatory, free radical-scavenging, and antiviral activity.

The quality of most clinical trials has been limited by use of multiple products and doses (including formulations containing multiple herbs) and the lack of rigorous methodology.

The majority of early trials reported that echinacea is effective in reducing the duration and severity of colds if started within several days of the onset of symptoms but no more effective when taken to prevent infection. A well-designed, 2005 trial studied three different E angustifolia root preparations for the prevention and treatment of laboratory-induced rhinovirus infections. Four hundred thirty-seven volunteers were randomized to receive either prophylaxis (beginning 7 days before a challenge with rhinovirus) or treatment (beginning at the time of viral challenge), with one of the three different echinacea preparations. No statistically significant effects were seen on rates of infection or severity of symptoms in patients taking the herb. The echinacea used in this trial was well characterized and of high quality, but some clinicians feel that the dose used was lower than that used in routine practice. In contrast, an updated meta-analysis of echinacea monopreparations found that 10 out of 16 trials showed the herb to be more effective than placebo for the treatment of colds. Enough data were available for preparations made of the above-the-ground parts of E purpurea that the authors concluded that there is some evidence that these specific formulations may be effective for the early treatment of colds in adults. Data for other echinacea formulations and for prevention of colds were less consistent.

In general, echinacea is well tolerated, with few reported adverse events. Rare allergic reactions including rash have been reported (especially in patients with ragweed allergies), and there was a single case of recurrent erythema nodosum. The German Commission E recommends that patients who are pregnant, have autoimmune disease, or who are immunocompromised not take echinacea because of its immune-stimulating effects. The Commission also recommends that its use be limited in others to less than 4 weeks. The data supporting these recommendations are not clear.

Barrett B et al: Treatment of the common cold with unrefined echinacea. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2002;137:939.

Goel V et al: A proprietary extract from the echinacea plant ( Echinacea purpurea ) enhances systemic immune response during a common cold. Phytother Res 2005;19:689.

Linde K et al: Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev 2006;(1):CD000530.

Sperber SJ: Echinacea purpurea for prevention of experimental rhinovirus colds. Clin Infect Dis 2004;38:1367.

Turner RB et al: An evaluation of Echinacea angustifolia in experimental rhinovirus infections. N Engl J Med 2005;353:341.

Yale SH et al: Echinacea purpurea therapy for the treatment of the common cold: a randomized, double-blind, placebo-controlled clinical trial. Arch Intern Med 2004;164:1237.

Kava

Kava beverages prepared from the dried rhizome of the Piper methysticum plant have been consumed for centuries as ceremonial drinks in the South Pacific islands. Its present-day uses include the treatment of anxiety, stress, and insomnia. The active ingredients (kavapyrones) have central muscle- relaxing properties and anticonvulsant activity. The precise anxiolytic mechanism of action is not fully understood .

A systematic review and meta-analysis of eleven randomized, double-blind, placebo-controlled trials concluded that kava was more effective than placebo in relieving anxiety, with effects observed after as few as 1 “2 doses and with progressive improvement over 1 “4 weeks. The longest study involved 101 German outpatients randomized to kava or placebo for 6 months. Compared with placebo, kava-treated patients had progressively lower Hamilton anxiety scale scores at 3 and 6 months. In two shorter trials, kava also relieved acute anxiety more effectively than placebo. A recent meta-analysis of six clinical trials that used a standardized kava preparation (WS1490) also concluded that the herb is more effective than placebo in treating anxiety, with greatest benefit seen in women and patients younger than 53 years.

Kava has been well tolerated in clinical trials. Less than 2.3% of patients report gastrointestinal complaints, drowsiness, tremor, headache, or allergic skin reactions. There are several case reports of patients feeling sedated, disoriented, or ataxic after consuming high doses of kava (or kava in combination with alcohol or prescription drugs that act on the central nervous system). These include two driving under the influence arrests of patients who had consumed 8 “16 cups of a kava beverage. Kava may have dopamine

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antagonist properties. Three patients using European kava preparations developed extrapyramidal dystonic reactions or worsening Parkinson's disease. A reversible kava toxic syndrome with dermopathy (dry, flaky, yellow skin), ataxia, partial hearing loss, and weight loss has been reported in South Pacific Islanders who consume kava at doses 100 times higher than recommended.

In 2001, the German government reported 29 cases of hepatitis, cirrhosis, and liver failure possibly associated with the use of kava. Although 18 of these reports were in patients who were also taking medications with known or potential liver toxicity, one case involved a previously healthy 50-year-old man who was not taking prescription medications or alcohol who required a liver transplant. As a result of almost 80 case reports, kava products have been taken off the market in the European Union, Australia and Canada. Warnings about possible hepatic toxicity have been issued to patients with acute or chronic liver disease. How kava causes hepatic toxicity is not clear, but possible mechanisms of action include idiosyncratic reactions, differences in preparation (commercial kava is prepared in acetone, methanol, or ethanol while traditional kava is aqueous), inhibition of the cytochrome P450, or reduction in liver glutathione levels.

Clouatre DL: Kava Kava: examining new reports of toxicity. Toxicol Lett 2004;150:85.

Cote CS et al: Composition and biological activity of traditional and commercial kava extracts. Biochem Biophys Res Commun 2004;322:147.

Ernst E: Herbal remedies for anxiety ”a systematic review of controlled clinical trials. Phytomedicine 2006;13:205.

From the Centers for Disease Control and Prevention. Hepatic toxicity possibly associated with kava-containing products ”United States, Germany, and Switzerland, 1999 “2002. JAMA 2003;289:36.

Perez J et al: Altered mental status and ataxia secondary to acute Kava ingestion . J Emerg Med 2005;28:49.

Witte S et al: Meta-analysis of the efficacy of the acetonic kava-kava extract WS1490 in patients with non-psychotic anxiety disorders. Phytother Res 2005;19:183.

Ginseng

Ginseng root has been used for medicinal purposes in Asia for over 2000 years. There are three major forms of ginseng in use today: Asian ginseng ( Panax ginseng ); American ginseng ( Panax quinquefolius ); and Siberian ginseng ( Eleutherococcus senticosus ), which is not a member of the Panax genus. The German Commission E monograph on ginseng root approves its use as a tonic to counteract weakness and fatigue, as a restorative for declining stamina and impaired concentration, and as an aid to convalescence. Extracts are made from dried roots and contain ginsenosides. Over 25 ginsenosides have been isolated, each with unique and sometimes oppositional effects on the cardiovascular, central nervous, and immune systems. The mechanisms of action have not been clearly delineated.

There is an extensive body of scientific literature on this subject, with over 4000 books and papers published. Multiple indications have been studied using different ginseng species, often with poor methodologic rigor. One European study identified 57 randomized controlled trials of ginseng in the world's literature, but only 16 studies were of good enough quality to be included in their systematic review. Insufficient evidence was available to support or refute the use of ginseng for any of the purported indications, including improvement of physical performance, cognitive functioning, and quality of life. Two small 2004 clinical trials suggest ginseng may improve cognitive performance in healthy persons and prevent acute respiratory illness in institutionalized older adults. A larger Canadian trial examined the efficacy of a proprietary North American ginseng extract, previously shown to stimulate the immune system in vitro, in preventing colds. Three hundred twenty-three healthy subjects who had at least two colds in the previous year were randomized to daily ginseng or placebo for 4 months, beginning just after the onset of influenza season . The mean number of colds per person and the severity and duration of symptoms were less in the ginseng-treated group. A study done in 2000 suggested that one form of American ginseng may attenuate postprandial glycemia in both normal and diabetic persons, but follow-up reports from the same researchers showed no or variable effects of ginsengs with different ginsenoside composition.

Ginseng is well tolerated at recommended doses, with few adverse effects. A recent systematic review of adverse reactions reports that the incidence is similar in ginseng monopreparations and placebo. Possible drug interactions have been reported between P ginseng and warfarin, phenelzine, calcium channel blockers, digoxin, and alcohol. Earlier reports of ginseng abuse syndrome and other toxicities are now attributed to adulterants found in earlier unregulated over-the-counter ginseng products. Indeed, 13 of 21 ginseng products recently evaluated for quality and purity failed because they contained unacceptable levels of pesticides or heavy metals or inadequate concentrations of ginsenosides.

Coon JT et al: Panax ginseng: a systematic review of adverse effects and drug interactions. Drug Safety 2002;25:323.

McElhaney JE et al: A placebo-controlled trial of a proprietary extract of North American ginseng (CVT-E002) to prevent acute respiratory illness in institutionalized older adults. J Am Geriatr Soc 2004;52:13.

Predy GN et al: Efficacy of an extract of North American ginseng containing poly-furanosyl-pyranosyl-saccharides for preventing upper respiratory tract infections: a randomized trial. CMAJ 2005;173:1043.

Sievenpiper JL et al: Decreasing, null and increasing effects of eight popular types of ginseng on acute postprandial glycemic indices in healthy humans : the role of ginsenosides. J Am Coll Nutr 2004;23:248.

Sievenpiper JL et al: Null and opposing effects of Asian ginseng ( Panax ginseng C.A. Meyer) on acute glycemia: results of two acute dose escalation studies. J Am Coll Nutr 2003;22:524.

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Vogler BK et al: The efficacy of ginseng. A systematic review of randomised clinical trials. Eur J Clin Pharmacol 1999;55:567.

Yuan CS et al: Brief communication: American ginseng reduces warfarin's effect in healthy patients: a randomized, controlled trial. Ann Intern Med 2004;141:23.

Saw Palmetto

Saw palmetto is used by over 2 million men in the United States to treat benign prostatic hyperplasia, and in Europe, it is often the first-line therapy for lower urinary tract symptoms. Lipophilic extracts are prepared from the berries of the dwarf palm tree ( Serenoa repens ) and are standardized to sterols and free fatty acids. Several mechanisms of action have been proposed, including inhibition of 5±-reductase activity, as well as antiandrogenic, anti-inflammatory, and antiproliferative activity. The most studied brand of saw palmetto (Permixon) is not available in the United States.

A 2004 meta-analysis of 17 trials (14 randomized) using Permixon in 4280 patients showed significant improvement in peak flow rate, reduction in nocturia relative to placebo, and a 5-point reduction in the International Prostate Symptom Score. These clinical data are comparable to effects of some ±-blockers. In contrast, a well-designed 2006 trial showed no difference in symptom scores, flow rates, prostate size, postvoid residual volume, quality of life, or prostate-specific antigen in 225 men with moderate to severe benign prostatic hyperplasia treated with saw palmetto (160 mg twice daily) or placebo for 1 year.

Saw palmetto is very well tolerated by most patients for up to 3 “5 years, with only mild and rare gastrointestinal symptoms being reported. Saw palmetto has not been shown to reduce prostate size or lower the serum level of prostate-specific antigen. No herb-drug interactions have been reported. In a 2003 study, the herb did not alter cytochrome P450 activity in healthy volunteers. Saw palmetto was one of eight ingredients in PC-SPES, a popular herbal product used by many men with prostate cancer. PC-SPES was withdrawn from the market when it was found to be contaminated with the prescription drugs diethylstilbestrol and warfarin.

Bent S et al: Saw palmetto for benign prostate hyperplasia. N Engl J Med 2006;354:557.

Boyle P et al: Updated meta-analysis of clinical trials of Serenoa repens extract in the treatment of symptomatic benign prostatic hyperplasia. BJU Int 2004;93:751.

Buck AC: Is there a scientific basis for the therapeutic effects of Serenoa repens in benign prostatic hyperplasia? Mechanisms of action. J Urol 2004;172:1792.

Fong YK et al: Role of phytotherapy in men with lower urinary tract symptoms. Curr Opin Urol 2005;15:45.

Markowitz JS et al: Multiple doses of saw palmetto ( Serenoa repens ) did not alter cytochrome P450 2D6 and 3A4 activity in normal volunteers. Clin Pharmacol Ther 2003;74:536.

Ephedra (Ma-huang)

The dried young stems of Ephedra sinica have been used for thousands of years in traditional Oriental medicine to treat respiratory disorders, especially bronchospasm and congestion. Ephedra has also been widely marketed for its stimulant and appetite suppressant effects (alone or in combination with caffeine-like herbs). Ephedra's alkaloids are structurally similar to amphetamines. A meta-analysis concluded that patients taking ephedra or ephedra plus caffeine products lost 1.3 or 2.2 more pounds per month respectively than those taking placebo. These products were associated with a twofold to threefold risk of psychiatric, autonomic, gastrointestinal symptoms, and heart palpitations. Of all the adverse effects caused by ingestion of herbs reported to US poison control centers, 64% were due to products containing ephedra, even though they represented only 0.82% of herbal product sales. Over 800 cases of adverse events, including more than 20 deaths, have been reported to the FDA, which prohibited the sales of ephedra-containing dietary supplements in February 2004. This ban was challenged in April 2005 when a supplement manufacturer argued in the Utah Federal District Court that the FDA had not demonstrated that ephedra was dangerous when used at lower doses. Many Ephedra-free weight loss products contain bitter orange (citrus aurantium), which could pose similar risks because it contains synepherine, which has sympathomimetic activity.

Bent S et al: The relative safety of ephedra compared with other herbal products. Ann Intern Med 2003;138:468.

Bent S et al: Safety and efficacy of citrus aurantium for weight loss. Am J Cardiol 2004;94:1359.

Haller CA et al: Hemodynamic effects of ephedra-free weight loss supplements in humans. Am J Med 2005;118:998.

McBride BF et al: Electrocardiographic and hemodynamic effects of a multicomponent dietary supplement containing ephedra and caffeine: a randomized controlled trial. JAMA 2004;291:216.

Shekelle PG et al: Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis. JAMA 2003;289:1537.

Dietary Supplements

Sales of dietary supplements have increased dramatically over the past decade. The Dietary Supplement Health Education Act of 1994 has made it possible for manufacturers to sell dietary supplements directly to the public without FDA approval or oversight. Reports of adulteration and contamination are available, but the magnitude of this problem remains unknown. Furthermore, there have been several reports of the

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dose printed on the label being different from the actual dose provided. (See section on herbal medicines , above, for further details on regulatory and quality assurance issues and advice for patients to follow when purchasing these products.) Table 42-3 provides an overview of selected dietary supplements commonly used in the United States today.

S-Adenosylmethionine

S -Adenosylmethionine (SAMe) is an endogenous compound that serves as a methyl group donor for hundreds of compounds, including neurotransmitters, fatty acids, nucleic acids, proteins , and membrane phospholipids. Endogenous production is dependent on vitamin B ₁₂ and folic acid metabolism. Primary uses of the drug are the treatment of depression, osteoarthritis , alcoholic liver disease, and migraine headaches. Originally discovered in the 1950s, SAMe was not synthesized as a stable compound that could be made commercially available until the 1970s. It is available by prescription throughout Europe. The mechanism of action is unclear for most conditions. Based on clinical trial data from over 22,000 patients, SAMe is well-tolerated and safe. Side effects include nausea, flatulence, headache, and anxiety. A phase 4 open -label clinical trial involving over 20,000 patients observed for 8 weeks found that 87% of the cohort reported good to very good tolerance with SAMe. There are no significant drug-herb interactions, although a case of serotonin syndrome in a patient taking SAMe with clomipramine has been reported.

A 2002 Evidence Report and Technology Assessment by the Agency for Healthcare Research and Quality concluded that SAMe is more effective than placebo for relief of symptoms of depression, pain of osteoarthritis, and pruritus in cholestasis of pregnancy, and in intrahepatic cholestasis. Furthermore, the authors concluded that SAMe was equivalent to standard therapy for depression and osteoarthritis but not for cholestasis of pregnancy. Early studies suggesting that SAMe may be helpful in treating depression were limited by short duration and poor methodology. SAMe may affect multiple neurotransmitters; increased levels of serotonin, 5-hydroxyindoleacetic acid, and dopamine as well as inhibition of norepinephrine reuptake have been noted after SAMe administration. An electroencephalogram mapping study of SAMe showed significant central effects of SAMe compared with placebo typical of activating antidepressants. Two recent multicenter trials of SAMe versus imipramine report that both oral and intramuscular preparations of SAMe are as effective as the tricyclic agent in reducing depression and with fewer side effects, though neither study was placebo-controlled. No head-to-head trials have compared SAMe with SSRIs. SAMe appears to have analgesic and anti-inflammatory properties and was studied extensively in the 1980s for the treatment of osteoarthritis. The mechanism of action for these effects is unknown. Although many early studies used a parenteral form of SAMe, only an oral formulation is available in the United States, and it is expensive ($50-$150 per month) and has poor bioavailability. A review of 11 randomized controlled trials (1418 patients) comparing SAMe with placebo or NSAIDs for osteoarthritis concluded that SAMe was as effective as NSAIDs in reducing pain and functional limitation and better-tolerated. Compared with placebo, SAMe was more effective in improving functional limitations and did not differ in adverse events.

Studies of alcohol-fed baboons suggest that SAMe increases glutathione levels and attenuates liver injury . There is some evidence that SAMe increases glutathione levels in humans as well. Investigators performed a multicenter clinical randomized, double-blind, placebo-controlled trial involving 123 patients with alcoholic liver cirrhosis treated with SAMe or placebo for 2 years. Combined mortality and liver transplantation rate was 30% in the placebo group compared with 16% in the SAMe group ( P = .08). When Child-Turcotte-Pugh class C subjects (n = 8) were excluded, respective rates were 29% and 12% ( P = .03). This study provides support for SAMe supplementation in alcoholic liver disease.

Arnold O et al: Double-blind, placebo-controlled pharmacodynamic studies with a nutraceutical and a pharmaceutical dose of ademetionine (SAMe) in elderly subjects, utilizing EEG mapping and psychometry. Eur Neuropsychopharmacol 2005;15:533.

Chiaie R et al: Efficacy and tolerability of oral and intramuscular S -adenosyl-L-methionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. Am J Clin Nutr 2002;76:1172S.

Hardy M et al: S -adenosyl-L-methoionine for treatment of depression, osteoarthritis, and liver disease. Agency for Healthcare Research and Quality (AHRQ) 2002; (Evidence Report/Technology Assessment 64):1.

Mato JM et al: S -Adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. J Hepatol 1999;30:1081.

Soeken KL et al: Safety and efficacy of S -adenosylmethionine (SAMe) for osteoarthritis. J Fam Pract 2002;51:425.

Dehydroepiandrosterone

Dehydroepiandroesterone (DHEA) and its sulfate ester, DHEAS, are secreted by the adrenal cortex and serve as precursors for the synthesis of male and female sex hormones . In healthy individuals there is a 25% decrease in serum DHEA levels per decade until age 70, when levels are at 20 “30% of lifetime peak levels. In addition, low DHEA levels have been reported in people who suffer from a wide variety of chronic illness, including depression, cancer, type 2 diabetes, HIV, Alzheimer's disease, renal failure, anorexia , and atherosclerosis. DHEA levels may be depleted by certain prescription medications, including insulin , corticosteroids, and opiates. Low levels of DHEA associated

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with aging and medical illness have been cited in the popular press as evidence that DHEA supplementation would be beneficial.

Table 42-3. Overview of selected dietary supplements.

	Leading Indications	Mechanism of Action	Dosage	Level of Evidence ¹ and Effect Size ²	Safety ³	Interactions; Side Effects	Comments
S -Adenosylmethionine (SAMe, SAM)	1. Depression2. Osteoarthritis3. Alcohol- related liver disease	Universal methyl donor	200-800 mg bid	1. B: moderate2. B: moderate3. C	I	None; may precipitate mania in persons with bipolar affective disorder
Dehydroepiandrosterone (DHEA, DHEAS)	1. Depression, dysthymia 2. Lupus 3. Insulin sensitivity 4. Adrenal insufficiency	1. Unknown 2. Possibly IL-10 3. Unknown 4. Replacement	50 mg qd	1. C: small 2. B: moderate 3. B: small 4. C: small	IV (with long-term use)	None reported; androgenic effects	Theoretical concerns that long-term use may result in hormone-dependent malignancies
Glucosamine sulfate and chondroitin	Osteoarthritis (knee)	Proteoglycan production	Glucosamine 500 mg tid; chondroitin 400 mg tid	A: moderate	I	None reported; rare reports of constipation, diarrhea, drowsiness	Insulin resistance not seen in clinical trials
Coenzyme Q ₁₀ (ubiquinone, ubidecarenone, Co-Q ₁₀ )	Congestive heart failure, cardiac arrest, angina, acute myocardial infarction, migraine prophylaxis	ATP production, membrane stabilization	50 qd-150 mg tid; goal is to achieve serum level of 2.1 mcg/mL	C	I	Patients taking statins noted to have lower serum levels of Co-Q ₁₀	Fat-soluble, so absorption improved when taken with meals
¹ Level of evidence: A, good evidence; B, some evidence; C, insufficient evidence. ² Effect size: none, small, moderate, large. ³ Safety: I, generally safe; II, relatively safe; III, insufficient evidence; IV, may be harmful; V, clear evidence of harm.

The mechanism of action of DHEA remains unknown. Preliminary evidence suggests that DHEA supplementation might be useful in depression, dysthymia, systemic lupus erythematosus (SLE), insulin sensitivity, and adrenal insufficiency.

Animal studies suggest that DHEA and DHEAS have excitatory effects on the central nervous system, which may account for their influence on mood and sense of well-being. A 6-week clinical trial randomized 52 subjects with major or minor depression to monotherapy with DHEA or placebo and found DHEA to be superior as measured by multiple well- validated depression scales .

Low DHEA levels in men and women with SLE and reduction in interleukin-10 levels after supplementation compared with placebo suggest that DHEA may play a causative role. One hundred women with active, mild to moderate SLE were randomized to receive 200 mg/d of oral DHEA or placebo for 24 weeks. DHEA was well tolerated, significantly reduced the number of SLE flares, and improved patients' global assessment of disease activity. DHEA supplementation has been shown to reduce abdominal visceral fat and insulin resistance. Villareal and colleagues randomized 56 adults to DHEA (50 mg/d) or placebo for 6 months and found reductions in visceral fat, subcutaneous fat, and insulin sensitivity. Women with adrenal insufficiency have unmeasurable DHEA serum levels. Treatment with DHEA in a 3-month randomized, double-blinded, placebo-controlled crossover study was associated with improvements in insulin sensitivity in this population. Using a similar design, a 4-month study of DHEA was associated with improvements in mood, well-being, and libido. In contrast, a 9-month randomized, placebo-controlled study of 39 women with adrenal failure failed to find a beneficial effect of DHEA supplementation on subjective health status or sexuality.

Side effects of DHEA include acne, deepening of the voice, and facial hair growth. No serious adverse events have been reported. The long-term effects of DHEA supplementation remain unknown. The safety issue of most concern is that DHEA ”as a potent precursor of sex steroids ”may increase the risk of estrogen- or androgen-dependent malignancies. Therefore, if supplementation is used, patients should be monitored closely. Furthermore, patients at high-risk for prostate, ovarian, breast , or uterine cancer should be counseled against DHEA supplementation.

Arlt W et al: Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med 1999;341:1013.

Chang D-M et al: Dehydroepiandrosterone treatment of women with mild-to-moderate systemic lupus erythematosus: a multicenter randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002;46:2924.

Dhatariya K et al: Effect of dehydroepiandrosterone replacement on insulin sensitivity and lipids in hypoadrenal women. Diabetes 2005;54:765.

Schmidt PJ et al: Dehydroepiandrosterone monotherapy in midlife-onset major and minor depression. Arch Gen Psychiatry 2005;62:154.

Villareal DT et al: Effect of DHEA on abdominal fat and insulin action in elderly women and men: a randomized controlled trial. JAMA 2004;292:2243.

Glucosamine & Chondroitin

Glucosamine and chondroitin have been used in Europe alone and in combination to treat osteoarthritis since the 1980s. These compounds are substrates for the production of articular cartilage. Glucosamine stimulates the production of glycosaminoglycans, leading to increased synthesis of cartilage. Chondroitin may help maintain articular fluid viscosity , inhibit enzymes that break down cartilage, and stimulate cartilage repair. Glucosamine is prepared commercially from crustacean shells . Chondroitin is extracted from bovine tissues such as cow trachea.

Two meta-analyses and a Cochrane Review of twenty randomized, double-blind, placebo-controlled trials involving more than 2570 patients with osteoarthritis support the use of glucosamine (or glucosamine and chondroitin) in the treatment of osteoarthritis of the knee. The Cochrane Review identified efficacy only for trials using preparations manufactured by Rotta Pharmaceuticals. GAIT is a multicenter randomized double-blind placebo- and celecoxib-controlled clinical trial involving 1583 persons randomized to glucosamine, chondroitin, glucosamine and chondroitin, celecoxib, or placebo. Investigators found no difference overall between the supplements alone and in combination and placebo. In a predefined subgroup of patients with moderate to severe pain, combined therapy with glucosamine and chondroitin sulfate provided greater pain relief than placebo, which in that subgroup was not different than celecoxib.

Glucosamine not only reduces the symptoms of osteoarthritis but may also slow the progression of the disease. Reginster and coworkers randomized 212 patients with osteoarthritis of the knee to receive either 1500 mg/d of glucosamine or placebo. After 3 years, patients taking glucosamine reported a 24% reduction in symptoms versus a 10% increase in the placebo group. X-rays revealed that the treatment patients experienced a loss of only 0.06 mm joint space versus 0.31 mm in the placebo group after 3 years. Glucosamine was very well-tolerated and did not elevate serum glucose levels. Similar results were found in 200 patients with mild to moderate knee osteoarthritis who were randomized to glucosamine sulfate or placebo for 3 years. Patients in the glucosamine group had greater pain relief and less joint space narrowing on radiographs. Several negative trials have been reported in patients with more severe arthritis and in those taking forms of glucosamine other than those made by the European manufacturer Rotta Pharmaceuticals. No drug-herb interactions have been reported. In contrast to NSAIDs, glucosamine is not an analgesic and may take weeks to months before improvement is noticed. In summary, clinical trial literature suggests that glucosamine with or without chondroitin is well tolerated,

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safe, and effective in the treatment of osteoarthritis, with fewer side effects than NSAIDs.

Clegg DO et al: Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354:795.

Hughes R et al: A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee. Rheumatology (Oxford) 2002;41:279.

Pavelka K et al: Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. Arch Intern Med 2002;162:2113.

Reginster JY et al: Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomized, placebo-controlled clinical trial. Lancet 2001;357:251.

Richy F et al: Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis. Arch Intern Med 2003;163:1514.

Towheed TE et al: Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev 2005;(2):CD002946.

Coenzyme Q ₁₀

Coenzyme Q ₁₀ (Ubidecarenon; also known as ubiquinone-10) is an endogenous provitamin that resides in the lipid layer of the mitochondria. It plays a crucial role in oxidative phosphorylation for adenosine triphosphate (ATP) production and is necessary for the basic functioning of all cells. It has also been observed to have effects on membrane stabilization, free radical scavenging, and calcium-dependent slow channels. Coenzyme Q ₁₀ levels decrease with age. Deficiencies have been observed among patients with certain chronic medical conditions, including cardiovascular disease (hypertension, acute coronary syndromes, congestive heart failure), renal failure, male infertility, periodontal disease, cancer, HIV/AIDS, muscular dystrophies, Parkinson's disease, and Alzheimer's disease. Certain prescription medications may also lower coenzyme Q ₁₀ levels, including HMG-CoA reductase inhibitors, diabetes medications, ²-blockers, diuretics, and antidepressants. Serum levels of coenzyme Q ₁₀ are increased by taking supplements, but whether this results in clinical benefit remains unproven.

Studies of coenzyme Q ₁₀ for the prevention and treatment of cardiovascular disease have had mixed results. A 2005 study of 121 patients undergoing elective cardiac surgery showed enhanced myocardial tolerance to in vitro hypoxia-reoxygenation stress among persons receiving coenzyme Q ₁₀ (300 mg daily) for 2 weeks preoperatively, compared with placebo. A preliminary study showed that combining coenzyme Q ₁₀ with mild hypothermia after cardiac arrest improved 3-month survival (17/25 vs 7/24; P = .04) and may improve neurologic outcomes. In parts of Russia, Europe, and Japan, coenzyme Q ₁₀ is part of standard therapy for congestive heart failure. Earlier trials in patients with congestive heart failure demonstrated fewer disease exacerbations, reduced hospitalizations, improved ejection fraction, and more favorable quality-of-life measurements. However, a 1999 study showed that coenzyme Q ₁₀ had no effect on ejection fraction, hemodynamic parameters, or quality of life. A study of 55 patients with class III and class IV congestive heart failure receiving standard medical therapy also showed no benefit of coenzyme Q ₁₀ on ejection fraction, peak oxygen consumption, or exercise duration. Other studies have evaluated coenzyme Q ₁₀ for acute myocardial infarction, angina, diabetes, hypertension, migraine prophylaxis, and periodontal disease. A year-long study of 144 patients who suffered an acute myocardial infarction had fewer nonfatal myocardial infarctions and cardiac deaths. A randomized, placebo-controlled trial of 74 subjects with uncomplicated type 2 diabetes and dyslipidemia showed that coenzyme Q ₁₀ supplementation may improve blood pressure control and long-term glycemic control. Although other medical conditions are also associated with low levels of coenzyme Q ₁₀ , additional randomized controlled clinical trials are needed before supplementation with coenzyme Q ₁₀ can be routinely recommended to improve outcomes for any particular condition.

Because coenzyme Q ₁₀ is lipophilic, it is often formulated with vegetable oil or vitamin E to enhance its absorption. Its bioavailability is also enhanced when it is taken with meals, especially fat-rich foods . Insomnia, elevated liver enzymes, rash, and abdominal complaints are among the mild adverse reactions reported in clinical trials. No serious adverse events have been noted with coenzyme Q ₁₀ use, and it is generally well tolerated. No significant drug-herb interactions have been reported, but coenzyme Q ₁₀ is chemically similar to vitamin K and so theoretically may reduce the effectiveness of warfarin.

Berman M et al: Coenzyme Q ₁₀ in patients with end-stage heart failure awaiting cardiac transplantation: a randomized, placebo-controlled study. Clin Cardiol 2004;27:295.

Damian MS et al: Coenzyme Q ₁₀ combined with mild hypothermia after cardiac arrest: a preliminary study. Circulation 2004;110:3011.

Hodgson JM et al: Coenzyme Q ₁₀ improves blood pressure and glycaemic control: a controlled trial in subjects with type 2 diabetes. Eur J Clin Nutr 2002;56:1137.

Rosenfeldt F et al: Coenzyme Q ₁₀ therapy before cardiac surgery improves mitochondrial function and in vitro contractility of myocardial tissue . J Thorac Cardiovasc Surg 2005;129:25.

Singh RB et al: Effect of coenzyme Q ₁₀ on risk of atherosclerosis in patients with recent myocardial infarction. Mol Cell Biochem 2003;246:75.

Acupuncture

In acupuncture, certain locations on the surface of the body are stimulated, often with needles , to treat illness and promote health. Practitioners trained in Oriental

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medicine believe that a vital energy called chi (pronounced chee ) circulates in the body through 12 main pathways called meridians. Each meridian is named after a particular organ or official, but the term actually relates to the energetic function more than the structure or anatomy of the organ. There are both surface and internal projections for each meridian . The surface projections contain sites called acupuncture points. Oriental medicine practitioners insert needles into these points to influence the body's chi to restore health.

History

The earliest reference to acupuncture can be traced to a text on Chinese medicine called The Yellow Emperor's Classic of Internal Medicine (the Huang Ti Nei Ching ), which dates from the second century BC. This text is often referenced to support the authenticity of a particular practice or theory and is used as part of the curriculum in training colleges. Acupuncture spread through much of Asia and by the sixteenth century Jesuit missionaries had brought the practice to Europe. As early as 1912, William Osler described its use in the first edition of The Principles and Practice of Medicine. For lumbago, he wrote, acupuncture is, in acute cases, the most efficient treatment. Research and enthusiasm in the United States grew dramatically in 1971 when James Reston wrote an article describing his experience with acupuncture for postoperative analgesia after undergoing an appendectomy while in China.

Mechanism of Action

Acupuncture for analgesia stimulates the nerve fibers that enter the dorsal horn of the spinal cord. An impulse is then sent to other levels within the spinal cord, the midbrain, and the hypothalamic- pituitary system, which then release neurotransmitters that cause analgesia. Therefore, when practitioners place a needle in the region of pain, all three centers are activated to provide an analgesic effect. When practitioners place needles in locations distant from the pain site, only the midbrain and hypothalamic-pituitary systems are activated. Although this theory implies that sham acupuncture may be as effective as real acupuncture, experimentally induced acute pain studies in animals and humans have consistently shown that real point stimulation is far superior to sham. These conflicting findings have prevented sham acupuncture from being widely accepted as an appropriate control. The 1998 NIH Consensus Statement on Acupuncture strongly recommends that future acupuncture research focus on finding such a control. A study of functional brain MRI imaging of healthy volunteers identified preferential activation of the hypothalamus and nucleus accumbens and deactivation of the rostral part of the anterior cingulate cortex, amygdala, and hippocampal complex among patients receiving active needling compared with minimally stimulated controls. Chronic pain studies, however, have shown less consistent results.

Yet, in 2003, Han found that acupuncture or electrical stimulation in specific frequencies can facilitate the release of certain neuropeptides in the central nervous system. Peripheral stimulation of the skin or deeper structures showed activation of specific brain structures and the spinal cord via neural pathways, producing profound physiologic effects and stimulating self-healing mechanisms.

Han JS: Acupuncture: neuropeptide release produced by electrical stimulation of different frequencies. Trends Neurosci 2003;26:17.

Stux G, Berman B, Pomeranz B (editors): Basics of Acupuncture. 5th ed. Springer, 2003.

Wu MT et al: Central nervous pathways for acupuncture stimulation: localization of processing with functional MR imaging of the brain ”preliminary experience. Radiology 1999;212:133.

Training, Licensure, & Regulation

Acupuncture educational programs are accredited by the Accreditation Commission for Acupuncture and Oriental Medicine (ACAOM). Typical acupuncture training for nonphysicians in the United States requires completion of an accredited 4-year (2500 hours) master's degree training program. In order to become a licensed acupuncturist (LAc), a national and, frequently, state board examination must be passed. Although many states do not require physicians to obtain additional training, most states require a minimum of 200 hours of training in an accredited program. There are currently over 10,000 licensed acupuncture practitioners and 3000 physician acupuncturists in the United States. In 22 of the 42 states that license, register, or certify acupuncturists, these practitioners are permitted to work independently.

Clinical Practice

In the United States and Europe, Oriental medicine-trained practitioners conduct a comprehensive multisystem history, observation, and physical examination during the initial consultation. Examination consists of palpation of the abdomen and selected acupuncture points; examination of the tongue to assess color , shape, and coating; and palpation of the pulse along the wrist at three locations on both arms to assess its quality, rhythm, and strength. Treatment by the classic acupuncture method is based on the belief that each patient presents with a unique constellation of symptoms and signs. What this means is that ten patients presenting with migraine headaches may receive ten different treatments. Western-style practitioners will conduct a conventional examination and include variable components of the Oriental medicine approach depending on the individual's depth of training. Treatment is based on the formula acupuncture method , which utilizes a fixed combination of acupuncture

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points for a given medical diagnosis such that a cohort of migraine sufferers will be treated in the same way.

Treatment involves inserting four to fifteen needles at selected acupuncture points for 10 “30 minutes ”though certain schools leave the needles in place for only a few seconds to minutes. Needles are approximately 37-gauge, stainless steel , and disposable. Needles are stimulated with electricity, heat, or manually. Follow-up consultations last from 20 minutes to 45 minutes.

Patients can expect to see the practitioner weekly or biweekly for 4 “10 weeks, followed by less frequent visits as the condition improves.

Adverse Events

In current practice in the United States and Europe, acupuncture is generally considered safe, associated with a very low incidence of adverse events. Precautions useful for avoiding serious adverse events are listed in Table 42-4 . The most frequent problems are vasovagal or sedating reactions such as presyncope, syncope, and drowsiness. These are easily prevented by having the patient lie flat on the table, monitoring patients during the initial visit, and permitting the patient to remain in the office until a normal state of awareness is achieved. Serious complications in the literature over the past 30 years have been due to the reuse of needles between patients, leading to transmission of infection such as hepatitis B and C or HIV, and needling the thorax in patients with emphysema, leading to pneumothorax. There have also been case reports of unusual serious adverse events, including endocarditis in patients with prosthetic heart valves who had small indwelling needles in place for several days, cardiac tamponade after needling directly over the heart, spinal cord trauma from deep insertion or migration of cut or broken retained needles, and pacemaker malfunction during acupuncture with electrical stimulation.

Table 42-4. How to avoid preventable adverse events associated with acupuncture.

Make certain that only sterile disposable needles are used.
When press-in needles are used, make certain that sterile technique is used.
Make certain that the patient is lying flat during the treatment.
Make certain that the practitioner counts the number of needles used before and after treatment.
Exert caution when patients are taking anticoagulants.
Avoid electrical stimulation in patients with pacemakers.
Exert caution when needling the thorax in patients with emphysema.

Modified, with permission, from Rampes H: Adverse reactions to acupuncture. In: Medical Acupuncture: A Western Scientific Approach. Filshie J, White A (editors). Churchill Livingstone, 1998.

Most surveys estimate that the frequency of adverse events is 1:100,000 to 1:10,000. A 14-year review of the world literature identified 193 complications and concluded that acupuncture is generally safe except for patients with emphysema, in whom the risk of pneumothorax is significant. Another review identified 300 complications reported in the literature over a 30-year period.

Clinical uses of Acupuncture

In the United States, acupuncture is frequently used to treat acute non-life- threatening conditions or chronic conditions that conventional medicine is unable to treat effectively ( Table 42-5 ). What follows is a survey of some conditions for which patients frequently seek acupuncture care.

Table 42-5. Overview of acupuncture literature for selected medical conditions.

	Condition	Study	Inclusion Criteria	No. of Studies	No. of Patients	Measures	Results
Park, 2001	Stroke rehabilitation	Systematic review	RCTs, all types of stroke.	9	538	Scandinavian and Chinese stroke scales, Barthel Index, Nottingham Health Profile, motor function, balance, and days in hospital.	Overall, acupuncture appears promising for stroke rehabilitation. 6 of 9 trials favor acupuncture compared with control. Future studies require higher study quality to confirm findings.
Sze et al, 2002	Stroke rehabilitation	Meta-analysis	RCTs, intervention within 6 months of stroke.	14	1213	Scandinavian and Chinese stroke scales, Rivermead Mobility Index, Brunnstom Stages, Fugl-Meyer motor scale, Barthel Index Functional Independence Measure, Sunnaas ADL Index	No additional effect on motor recovery, but small positive effect on disability; future studies require higher qualities to ascertain whether effect on disability is due to placebo effect.
Ezzo, 2000	Chronic pain	Systematic review	RCTs published in English. Pain > 3 months.	47	N/A	Positive report of pain relief; otherwise , not specified.	Inconclusive.
Manheimer, 2005	Low back pain	Meta-analysis	RCTs, acute or chronic low back pain.	33	2138	Pain relief.	Acupuncture is significantly more effective than sham treatment for short-term relief of chronic pain, but it is not more effective than other active therapies for chronic low back pain. The data were sparse and inconclusive for acute low back pain.
Furlan, 2005	Low back pain	Systematic review	RCTs, acute and chronic low back pain.	35	2861	Pain and function.	Acupuncture is better than sham or no treatment for short-term relief and improvement of function in chronic low back pain. The data suggest it is a useful adjunct to other therapies.
Ezzo et al, 2001	Osteoarthritis of the knee	Systematic review	RCTs, quasi-RCTs of all languages.	7	393	Pain, function, global improvement, imaging.	For pain and functioning, limited evidence of acupuncture efficacy over control. For pain, real acupuncture is more effective than sham. For functioning, inconclusive evidence that real acupuncture is better than sham.
Ernst, 1998	Acute dental pain	Systematic review	Controlled trials.	16	941	Pain relief.	Definitive conclusion that acupuncture is superior to sham and placebo-controlled acupuncture. Evidence for use as adjunctive therapy.
Melchart, 2002	Recurrent headache	Systematic review	RCTs, quasi-RCTs.	26	1151	Any one clinical outcome related to headache, eg, pain intensity, global assessment.	Overall, the data support acupuncture for the treatment of recurrent headaches. 8/16 found real acupuncture superior to sham acupuncture; 4/16 found a trend favoring real acupuncture.
Linde, 2000	Asthma	Systematic review	Randomized and quasi-randomized trials.	7	174	All subjective and objective outcomes.	There is insufficient evidence to make recommendations about the value of acupuncture for chronic asthma.
Martin et al, 2002	Asthma	Systematic review and meta-analysis	RCTs.	11	N/A	Peak expiratory flow rate, FEV ₁ , and FVC.	Inconclusive. Did not find evidence for value of acupuncture in reducing asthma. However, methodologic limitations of trials were present.
Lee, 1999	Postoperative nausea and vomiting	Meta-analysis	RCTs, trials stimulating P6 acupuncture point by needling, manual pressure, or electricity.	19	N/A	Number of episodes of nausea, vomiting or both 0-6 h or 0-48 h after surgery.	Equal benefit compared with first-line antiemetics. Clear benefit compared with placebo.
White, 2002	Tobacco addiction	Meta-analysis	RCTs.	22	4608	Abstinence	No better than sham acupuncture at 6 weeks, 6 months, 12 months.
RCT = randomized controlled trial; N/A = not applicable ; FEV ₁ = forced expiratory volume in 1 second; FVC = forced vital capacity.

Stroke Rehabilitation

A 2001 systematic review of randomized controlled trials of acupuncture for stroke rehabilitation identified nine trials, including 538 persons meeting study entry criteria. Six of nine trials found acupuncture superior to control interventions, but study quality was poor. These findings suggest that acupuncture appears promising for the treatment of stroke, but studies of high quality are needed to confirm these preliminary findings.

Sze et al performed a meta-analysis assessing the efficacy of acupuncture with and without stroke rehabilitation. Fourteen trials with 1213 patients met the study inclusion criteria. The pooled random-effects estimates of change in motor impairment and disability were 0.06 (95% CI, “0.12 to 0.24) and 0.49 (95% CI, 0.03 to 0.96) for acupuncture and no acupuncture in addition to stroke rehabilitation, respectively. For the comparison of real acupuncture with sham acupuncture, the pooled random-effects estimate of the change in disability was 0.07 (95% CI, “0.34 to 0.48). This study suggests that in conjunction with stroke rehabilitation, acupuncture has no additional effect on motor recovery but has a small positive effect on disability. This may be due to a true placebo effect or to the wide variation in study quality. More high-quality studies are needed to assess the efficacy of acupuncture as an adjunct for stroke rehabilitation.

Park J et al: Effectiveness of acupuncture for stroke: a systematic review. J Neurol 2001;248:558.

Sze FK et al: Does acupuncture improve motor recovery after stroke? A meta-analysis of randomized controlled trials. Stroke 2002;33:2604.

Chronic Pain

A criterion-based review of 51 controlled trials of acupuncture for the treatment of chronic pain found 24 trials reporting results favoring acupuncture. Using a 100-point quality scale, only 11 trials scored at least 50 points. The investigators concluded that poor study quality made it impossible to arrive at definitive

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conclusions. Preliminary results from studies of auricular acupuncture for cancer pain and acupuncture for chronic epicondylitis and chronic neck pain show that acupuncture may be beneficial.

Overall, there is some evidence suggesting benefit of acupuncture for persons with chronic pain when compared with placebo and insufficient evidence to suggest acupuncture is superior to standard medical care or sham acupuncture. The ability to make definitive recommendations regarding efficacy for chronic pain is hampered by poor methodologic study quality.

Alimi D et al: Analgesic effect of auricular acupuncture for cancer pain: A randomized, blinded, controlled trial. J Clin Oncol 2003;15:4120.

Ezzo J et al: Is acupuncture effective for the treatment of chronic pain? A systematic review. Pain 2000;86:217.

Green S et al: Acupuncture for lateral elbow pain. Cochrane Database Syst Rev 2002;(1):CD003527.

Lewith et al: Acupuncture versus placebo for the treatment of chronic mechanical neck pain. A randomized, controlled trial. Ann Intern Med 2004;141:911.

Low Back Pain

Manheimer and colleagues published a meta-analysis in 2005 on acupuncture in the treatment of low back pain that included 33 randomized, controlled trials that met inclusion criteria, involving a total of 2138 patients. For the primary outcome of short-term relief of chronic pain, the meta-analysis showed that acupuncture is significantly more effective than sham treatment and no additional treatment. Similar conclusions were reached in a Cochrane systematic review of 35 randomized controlled trials (involving 2861 patients) published by Furlan and coworkers. Furlan et al also concluded that acupuncture improved function in patients with chronic low back pain. Neither review found that acupuncture was more effective than other active therapies for chronic low back pain. However, when acupuncture was added to other conventional therapies, it relieved pain and improved function more than the conventional therapies alone. Effect sizes tended to be small. The data was sparse and inconclusive for acute low back pain.

Furlan AD et al: Acupuncture and dry-needling for low back pain: an updated systematic review within the framework of the cochrane collaboration. Spine 2005;30:944.

Manheimer E et al: Meta analysis: acupuncture for low back pain. Ann Intern Med 2005;142:651.

Osteoarthritis

In 2001, Ezzo and colleagues performed a systematic review of acupuncture for osteoarthritis of the knee. Seven trials assessed 393 patients on the outcomes of pain, function, global improvement, and imaging. For pain and function, limited support was found for the efficacy of acupuncture over a wait list control or treatment as usual. For pain, real acupuncture was more effective than sham acupuncture. For level of function, however, real acupuncture was not found to be more effective than sham acupuncture.

Vas and colleagues performed a randomized, controlled trial of 97 patients suffering from osteoarthritis of the knee. The patients were separated into two groups: one received acupuncture in conjunction with diclofenac and the other received placebo acupuncture with diclofenac. The study concluded that acupuncture, as an adjunctive therapy to pharmacologic treatment for osteoarthritis of the knee, was more effective than pharmacologic treatment alone.

In a larger and more extensive trial, the NIH funded a multicenter randomized controlled trial based at the University of Maryland; 570 patients were tested to see whether acupuncture provides greater pain relief and improved function compared with sham acupuncture or education in patients with osteoarthritis of the knee. The 570 patients were separated into three groups: 190 patients received true acupuncture, 191 received sham acupuncture, and 189 received educational treatment. Over a period of 26 weeks the two acupuncture groups received a total of 23 sessions. After 8 weeks, optimal acupuncture effects were observed in the experimental, true acupuncture group compared with the sham acupuncture. Overall, Berman and colleagues concluded that acupuncture may have an important role in adjunctive therapy as a part of a multidisciplinary integrative approach to treating symptoms related to knee osteoarthritis.

An additional randomized controlled trial of 300 patients with osteoarthritis of the knee was published in 2005 by Witt et al, comparing acupuncture with sham and no acupuncture. The acupuncture and sham acupuncture groups received twelve treatments over 8 weeks. Sham acupuncture involved superficial needling at nonacupuncture points not at the knee, whereas in the Vas and Berman studies there was no needle penetration. There was greater improvement in the acupuncture group than both the sham and waiting list groups in both pain and function at end of treatment. However, the benefit appeared to decrease over time and was no longer significant at 26 weeks.

Berman BM et al: Effectiveness of acupuncture as adjunctive therapy in osteoarthritis of the knee. Ann Intern Med 2004;141:901.

Ezzo J et al: Acupuncture for osteoarthritis of the knee: A systematic review. Arthritis Rheum 2001;44:819.

Vas J et al: Acupuncture as a complementary therapy to the pharmacological treatment of osteoarthritis of the knee: randomised controlled trial. BMJ 2004;329:1216.

Witt C et al: Acupuncture in patients with osteoarthritis of the knee: a randomised trial. Lancet 2005;366:136.

Acute Dental Pain

The NIH consensus development statement on acupuncture states, There is evidence of efficacy for postoperative dental pain. A review in 1998 identified 16 controlled trials of acupuncture for the treatment of acute dental pain. Among the eight randomized and at

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least partially blinded trials, seven showed benefit. Among the seven trials using sham control, six showed benefit. Subsequent to this review, a randomized, double-blind, placebo acupuncture-controlled trial involving 39 patients evaluated acupuncture for the treatment of postsurgical dental pain. Controls experienced a similar tap sensation next to the acupuncture sites to produce a noticeable sensation; however, needle insertion was not performed. Patients receiving acupuncture scored more favorably than controls on multiple outcomes. There is thus sufficient evidence to recommend the use of acupuncture as effective adjunctive treatment for the treatment of acute dental pain. Multiple studies have demonstrated its efficacy when compared with sham acupuncture.

Ernst E et al: The effectiveness of acupuncture in treating acute dental pain: a systematic review. Br Dent J 1998; 184:443.

Lao L et al: Evaluation of acupuncture for pain control after oral surgery: a placebo-controlled trial. Arch Otolaryngol Head Neck Surg 1999;125:567.

Headache

Melchart et al performed a systematic review in 2002 to evaluate the treatment of acupuncture for recurrent headaches. That group identified 26 randomized and quasi-randomized trials involving 1151 subjects in which 16 trials studied migraine headaches, 6 studied tension headaches, and 4 studied mixed headaches. Of the 16 trials that used sham acupuncture, 8 found real acupuncture superior to sham acupuncture and 4 found a trend in favor of real acupuncture. Two trials found no difference between groups, and 2 trials were uninterpretable. In the remaining 10 trials, conflicting results were reported. Overall, investigators believed there was evidence that acupuncture is effective in the treatment of recurrent headaches.

In a 2004 trial performed by Vickers and colleagues, 401 patients with chronic headache, predominantly migraine, received up to 12 acupuncture treatments and the results showed that the experimental group experienced 22 fewer days of headache per year, used 15% less medication, made 25% fewer visits to general practitioners, and took 15% fewer sick days, in comparison to the group that received no acupuncture in addition to medication . Overall, the study showed that acupuncture leads to persisting , clinically relevant benefits for primary care patients with chronic headache, particularly migraine.

Melchart D et al: Acupuncture for idiopathic headache. Cochrane Database Syst Rev 2002;(1):CD001218.

Vickers AJ et al: Acupuncture for chronic headache in primary care: large, pragmatic, randomised trial. BMJ 2004;328:744.

Asthma

Linde performed a systematic review of randomized and possibly randomized clinical trials that evaluated the effects of acupuncture for the treatment of asthma. Seven trials met study entry criteria, including 174 participants . All trials compared real acupuncture with sham acupuncture. Among the three trials that measured postexpiratory flow rates, there was no difference between the real and sham acupuncture groups. The authors conclude that there is insufficient evidence that acupuncture has a significant treatment effect for people with asthma. No research has evaluated the efficacy of acupuncture as part of a comprehensive treatment program. Among trials reporting positive results, benefit was primarily identified in subjective rather than objective measures. Because asthma can be a life-threatening condition for which effective standard medical therapy exists, acupuncture should be used only as an adjunct to conventional therapy.

Martin performed a systematic review and meta-analysis from 11 randomized controlled trials. Trials compared acupuncture at real and placebo points with outcome measures consisting of at least one of the following: peak expiratory flow rate, forced expiratory volume in 1 second (FEV ₁ ), and vital capacity. Studies in which bronchoconstriction was experimentally induced showed a significant effect favoring real acupuncture. Overall, no evidence for an effect of acupuncture in reducing asthma was found; however, methodologic shortcomings such as small sample size may have precluded identifying statistically significant differences between groups.

Linde K et al: Acupuncture for chronic asthma. Cochrane Database Syst Rev 2000;(2):CD000008.

Martin J et al: Efficacy of acupuncture in asthma: systematic review and meta-analysis of published data from 11 randomised controlled trials. Eur Respir J 2002;20:846.

Nausea & Vomiting

Based on multiple randomized controlled trials, there is strong evidence demonstrating effectiveness of acupuncture in the treatment of pregnancy-induced, chemotherapy-induced, and postoperative nausea and vomiting. One review identified 33 trials using a particular acupuncture point (P6) for treatment of nausea and vomiting. None of the four trials in which acupuncture was given while the patient was under general anesthesia demonstrated a positive effect. Among the remaining 29 trials, 27 identified real acupuncture as being more effective than sham acupuncture or placebo control. In subgroup analyses, all five studies evaluating acupuncture for cancer chemotherapy-induced nausea and vomiting were positive. Six of the seven studies for pregnancy-induced symptoms were positive. Among trials in which acupuncture was performed while the subjects were not under general anesthesia, 16 of 17 studies of treatment for postoperative nausea and vomiting were positive. In sensitivity analyses, 11 of the 12 high-quality trials involving over 2000 patients identified acupuncture as superior to control. A subsequent review on studies of treatment

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for postoperative nausea and vomiting reported acupuncture to be equivalent to first-line antiemetics in preventing early and late vomiting. The NIH consensus development panel on acupuncture stated, There is clear evidence that needle acupuncture is efficacious for adult postoperative and chemotherapy induced nausea and vomiting and probably for the nausea of pregnancy.

Lee A et al: The use of nonpharmacologic techniques to prevent postoperative nausea and vomiting: a meta-analysis. Anesth Analg 1999;88:1362.

Shen J et al: Electroacupuncture for control of myeloablative chemotherapy-induced emesis. JAMA 2000;284:2755.

Vickers AJ: Can acupuncture have specific effects on health? A systematic review of acupuncture antiemesis trials. J R Soc Med 1996;89:303.

Nicotine, Heroin, Cocaine, & Alcohol Addiction

There is good evidence suggesting that acupuncture is not effective in maintaining abstinence from nicotine addiction. Systematic reviews have identified multiple trials of sufficient quality to determine that there is no evidence to support its use. In a randomized trial comparing electroacupuncture and sham control for nicotine withdrawal symptoms, there was no difference in nicotine withdrawal symptoms or abstinence rates at day 14. The NIH consensus development statement acupuncture states, There is evidence that acupuncture does not demonstrate efficacy for cessation of smoking.

Despite insufficient evidence to support its use, auricular acupuncture is in widespread use throughout American drug treatment facilities. Although heroin, alcohol, and cocaine addiction studies have frequently reported positive outcomes, serious methodologic flaws are present. For example, an 8-week clinical trial showed patients assigned to acupuncture were significantly more likely to remain abstinent from cocaine use. However, analyses did not adjust for the 50% versus 20% dropout rate in the acupuncture and relaxation groups, respectively. A randomized controlled, single-blind trial conducted in six community-based clinics in the United States found that acupuncture was not more effective than needle insertion control or relaxation alone in reducing cocaine use. Until scientifically rigorous studies can demonstrate efficacy, acupuncture should not be used as monotherapy in the treatment of these addictions.

Avants SK et al: A randomized controlled trial of auricular acupuncture for cocaine dependence. Arch Intern Med 2000;160:2305.

Margolin A et al: Acupuncture for the treatment of cocaine addition: a randomized controlled trial. JAMA 2002;287:55.

White A et al: Acupuncture for smoking cessation. Cochrane Database Syst Rev 2002;(2):CD000009.

Homeopathy

Christian F.S. Hahnemann is credited with devising the system of homeopathy in 1790. Three main principles of homeopathy include the law of similars, the use of dilute concentrations of medicines, and potentization. The second and third principles remain the most controversial for many scientists and conventionally trained physicians.

The law of similars is also known as the principle of like cures like ; it is derived from the observation that a homeopathic medicine when given to a healthy volunteer will produce a constellation of symptoms similar to those it will cure in an ill patient. Since the 1800s, the process of testing medicines on healthy volunteers to record the symptoms provoked (known as provings ) has been recorded and compiled to create several materia medicas. A randomized double-blind crossover trial was performed to evaluate whether homeopathic substances can bring about symptoms different from observation and placebo. Investigators report an insignificant tendency to report more symptoms when taking belladonna 30CH compared with control arms. However, there was no indication that symptoms were different between groups or compared with baseline presentations.

The second principle ”the use of dilute concentrations of medicine ”entails serially diluting and succussing (shaking) a substance to concentrations in which there is little probability of any molecules remaining in solution. Homeopathic physicians assert that these remedies remain pharmacologically active and allude to allergy desensitization and immunization as sharing similar approaches to homeopathy in that both use low doses of potentially toxic substances to achieve beneficial clinical effects.

Potentization is based on the claim that once a medicine is at low concentration, the more dilute the solute the more potent the effect.

The World Health Organization states that homeopathy is the second most used medical system internationally, with over $1 billion in expenditures for such therapy. Twenty to 30 percent of French and German physicians use homeopathy in clinical practice. In Great Britain, five homeopathic hospitals are part of the National Health System, and over 30% of generalists use homeopathy. In the United States, there are more than 500 physicians and 5000 nonphysicians using homeopathy in clinical practice, and 2.5 million Americans currently use homeopathic medicines ”of which two- thirds are self-prescribed ”spending more than $250 million annually.

Mechanisms of Action

Although there are several mechanisms under investigation, none are well validated. One of the more interesting findings in the chemistry literature reports the

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presence of the solute clusters in highly diluted water. This report requires independent replication and if confirmed requires demonstration of the clinical effects in living organisms.

Adverse Events & Interactions

Given the low concentration of homeopathic medicines, the probability of adverse events is remote. However, adverse events have been reported from ingestion of large quantities of remedies containing heavy metals. Some patients report an exacerbation of symptoms initially. Homeopaths explain this reaction as the initial phase of the healing response. Homeopathic remedies are not known to have interaction with conventional medicines.

Training, Licensure, & Regulation

In Europe, practitioners usually enroll in a 3 “6 year professional degree program or physicians enroll in postgraduate training. In the United States, homeopathic educational programs are accredited by the Council for Homeopathic Education, which was founded in 1982 as an independent agency to assess homeopathic training in the United States and Canada. There are two levels of training for homeopaths. The Primary Care Certificate in Homeotherapeutics requires 60 “100 hours of course work and passage of a written examination. The more advanced level, the Diplomate in Homeotherapeutics (DHt), requires an additional 3 years of clinical practice. There is comprehensive homeopathic training that involves 3 or more years of part-time to full-time study. Nonphysicians may practice homeopathy within the scope of practice of their specific profession. The American Board of Homeotherapeutics governs certification for physicians; the Homeopathic Association of Naturopathic Physicians governs naturopaths; and the Council for Homeopathic Certification governs all other practitioners. Physicians are licensed to practice homeopathy in three states (Connecticut, Arizona, and Nevada).

The Homeopathic Pharmacopoeia of the United States was included in the original Food and Drug Act of 1938, which declared that homeopathic remedies may be purchased without a physician prescription, in the same manner as over-the-counter, nonprescription compounds. Unlike over-the-counter drugs in the United States, there is no requirement for testing for safety and effectiveness. However, the FDA does require the products to meet good manufacturing practices for quality, purity, packaging, and strength. In addition, the FDA requires companies to include on the label indications for use, dilutions, and ingredients.

Clinical Encounter

The initial consultation takes about 1 “1.5 hours, with significant time spent on obtaining a detailed history. Attention is given to the physical, mental, and emotional symptoms, overall personality type, and any internal or external factors that influence the presenting symptoms, such as emotions, wind, season of the year, and reactions to different foods. The symptom inventory is then matched to an appropriate remedy taken from the materia medica. Follow-up visits may last for a few minutes to 40 minutes. During the follow-up visit, the practitioner determines if there has been improvement in symptoms, no change, or aggravation of symptoms. The latter scenario, if transient, is viewed as the first sign of recovery.

Clinical Uses

Homeopathic physicians are trained to treat a broad range of conditions in the primary care and specialty setting. In clinical practice, however, practitioners frequently treat patients with chronic conditions that conventional medicine cannot adequately address, including arthritis, allergies, autoimmune diseases, or non-life-threatening acute conditions such as viral infections or minor trauma. Parents may take their children to homeopathic physicians for recurrent conditions such as otitis media and allergies with the goal of avoiding repetitive antibiotic, corticosteroid, or long-term conventional medications.

Research

The findings for individual randomized controlled trials on homeopathy have been contradictory. Over 180 controlled trials and over 10 reviews have been published on the effects of homeopathy compared with placebo. The majority of trials are published in non-English language journals and are frequently not listed in Medline. A few methodologically rigorous reviews have been published in English ( Table 42-6 ). The majority of systematic reviews have pooled trials on homeopathy regardless of the medical condition being treated. Many reviews have found that patient outcomes in homeopathic treatment groups were superior to placebo group outcomes. Since many of the trials do not provide in-depth reports on the treatment encounter, it remains unclear whether these positive effects are specific to the homeopathic remedy itself or to nonspecific effects that occur as part of the treatment encounter. Since few trials have been replicated by independent investigators, there is insufficient evidence to determine whether treatment effects found for a single medical condition are reproducible. Conditions with the best evidence for a positive clinical effect include acute childhood diarrhea, influenza, and postoperative ileus; whereas, the homeopathic remedy arnica frequently used to reduce tissue trauma appears to have no clinical benefit over placebo ( Table 42-6 ).

Table 42-6. Overview of English language homeopathy systematic reviews.

	Condition or Remedy	Inclusion Criteria	No. of Studies	Measures	Results	Conclusions
Linde, 1997	No limitation	RBTs or RCTs	89	Pooled summary estimates	Overall: OR = 2.45 (95% CI 2.0-2.9) High-quality: OR = 1.7 (95% CI 1.3-2.1) Publication-bias correction: OR = 1.8 (95% CI 1.0-3.1) Seasonal allergies ¹ : OR = 2.0 (95% CI 1.5-2.7) Postoperative ileus ² : effect-size difference = -0.22 SD (95% CI -0.33 to -0.03)	Positive findings. Unable to determine whether homeopathy is effective for any single clinical condition under prior defined criteria.
Cucherat, 2000	No limitation	RCTs with clearly defined primary outcome	16	Pooled summary estimates	Overall: P = 0.000036 High-quality trials: P = .08	Positive findings overall. Study quality is inversely associated with probability of obtaining a statistically significant result.
Barnes, 1997	Postoperative ileus/no limitations	RCTs	6	Pooled summary estimates	Time to first flatus: 7.4 hours earlier favoring homeopathy ( P < .05). Effect remained after adjustment for study quality.	Clinically meaningful effect with reservation due to variable study quality of trials.
Ernst, 1998	No limitation/Arnica	RCTs	8	Descriptive analysis	6 of 8 trials showed no statistically significant benefit over placebo.	Arnica appears no more effective than placebo. Most studies evaluated Arnica for tissue trauma and bruising.
Vickers, 2004	Influenza/Oscillococcinum	RBTs	7	Pooled summary estimates	Length of illness: 0.28 days reduction (95% CI 0.50-0.06). Prevention of influenza: RR = 0.64 (95% CI 0.28-1.43)	Reduction in length of illness promising; however, not sufficient to recommend as first-line therapy. Current evidence does not support Oscillococcinum for influenza prevention.
Jacobs, 2003	Childhood diarrhea/individualized treatment	Convenient sample of RBTs	3	Pooled summary estimate	Duration of diarrhea: 0.66 day reduction ( P = .008)	Individualized homeopathic treatment decreases duration of childhood diarrhea.
McCarney, 2004	Chronic asthma/no limitation	RCTs	6	Descriptive analysis	Conflicting results for lung function between studies. No trial reported significant difference on validated symptom scales.	Insufficient evidence to assess effectiveness.
¹ Not independent investigators. ² Different remedies used. RBT = randomized double-blind trial; RCT = randomized controlled trial; OR = odds ratio; CI = confidence interval.

A 1997 systematic review identified 89 double-blind or randomized placebo-controlled trials and found the overall combined odds ratio was 2.45 (95% CI, 2.0 “2.9) favoring patients in the homeopathy-treated group. Analyses restricted to high-quality studies

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found similar statistically significant results with an odds ratio of 1.66 (95% CI, 1.3 “2.1); this effect persisted after adjustment for publication bias. Pooled analysis of four multicenter trials by the same investigator evaluating the effects of Galphimia glauca for seasonal allergies found an odds ratio of 2.0 (95% CI, 1.5 “2.7) for improvement in ocular and nasal symptoms at 4 weeks.

A meta-analysis conducted in 2000 identified 118 randomized controlled clinical trials of which 16 satisfied inclusion criteria. Investigators reported that patients receiving homeopathic remedies compared with placebo were significantly more likely to have improved treatment outcomes (P = .00003); however, analyses limited to the five high-quality studies revealed only a trend for improvement (P = .08). Overall, there is some evidence that homeopathy is more effective than placebo; however, multiple high-quality studies of individual conditions are needed to validate these findings.

Cucherat M et al: Evidence of clinical efficacy of homeopathy: a meta-analysis of clinical trials. Eur J Clin Pharmacol 2000;56:27.

Jacobs J et al: Homeopathy for childhood diarrhea: combined results and meta-analysis from three randomized, controlled clinical trials. Pediatr Infect Dis J 2003:22:229.

Jonas W: Neuroprotection from glutamate toxicity with ultra -low dose glutamate. Neuroreport 2001;12:335.

Linde K et al: Are the clinical effects of homeopathy placebo effects? A meta-analysis of placebo-controlled trials. Lancet 1997;350:834.

McCarney R et al: Homeopathy for chronic asthma. Cochrane Database Syst Rev 2004;1:CD000353.

Reilly D et al: Is evidence for homoeopathy reproducible? Lancet 1994;344:1601.

Samal S et al: Unexpected solute aggregation in water on dilution. Chem Commun (Camb) 2001;(21):2224.

Vickers AJ: Homoeopathic Oscillococcinum for preventing and treating influenza and influenza-like syndromes. Cochrane Database Syst Rev 2004;(1):CD001957.

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