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Prescribing herbal medications appropriately
Do you know how many of your patients are taking herbal preparations? With the proliferation of herbal products, the number could be greater than you think. Between 1990 and 1997, the US population increased its use of herbal medicines by 380%.1 Total out-of-pocket expenditure for herbal medicines in 1997 was $5.1 billion.1Table 1 lists the 10 best-selling herbal medicines in the US.2
Safety issues related to herbal medicine are complex: possible toxicity of herbal constituents, presence of contaminants or adulterants, and potential interactions between herbs and prescription drugs. The quality of herbal medicines is often suboptimal. One reason for this is that they are not adequately regulated, and many experts are calling for a change in this situation. Cost-evaluations of herbal medicine are not available, so they cannot form the basis for clinical decisions.
This article provides guidelines for prescribing herbal medications appropriately.
TABLE 1
10 best-selling herbal medicines (United States, 2001)
| Rank | Herb | Retail sales |
|---|---|---|
| 1 | Ginkgo biloba | 46 |
| 2 | Echinacea | 40 |
| 3 | Garlic | 35 |
| 4 | Ginseng | 31 |
| 5 | Soy | 28 |
| 6 | Saw palmetto | 25 |
| 7 | St John’s wort | 24 |
| 8 | Valerian | 12 |
| 9 | Cranberry | 10 |
| 10 | Black cohosh | 10 |
| Retail sales are rounded figures in million US dollars. | ||
Efficacy
One of the first things to consider when a patient proposes trying an herbal medicine is efficacy. Data on efficacy of herbal medicines are incomplete, yet some treatments have shown promise. The critical question is, Does the remedy work for the patient’s condition? Clinicians should not prescribe or recommend herbal remedies if that question cannot be answered with a firm Yes.
Medical herbalism (ie, the medicinal use of preparations that contain exclusively plant material) once dominated our pharmacopeia but went into rapid decline when pharmacology established itself as a leading branch of therapeutics. During the last part of the 19th and the early 20th century, herbalism virtually vanished from the therapeutic map of the US and the UK. In contrast, many developing countries never abandoned medical herbalism (Ayurvedic medicine in India, Kampo medicine in Japan, and Chinese herbalism in China). In other countries (such as Germany and France), medical herbalism continued a “low-key” coexistence with modern pharmacology. More recently, herbal medicine has experienced a remarkable comeback.
Herbal medicines usually contain a range of pharmacologically active compounds. In some cases it is not known which of these constituents produces the therapeutic effect. Testing for efficacy in this situation is obviously more complex than with synthetic drugs. One approach is to view the entire herbal extract as the active component. To optimise the reproducibility of efficacy studies, extracts must be sufficiently characterised. This is often achieved by standardizing the amount of a single key constituent of the extract (eg, a pharmacologically active ingredient or, if such an ingredient is not known, a marker suitable substance).
Other than the dilemma of standardization, herbal medicines can be scrutinized in clinical trials in much the same way as are other drugs. Several randomized clinical trials of herbal medicines have been published, and systematic reviews/meta-analyses of these studies have become available (Table 2).3,4 The Cochrane database includes about 30 systematic reviews of herbal medicines, and several authoritative books have recently become available.3-6 The conclusions of systematic reviews are often limited by the paucity and varied methodological quality of the primary studies.3,7 Research funds in this area are generally scarce, not least because plants are not patentable.
Generalizations about efficacy of herbal medicines are not possible; each one must be judged on its own merits. Some herbal products have demonstrated efficacy for certain conditions, while others have not. Most products have not been submitted to extensive clinical testing.3 “Clinicians should not prescribe or recommend herbal remedies without well-established efficacy….”7
TABLE 2
Examples of systematic reviews and meta-analyses of herbal remedies
| Common (Latin) name | Active ingredients | Indications | No. of trials | Avg. methodological quality of primary studies | Efficacy | Main result |
|---|---|---|---|---|---|---|
| Feverfew (Tanacetum parthenium) | Parthenolide | Migraine prevention | 5 | Good | Likely | 3 trials were positive, 2 were negative |
| Garlic (Allium sativum) | Alliin | Hypercholesterolemia | 13 | Good (some excellent) | Certain but effect small | Overall effect is significant but of debateable clinical relevance |
| Ginkgo (Ginkgo biloba) | Ginkgolides, bilobalide | Intermittent claudication | 8 | Good to excellent | Certain | Overall positive result |
| Horse chestnut seed extract (Aesculus hippocastanum) | Triterpene saponins | Chronic venous insufficiency | 8/5* | Good | Likely | Active treatment more effective than placebo and equally effective as reference treatments |
| Peppermint oil (Menta x piperial)† | Menthol | Symptoms of irritable bowel syndrome | 8 | Good | Likely | Positive effect of peppermint oil compared with placebo |
| Sources: Ernst et al 20013; Fugh-Berman 2003.4 | ||||||
| *8 trials vs placebo; 5 trials vs reference treatments. † Am J Gastroenterol 1997; 93:1131–1135. | ||||||
Safety
Consumers are attracted to herbal medicines in part because they equate “natural” with “safe.” Yet some herbal medicines pose serious risks.7
First, the active ingredients in herbal preparations can, of course, cause desirable as well as undesirable effects. Table 3 lists examples of commonly used herbal medicines that have been associated with serious adverse effects.3 Traditional use is no guarantee of safety and no acceptable substitute for data.8
A poignant example is kava (Piper methysticum), an herbal remedy that has been used for centuries apparently without problems. Numerous rigorous clinical trials have shown it to be a powerful anxiolytic medicine.9 Recently it has been associated with several cases of serious liver damage.10 Hence it has been withdrawn from the markets of several European countries, and the FDA has issued warnings about its hepatotoxic potential.
Second, the active ingredients in herbal medicines might interact with prescription drugs. For instance, extracts of St. John’s wort (Hypericum perforatum) act as an enzyme inducer on the cytochrome P450 system and increase the activity of the P-glycoprotein transmembrane transporter mechanism. Both effects lead to a reduction of the plasma level of several conventional drugs.11 Perhaps the most serious consequence could be insufficiently low cyclosporine levels in patients after organ transplantation, which jeopardize the success of this procedure.12
Third, some herbal medicines (particularly Asian herbal mixtures) have repeatedly been shown to be contaminated with heavy metals,13 or to contain misidentified herbal ingredients that turned out to be toxic,14 or to be adulterated with prescription drugs.15
Before prescribing or recommending an herbal medication, clinicians must ensure that it cannot generate undue harm.
TABLE 3
Examples of herbal medicines associated with serious adverse effects
| Common (Latin) name | Indication | Adverse effects (examples) |
|---|---|---|
| Aloe vera (Aloe barbadensis) | Various | Juice may cause intestinal pain and electrolyte loss |
| Feverfew (Tanacetum parthenium) | Migraine prevention | “Post-fever syndrome” after discontinuation (migraine, anxiety, insomnia, muscle stiffness) |
| Hawthorn (Crataegus) | Congestive heart failure | Additive effects with other cardiac glycosides |
| Kava (Piper methysticum) | Anxiety | Toxic liver damage |
| St. John’s wort (Hypericum perforatum) | Depression | Increased clearance of a range of prescribeddrugs |
| Tea tree oil (Malaleuca alternifolia) | Skin problems (external) | Allergic reactions |
| Valerian (Valeriana officinalis) | Insomnia | Morning hangover |
| Without positive data demonstrating safety, herbal medications cannot automatically be considered safe for pregnant or nursing women. | ||
Quality
The quality of an herbal preparation partly determines its efficacy as well as its safety. Herbal dietary supplements are not usually regulated as drugs and have repeatedly been found to vary in quality, sometimes being suboptimal.7,16
In the US, such preparations have to meet the requirements set forth in the Dietary Supplement and Health Education Act (DSHEA) of 1994. Thus they are marketed without approval of their efficacy and safety by the FDA. The DSHEA does not allow medical claims to be made for such products. Structure or functional claims are, however, allowed. If safety concerns of a product arise, the burden of proof lies not with its manufacturer but with the FDA. Many experts find this regulation insufficient to guarantee consumer safety and argue for it to be changed.16 In Europe, new legislation will soon regulate herbal medicines. Essentially the legislation will provide that efficacy be demonstrated on the basis of bibliographic data; safety, too, will be governed as it is with conventional drugs.17
Cost
Clinicians should recommend treatments that save money for patients and the healthcare system. Many herbal medications are relatively inexpensive. However, very few proper economic analyses of herbal medicines exist.18,19 So far, only 1 cost evaluation of an herbal medicine has been published.20 This study of symptomatic treatment of chronic venous insufficiency compared the cost-effectiveness of compression stockings with that of an extract of horse chestnut seeds. Its results implied that the treatments were similarly effective and associated with similar costs.
For the prescribing physician, this means decisions cannot presently be based on conclusive cost-analyses. While waiting for such data to become available, decisions will have to be informed by our knowledge on the efficacy, safety, and quality of herbal medications.
Correspondence
Edzard Ernst, MD, PhD, Complementary Medicine, Peninsula Medical School, Universities of Exeter and Plymouth, 25 Victoria Park Road, Exeter EX2 4NT, United Kingdom. E-mail: [email protected].
1. Eisenberg DM, David RB, Ettner SL, et al. Trends in alternative medicine use in the United States. JAMA 1998;280:1569-1575.
2. Blumenthal M. Herb sales down in mainstream market, up in natural food stores. Herbal Gram 2002;55:60.-
3. Ernst E, Pittler MH, Stevinson C, White AR. The Desktop Guide to Complementary and Alternative Medicine. Edinburgh: Mosby; 2001.
4. Fugh-Berman A. The 5-minute herb & dietary supplement consult. Philadelphia: Lippincott Williams & Wilkins; 2003.
5. Capasso F, Gaginella TS, Grandolini G, Izzo AA. Phytotherapy: A Quick Reference to Herbal Medicine. Berlin: Springer-Verlag; 2003.
6. Schulz V, Hänsel R, Tyler VE. Rational Phytotherapy. Berlin: Springer-Verlag; 2001.
7. De Smet PAGM. Herbal remedies. N Engl J Med 2002;347:2046-2056.
8. Ernst E, De Smet PAGM, Shaw D, Murray V. Traditional remedies and the “test of time.” Eur J Clin Pharmacol 1998;54:99-100.
9. Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Library 2002.
10. Teschke R, Gaus W, Loew D. Kava extracts: safety and risks including rare hepatotoxicity. Phytomed 2003;10:440-446.
11. Carlo GD, Borrelli F, Ernst E, Izzo AA. St. John’s wort: Prozac from the plant kingdom. TRENDS in Pharmacol Sci 2001;22:292-297.
12. Ernst E. St John’s wort supplements endanger the success of organ transplantation. Arch Surg 2002;137:316-319.
13. Ernst E, Thompson Coon J. Heavy metals in traditional Chinese medicines: a systematic review. Clin Pharmacol Ther 2001;70:497-504.
14. Nortier JL, Muniz Martinez. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med 2000;342:1686-1692.
15. Ernst E. Adulteration of Chinese herbal medicines with synthetic drugs: a systematic review. J Int Med 2002;251:107-113.
16. De Angelis CD, Fontanarosa PB. Drugs alias dietary supplements. JAMA 2003;290:1519-1520.
17. Silano M, De Vincenzi M, De Vincenzi A, Silano V. The new European legislation on traditional herbal medicines: main features and perspectives. Fitoterapia 2004;75:107-116.
18. Kernick D, White A. Applying economic evaluation to complementary and alternative medicine. In: Getting Health Economics into Practice, ed. Kernick DE. Oxford: Radcliffe Medical Press; 2002;173-180.
19. De Smet PAGM, Bonsel G, Van der Kuy A, et al. Introduction to the pharmacoeconomics of herbal medicines. Pharmacoeonomics 2000;18:1-7.
20. Rychlik R, Marshall M, Bachinger A, et al. Ökonomische Aspekte der Therapie der chronisch venösen Insuffizienz. Gesundh ökon Qual Manag 1997;2:86-91.
Do you know how many of your patients are taking herbal preparations? With the proliferation of herbal products, the number could be greater than you think. Between 1990 and 1997, the US population increased its use of herbal medicines by 380%.1 Total out-of-pocket expenditure for herbal medicines in 1997 was $5.1 billion.1Table 1 lists the 10 best-selling herbal medicines in the US.2
Safety issues related to herbal medicine are complex: possible toxicity of herbal constituents, presence of contaminants or adulterants, and potential interactions between herbs and prescription drugs. The quality of herbal medicines is often suboptimal. One reason for this is that they are not adequately regulated, and many experts are calling for a change in this situation. Cost-evaluations of herbal medicine are not available, so they cannot form the basis for clinical decisions.
This article provides guidelines for prescribing herbal medications appropriately.
TABLE 1
10 best-selling herbal medicines (United States, 2001)
| Rank | Herb | Retail sales |
|---|---|---|
| 1 | Ginkgo biloba | 46 |
| 2 | Echinacea | 40 |
| 3 | Garlic | 35 |
| 4 | Ginseng | 31 |
| 5 | Soy | 28 |
| 6 | Saw palmetto | 25 |
| 7 | St John’s wort | 24 |
| 8 | Valerian | 12 |
| 9 | Cranberry | 10 |
| 10 | Black cohosh | 10 |
| Retail sales are rounded figures in million US dollars. | ||
Efficacy
One of the first things to consider when a patient proposes trying an herbal medicine is efficacy. Data on efficacy of herbal medicines are incomplete, yet some treatments have shown promise. The critical question is, Does the remedy work for the patient’s condition? Clinicians should not prescribe or recommend herbal remedies if that question cannot be answered with a firm Yes.
Medical herbalism (ie, the medicinal use of preparations that contain exclusively plant material) once dominated our pharmacopeia but went into rapid decline when pharmacology established itself as a leading branch of therapeutics. During the last part of the 19th and the early 20th century, herbalism virtually vanished from the therapeutic map of the US and the UK. In contrast, many developing countries never abandoned medical herbalism (Ayurvedic medicine in India, Kampo medicine in Japan, and Chinese herbalism in China). In other countries (such as Germany and France), medical herbalism continued a “low-key” coexistence with modern pharmacology. More recently, herbal medicine has experienced a remarkable comeback.
Herbal medicines usually contain a range of pharmacologically active compounds. In some cases it is not known which of these constituents produces the therapeutic effect. Testing for efficacy in this situation is obviously more complex than with synthetic drugs. One approach is to view the entire herbal extract as the active component. To optimise the reproducibility of efficacy studies, extracts must be sufficiently characterised. This is often achieved by standardizing the amount of a single key constituent of the extract (eg, a pharmacologically active ingredient or, if such an ingredient is not known, a marker suitable substance).
Other than the dilemma of standardization, herbal medicines can be scrutinized in clinical trials in much the same way as are other drugs. Several randomized clinical trials of herbal medicines have been published, and systematic reviews/meta-analyses of these studies have become available (Table 2).3,4 The Cochrane database includes about 30 systematic reviews of herbal medicines, and several authoritative books have recently become available.3-6 The conclusions of systematic reviews are often limited by the paucity and varied methodological quality of the primary studies.3,7 Research funds in this area are generally scarce, not least because plants are not patentable.
Generalizations about efficacy of herbal medicines are not possible; each one must be judged on its own merits. Some herbal products have demonstrated efficacy for certain conditions, while others have not. Most products have not been submitted to extensive clinical testing.3 “Clinicians should not prescribe or recommend herbal remedies without well-established efficacy….”7
TABLE 2
Examples of systematic reviews and meta-analyses of herbal remedies
| Common (Latin) name | Active ingredients | Indications | No. of trials | Avg. methodological quality of primary studies | Efficacy | Main result |
|---|---|---|---|---|---|---|
| Feverfew (Tanacetum parthenium) | Parthenolide | Migraine prevention | 5 | Good | Likely | 3 trials were positive, 2 were negative |
| Garlic (Allium sativum) | Alliin | Hypercholesterolemia | 13 | Good (some excellent) | Certain but effect small | Overall effect is significant but of debateable clinical relevance |
| Ginkgo (Ginkgo biloba) | Ginkgolides, bilobalide | Intermittent claudication | 8 | Good to excellent | Certain | Overall positive result |
| Horse chestnut seed extract (Aesculus hippocastanum) | Triterpene saponins | Chronic venous insufficiency | 8/5* | Good | Likely | Active treatment more effective than placebo and equally effective as reference treatments |
| Peppermint oil (Menta x piperial)† | Menthol | Symptoms of irritable bowel syndrome | 8 | Good | Likely | Positive effect of peppermint oil compared with placebo |
| Sources: Ernst et al 20013; Fugh-Berman 2003.4 | ||||||
| *8 trials vs placebo; 5 trials vs reference treatments. † Am J Gastroenterol 1997; 93:1131–1135. | ||||||
Safety
Consumers are attracted to herbal medicines in part because they equate “natural” with “safe.” Yet some herbal medicines pose serious risks.7
First, the active ingredients in herbal preparations can, of course, cause desirable as well as undesirable effects. Table 3 lists examples of commonly used herbal medicines that have been associated with serious adverse effects.3 Traditional use is no guarantee of safety and no acceptable substitute for data.8
A poignant example is kava (Piper methysticum), an herbal remedy that has been used for centuries apparently without problems. Numerous rigorous clinical trials have shown it to be a powerful anxiolytic medicine.9 Recently it has been associated with several cases of serious liver damage.10 Hence it has been withdrawn from the markets of several European countries, and the FDA has issued warnings about its hepatotoxic potential.
Second, the active ingredients in herbal medicines might interact with prescription drugs. For instance, extracts of St. John’s wort (Hypericum perforatum) act as an enzyme inducer on the cytochrome P450 system and increase the activity of the P-glycoprotein transmembrane transporter mechanism. Both effects lead to a reduction of the plasma level of several conventional drugs.11 Perhaps the most serious consequence could be insufficiently low cyclosporine levels in patients after organ transplantation, which jeopardize the success of this procedure.12
Third, some herbal medicines (particularly Asian herbal mixtures) have repeatedly been shown to be contaminated with heavy metals,13 or to contain misidentified herbal ingredients that turned out to be toxic,14 or to be adulterated with prescription drugs.15
Before prescribing or recommending an herbal medication, clinicians must ensure that it cannot generate undue harm.
TABLE 3
Examples of herbal medicines associated with serious adverse effects
| Common (Latin) name | Indication | Adverse effects (examples) |
|---|---|---|
| Aloe vera (Aloe barbadensis) | Various | Juice may cause intestinal pain and electrolyte loss |
| Feverfew (Tanacetum parthenium) | Migraine prevention | “Post-fever syndrome” after discontinuation (migraine, anxiety, insomnia, muscle stiffness) |
| Hawthorn (Crataegus) | Congestive heart failure | Additive effects with other cardiac glycosides |
| Kava (Piper methysticum) | Anxiety | Toxic liver damage |
| St. John’s wort (Hypericum perforatum) | Depression | Increased clearance of a range of prescribeddrugs |
| Tea tree oil (Malaleuca alternifolia) | Skin problems (external) | Allergic reactions |
| Valerian (Valeriana officinalis) | Insomnia | Morning hangover |
| Without positive data demonstrating safety, herbal medications cannot automatically be considered safe for pregnant or nursing women. | ||
Quality
The quality of an herbal preparation partly determines its efficacy as well as its safety. Herbal dietary supplements are not usually regulated as drugs and have repeatedly been found to vary in quality, sometimes being suboptimal.7,16
In the US, such preparations have to meet the requirements set forth in the Dietary Supplement and Health Education Act (DSHEA) of 1994. Thus they are marketed without approval of their efficacy and safety by the FDA. The DSHEA does not allow medical claims to be made for such products. Structure or functional claims are, however, allowed. If safety concerns of a product arise, the burden of proof lies not with its manufacturer but with the FDA. Many experts find this regulation insufficient to guarantee consumer safety and argue for it to be changed.16 In Europe, new legislation will soon regulate herbal medicines. Essentially the legislation will provide that efficacy be demonstrated on the basis of bibliographic data; safety, too, will be governed as it is with conventional drugs.17
Cost
Clinicians should recommend treatments that save money for patients and the healthcare system. Many herbal medications are relatively inexpensive. However, very few proper economic analyses of herbal medicines exist.18,19 So far, only 1 cost evaluation of an herbal medicine has been published.20 This study of symptomatic treatment of chronic venous insufficiency compared the cost-effectiveness of compression stockings with that of an extract of horse chestnut seeds. Its results implied that the treatments were similarly effective and associated with similar costs.
For the prescribing physician, this means decisions cannot presently be based on conclusive cost-analyses. While waiting for such data to become available, decisions will have to be informed by our knowledge on the efficacy, safety, and quality of herbal medications.
Correspondence
Edzard Ernst, MD, PhD, Complementary Medicine, Peninsula Medical School, Universities of Exeter and Plymouth, 25 Victoria Park Road, Exeter EX2 4NT, United Kingdom. E-mail: [email protected].
Do you know how many of your patients are taking herbal preparations? With the proliferation of herbal products, the number could be greater than you think. Between 1990 and 1997, the US population increased its use of herbal medicines by 380%.1 Total out-of-pocket expenditure for herbal medicines in 1997 was $5.1 billion.1Table 1 lists the 10 best-selling herbal medicines in the US.2
Safety issues related to herbal medicine are complex: possible toxicity of herbal constituents, presence of contaminants or adulterants, and potential interactions between herbs and prescription drugs. The quality of herbal medicines is often suboptimal. One reason for this is that they are not adequately regulated, and many experts are calling for a change in this situation. Cost-evaluations of herbal medicine are not available, so they cannot form the basis for clinical decisions.
This article provides guidelines for prescribing herbal medications appropriately.
TABLE 1
10 best-selling herbal medicines (United States, 2001)
| Rank | Herb | Retail sales |
|---|---|---|
| 1 | Ginkgo biloba | 46 |
| 2 | Echinacea | 40 |
| 3 | Garlic | 35 |
| 4 | Ginseng | 31 |
| 5 | Soy | 28 |
| 6 | Saw palmetto | 25 |
| 7 | St John’s wort | 24 |
| 8 | Valerian | 12 |
| 9 | Cranberry | 10 |
| 10 | Black cohosh | 10 |
| Retail sales are rounded figures in million US dollars. | ||
Efficacy
One of the first things to consider when a patient proposes trying an herbal medicine is efficacy. Data on efficacy of herbal medicines are incomplete, yet some treatments have shown promise. The critical question is, Does the remedy work for the patient’s condition? Clinicians should not prescribe or recommend herbal remedies if that question cannot be answered with a firm Yes.
Medical herbalism (ie, the medicinal use of preparations that contain exclusively plant material) once dominated our pharmacopeia but went into rapid decline when pharmacology established itself as a leading branch of therapeutics. During the last part of the 19th and the early 20th century, herbalism virtually vanished from the therapeutic map of the US and the UK. In contrast, many developing countries never abandoned medical herbalism (Ayurvedic medicine in India, Kampo medicine in Japan, and Chinese herbalism in China). In other countries (such as Germany and France), medical herbalism continued a “low-key” coexistence with modern pharmacology. More recently, herbal medicine has experienced a remarkable comeback.
Herbal medicines usually contain a range of pharmacologically active compounds. In some cases it is not known which of these constituents produces the therapeutic effect. Testing for efficacy in this situation is obviously more complex than with synthetic drugs. One approach is to view the entire herbal extract as the active component. To optimise the reproducibility of efficacy studies, extracts must be sufficiently characterised. This is often achieved by standardizing the amount of a single key constituent of the extract (eg, a pharmacologically active ingredient or, if such an ingredient is not known, a marker suitable substance).
Other than the dilemma of standardization, herbal medicines can be scrutinized in clinical trials in much the same way as are other drugs. Several randomized clinical trials of herbal medicines have been published, and systematic reviews/meta-analyses of these studies have become available (Table 2).3,4 The Cochrane database includes about 30 systematic reviews of herbal medicines, and several authoritative books have recently become available.3-6 The conclusions of systematic reviews are often limited by the paucity and varied methodological quality of the primary studies.3,7 Research funds in this area are generally scarce, not least because plants are not patentable.
Generalizations about efficacy of herbal medicines are not possible; each one must be judged on its own merits. Some herbal products have demonstrated efficacy for certain conditions, while others have not. Most products have not been submitted to extensive clinical testing.3 “Clinicians should not prescribe or recommend herbal remedies without well-established efficacy….”7
TABLE 2
Examples of systematic reviews and meta-analyses of herbal remedies
| Common (Latin) name | Active ingredients | Indications | No. of trials | Avg. methodological quality of primary studies | Efficacy | Main result |
|---|---|---|---|---|---|---|
| Feverfew (Tanacetum parthenium) | Parthenolide | Migraine prevention | 5 | Good | Likely | 3 trials were positive, 2 were negative |
| Garlic (Allium sativum) | Alliin | Hypercholesterolemia | 13 | Good (some excellent) | Certain but effect small | Overall effect is significant but of debateable clinical relevance |
| Ginkgo (Ginkgo biloba) | Ginkgolides, bilobalide | Intermittent claudication | 8 | Good to excellent | Certain | Overall positive result |
| Horse chestnut seed extract (Aesculus hippocastanum) | Triterpene saponins | Chronic venous insufficiency | 8/5* | Good | Likely | Active treatment more effective than placebo and equally effective as reference treatments |
| Peppermint oil (Menta x piperial)† | Menthol | Symptoms of irritable bowel syndrome | 8 | Good | Likely | Positive effect of peppermint oil compared with placebo |
| Sources: Ernst et al 20013; Fugh-Berman 2003.4 | ||||||
| *8 trials vs placebo; 5 trials vs reference treatments. † Am J Gastroenterol 1997; 93:1131–1135. | ||||||
Safety
Consumers are attracted to herbal medicines in part because they equate “natural” with “safe.” Yet some herbal medicines pose serious risks.7
First, the active ingredients in herbal preparations can, of course, cause desirable as well as undesirable effects. Table 3 lists examples of commonly used herbal medicines that have been associated with serious adverse effects.3 Traditional use is no guarantee of safety and no acceptable substitute for data.8
A poignant example is kava (Piper methysticum), an herbal remedy that has been used for centuries apparently without problems. Numerous rigorous clinical trials have shown it to be a powerful anxiolytic medicine.9 Recently it has been associated with several cases of serious liver damage.10 Hence it has been withdrawn from the markets of several European countries, and the FDA has issued warnings about its hepatotoxic potential.
Second, the active ingredients in herbal medicines might interact with prescription drugs. For instance, extracts of St. John’s wort (Hypericum perforatum) act as an enzyme inducer on the cytochrome P450 system and increase the activity of the P-glycoprotein transmembrane transporter mechanism. Both effects lead to a reduction of the plasma level of several conventional drugs.11 Perhaps the most serious consequence could be insufficiently low cyclosporine levels in patients after organ transplantation, which jeopardize the success of this procedure.12
Third, some herbal medicines (particularly Asian herbal mixtures) have repeatedly been shown to be contaminated with heavy metals,13 or to contain misidentified herbal ingredients that turned out to be toxic,14 or to be adulterated with prescription drugs.15
Before prescribing or recommending an herbal medication, clinicians must ensure that it cannot generate undue harm.
TABLE 3
Examples of herbal medicines associated with serious adverse effects
| Common (Latin) name | Indication | Adverse effects (examples) |
|---|---|---|
| Aloe vera (Aloe barbadensis) | Various | Juice may cause intestinal pain and electrolyte loss |
| Feverfew (Tanacetum parthenium) | Migraine prevention | “Post-fever syndrome” after discontinuation (migraine, anxiety, insomnia, muscle stiffness) |
| Hawthorn (Crataegus) | Congestive heart failure | Additive effects with other cardiac glycosides |
| Kava (Piper methysticum) | Anxiety | Toxic liver damage |
| St. John’s wort (Hypericum perforatum) | Depression | Increased clearance of a range of prescribeddrugs |
| Tea tree oil (Malaleuca alternifolia) | Skin problems (external) | Allergic reactions |
| Valerian (Valeriana officinalis) | Insomnia | Morning hangover |
| Without positive data demonstrating safety, herbal medications cannot automatically be considered safe for pregnant or nursing women. | ||
Quality
The quality of an herbal preparation partly determines its efficacy as well as its safety. Herbal dietary supplements are not usually regulated as drugs and have repeatedly been found to vary in quality, sometimes being suboptimal.7,16
In the US, such preparations have to meet the requirements set forth in the Dietary Supplement and Health Education Act (DSHEA) of 1994. Thus they are marketed without approval of their efficacy and safety by the FDA. The DSHEA does not allow medical claims to be made for such products. Structure or functional claims are, however, allowed. If safety concerns of a product arise, the burden of proof lies not with its manufacturer but with the FDA. Many experts find this regulation insufficient to guarantee consumer safety and argue for it to be changed.16 In Europe, new legislation will soon regulate herbal medicines. Essentially the legislation will provide that efficacy be demonstrated on the basis of bibliographic data; safety, too, will be governed as it is with conventional drugs.17
Cost
Clinicians should recommend treatments that save money for patients and the healthcare system. Many herbal medications are relatively inexpensive. However, very few proper economic analyses of herbal medicines exist.18,19 So far, only 1 cost evaluation of an herbal medicine has been published.20 This study of symptomatic treatment of chronic venous insufficiency compared the cost-effectiveness of compression stockings with that of an extract of horse chestnut seeds. Its results implied that the treatments were similarly effective and associated with similar costs.
For the prescribing physician, this means decisions cannot presently be based on conclusive cost-analyses. While waiting for such data to become available, decisions will have to be informed by our knowledge on the efficacy, safety, and quality of herbal medications.
Correspondence
Edzard Ernst, MD, PhD, Complementary Medicine, Peninsula Medical School, Universities of Exeter and Plymouth, 25 Victoria Park Road, Exeter EX2 4NT, United Kingdom. E-mail: [email protected].
1. Eisenberg DM, David RB, Ettner SL, et al. Trends in alternative medicine use in the United States. JAMA 1998;280:1569-1575.
2. Blumenthal M. Herb sales down in mainstream market, up in natural food stores. Herbal Gram 2002;55:60.-
3. Ernst E, Pittler MH, Stevinson C, White AR. The Desktop Guide to Complementary and Alternative Medicine. Edinburgh: Mosby; 2001.
4. Fugh-Berman A. The 5-minute herb & dietary supplement consult. Philadelphia: Lippincott Williams & Wilkins; 2003.
5. Capasso F, Gaginella TS, Grandolini G, Izzo AA. Phytotherapy: A Quick Reference to Herbal Medicine. Berlin: Springer-Verlag; 2003.
6. Schulz V, Hänsel R, Tyler VE. Rational Phytotherapy. Berlin: Springer-Verlag; 2001.
7. De Smet PAGM. Herbal remedies. N Engl J Med 2002;347:2046-2056.
8. Ernst E, De Smet PAGM, Shaw D, Murray V. Traditional remedies and the “test of time.” Eur J Clin Pharmacol 1998;54:99-100.
9. Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Library 2002.
10. Teschke R, Gaus W, Loew D. Kava extracts: safety and risks including rare hepatotoxicity. Phytomed 2003;10:440-446.
11. Carlo GD, Borrelli F, Ernst E, Izzo AA. St. John’s wort: Prozac from the plant kingdom. TRENDS in Pharmacol Sci 2001;22:292-297.
12. Ernst E. St John’s wort supplements endanger the success of organ transplantation. Arch Surg 2002;137:316-319.
13. Ernst E, Thompson Coon J. Heavy metals in traditional Chinese medicines: a systematic review. Clin Pharmacol Ther 2001;70:497-504.
14. Nortier JL, Muniz Martinez. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med 2000;342:1686-1692.
15. Ernst E. Adulteration of Chinese herbal medicines with synthetic drugs: a systematic review. J Int Med 2002;251:107-113.
16. De Angelis CD, Fontanarosa PB. Drugs alias dietary supplements. JAMA 2003;290:1519-1520.
17. Silano M, De Vincenzi M, De Vincenzi A, Silano V. The new European legislation on traditional herbal medicines: main features and perspectives. Fitoterapia 2004;75:107-116.
18. Kernick D, White A. Applying economic evaluation to complementary and alternative medicine. In: Getting Health Economics into Practice, ed. Kernick DE. Oxford: Radcliffe Medical Press; 2002;173-180.
19. De Smet PAGM, Bonsel G, Van der Kuy A, et al. Introduction to the pharmacoeconomics of herbal medicines. Pharmacoeonomics 2000;18:1-7.
20. Rychlik R, Marshall M, Bachinger A, et al. Ökonomische Aspekte der Therapie der chronisch venösen Insuffizienz. Gesundh ökon Qual Manag 1997;2:86-91.
1. Eisenberg DM, David RB, Ettner SL, et al. Trends in alternative medicine use in the United States. JAMA 1998;280:1569-1575.
2. Blumenthal M. Herb sales down in mainstream market, up in natural food stores. Herbal Gram 2002;55:60.-
3. Ernst E, Pittler MH, Stevinson C, White AR. The Desktop Guide to Complementary and Alternative Medicine. Edinburgh: Mosby; 2001.
4. Fugh-Berman A. The 5-minute herb & dietary supplement consult. Philadelphia: Lippincott Williams & Wilkins; 2003.
5. Capasso F, Gaginella TS, Grandolini G, Izzo AA. Phytotherapy: A Quick Reference to Herbal Medicine. Berlin: Springer-Verlag; 2003.
6. Schulz V, Hänsel R, Tyler VE. Rational Phytotherapy. Berlin: Springer-Verlag; 2001.
7. De Smet PAGM. Herbal remedies. N Engl J Med 2002;347:2046-2056.
8. Ernst E, De Smet PAGM, Shaw D, Murray V. Traditional remedies and the “test of time.” Eur J Clin Pharmacol 1998;54:99-100.
9. Pittler MH, Ernst E. Kava extract for treating anxiety. Cochrane Library 2002.
10. Teschke R, Gaus W, Loew D. Kava extracts: safety and risks including rare hepatotoxicity. Phytomed 2003;10:440-446.
11. Carlo GD, Borrelli F, Ernst E, Izzo AA. St. John’s wort: Prozac from the plant kingdom. TRENDS in Pharmacol Sci 2001;22:292-297.
12. Ernst E. St John’s wort supplements endanger the success of organ transplantation. Arch Surg 2002;137:316-319.
13. Ernst E, Thompson Coon J. Heavy metals in traditional Chinese medicines: a systematic review. Clin Pharmacol Ther 2001;70:497-504.
14. Nortier JL, Muniz Martinez. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med 2000;342:1686-1692.
15. Ernst E. Adulteration of Chinese herbal medicines with synthetic drugs: a systematic review. J Int Med 2002;251:107-113.
16. De Angelis CD, Fontanarosa PB. Drugs alias dietary supplements. JAMA 2003;290:1519-1520.
17. Silano M, De Vincenzi M, De Vincenzi A, Silano V. The new European legislation on traditional herbal medicines: main features and perspectives. Fitoterapia 2004;75:107-116.
18. Kernick D, White A. Applying economic evaluation to complementary and alternative medicine. In: Getting Health Economics into Practice, ed. Kernick DE. Oxford: Radcliffe Medical Press; 2002;173-180.
19. De Smet PAGM, Bonsel G, Van der Kuy A, et al. Introduction to the pharmacoeconomics of herbal medicines. Pharmacoeonomics 2000;18:1-7.
20. Rychlik R, Marshall M, Bachinger A, et al. Ökonomische Aspekte der Therapie der chronisch venösen Insuffizienz. Gesundh ökon Qual Manag 1997;2:86-91.
Complementary medicine: Where is the evidence?
- Herbal medicines have been submitted to systematic reviews more frequently than any other complementary therapy, and it is here where the most positive evidence can be found.
- There is not much research into potential serious risks of complementary medicine. Possible risks range from the toxicity of herbs to vertebral artery dissection or nerve damage after chiropractic manipulation.
- Currently the Cochrane Library contains 34 systematic reviews of complementary medicine: 20 of herbal medicines, 7 of acupuncture, 3 of homeopathy, 2 of manual therapies, and 2 of other forms.
Complementary or alternative medicine has moved from the fringe of health care toward its center; recent figures show that in Germany, for instance, no less than three quarters of the general population use at least 1 complementary therapy.1 In the United States, the equivalent figures have increased from 33% in 1990 to 42% in 1997.2
Virtually all survey data agree that those most fascinated with complementary medicine are predominantly female, affluent, middleaged, and well-educated. Seventy-eight percent of all Medicaid programs provide coverage of at least 1 form of complementary medicine.3
At the same time, critics of complementary medicine often insist there is no good evidence to support these therapies,4,5 and that it is a waste of resources and a misuse of science to try establishing an evidence base for therapies that are essentially nonscientific, irrational, and implausible fads.6 But is this really true?
Research in complementary medicine
Over the last 30 years, the level of original research activity in complementary medicine has increased considerably.7 The best quality of evidence for or against the effectiveness of any therapy is usually provided by Cochrane reviews.8,9
Cochrane reviews
Currently the Cochrane Library contains 34 systematic reviews and 35 protocols of complementary medicine10 (depending on what one considers complementary/alternative and what mainstream, this figure might vary marginally). Twenty of the reviews are of herbal medicines, 7 of acupuncture, 3 of homeopathy, 2 of manual therapies, and 2 of other forms of comple-mentary medicine. Twelve reviews include a meta-analytic approach.
The 34 reviews comprise a total of 286 clinical, mostly randomized and often placebo-controlled, double-blind studies. In 1999, the Cochrane Library listed more than 4000 controlled trials of complementary medicine and a further 4000 awaited assessment.11
The single largest Cochrane review of complementary medicine is a meta-analysis of randomized clinical trials of St John’s wort for depression, based on 27 primary studies with a total of 2291 patients.12 Seven of the 34 Cochrane reviews are “negative”ie, do not suggest a positive clinical effect of the intervention under evaluation. Eleven are entirely inconclusive and 16 draw at least tentatively positive conclusions (Table). Given the dire funding situation for research in complementary medicine,13 this evidence base is remarkable.
TABLE
Cochrane reviews in complementary medicine with (tentatively) positive results
| First author (primary studies)* | Therapy | Indication | Reservations* |
|---|---|---|---|
| Furlan (8) | Massage | Low back pain | More studies required, some trials of poor quality |
| Green (4) | Acupuncture | Lateral elbow pain | More studies required, most trials of poor quality |
| Linde (7) | Acupuncture | Asthma | Evidence only positive for peak expiratory flow rate, effect size small |
| Linde (27) | St John’s wort (Hypericum perforatum)† | Depression | Some trials of poor quality, few equivalence studies |
| Little (11) | Various herbal medicines | Rheumatoid arthritis | More studies required, some trials of poor quality |
| Little (5) | Various herbal medicines | Osteoarthritis | More studies required, some trials of poor quality |
| Melchart (26) | Acupuncture | Headache | Evidence positive only for migraine headaches, effect size small |
| Pittler (7) | Kava (Piper methysticum)† | Anxiety | Concern over safety |
| Pittler (13) | Horse chestnut (Aesculus hippocastanum)† | Chronic venous insufficiency | Scarcity of long-term studies |
| Pittler (4) | Feverfew (Tanacetum parthenium)† | Migraine prevention | More studies required, effect size small |
| Pittler (2) | Globe artichoke (Cynara scolymus)† | Hypercholesterolemia | More studies required effect size small |
| Vickers (7) | Oscillococcinum | Influenza | More studies required, effect size small |
| Wilt (21) | Saw palmetto (Serenoa repens)† | Benign prostate hypertrophy | Effect size moderate, scarcity of long-term studies |
| Wilt (18) | African prune (Pygeum africanum)† | Benign prostate hypertrophy | Scarcity of long-term studies |
| Wilt (4) | Cernilton† | Benign prostate hypertrophy | More studies required, scarcity of long-term trials |
| Wilt (4) | Beta-sitosterols† | Benign prostate hypertrophy | More studies required, scarcity of long-term trials |
| All data extracted from The Cochrane Library, 2003. “More studies required” means that volume of data was small; “trials of poor quality” means that the average quality of the evidence was lowered by flawed studies; “effect size” describes the difference in clinical response to active and control treatment. | |||
| *As expressed by authors of respective review. | |||
| †Plant-based treatments. | |||
Other reviews
The Cochrane database may be the best but certainly is not the only source of systematic reviews of complementary medicine. My unit has published about 100 systematic reviews (a full list is available from the author), and most were not in the Cochrane format.
Linde and Willich have analyzed selected systematic reviews of acupuncture, homeopathy, and herbal medicine, and have shown that their methodological approach differed considerably.14
Methods of reviewing complementary medicine
The conclusions of these methodologically diverse articles were still surprisingly consistent.15 Some maintain that complementary medicine cannot be evidence-based in the conventional sense of the word16 ; that “softer” types of evidence need to be taken into consideration as well17 ; that placebo effects must not be dismissed as nonbeneficial18 ; that the healing encounter includes significant factors that may never be quantifiable19 ; that “the scientific method cannot measure hope, divine intervention, or the power of belief.”20 And, obviously, research in complementary medicine “must consider social, cultural, political, and economic contexts.”21
The debate about what constitutes the best research methods for complementary medicine has been going on for decades. There are no simple answers except that, like in any type of scientific inquiry, there are no intrinsically good or bad methods, only good and bad matches between the research question posed and the methodology employed.22
Herbal medicines have been submitted to systematic reviews more frequently than any other complementary therapy, and it is in this area where most of the positive evidence can be found (also outside Cochrane reviews).23 The medical conditions treated with complementary medicine are often chronic benign diseases for which existing conventional treatments fail to offer a cure or a risk-free reduction of symptoms (Table). Given the popularity of complementary medicine and the economic importance of these conditions, it seems ill-conceived to argue against further research in this area. 6
Firm conclusions of the Cochrane (or other) reviews of complementary medicine are often hampered by the paucity of primary studies; 10 of the 16 reviews in Table are based on fewer than 10 primary studies. The average methodological quality of the primary data is in some but by no means all disappointing.24-26
Problems in testing complementary medicine
There is little doubt that rigorous trials of complementary medicine can pose formidable problems.22 What, for instance, is an adequate placebo for a study of massage therapy, and how should one blind patients in such a trial? The biggest obstacle to good research is perhaps the notorious lack of research funding in this area, which is all the more acute because costs can be particularly high for trials of time-intensive forms of complementary medicine.13
The average size of the overall therapeutic effect associated with complementary medicine is usually modest and the numbers needed to treat are often high. In other words, the difference between benefit from complementary medicine and no therapy or placebo may be statistically significant but critics might argue that it is of debatable clinical relevance.5 Even minor adverse effects would therefore critically disturb the delicate balance of risk and benefit.23
Assessing the risks
It follows that the potential risks of complementary medicine require careful attention and more systematic study. Our fragmentary knowledge indicates that the issues are complex.27 They range from toxicity of herbs to vertebral artery dissection or nerve damage after chiropractic manipulation.
They also include more subtle indirect hazards. Some practitioners of complementary medicine, for instance, tend to advise their clients against employing important medical interventions.28 At present there are no reliable incident figures regarding serious adverse effects of complementary medicine,5,23,27 rendering this area perhaps the most urgent topic for further research.
Moving forward
At a time when healthcare systems universally are strapped for money, the decision whether to integrate complementary medicine into routine medicine will undoubtedly be influenced by economic considerations. Virtually all research on this issue is inconclusive or flawed or both.29 We therefore cannot be sure whether such an integration would save public funds or cost extra money.
In the US, about 41 million people have no health insurance and are thus not covered for even the most basic health care. About the same number of Americans are underinsured. In this situation, it seems difficult to argue without convincing data that the integration of complementary medicine would present a solution to the economic problems in healthcare.
In conclusion, during recent years the evidence in support of complementary medicine has been considerably strengthened, primarily through numerous Cochrane reviews10 and other documents.7,23,30 A large range of promising interventions could be at our fingertips. At a time when whole populations are voting with their feet in favor of complementary medicine,1,2 it would be in everyone’s interest to invest in rigorous research of this area.
Correspondence
Complementary Medicine, Peninsula Medical School, Universities of Exeter and Plymouth, 25 Victoria Park Road, Exeter EX2 4NT, United Kingdom. E-mail: [email protected].
1. Institut fÜr Demoskopie Allensbach. Naturheilmittel: Wichtigste Erkenntnisse aus Allensbacher Trendstudien. [Natural cures: The most important conclusions from Allensbach trend studies.] Available at: www.demoskopie.de.Accessed on May 27, 2003.
2. Eisenberg DM, David RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990–1997: results of a follow-up national survey. JAMA 1998;280:1569-1575.
3. Steyer TE, Freed GL, Lantz PM. Medicaid reimbursement for alternative therapies. Alt Ther Health Med 2002;8:84-88.
4. Marcus DM. Alternative medicine and the Arthritis Foundation. Arthritis Rheum 2002;47:5-7.
5. Fitzcharles M. Is it time for rheumatologists to rethink the use of manual therapies? J Rheumatol 2002;29:1117-1120.
6. Charlton BG. Randomized trials in alternative/complementary medicine. Q J Med 2002;95:643-645.
7. Barnes J, Abbot NC, Harkness E, Ernst E. Articles on complementary medicine in the mainstream medical literature: an investigation of MEDLINE, 1966 through 1996. Arch Intern Med 1999;159:1721-1725.
8. Olsen O, Middleton P, Ezzo J, et al. Quality of Cochrane reviews: assessment of sample from 1998. BMJ 2001;323:829-832.
9. Jadad AR, Moher M, Browman GP, et al. Systematic reviews and meta-analyses on treatment of asthma: critical evaluation. BMJ 2000;320:537-540.
10. The Cochrane Library [database online] Oxford, UK: Update Software; 2002.Available at: www.cochranelibrary.com. Accessed on May 23, 2003.
11. Vickers A. Evidence-based medicine and complementary medicine. ACP J Club 1999;130:A13-14.
12. Linde K. St John’s wort for depression. The Cochrane Library 2000;4:1-17.
13. Ernst E. Funding research into complementary medicine: the situation in Britain. Complement Ther Med 1999;7:250-253.
14. Linde K, Willich SN. How objective are systematic reviews? Differences between reviews on complementary medicine. J R Soc Med 2003;96:17-22.
15. Ernst E. How objective are systematic reviews? J R Soc Med 2003;96:56-57.
16. Tonelli MR, Callahan TC. Why alternative medicine cannot be evidence-based. Acad Med 2001;76:1213-1220.
17. Jonas WB. The evidence house: how to build an inclusive base for complementary medicine. West J Med 2001;175:79-80.
18. Walach H. The efficacy paradox in randomized controlled trials of CAM and elsewhere: beware of the placebo trap. J Altern Complement Med 2001;7:213-218.
19. Redwood D. Methodological changes in the evaluation of complementary and alternative medicine: issued raised by Sherman et al and Hawk et al. J Altern Complement Med 2002;8:5-6.
20. Puchalski CM. Reconnecting the science and art of medicine. Acad Med 2001;76:1224-1225.
21. Bodeker G, Kronenberg F. A public health agenda for traditional, complementary, and alternative medicine. Am J Public Health 2002;92:1582-1591.
22. Vickers A, Cassileth B, Ernst E, et al. How should we research unconventional therapies? A panel report from the conference on Complementary and Alternative Medicine Research Methodology, National Institute of Health. Int J Technol Assess Health Care 1997;13:111-121.
23. Ernst E, Pittler MH, Stevinson C, White AR. The desktop guide to complementary and alternative medicine. London: Mosby; 2001.
24. Bloom BS, Retbi A, Dahan S, Jonsson E. Evaluation of randomized controlled trials on complementary and alternative medicine. Int J Technol Assess Health Care 2000;16:13-21.
25. Linde K, Jonas WB, Melchart D, Willich S. The methodological quality of randomised controlled trials of homeopathy, herbal medicines and acupuncture. Int J Epidemiol 2001;30:526-531.
26. Moher D, Sampson M, Campbell K, et al. Assessing the quality of reports of randomised trials in pediatric complementary and alternative medicine. BMC Pediatr 2002;2:1-6.
27. Ernst E. Risks associated with complementary therapies. In MNG Dukes and JR Aronson, eds, Meyler’s Side Effects of Drugs. 14th ed. Oxford and New York: Elsevier Science; 2000:1649-1681.
28. Schmidt K, Ernst E. Aspects of MMR. Survey shows that some homeopaths and chiropractors advise against MMR. BMJ 2002;325-597.
29. White AR, Ernst E. Economic analysis of complementary medicine a systematic review. Complement Ther Med 2000;8:111-118.
30. Yuan C-S, Bieber EJ, eds. Textbook of complementary and alternative medicine. Boca Raton, Fla: Parthenon; 2003.
- Herbal medicines have been submitted to systematic reviews more frequently than any other complementary therapy, and it is here where the most positive evidence can be found.
- There is not much research into potential serious risks of complementary medicine. Possible risks range from the toxicity of herbs to vertebral artery dissection or nerve damage after chiropractic manipulation.
- Currently the Cochrane Library contains 34 systematic reviews of complementary medicine: 20 of herbal medicines, 7 of acupuncture, 3 of homeopathy, 2 of manual therapies, and 2 of other forms.
Complementary or alternative medicine has moved from the fringe of health care toward its center; recent figures show that in Germany, for instance, no less than three quarters of the general population use at least 1 complementary therapy.1 In the United States, the equivalent figures have increased from 33% in 1990 to 42% in 1997.2
Virtually all survey data agree that those most fascinated with complementary medicine are predominantly female, affluent, middleaged, and well-educated. Seventy-eight percent of all Medicaid programs provide coverage of at least 1 form of complementary medicine.3
At the same time, critics of complementary medicine often insist there is no good evidence to support these therapies,4,5 and that it is a waste of resources and a misuse of science to try establishing an evidence base for therapies that are essentially nonscientific, irrational, and implausible fads.6 But is this really true?
Research in complementary medicine
Over the last 30 years, the level of original research activity in complementary medicine has increased considerably.7 The best quality of evidence for or against the effectiveness of any therapy is usually provided by Cochrane reviews.8,9
Cochrane reviews
Currently the Cochrane Library contains 34 systematic reviews and 35 protocols of complementary medicine10 (depending on what one considers complementary/alternative and what mainstream, this figure might vary marginally). Twenty of the reviews are of herbal medicines, 7 of acupuncture, 3 of homeopathy, 2 of manual therapies, and 2 of other forms of comple-mentary medicine. Twelve reviews include a meta-analytic approach.
The 34 reviews comprise a total of 286 clinical, mostly randomized and often placebo-controlled, double-blind studies. In 1999, the Cochrane Library listed more than 4000 controlled trials of complementary medicine and a further 4000 awaited assessment.11
The single largest Cochrane review of complementary medicine is a meta-analysis of randomized clinical trials of St John’s wort for depression, based on 27 primary studies with a total of 2291 patients.12 Seven of the 34 Cochrane reviews are “negative”ie, do not suggest a positive clinical effect of the intervention under evaluation. Eleven are entirely inconclusive and 16 draw at least tentatively positive conclusions (Table). Given the dire funding situation for research in complementary medicine,13 this evidence base is remarkable.
TABLE
Cochrane reviews in complementary medicine with (tentatively) positive results
| First author (primary studies)* | Therapy | Indication | Reservations* |
|---|---|---|---|
| Furlan (8) | Massage | Low back pain | More studies required, some trials of poor quality |
| Green (4) | Acupuncture | Lateral elbow pain | More studies required, most trials of poor quality |
| Linde (7) | Acupuncture | Asthma | Evidence only positive for peak expiratory flow rate, effect size small |
| Linde (27) | St John’s wort (Hypericum perforatum)† | Depression | Some trials of poor quality, few equivalence studies |
| Little (11) | Various herbal medicines | Rheumatoid arthritis | More studies required, some trials of poor quality |
| Little (5) | Various herbal medicines | Osteoarthritis | More studies required, some trials of poor quality |
| Melchart (26) | Acupuncture | Headache | Evidence positive only for migraine headaches, effect size small |
| Pittler (7) | Kava (Piper methysticum)† | Anxiety | Concern over safety |
| Pittler (13) | Horse chestnut (Aesculus hippocastanum)† | Chronic venous insufficiency | Scarcity of long-term studies |
| Pittler (4) | Feverfew (Tanacetum parthenium)† | Migraine prevention | More studies required, effect size small |
| Pittler (2) | Globe artichoke (Cynara scolymus)† | Hypercholesterolemia | More studies required effect size small |
| Vickers (7) | Oscillococcinum | Influenza | More studies required, effect size small |
| Wilt (21) | Saw palmetto (Serenoa repens)† | Benign prostate hypertrophy | Effect size moderate, scarcity of long-term studies |
| Wilt (18) | African prune (Pygeum africanum)† | Benign prostate hypertrophy | Scarcity of long-term studies |
| Wilt (4) | Cernilton† | Benign prostate hypertrophy | More studies required, scarcity of long-term trials |
| Wilt (4) | Beta-sitosterols† | Benign prostate hypertrophy | More studies required, scarcity of long-term trials |
| All data extracted from The Cochrane Library, 2003. “More studies required” means that volume of data was small; “trials of poor quality” means that the average quality of the evidence was lowered by flawed studies; “effect size” describes the difference in clinical response to active and control treatment. | |||
| *As expressed by authors of respective review. | |||
| †Plant-based treatments. | |||
Other reviews
The Cochrane database may be the best but certainly is not the only source of systematic reviews of complementary medicine. My unit has published about 100 systematic reviews (a full list is available from the author), and most were not in the Cochrane format.
Linde and Willich have analyzed selected systematic reviews of acupuncture, homeopathy, and herbal medicine, and have shown that their methodological approach differed considerably.14
Methods of reviewing complementary medicine
The conclusions of these methodologically diverse articles were still surprisingly consistent.15 Some maintain that complementary medicine cannot be evidence-based in the conventional sense of the word16 ; that “softer” types of evidence need to be taken into consideration as well17 ; that placebo effects must not be dismissed as nonbeneficial18 ; that the healing encounter includes significant factors that may never be quantifiable19 ; that “the scientific method cannot measure hope, divine intervention, or the power of belief.”20 And, obviously, research in complementary medicine “must consider social, cultural, political, and economic contexts.”21
The debate about what constitutes the best research methods for complementary medicine has been going on for decades. There are no simple answers except that, like in any type of scientific inquiry, there are no intrinsically good or bad methods, only good and bad matches between the research question posed and the methodology employed.22
Herbal medicines have been submitted to systematic reviews more frequently than any other complementary therapy, and it is in this area where most of the positive evidence can be found (also outside Cochrane reviews).23 The medical conditions treated with complementary medicine are often chronic benign diseases for which existing conventional treatments fail to offer a cure or a risk-free reduction of symptoms (Table). Given the popularity of complementary medicine and the economic importance of these conditions, it seems ill-conceived to argue against further research in this area. 6
Firm conclusions of the Cochrane (or other) reviews of complementary medicine are often hampered by the paucity of primary studies; 10 of the 16 reviews in Table are based on fewer than 10 primary studies. The average methodological quality of the primary data is in some but by no means all disappointing.24-26
Problems in testing complementary medicine
There is little doubt that rigorous trials of complementary medicine can pose formidable problems.22 What, for instance, is an adequate placebo for a study of massage therapy, and how should one blind patients in such a trial? The biggest obstacle to good research is perhaps the notorious lack of research funding in this area, which is all the more acute because costs can be particularly high for trials of time-intensive forms of complementary medicine.13
The average size of the overall therapeutic effect associated with complementary medicine is usually modest and the numbers needed to treat are often high. In other words, the difference between benefit from complementary medicine and no therapy or placebo may be statistically significant but critics might argue that it is of debatable clinical relevance.5 Even minor adverse effects would therefore critically disturb the delicate balance of risk and benefit.23
Assessing the risks
It follows that the potential risks of complementary medicine require careful attention and more systematic study. Our fragmentary knowledge indicates that the issues are complex.27 They range from toxicity of herbs to vertebral artery dissection or nerve damage after chiropractic manipulation.
They also include more subtle indirect hazards. Some practitioners of complementary medicine, for instance, tend to advise their clients against employing important medical interventions.28 At present there are no reliable incident figures regarding serious adverse effects of complementary medicine,5,23,27 rendering this area perhaps the most urgent topic for further research.
Moving forward
At a time when healthcare systems universally are strapped for money, the decision whether to integrate complementary medicine into routine medicine will undoubtedly be influenced by economic considerations. Virtually all research on this issue is inconclusive or flawed or both.29 We therefore cannot be sure whether such an integration would save public funds or cost extra money.
In the US, about 41 million people have no health insurance and are thus not covered for even the most basic health care. About the same number of Americans are underinsured. In this situation, it seems difficult to argue without convincing data that the integration of complementary medicine would present a solution to the economic problems in healthcare.
In conclusion, during recent years the evidence in support of complementary medicine has been considerably strengthened, primarily through numerous Cochrane reviews10 and other documents.7,23,30 A large range of promising interventions could be at our fingertips. At a time when whole populations are voting with their feet in favor of complementary medicine,1,2 it would be in everyone’s interest to invest in rigorous research of this area.
Correspondence
Complementary Medicine, Peninsula Medical School, Universities of Exeter and Plymouth, 25 Victoria Park Road, Exeter EX2 4NT, United Kingdom. E-mail: [email protected].
- Herbal medicines have been submitted to systematic reviews more frequently than any other complementary therapy, and it is here where the most positive evidence can be found.
- There is not much research into potential serious risks of complementary medicine. Possible risks range from the toxicity of herbs to vertebral artery dissection or nerve damage after chiropractic manipulation.
- Currently the Cochrane Library contains 34 systematic reviews of complementary medicine: 20 of herbal medicines, 7 of acupuncture, 3 of homeopathy, 2 of manual therapies, and 2 of other forms.
Complementary or alternative medicine has moved from the fringe of health care toward its center; recent figures show that in Germany, for instance, no less than three quarters of the general population use at least 1 complementary therapy.1 In the United States, the equivalent figures have increased from 33% in 1990 to 42% in 1997.2
Virtually all survey data agree that those most fascinated with complementary medicine are predominantly female, affluent, middleaged, and well-educated. Seventy-eight percent of all Medicaid programs provide coverage of at least 1 form of complementary medicine.3
At the same time, critics of complementary medicine often insist there is no good evidence to support these therapies,4,5 and that it is a waste of resources and a misuse of science to try establishing an evidence base for therapies that are essentially nonscientific, irrational, and implausible fads.6 But is this really true?
Research in complementary medicine
Over the last 30 years, the level of original research activity in complementary medicine has increased considerably.7 The best quality of evidence for or against the effectiveness of any therapy is usually provided by Cochrane reviews.8,9
Cochrane reviews
Currently the Cochrane Library contains 34 systematic reviews and 35 protocols of complementary medicine10 (depending on what one considers complementary/alternative and what mainstream, this figure might vary marginally). Twenty of the reviews are of herbal medicines, 7 of acupuncture, 3 of homeopathy, 2 of manual therapies, and 2 of other forms of comple-mentary medicine. Twelve reviews include a meta-analytic approach.
The 34 reviews comprise a total of 286 clinical, mostly randomized and often placebo-controlled, double-blind studies. In 1999, the Cochrane Library listed more than 4000 controlled trials of complementary medicine and a further 4000 awaited assessment.11
The single largest Cochrane review of complementary medicine is a meta-analysis of randomized clinical trials of St John’s wort for depression, based on 27 primary studies with a total of 2291 patients.12 Seven of the 34 Cochrane reviews are “negative”ie, do not suggest a positive clinical effect of the intervention under evaluation. Eleven are entirely inconclusive and 16 draw at least tentatively positive conclusions (Table). Given the dire funding situation for research in complementary medicine,13 this evidence base is remarkable.
TABLE
Cochrane reviews in complementary medicine with (tentatively) positive results
| First author (primary studies)* | Therapy | Indication | Reservations* |
|---|---|---|---|
| Furlan (8) | Massage | Low back pain | More studies required, some trials of poor quality |
| Green (4) | Acupuncture | Lateral elbow pain | More studies required, most trials of poor quality |
| Linde (7) | Acupuncture | Asthma | Evidence only positive for peak expiratory flow rate, effect size small |
| Linde (27) | St John’s wort (Hypericum perforatum)† | Depression | Some trials of poor quality, few equivalence studies |
| Little (11) | Various herbal medicines | Rheumatoid arthritis | More studies required, some trials of poor quality |
| Little (5) | Various herbal medicines | Osteoarthritis | More studies required, some trials of poor quality |
| Melchart (26) | Acupuncture | Headache | Evidence positive only for migraine headaches, effect size small |
| Pittler (7) | Kava (Piper methysticum)† | Anxiety | Concern over safety |
| Pittler (13) | Horse chestnut (Aesculus hippocastanum)† | Chronic venous insufficiency | Scarcity of long-term studies |
| Pittler (4) | Feverfew (Tanacetum parthenium)† | Migraine prevention | More studies required, effect size small |
| Pittler (2) | Globe artichoke (Cynara scolymus)† | Hypercholesterolemia | More studies required effect size small |
| Vickers (7) | Oscillococcinum | Influenza | More studies required, effect size small |
| Wilt (21) | Saw palmetto (Serenoa repens)† | Benign prostate hypertrophy | Effect size moderate, scarcity of long-term studies |
| Wilt (18) | African prune (Pygeum africanum)† | Benign prostate hypertrophy | Scarcity of long-term studies |
| Wilt (4) | Cernilton† | Benign prostate hypertrophy | More studies required, scarcity of long-term trials |
| Wilt (4) | Beta-sitosterols† | Benign prostate hypertrophy | More studies required, scarcity of long-term trials |
| All data extracted from The Cochrane Library, 2003. “More studies required” means that volume of data was small; “trials of poor quality” means that the average quality of the evidence was lowered by flawed studies; “effect size” describes the difference in clinical response to active and control treatment. | |||
| *As expressed by authors of respective review. | |||
| †Plant-based treatments. | |||
Other reviews
The Cochrane database may be the best but certainly is not the only source of systematic reviews of complementary medicine. My unit has published about 100 systematic reviews (a full list is available from the author), and most were not in the Cochrane format.
Linde and Willich have analyzed selected systematic reviews of acupuncture, homeopathy, and herbal medicine, and have shown that their methodological approach differed considerably.14
Methods of reviewing complementary medicine
The conclusions of these methodologically diverse articles were still surprisingly consistent.15 Some maintain that complementary medicine cannot be evidence-based in the conventional sense of the word16 ; that “softer” types of evidence need to be taken into consideration as well17 ; that placebo effects must not be dismissed as nonbeneficial18 ; that the healing encounter includes significant factors that may never be quantifiable19 ; that “the scientific method cannot measure hope, divine intervention, or the power of belief.”20 And, obviously, research in complementary medicine “must consider social, cultural, political, and economic contexts.”21
The debate about what constitutes the best research methods for complementary medicine has been going on for decades. There are no simple answers except that, like in any type of scientific inquiry, there are no intrinsically good or bad methods, only good and bad matches between the research question posed and the methodology employed.22
Herbal medicines have been submitted to systematic reviews more frequently than any other complementary therapy, and it is in this area where most of the positive evidence can be found (also outside Cochrane reviews).23 The medical conditions treated with complementary medicine are often chronic benign diseases for which existing conventional treatments fail to offer a cure or a risk-free reduction of symptoms (Table). Given the popularity of complementary medicine and the economic importance of these conditions, it seems ill-conceived to argue against further research in this area. 6
Firm conclusions of the Cochrane (or other) reviews of complementary medicine are often hampered by the paucity of primary studies; 10 of the 16 reviews in Table are based on fewer than 10 primary studies. The average methodological quality of the primary data is in some but by no means all disappointing.24-26
Problems in testing complementary medicine
There is little doubt that rigorous trials of complementary medicine can pose formidable problems.22 What, for instance, is an adequate placebo for a study of massage therapy, and how should one blind patients in such a trial? The biggest obstacle to good research is perhaps the notorious lack of research funding in this area, which is all the more acute because costs can be particularly high for trials of time-intensive forms of complementary medicine.13
The average size of the overall therapeutic effect associated with complementary medicine is usually modest and the numbers needed to treat are often high. In other words, the difference between benefit from complementary medicine and no therapy or placebo may be statistically significant but critics might argue that it is of debatable clinical relevance.5 Even minor adverse effects would therefore critically disturb the delicate balance of risk and benefit.23
Assessing the risks
It follows that the potential risks of complementary medicine require careful attention and more systematic study. Our fragmentary knowledge indicates that the issues are complex.27 They range from toxicity of herbs to vertebral artery dissection or nerve damage after chiropractic manipulation.
They also include more subtle indirect hazards. Some practitioners of complementary medicine, for instance, tend to advise their clients against employing important medical interventions.28 At present there are no reliable incident figures regarding serious adverse effects of complementary medicine,5,23,27 rendering this area perhaps the most urgent topic for further research.
Moving forward
At a time when healthcare systems universally are strapped for money, the decision whether to integrate complementary medicine into routine medicine will undoubtedly be influenced by economic considerations. Virtually all research on this issue is inconclusive or flawed or both.29 We therefore cannot be sure whether such an integration would save public funds or cost extra money.
In the US, about 41 million people have no health insurance and are thus not covered for even the most basic health care. About the same number of Americans are underinsured. In this situation, it seems difficult to argue without convincing data that the integration of complementary medicine would present a solution to the economic problems in healthcare.
In conclusion, during recent years the evidence in support of complementary medicine has been considerably strengthened, primarily through numerous Cochrane reviews10 and other documents.7,23,30 A large range of promising interventions could be at our fingertips. At a time when whole populations are voting with their feet in favor of complementary medicine,1,2 it would be in everyone’s interest to invest in rigorous research of this area.
Correspondence
Complementary Medicine, Peninsula Medical School, Universities of Exeter and Plymouth, 25 Victoria Park Road, Exeter EX2 4NT, United Kingdom. E-mail: [email protected].
1. Institut fÜr Demoskopie Allensbach. Naturheilmittel: Wichtigste Erkenntnisse aus Allensbacher Trendstudien. [Natural cures: The most important conclusions from Allensbach trend studies.] Available at: www.demoskopie.de.Accessed on May 27, 2003.
2. Eisenberg DM, David RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990–1997: results of a follow-up national survey. JAMA 1998;280:1569-1575.
3. Steyer TE, Freed GL, Lantz PM. Medicaid reimbursement for alternative therapies. Alt Ther Health Med 2002;8:84-88.
4. Marcus DM. Alternative medicine and the Arthritis Foundation. Arthritis Rheum 2002;47:5-7.
5. Fitzcharles M. Is it time for rheumatologists to rethink the use of manual therapies? J Rheumatol 2002;29:1117-1120.
6. Charlton BG. Randomized trials in alternative/complementary medicine. Q J Med 2002;95:643-645.
7. Barnes J, Abbot NC, Harkness E, Ernst E. Articles on complementary medicine in the mainstream medical literature: an investigation of MEDLINE, 1966 through 1996. Arch Intern Med 1999;159:1721-1725.
8. Olsen O, Middleton P, Ezzo J, et al. Quality of Cochrane reviews: assessment of sample from 1998. BMJ 2001;323:829-832.
9. Jadad AR, Moher M, Browman GP, et al. Systematic reviews and meta-analyses on treatment of asthma: critical evaluation. BMJ 2000;320:537-540.
10. The Cochrane Library [database online] Oxford, UK: Update Software; 2002.Available at: www.cochranelibrary.com. Accessed on May 23, 2003.
11. Vickers A. Evidence-based medicine and complementary medicine. ACP J Club 1999;130:A13-14.
12. Linde K. St John’s wort for depression. The Cochrane Library 2000;4:1-17.
13. Ernst E. Funding research into complementary medicine: the situation in Britain. Complement Ther Med 1999;7:250-253.
14. Linde K, Willich SN. How objective are systematic reviews? Differences between reviews on complementary medicine. J R Soc Med 2003;96:17-22.
15. Ernst E. How objective are systematic reviews? J R Soc Med 2003;96:56-57.
16. Tonelli MR, Callahan TC. Why alternative medicine cannot be evidence-based. Acad Med 2001;76:1213-1220.
17. Jonas WB. The evidence house: how to build an inclusive base for complementary medicine. West J Med 2001;175:79-80.
18. Walach H. The efficacy paradox in randomized controlled trials of CAM and elsewhere: beware of the placebo trap. J Altern Complement Med 2001;7:213-218.
19. Redwood D. Methodological changes in the evaluation of complementary and alternative medicine: issued raised by Sherman et al and Hawk et al. J Altern Complement Med 2002;8:5-6.
20. Puchalski CM. Reconnecting the science and art of medicine. Acad Med 2001;76:1224-1225.
21. Bodeker G, Kronenberg F. A public health agenda for traditional, complementary, and alternative medicine. Am J Public Health 2002;92:1582-1591.
22. Vickers A, Cassileth B, Ernst E, et al. How should we research unconventional therapies? A panel report from the conference on Complementary and Alternative Medicine Research Methodology, National Institute of Health. Int J Technol Assess Health Care 1997;13:111-121.
23. Ernst E, Pittler MH, Stevinson C, White AR. The desktop guide to complementary and alternative medicine. London: Mosby; 2001.
24. Bloom BS, Retbi A, Dahan S, Jonsson E. Evaluation of randomized controlled trials on complementary and alternative medicine. Int J Technol Assess Health Care 2000;16:13-21.
25. Linde K, Jonas WB, Melchart D, Willich S. The methodological quality of randomised controlled trials of homeopathy, herbal medicines and acupuncture. Int J Epidemiol 2001;30:526-531.
26. Moher D, Sampson M, Campbell K, et al. Assessing the quality of reports of randomised trials in pediatric complementary and alternative medicine. BMC Pediatr 2002;2:1-6.
27. Ernst E. Risks associated with complementary therapies. In MNG Dukes and JR Aronson, eds, Meyler’s Side Effects of Drugs. 14th ed. Oxford and New York: Elsevier Science; 2000:1649-1681.
28. Schmidt K, Ernst E. Aspects of MMR. Survey shows that some homeopaths and chiropractors advise against MMR. BMJ 2002;325-597.
29. White AR, Ernst E. Economic analysis of complementary medicine a systematic review. Complement Ther Med 2000;8:111-118.
30. Yuan C-S, Bieber EJ, eds. Textbook of complementary and alternative medicine. Boca Raton, Fla: Parthenon; 2003.
1. Institut fÜr Demoskopie Allensbach. Naturheilmittel: Wichtigste Erkenntnisse aus Allensbacher Trendstudien. [Natural cures: The most important conclusions from Allensbach trend studies.] Available at: www.demoskopie.de.Accessed on May 27, 2003.
2. Eisenberg DM, David RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990–1997: results of a follow-up national survey. JAMA 1998;280:1569-1575.
3. Steyer TE, Freed GL, Lantz PM. Medicaid reimbursement for alternative therapies. Alt Ther Health Med 2002;8:84-88.
4. Marcus DM. Alternative medicine and the Arthritis Foundation. Arthritis Rheum 2002;47:5-7.
5. Fitzcharles M. Is it time for rheumatologists to rethink the use of manual therapies? J Rheumatol 2002;29:1117-1120.
6. Charlton BG. Randomized trials in alternative/complementary medicine. Q J Med 2002;95:643-645.
7. Barnes J, Abbot NC, Harkness E, Ernst E. Articles on complementary medicine in the mainstream medical literature: an investigation of MEDLINE, 1966 through 1996. Arch Intern Med 1999;159:1721-1725.
8. Olsen O, Middleton P, Ezzo J, et al. Quality of Cochrane reviews: assessment of sample from 1998. BMJ 2001;323:829-832.
9. Jadad AR, Moher M, Browman GP, et al. Systematic reviews and meta-analyses on treatment of asthma: critical evaluation. BMJ 2000;320:537-540.
10. The Cochrane Library [database online] Oxford, UK: Update Software; 2002.Available at: www.cochranelibrary.com. Accessed on May 23, 2003.
11. Vickers A. Evidence-based medicine and complementary medicine. ACP J Club 1999;130:A13-14.
12. Linde K. St John’s wort for depression. The Cochrane Library 2000;4:1-17.
13. Ernst E. Funding research into complementary medicine: the situation in Britain. Complement Ther Med 1999;7:250-253.
14. Linde K, Willich SN. How objective are systematic reviews? Differences between reviews on complementary medicine. J R Soc Med 2003;96:17-22.
15. Ernst E. How objective are systematic reviews? J R Soc Med 2003;96:56-57.
16. Tonelli MR, Callahan TC. Why alternative medicine cannot be evidence-based. Acad Med 2001;76:1213-1220.
17. Jonas WB. The evidence house: how to build an inclusive base for complementary medicine. West J Med 2001;175:79-80.
18. Walach H. The efficacy paradox in randomized controlled trials of CAM and elsewhere: beware of the placebo trap. J Altern Complement Med 2001;7:213-218.
19. Redwood D. Methodological changes in the evaluation of complementary and alternative medicine: issued raised by Sherman et al and Hawk et al. J Altern Complement Med 2002;8:5-6.
20. Puchalski CM. Reconnecting the science and art of medicine. Acad Med 2001;76:1224-1225.
21. Bodeker G, Kronenberg F. A public health agenda for traditional, complementary, and alternative medicine. Am J Public Health 2002;92:1582-1591.
22. Vickers A, Cassileth B, Ernst E, et al. How should we research unconventional therapies? A panel report from the conference on Complementary and Alternative Medicine Research Methodology, National Institute of Health. Int J Technol Assess Health Care 1997;13:111-121.
23. Ernst E, Pittler MH, Stevinson C, White AR. The desktop guide to complementary and alternative medicine. London: Mosby; 2001.
24. Bloom BS, Retbi A, Dahan S, Jonsson E. Evaluation of randomized controlled trials on complementary and alternative medicine. Int J Technol Assess Health Care 2000;16:13-21.
25. Linde K, Jonas WB, Melchart D, Willich S. The methodological quality of randomised controlled trials of homeopathy, herbal medicines and acupuncture. Int J Epidemiol 2001;30:526-531.
26. Moher D, Sampson M, Campbell K, et al. Assessing the quality of reports of randomised trials in pediatric complementary and alternative medicine. BMC Pediatr 2002;2:1-6.
27. Ernst E. Risks associated with complementary therapies. In MNG Dukes and JR Aronson, eds, Meyler’s Side Effects of Drugs. 14th ed. Oxford and New York: Elsevier Science; 2000:1649-1681.
28. Schmidt K, Ernst E. Aspects of MMR. Survey shows that some homeopaths and chiropractors advise against MMR. BMJ 2002;325-597.
29. White AR, Ernst E. Economic analysis of complementary medicine a systematic review. Complement Ther Med 2000;8:111-118.
30. Yuan C-S, Bieber EJ, eds. Textbook of complementary and alternative medicine. Boca Raton, Fla: Parthenon; 2003.