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EPIDEMIOLOGY OF COMPLEMENTARY AND ALTERNATIVE PRACTICES IN RHEUMATOLOGY
T FOR RHEUMATIC DISEASES I
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EPIDEMIOLOGY OF COMPLEMENTARY AND ALTERNATIVE PRACTICES IN RHEUMATOLOGY Cesar Ramos-Remus, MD, MSc, Sergio Gutierrez-UreAa, MD, and Paul Davis, FRCPC, FRCP(UK)
Over 130 nonconventional treatment modalities and more than 500 remedies have been described to treat patients with diverse diseases. These range from rubbing creams to the implantation of the hypophysis of a stillborne pig. Whatever term is used, be it non-conventional remedies or complementary and alternative medicine (CAM), these modalities have become an increasingly prominent part of the health care practices of the general population and of patients with various diseases even in an era of rapidly advancing medical technology. CAM has become a significant topic not just in the lay press but also in the biomedical literature. Since 1966, more than 38,000 publications bearing this or a related term appear in titles or abstracts that have been referenced in Medline alone. Indeed, several important journals have recently devoted editorials and original papers to this subject. This article reviews the most relevant aspects of the biomedical literature on the epidemiology related to CAM use, with special emphasis on the magnitude,
From the University of Guadalajara (CR, SG); Department of Rheumatology, Hospital de Especialidades del Centro Mkdico Nacional de Occidente, IMSS-Instituto Mexican0 del Seguro Social (CR); Antiguo Hospital Civil, Guadalajara, Mexico (SG); and University of Alberta, Edmonton, Alberta, Canada (PD)
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patterns, and costs of CAM modalities and remedies employed by rheumatic disease patients. WHO USES COMPLEMENTARY AND ALTERNATIVE MEDICINE?
Population-Based Studies It appears that the use of CAM is a worldwide phenomenon not restricted to any particular ethnic group, social status, or economic situation (Fig. 1). Prevalence ranges from 6% to 73% of the general population. Variations in the prevalence of CAM use are better explained by differences in the study design, definition of CAM, instruments used, and population selection rather than by geographic, economic, or ethnic factors. In one large study, MacLennan et a136conducted a population survey through personal interviews with 3004 persons aged 15 years or older living in South Australia. The overall response rate was 73%, and the survey focused on 12 CAM modalities, including nonprescribed vitamins. The overall use of at least one CAM modality or remedy was 48.5% in the past 12 months, and 20.3% of these individuals had visited at least one CAM practitioner in the same period.36 The National Population Health Survey of Canada conducted in 1994 through 1995 revealed that 15% of the 17,626 respondents had visited at least one CAM provider in the previous 12 months.38 In another population-based study of a rural population in the province of Alberta in Canada, Verhoef 6t a157found that 32.3% of the adult respondents had visited CAM providers at least once in the previous 6 months. This figure represents a 170% increase in the use of CAM providers compared with a similar study performed 3 years earlier. Spigelblatt et a153 reported on a mail survey of 1911 parents of children consulting the general outpatient clinic of a university hospital in Quebec, Canada. The response rate was 93%, and the authors reported that 11%of the children had used at least one CAM modality or remedy, with 8% of them having used three or more.53 In 1993, Eisenberg et all7 published the results of a national telephone survey of adults aged 18 years or older across the United States. The overall response rate was 679'0, and the authors elected to limit the survey to English-speaking persons, to households with telephones, and to 16 commonly used CAM modalities and remedies. Thirty-four percent of the 1539 individuals surveyed used at least one CAM modality or remedy in 1990, and 35% of them visited a provider of CAM, with an average of 19 visits the preceding year.I7
+ CAM use by gsneral papllalion:
Figure 1. Worldwide prevalence of CAM use.
UNITED STATES OF AMERICA
e by rheumatic palierds:
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The adult members of the Kaiser Permanente Medical Care Program of Northern California were recently surveyed by a mail questionnaire to assess their CAM use, with a response rate of 51%. The authors found that 25% of the respondents had used in the past year at least 1 of the 20 CAMS listed, and 43% reported having used 1 or more in the past.25 In another mail survey conducted through National Family Opinion, which maintains a panel of persons who have agreed to be participants in mail surveys in the United States, the response rate was 69% (N = 1035), and the survey focused on 17 CAM modalities. Forty percent of respondents reported using some form of alternative health care during the past year. The top four treatment categories were chiropractic (15.7%), lifestyle diet (8%),exercise/movement (7.2%),and relaxation (6.9%).2 Cook and Baisden" reported the results of face-to-face interviews to assess the prevalence of the use of 61 popular folk remedies in 3 urban and 3 rural southwestern West Virginia primary care clinics. There were 170 respondents, but the response rate was not stated. Seventy-three percent of respondents indicated that they had used at least 1 such remedy during the preceding 12 months, with a mean use of 4.5 remedies per person and a range from 1 to 18 remedies.l' Bernstein and Shuva14recently reported the results of face-to-face interviews with 2030 Jewish adults aged 45 to 75 years. The aim of the study was to assess the prevalence of CAM practitioner use. They found that 6% of their sample had visited at least one CAM provider in the past year, and 23% of them had visited CAM providers more than once.4 Data cited by Fisher and Wardzzindicate that in 1981, 6.4% of the Dutch population attended a therapist or doctor providing CAM, and that this increased to 9.i% by 1985 and 15.7% by 1990. These authors also cite data from the Consumers Association of the United Kingdom that the use of CAM in the preceding 12 months rose from 14% in 1985 to almost 25% in 1991. Homeopathy is the most popular form of CAM in France, rising in use from 16% of the population in 1982 to 29% in 1987 and 36% in 1992.22 Nonrheumatic Disease Patients
A high prevalence of CAM use has been reported for a number of disease-specific groups. For instance, between 7% and 64% of patients with cancer use CAM according to a recently published systematic review,2O 27% of patients attending a gastroenterology 20% of patients with inflammatory bowel disease,4O and 29% of the attendees of a rehabilitation outpatient clinic in New Y ~ r as k ~well ~ as patients with acquired immunodeficiency syndrome, irritable bowel syndrome, and 37, 52 depression among other conditions.lO,
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Rheumatic Disease Patients The scope of rheumatic diseases involves more than 150 different entities, which are often chronic and carry significant morbidity and potential disability. Given these characteristics and the lack of curative therapies for many of these entities, the use of CAM should not be a surprise. Evidence exists that rheumatic disease patients use CAM whether they live in developed or developing countries, are well or less educated, and are richer or less fortunate. For instance, in the study of Eisenberg et al,I7 16% of the 1539 adults interviewed by telephone across the United States self-reported a history of "arthritis," with 18% of these individuals acknowledging the use of CAM and 7% having attended CAM providers in the previous 12 months. In the survey by Astin: arthritis was the sixth most frequently cited health problem treated with CAM (25%). Kronenfeld and Wasne132 reported the results of a face-to-face interview with 98 rheumatic disease patients attending a rheumatology clinic in a university setting in the United States. Sixty patients had rheumatoid arthritis, 10 had osteoarthritis, and 28 had diverse rheumatic disorders. Ninety-four percent of the interviewed patients reported that they had used or attended CAM practitioners; the mean use was 3.7 different remedies, with 3 patients each having tried 13 different modalities. Topical remedies were used by over 80% of all respondents, including alcohol, whiskey, snake oil, and gasoline. Thirty-six percent of the respondents had visited a CAM provider at least once for their arthritis. Surprisingly, 5% had used CAM-before contacting a physician, whereas 83% had been seeing a physician for more than 1 year before they sought CAM remedies.32In another survey from California, 84% of the patients with self-reported osteoarthritis or rheumatoid arthritis had used CAM during the past 6 months.13 We identified three studies from Canada related to the use of CAM by patients with rheumatic diseases. In the first study, 235 consecutive patients attending a rheumatology clinic in Montreal were evaluated by a face-to-face q~estionnaire.~ The response rate was 100%. Forty-eight percent of the interviewed patients had "inflammatory" rheumatic diseases, 28% had "degenerative" diseases, and 24% had soft-tissue rheumatism. Sixty-six percent of these patients had used at least one CAM modality or remedy in the past 12 months, and 13% had visited a CAM provider in the same period. Five percent of those who saw CAM providers had visited the providers six or more times.5 The second study was conducted by the same group in the same setting4 Here, an interviewer-based questionnaire was administered to 221 consecutive rheumatology patients and 80 patients with fibromyalgia syndrome, with a 38% response rate for this latter condition. The mean
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age was 50 years for the fibromyalgia group and 43 years for the other group. CAM use was identified in 91% of fibromyalgia patients and 63% of the other rheumatic disease patients. All CAM modalities were used more commonly by the fibromyalgia patients than by the other rheumatic disease patients. CAM practitioners and dietary manipulation were used much more frequently by the fibromyalgia patients. Seventynine percent of the fibromyalgia patients had visited CAM practitioners, and 63% of them reported frequent use as defined by more than six visits per year. Fibromyalgia patients were asked to rate their satisfaction with CAM on a scale from 0 to 10. The overall score given was 6.7. Use of orthodox health care by the fibromyalgia patients was more frequent in the CAM users (average of 7.5 medical doctor visits per year) than in those who did not use CAM (average of 4.5 medical doctor visits per year).& The third Canadian study was a cross-sectional survey of 200 patients with rheumatic diseases at three outpatient rheumatology clinics in A face-to-face structured interview was administered by a trained assistant to evaluate the prevalence of CAM use as well as patient beliefs, perceptions, and expectations in relation to CAM. The response rate was 100%. The mean age of these patients was 56 years, and 46% had rheumatoid arthritis. Sixty percent of the patients had used a total of 530 CAM modalities and remedies (range, 1-25 CAM practices), and 79% of these patients had used 309 CAM remedies in the previous 12 months (mean, 3; range, 1-15 remedies). Overall, 47% had used at least one CAM practice before the first rheumatology consultation, but an additional 8% initiated CAM practices after their first contact with a rheumatologist. The group of CAM users saw a rheumatologist an average of 6 times dbring the past year (range, 1-52 visits) and their family physicians 11 times (range, 0-52 visits). Forty-one (34%) of the 119 users of CAM visited CAM providers at least once in the past 12 months (mean, 11; range, 1-105 visits). Among the 41 patients who not only used CAM but also visited a CAM provider, there was a similar number of total visits to family physicians (mean, 11; range, 0-52 visits) but a reduction in the number of visits to rheumatologists (mean, 3; range, 0-25 visits). Most of the patients (72%) used CAM in the expectation of pain relief. Patients perceived great improvement with 11%of the CAM remedies used, mild improvement with 29%, and no improvement at all with 59Y0.~~ In a similar study conducted in Guadalajara, Mexico, 300 consecutive rheumatic disease patients at three outpatient rheumatology clinics were interviewed by a trained assistant using a structured questionnaire.& The mean age of the interviewed patients was 41 years, 80% were women, the mean disease duration was 10 years, and patients had been attending the clinic for a mean of 5 years. Most of the patients had
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rheumatoid arthritis (41%) and systemic lupus erythematosus (SLE) (27%). Two hundred fifty patients (83%) had a lifetime use of 1386 CAM remedies (mean, 5.5; range, 1-19 remedies), and 203 (68%)patients had used CAM in the previous 12 months (mean, 3.5; range, 1-15 remedies). Sixty-one percent of these patients had received at least one CAM treatment before the first rheumatology consultation, but an additional 18%initiated these treatments after their initial contact with a rheumatologist. Of note is the fact that 14% of the interviewed patients discontinued conventional treatment on at least one occasion in order to receive CAM treatments. Patients claimed that CAM practitioners recommended discontinuation of conventional therapy on 57% of the occasions when conventional treatments were discontinued.48 The same group conducted a face-to-face interview with 107 consecutive patients with SLE attending the same clinics.47The mean age of these patients was 33 years, the mean disease duration was 8 +- 6 years, and the mean follow-up interval in the clinics was 6 years. Seventy patients (65%) had used CAM for a total of 121 remedies, which is equivalent to 14 new remedies per 100 person years. There were 52 discontinuations of treatments prescribed by rheumatologists in 33 (31%) patients (1.6 per patient). Of the 33 patients who had used CAM, 28 (85%)discontinued conventional treatment during the period when they used CAM compared with 42 of 74 (60%)who never used CAM (OR = 4.3; 95% CI, 1.5-12.3). Previous hospitalizations as a result of severity of their disease or complications were more frequent in users of CAM (0.83 per patient vs 0.32 per patient in nonusers; P = 0.008)!7 In Australia, Kestin et aPOinterviewed 90 consecutive patients with rheumatoid arthritis attending a rheumatology clinic at a teaching hospital. They found that 8ZYo had used more than one CAM modality or remedy since the diagnosis of rheumatoid arthritis was made and that 52% were currently using a CAM treatment. In all, 352 CAM modalities were used, with a mean of 4 modalities per patient.3O More recently, V e c ~ h i ohas ~ ~reported on a self-administered questionnaire distributed to 314 rheumatology outpatients of a teaching hospital in Woolloongabba, Australia. The response rate was 89%.Forty percent of the respondents had accessed CAM at some stage of their rheumatic illness.55 The prevalence of CAM use by German rheumatic disease patients is similar (78Y0).~~ Complementary and Alternative Medicine Use by Health Professionals
The common assumption that Western physicians discourage the use of both CAM practices and providers is not supported by the
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recently published data on referral patterns of general practitioners and some specialists. For instance, the Kaiser Permanente study cited abovezs also surveyed primary care physicians, obstetricians, and nurse practitioners. The response rate was 61% (N = 624) for the adult primary care physicians and 70.4% (N = 157) for obstetricians and nurse practitioners. Overall, 89% of both adult primary care physicians and obstetricians had used or recommended to patients at least 1 of the 20 CAM practices listed in the survey during the previous 12 months, excluding psychological counseling, prayer, or special diet. Worthy of note is the fact that 40% of those physicians interested in CAM were motivated by uncontrolled observations or anecdotal experiences, whereas only 5% were motivated by articles read in professional A 1992 survey of community physicians in Washington State, New Mexico, and southern Israel, with a 50% response rate, found that more than 60% had referred at least one patient for CAM techniques in the past year (mean number of referrals, 3.7 per year). Twelve percent of the respondents incorporated CAM techniques into their practice, and 47% had used CAM for themselves, family members, or both. Primary care physicians were more likely than specialist to make referrals for CAM treatment^.^ In Canada and some European countries, similar referral patterns can be observed. For instance, in a recent survey of general practitioners in the provinces of Ontario and Alberta, 54% of the 200 respondents (52% response rate) indicated that they refer patients to CAM practitioners, and 16% indicated they practiced some form of CAM.56In another study, 76% of 200 general practitioners in both rural and urban sites in Britain had referred patients to CAM providers during the year preceding the investigation.60Their views about the efficacy of different therapies were influenced primarily by either uncontrolled observations or personal experiences (79%) and the media (14%).60In the district of Kassel, Germany, 95% of the general practitioners who replied to a mail survey (56% response rate) occasionally used at least some form of CAM, most commonly herbal medicine, neural therapy, or homeopathy.26Emst and Kaptchuk19cited that 67% of local health authorities in the United Kingdom purchase at least one form of CAM. PATTERNS OF COMPLEMENTARY AND ALTERNATIVE MEDICINE CONSUMERS
In general, people who use CAM come from all social classes but tend to be overrepresented in the middle and upper classes, whether class is measured by income or level of education.2,*, 17, 36, 38 They are more likely to be women, who are also more likely than men to use
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CAM services, and to be middle-aged rather than under 25 years or over 50 years of age.4,36,38,57 Many use CAM for mild, chronic, and musculoskeletal conditions.2,4, l7 It appears that many patients concurrently use physicians and CAM treatments or providers for the same medical condition2,4, l7 but that a minority of patients rely primarily on CAM to treat a medical condition?, l7 A significant portion of patients do not tell their physician that they are using CAM.17 Rheumatic disease patients who use CAM also come from all social classes, but an association with income or level of education has not been consistent?, 32, 44, 4648 It seems that CAM users are slightly more disabled than nonusers,46,48 but associations with other disease characteristics have not been found. More patients used more CAM remedies 48 This pattern could after their first rheumatology perhaps be explained by longer disease duration with more opportunity to use CAM remedies or a discrepancy between patient expectations of conventional treatment and actual response to therapy. Another CAM-related pattern emerges regarding health care use. As shown in population studies, most of the rheumatic disease patients who use CAM concurrently use conventional therapies and do not inform their attending physicians of its use. It appears that CAM users tend to be more frequent users of health care than non-CAM users and that those users of CAM tend to visit CAM providers more frequently than general practitioners or rheumatologists.44,46, 48 Moreover, several studies have identified a particular subgroup of frequent CAM users at around 5% of their samples.32,44,46, 48 463
GENERAL CONSIDERATIONS ON THE USE AND SAFETY PROFILE OF TREATMENTS AND PROVIDERS OF COMPLEMENTARY AND ALTERNATIVE MEDICINE
There is a growing knowledge about the use of CAM by both the general population and rheumatic disease patients. Interpretation of the medical literature should be made with caution, however. The prevalence of CAM users largely rests on the definition of CAM and on what is listed as CAM treatments in the surveys. For instance, nonprescribed vitamins were considered to be a CAM treatment in the Australian survey,36and their inclusion contributed up to 50% of the prevalence of CAM use; others studies have specifically excluded vitamins. The crosssectional design of most studies precludes cause and effect inferences on the explanatory models for CAM use. In the same way, cross-sectional surveys of rheumatic disease patients attending rheumatology clinics prevent assumptions on efficacy, satisfaction, and safety of different CAM modalities and remedies. The safety profile of each CAM modality
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should be a primary concern; however, most of the literature on CAMrelated side effects are case reports, where publication bias should be considered. Over 130 nonconventional modalities and more than 500 remedies to treat patients with diverse diseases have been described. Some of them are harmless, others are mysterious, but some may have significant toxicity. It seems that for Europeans, the most popular applications of CAM are those for acupuncture, homeopathy, reflexology, and manipulaThe Dutch use acupunction (including osteopathy and ture, homeopathy, and hand healing, and the English use herbalists and homeopaths. People living in Canada and the United States more frequently use chiropractic, massage, acupuncture, relaxation techniques, imagery, and spiritual healing? l7 but homeopathy is employed less frequently. The Australians prefer chiropractic and naturopathy? Rheumatic disease patients use more CAM products than CAM providers. Differences among countries depend mainly on the characteristics of the ”folk” medicine, “faddish” CAM practices, and availability of CAM providers rather than on geographic, ethnic, or disease characteristics. For instance, the products used by Australians include nonprescribed vitamins and herbs; in the United States, topical remedies such as alcohol, whiskey, peanut oil, snake oil, gasoline, kerosene, motor oil, and copper or other jewelry are used*1,32; in Canada, chiropractic, deep heat rubs, fish oil, and acupuncture are used4; and in Mexico, local herbs, homeopathy, topical marijuana diluted in alcohol, and snake pills are used.48Overall, the CAM treatments most used by rheumatic disease patients are chiropractic, acupuncture, massage, and homeopathy.
Safety Considerations
There is growing evidence that the use of CAM modalities and remedies can be a morbid factor even if they are “natural.” Safety concerns related to the use of CAM treatments include the following: Direct toxicity Undeclared addition of prescribed drugs Nonsteroidal anti-inflammatory drugs Analgesics Steroids Others Contamination Heavy metals Microorganisms Additives
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Authenticity and adulterants Pharmacologic interactions between CAM and prescription drugs Behavioral patterns Conventional treatment discontinuations Frequent CAM users CAM users under no professional supervision Low willingness to report CAM-associated adverse reactions In many instances, CAM products have flooded the international market without any monitoring on safety. CAM market products may contain the substances listed on the label in the amounts claimed, but they need not. By way of illustration, the remedy itself may prove to be directly harmful6,15, 29, 33, 34, 39 or harmful through the undeclared addition of drugs such as NSAIDs, benzodiazepines, ephedrine, or ster0ids.2~. 24, 27, 49 In a recent study, 23% of the 2609 samples of traditional Chinese medicines were adulterated, largely those claimed to be effective for rheumatic diseases or to have analgesic or anti-inflammatory activity. More than half of the adulterated samples contained two or more adulterants such as caffeine, analgesics, NSAIDs, and p r e d n i ~ o n e .In ~ ~a recent review of Chinese medicinal herbs available in the United Kingdom, it was estimated that 10% to 25% were of doubtful authenticity.61 In another review of 50 commercial ginseng preparations sold in 11 countries, 12% did not contain ginseng, 1 contained ephedrine, and in 44 of these preparations, the concentration of ginseng varied from 1.9% to 9.9Y0.l~Asian patent medicines were recently screened for adulterants in California; of the 260 products, 83 (32%) contained undeclared pharmaceutic agents or heavy metals, and 23 had more than one a d ~ l t e r a n t . ~ ~ Another source of CAM-associated morbidity is contamination with arsenic, mercury, microorganisms? 14,21, 41, 51 or additives such as those in the myalgia-eosinophilia syndrome.28Drug interactions between conventional and CAM therapy are another potential concern.16,50 Some specific practices related to CAM use deserve further comment. A 1982 survey in the United Kingdom identified a total of 30,000 CAM practitioners of one variety or an0ther.4~The majority of CAM providers in Britain and the United States are nonmedically trained practitioners.%On the other hand, approximately 50% of the individuals who used CAM for a medical condition do so on their own without any supervision, that is, without either visiting a provider of CAM or discussing their CAM use with their medical doctor.17 In the United States, less than 10% of the rheumatic disease patients are attended by rheumatologists." Extrapolation of the above data suggests that many rheumatic disease patients are without any supervision at all. Patients may discontinue conventional treatment to use CAM. In one series, 5% of the cancer patients did and in another series,
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14% of the rheumatic disease patients discontinued conventional treatment.48This practice has been identified as a leading contributing cause of death in patients with SLE.47One concern relates to those patients who use CAM treatments above the mean (>6 treatments). This subgroup of frequent CAM users has been identified in several reports at a prevalence around 5%. For instance, one study found that patients at the upper limits of CAM use received up to 19 remedies, discontinued their conventional treatment 11 times, visited CAM providers up to 180 times, and spent the equivalent of 1333 days’ wages on CAM, all of these in 1 year.48 Those patients who are exposed to more CAM modalities consequently have a higher risk of side effects. Another concern is related to secondary prevention. Patients may use CAM at the beginning of their disease, delaying proper diagnosis and timely treatment.I2As discussed previously, many individuals with chronic diseases use CAM without the knowledge of their attending physician, and in one study, 26% of the CAM users would not consult their physician in case of presenting an adverse reaction associated with CAM? EXTRAPOLATIONS, PROJECTIONS, EXPENDITURES, AND MARKETING CONSIDERATIONS
The market for the use of CAM is substantial and growing rapidly worldwide. The reported prevalence rates of CAM use by the general population range from 30% to 50% in countries such as Australia, Belgium, France, Germany, the United Kingdom, Canada, and the United States. Expenditures associated with the use of CAM are rated in the billions. For instance, extrapolations suggest that in 1990, the US population made an estimated 425 million visits to providers of CAM. This number exceeds the number of visits to all US primary care physicians (388 million). The average charge per visit to CAM providers was $27.60 US and the overall estimated expenditure associated with CAM use in that year amounted to $13.7 billion US.17 The Australian survey estimates a natural expenditure of $930 million AU for CAM items and providers in 1993.36In 1990, sales in the European Union totaled 1billion pounds, with sales in the United Kingdom estimated at 200 million pounds.8 The high prevalence of CAM use among patients with rheumatic diseases is not a surprise. In spite of the disparity in the prevalence rates, 2 of 10 for rheumatic disease patients in the general population and 9 of 10 for clinic-based populations, which is likely the result of methodology issues, these figures are impressive. The reported prevalence rate of CAM provider consultation, which ranges from 12% to 33%, with an average of 4 to 9 visits per year, is superior to the reported
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rheumatology care prevalence rate. In Canada, the reported expenditures are $489.00 C for CAM providers and $133.00 C for CAM products per patient, per year.5,44 In Mexico, the mean expenditure per patient for fees to CAM providers is equivalent to 28 days of the official minimum daily wage, and for the remedies themselves, it is equivalent to 13 days of the official minimum daily In order to better appreciate the potential market for CAM use by rheumatic disease patients, the following presents some extrapolations from known data. The Americas are composed of approximately 35 independent countries, with a reported population of 774,221,000 inhabitants in 1996.' If we accept that the prevalence of CAM use is at least 22% of the general population, including children, the potential market for CAM modalities and remedies in Pan-America would be 174 million people in 1 year. Knowing that 15% of the general population suffers from some form of arthritis or rheumatic condition34and that the prevalence of CAM use by these patients would be 209'0, around 23 million rheumatic disease patients living in the Americas are users of CAM. Given that the prevalence of rheumatoid arthritis is 1% of the general populations and that the prevalence of CAM use by these patients would be 6070, it can be deduced that around 4.6 million patients with rheumatoid arthritis are using CAM. The same extrapolation can be done for patients with SLE. Given that the prevalence of SLE is 0.04% of the general populationMand that 65% of these individuals use CAM, there would be 300,000 SLE patients using CAM. If we accept that there are at least 23 million patients with rheumatic diseases in the Americas who used at least one CAM in 1996 and that the mean expenditure for CAM items is $lOO.OO.US per patient, per year (some reported expenditures exceed this amount even in developing countries), the potential market for CAM products alone used by rheumatic disease patients would be $23 billion US per year. This figure would certainly provide significant relief to the already limited health care budgets of many countries. CONCLUSIONS
The evidence is clear that the use of CAM by sufferers of rheumatic diseases is highly prevalent. Furthermore, not withstanding the significant advances in our understanding and in conventional treatment programs for these diseases, the evidence would suggest that the use of alternative therapies is increasing. In many cases, patients combine conventional therapies prescribed by their physician with those provided by alternative practitioners. It is therefore judicious for physicians and rheumatologists alike to ensure that they are not only acquainted with
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the alternative therapies that their patients may be taking but that they also have some insight into the nature of these remedies, as they may have a significant impact on patient management. Although many patients appear to successfully blend conventional and alternative treatment programs, it is of particular concern that some patients clearly stop physician-prescribed treatments and replace them exclusively with alternative remedies. These issues need to be clearly understood and dealt with both sensitively and insightfully by physicians. It is clear that a need to prove or disprove the potential efficacy of these therapies is an important issue. Physicians can no longer ”bury their head in the sand” but must be prepared to address as scientifically and as accurately as possible any claims for traditional therapies in the same way that they would approach new prescription medications. It is only in this way that they are likely to gain the confidence of their patients when addressing these issues openly with them. It is also clear that such alternative therapies may not be without toxicity; consequently, physicians are obliged to understand the nature of these alternative therapies such that they can appropriately deal with problems that may result from CAM use in exactly the same way as with what is considered to be conventional therapies. Finally, there is clearly a huge market for the use of these alternative therapies, which has a significant socioeconomic impact on individual patient and societal finances. It would certainly be an attractive goal to be able to capture some of the monies that are being spent on this type of therapy and redirect them to the use of more evidence-based treatments. This goal, however, is unlikely to be achieved unless the medical profession actively addresses the issue of the potential effectiveness and toxicity of these therapies in the management of commonly treated diseases. The epidemiological evidence would suggest that this issue in the management of patients with rheumatic diseases is unlikely to disappear and indeed continues to increasingly command our attention.
References 1. Almanaque mundial 1998: Editorial Televisa, Mexico, 1998 2. Astin J A Why patients use alternative medicine. JAMA 279:1548-1553, 1998 3. Barnes J, Mills SY, Abbot NC, et al: Different standards for reporting AD& to herbal remedies and conventional OTC medicines: Face-to-face interviews with 515 users of herbal remedies. Br J Clin Pharmacol45:496-500, 1998 4. Bemstein JH, Shuval JF Nonconventional medicine in Israel: Consultation patterns of the Israeli population and attitudes of primary care physicians. SOCSci Med 44:13411348, 1997 5. Boisset M, Fittzcharles MA: Alternative medicine use by rheumatic patients in a universal health care setting. J Rheumatol21:14&152, 1994 6. Borins M: The dangers of using herbs. Postgrad Med 104:91-100, 1998 7. Borkan J, Neher J, Anson 0, et al: Referrals for alternative therapies. J Fam Pract 39:545-550, 1994
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8. British Medical Association: Complementary Medicine: New Approaches to Good Practice. Oxford, Oxford University Press, 1993 9. But PP: Herbal poisoning caused by adulterants or erroneous substitutes. J Trop Med Hyg 97371-374,1994 10. Cohen CJ, Eisenberg DM, Mayer KH, et a1 Prevalence of alternative medical treatments in HIV-infected patients: Implications for primary care [abstract]. Clin Res 38:692, 1990 11. Cook Ch, Baisden D Ancillary use of folk medicine by patients in primary care clinics in southwestem West Virginia. South Med J 79:1098-1101,1986 12. Coppes MJ, Anderson RA, Egeler Rh4, et a1 Alternative therapies for the treatment of childhood cancer [letter]. N Engl J Med 339896447, 1998 13. Cronan TA, Kaplan RM, Kozin F Factors affecting unprescribed remedy use among people with self-reported arthritis. Arthritis Care Research 6149-155,1993 14. Cui J, Garle M, Eneroth P, et a1 What d o commercial ginseng preparations contain [Letter]? Lancet 344.134, 1994 15. Davis C: Risks of manipulation. J R SOCMed 87182, 1994 16. DiPaola RS,Zhang H, Lambert GH, et a1 Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. N Engl J Med 339:785-791,1998 17. Eisenberg DM, Kessler RC, Foster C, et al: Unconventional medicine in the United States. N Engl J Med 328246-252, 1993 18. Emst E Harmless herbs? A review of the recent literature. Am J Med 104:170-178,1998 19. Emst E, Kaptchuk TJ: Complementary medicine-the case for dialogue. J R C Physicians Lond 30410412,1996 20. Emst E, Cassileth BR The prevalence of complementary/altemative medicine in cancer. Cancer 83:777-782, 1998 21. Espinoza EO, Mann M-J: Arsenic and mercury in traditional Chinese herbal balls. N Engl J Med 33803-804, 1995 22. Fisher P, Ward A: Complementary medicine in Europe. BMJ 309107-110,1994 23. Gertner E, Marshall PS, Filandrinos D, et a1 Complications resulting from the use of Chinese herbal medications containing undeclared prescription drugs. Arthritis Rheum 38:614417, 1995 24. Goldman J A Chinese herbal medicine: Camouflaged prescription antiinflammatory drugs, corticosteroids, and lead [letter]. Arthritis Rheum X1207, 1991 25. Gordon NP, Sobel DS, Tarazona E Z Use of and interest in alternative therapies among adult primary care clinicians and adult members in a large health maintenance organization. West J Med 169:153-161,1998 26. Himmel W, Schulte M, ICochen MM. Complementary medicine: Are patients’ expectations being met by their general practitioners? Br J Gen Pract 43232-235,1993 27. Huang WF, Wen K-Ch, Hsiao M-L Adulteration by synthetic therapeutic substances of traditional Chinese medicines in Taiwan. J Clin Pharmacol37344-350,1997 28. Kamb ML, Murphy JJ,Jones JL, et a1 Eosinophilia-myalgia syndrome in L-tryptophan exposed patients. JAMA 26777-82, 1992 29. Katz M, Saibil F Herbal hepatitis: Subacute hepatic necrosis secondary to chaparral leaf. J Clin Gastroenterol 12203-206, 1990 30. Kestin M, Miller L, Littlejohn G, et a 1 The use of unproven remedies for rheumatoid arthritis in Australia. Med J Aust 143516-518,1985 31. KO RJ: Adulterants in Asian patent medicines [letter]. N Engl J Med 339:847, 1998 32. Kronenfeld JJ, Wasner C: The use of unorthodox therapies and marginal practitioners. SOCSci Med 16:1119-1125,1982 33. Larrey D, Vial T, Pauwels A, et a 1 Hepatitis after germander (Teucrium chamaedtys) administration: Another instance of herbal medicine hepatotoxicity. Ann Intern Med 117129-132, 1992 34. Lawrence RC, Helmick Ch G, Arnett F, et a1 Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 41:778799, 1998 35. MacGregor FB, Abernethy VE, Dahabra S, et a1 Hepatotoxicity of herbal remedies. BMJ 299:1156-1157, 1989 36. MacLennan AH, Wilson DH, Taylor AW. Prevalence and cost of alternative medicine in Australia. Lancet 347569-573,1996 37. McGinnis LS: Alternative therapies, 1990 An overview. Cancer 671788-1792,1991 38. Millar WJ: Revue Canadienne de Sant6 Publique 88:154-158,1997
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39. Mohabbat 0, Younos MS, Merzad AA, et al: An outbreak of hepatic veno-occlusive disease in north-western Afghanistan. Lancet 2269-271, 1976 40. Moody GA, Eaden JA, Bhakta P, et a1 The role of complementary medicine in European and Asian patients with inflammatory bowel disease. Public Health 112269-271, 1998 41. Obt AB, Oh JY, Huntington RA, et a1 Chinese herbal medicine induces acute renal failure. Arch Intern Med 155911-212, 1995 42. Panush Rs: Reflections on unproven remedies. Rheum Dis Clin North Am 19:201206, 1993 43. Pietroni PC: Beyond the boundaries: Relationship between general practice and complementary medicine. BMJ 305:564-566, 1992 44. Pioro-Boisset M, Esdaile JM, Fitzcharles MA: Alternative medicine use in fibromyalgia syndrome. Arthritis Care Research 9:13-17, 1996 45. Rainer F, Ulreich A, Pfeiffer KP: Art und ausmai3 der selbstmedikation mit sogenannten "hausmitteln" bei patienten mit rheumatischen erkrankungen. Z Rheumatol 41:276279, 1982 46. Ramos-Remus C, Watters CA, Dyke L, et al: Prevalence and health locus of control in the use of non-conventional remedies by patients with rheumatic diseases. J Rheumatol, 1998 47. Ramos-Remus C, Gamez-Nava JI, Gonzalez-Lopez L, et a1 Use of alternative medicine in a consecutive sample of patients with systemic lupus erythematosus. J Rheumatol 242490-2491, 1997 48. Ramos-Remus C, Gamez-Nava JI, Gonzalez-Lopez L, et al: Use of non-conventional therapies by patients with rheumatic diseases in Guadalajara, Mexico: Prevalence, beliefs and expectations. Arthritis Care Research 11:411-418, 1998 49. Ries CA, Sahud MA: Agranulocytosis caused by Chinese herbal medicines. Dangers of medications containing aminopyrine and phenylbutazone. JAMA 231:352-355, 1975 50. Shaw D, Leon Ch, Kolev S, et al: Traditional remedies and food supplements. A 5-year toxicological study (1991-1995). Drug Safety 17342-356, 1997 51. Slifman N, Obermeyer WR, Aloi BK, et a1 Contamination of botanical dietary supplements by digitalis lanata. N Engl J Med 339:806-811, 1998 52. Smart HLA, Maybemy JT,Atkinson M. Alternative medicine consultations and remedies in patients with the irritable bowel syndrome. Gut 27826-828, 1986 53. Spigelblatt L, Lain&-Ammara G, Pless IB, et al: The use of alternative medicine by children. Pediatrics 94:811-814, 1994 54. Thomas KJ, Carr J, Westlake L, et al: Use of non-orthodox and conventional healthcare in Britain. BMJ 302:207-210, 1991 55. Vecchio PC: Attitudes to alternative medicine by rheumatology outpatient attenders. J Rheumatol21:14.5147, 1994 * 56. Verhoef MJ, Sutherland L R Alternative medicine and general practitioners. Can Fam Physician 41:1005-1011, 1995 57. Verhoef MJ, Russell ML, Love EJ: Alternative medicine use in rural Alberta. Revue Canadienne de Santt? Publique 85:308-309,1994 58. Verhoef MJ, Sutherland LR, Brkich L: Use of alternative medicine by patients attending a gastroenterology clinic. Can Med Assoc J 142:121-125, 1990 59. Wainapel SF, Thomas AD, Kahan B: Use of alternative therapies by rehabilitation outpatients. Arch Phys Med Rehabil 79:1003-1005, 1998 60. Wharton R, Lewith G: Complementary medicine and the general practitioner. BMJ 292:1498-1500,1986 61. Yu H, Zhong S, Chan K, et al: Pharmacognostical investigations on traditional Chinese medicinal herbs. J Pharm Pharmacol47:1129-1131, 1995
Address reprint requests to Paul Davis, FRCPC, FRCP(UK) Division of Rheumatology 562 Heritage Medical Research Centre University of Alberta Edmonton, Alberta Canada, T6G 2S2
0889-857)
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EPIDEMIOLOGY OF COMPLEMENTARY AND ALTERNATIVE PRACTICES IN RHEUMATOLOGY Cesar Ramos-Remus, MD, MSc, Sergio Gutierrez-UreAa, MD, and Paul Davis, FRCPC, FRCP(UK)
Over 130 nonconventional treatment modalities and more than 500 remedies have been described to treat patients with diverse diseases. These range from rubbing creams to the implantation of the hypophysis of a stillborne pig. Whatever term is used, be it non-conventional remedies or complementary and alternative medicine (CAM), these modalities have become an increasingly prominent part of the health care practices of the general population and of patients with various diseases even in an era of rapidly advancing medical technology. CAM has become a significant topic not just in the lay press but also in the biomedical literature. Since 1966, more than 38,000 publications bearing this or a related term appear in titles or abstracts that have been referenced in Medline alone. Indeed, several important journals have recently devoted editorials and original papers to this subject. This article reviews the most relevant aspects of the biomedical literature on the epidemiology related to CAM use, with special emphasis on the magnitude,
From the University of Guadalajara (CR, SG); Department of Rheumatology, Hospital de Especialidades del Centro Mkdico Nacional de Occidente, IMSS-Instituto Mexican0 del Seguro Social (CR); Antiguo Hospital Civil, Guadalajara, Mexico (SG); and University of Alberta, Edmonton, Alberta, Canada (PD)
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patterns, and costs of CAM modalities and remedies employed by rheumatic disease patients. WHO USES COMPLEMENTARY AND ALTERNATIVE MEDICINE?
Population-Based Studies It appears that the use of CAM is a worldwide phenomenon not restricted to any particular ethnic group, social status, or economic situation (Fig. 1). Prevalence ranges from 6% to 73% of the general population. Variations in the prevalence of CAM use are better explained by differences in the study design, definition of CAM, instruments used, and population selection rather than by geographic, economic, or ethnic factors. In one large study, MacLennan et a136conducted a population survey through personal interviews with 3004 persons aged 15 years or older living in South Australia. The overall response rate was 73%, and the survey focused on 12 CAM modalities, including nonprescribed vitamins. The overall use of at least one CAM modality or remedy was 48.5% in the past 12 months, and 20.3% of these individuals had visited at least one CAM practitioner in the same period.36 The National Population Health Survey of Canada conducted in 1994 through 1995 revealed that 15% of the 17,626 respondents had visited at least one CAM provider in the previous 12 months.38 In another population-based study of a rural population in the province of Alberta in Canada, Verhoef 6t a157found that 32.3% of the adult respondents had visited CAM providers at least once in the previous 6 months. This figure represents a 170% increase in the use of CAM providers compared with a similar study performed 3 years earlier. Spigelblatt et a153 reported on a mail survey of 1911 parents of children consulting the general outpatient clinic of a university hospital in Quebec, Canada. The response rate was 93%, and the authors reported that 11%of the children had used at least one CAM modality or remedy, with 8% of them having used three or more.53 In 1993, Eisenberg et all7 published the results of a national telephone survey of adults aged 18 years or older across the United States. The overall response rate was 679'0, and the authors elected to limit the survey to English-speaking persons, to households with telephones, and to 16 commonly used CAM modalities and remedies. Thirty-four percent of the 1539 individuals surveyed used at least one CAM modality or remedy in 1990, and 35% of them visited a provider of CAM, with an average of 19 visits the preceding year.I7
+ CAM use by gsneral papllalion:
Figure 1. Worldwide prevalence of CAM use.
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e by rheumatic palierds:
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The adult members of the Kaiser Permanente Medical Care Program of Northern California were recently surveyed by a mail questionnaire to assess their CAM use, with a response rate of 51%. The authors found that 25% of the respondents had used in the past year at least 1 of the 20 CAMS listed, and 43% reported having used 1 or more in the past.25 In another mail survey conducted through National Family Opinion, which maintains a panel of persons who have agreed to be participants in mail surveys in the United States, the response rate was 69% (N = 1035), and the survey focused on 17 CAM modalities. Forty percent of respondents reported using some form of alternative health care during the past year. The top four treatment categories were chiropractic (15.7%), lifestyle diet (8%),exercise/movement (7.2%),and relaxation (6.9%).2 Cook and Baisden" reported the results of face-to-face interviews to assess the prevalence of the use of 61 popular folk remedies in 3 urban and 3 rural southwestern West Virginia primary care clinics. There were 170 respondents, but the response rate was not stated. Seventy-three percent of respondents indicated that they had used at least 1 such remedy during the preceding 12 months, with a mean use of 4.5 remedies per person and a range from 1 to 18 remedies.l' Bernstein and Shuva14recently reported the results of face-to-face interviews with 2030 Jewish adults aged 45 to 75 years. The aim of the study was to assess the prevalence of CAM practitioner use. They found that 6% of their sample had visited at least one CAM provider in the past year, and 23% of them had visited CAM providers more than once.4 Data cited by Fisher and Wardzzindicate that in 1981, 6.4% of the Dutch population attended a therapist or doctor providing CAM, and that this increased to 9.i% by 1985 and 15.7% by 1990. These authors also cite data from the Consumers Association of the United Kingdom that the use of CAM in the preceding 12 months rose from 14% in 1985 to almost 25% in 1991. Homeopathy is the most popular form of CAM in France, rising in use from 16% of the population in 1982 to 29% in 1987 and 36% in 1992.22 Nonrheumatic Disease Patients
A high prevalence of CAM use has been reported for a number of disease-specific groups. For instance, between 7% and 64% of patients with cancer use CAM according to a recently published systematic review,2O 27% of patients attending a gastroenterology 20% of patients with inflammatory bowel disease,4O and 29% of the attendees of a rehabilitation outpatient clinic in New Y ~ r as k ~well ~ as patients with acquired immunodeficiency syndrome, irritable bowel syndrome, and 37, 52 depression among other conditions.lO,
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Rheumatic Disease Patients The scope of rheumatic diseases involves more than 150 different entities, which are often chronic and carry significant morbidity and potential disability. Given these characteristics and the lack of curative therapies for many of these entities, the use of CAM should not be a surprise. Evidence exists that rheumatic disease patients use CAM whether they live in developed or developing countries, are well or less educated, and are richer or less fortunate. For instance, in the study of Eisenberg et al,I7 16% of the 1539 adults interviewed by telephone across the United States self-reported a history of "arthritis," with 18% of these individuals acknowledging the use of CAM and 7% having attended CAM providers in the previous 12 months. In the survey by Astin: arthritis was the sixth most frequently cited health problem treated with CAM (25%). Kronenfeld and Wasne132 reported the results of a face-to-face interview with 98 rheumatic disease patients attending a rheumatology clinic in a university setting in the United States. Sixty patients had rheumatoid arthritis, 10 had osteoarthritis, and 28 had diverse rheumatic disorders. Ninety-four percent of the interviewed patients reported that they had used or attended CAM practitioners; the mean use was 3.7 different remedies, with 3 patients each having tried 13 different modalities. Topical remedies were used by over 80% of all respondents, including alcohol, whiskey, snake oil, and gasoline. Thirty-six percent of the respondents had visited a CAM provider at least once for their arthritis. Surprisingly, 5% had used CAM-before contacting a physician, whereas 83% had been seeing a physician for more than 1 year before they sought CAM remedies.32In another survey from California, 84% of the patients with self-reported osteoarthritis or rheumatoid arthritis had used CAM during the past 6 months.13 We identified three studies from Canada related to the use of CAM by patients with rheumatic diseases. In the first study, 235 consecutive patients attending a rheumatology clinic in Montreal were evaluated by a face-to-face q~estionnaire.~ The response rate was 100%. Forty-eight percent of the interviewed patients had "inflammatory" rheumatic diseases, 28% had "degenerative" diseases, and 24% had soft-tissue rheumatism. Sixty-six percent of these patients had used at least one CAM modality or remedy in the past 12 months, and 13% had visited a CAM provider in the same period. Five percent of those who saw CAM providers had visited the providers six or more times.5 The second study was conducted by the same group in the same setting4 Here, an interviewer-based questionnaire was administered to 221 consecutive rheumatology patients and 80 patients with fibromyalgia syndrome, with a 38% response rate for this latter condition. The mean
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age was 50 years for the fibromyalgia group and 43 years for the other group. CAM use was identified in 91% of fibromyalgia patients and 63% of the other rheumatic disease patients. All CAM modalities were used more commonly by the fibromyalgia patients than by the other rheumatic disease patients. CAM practitioners and dietary manipulation were used much more frequently by the fibromyalgia patients. Seventynine percent of the fibromyalgia patients had visited CAM practitioners, and 63% of them reported frequent use as defined by more than six visits per year. Fibromyalgia patients were asked to rate their satisfaction with CAM on a scale from 0 to 10. The overall score given was 6.7. Use of orthodox health care by the fibromyalgia patients was more frequent in the CAM users (average of 7.5 medical doctor visits per year) than in those who did not use CAM (average of 4.5 medical doctor visits per year).& The third Canadian study was a cross-sectional survey of 200 patients with rheumatic diseases at three outpatient rheumatology clinics in A face-to-face structured interview was administered by a trained assistant to evaluate the prevalence of CAM use as well as patient beliefs, perceptions, and expectations in relation to CAM. The response rate was 100%. The mean age of these patients was 56 years, and 46% had rheumatoid arthritis. Sixty percent of the patients had used a total of 530 CAM modalities and remedies (range, 1-25 CAM practices), and 79% of these patients had used 309 CAM remedies in the previous 12 months (mean, 3; range, 1-15 remedies). Overall, 47% had used at least one CAM practice before the first rheumatology consultation, but an additional 8% initiated CAM practices after their first contact with a rheumatologist. The group of CAM users saw a rheumatologist an average of 6 times dbring the past year (range, 1-52 visits) and their family physicians 11 times (range, 0-52 visits). Forty-one (34%) of the 119 users of CAM visited CAM providers at least once in the past 12 months (mean, 11; range, 1-105 visits). Among the 41 patients who not only used CAM but also visited a CAM provider, there was a similar number of total visits to family physicians (mean, 11; range, 0-52 visits) but a reduction in the number of visits to rheumatologists (mean, 3; range, 0-25 visits). Most of the patients (72%) used CAM in the expectation of pain relief. Patients perceived great improvement with 11%of the CAM remedies used, mild improvement with 29%, and no improvement at all with 59Y0.~~ In a similar study conducted in Guadalajara, Mexico, 300 consecutive rheumatic disease patients at three outpatient rheumatology clinics were interviewed by a trained assistant using a structured questionnaire.& The mean age of the interviewed patients was 41 years, 80% were women, the mean disease duration was 10 years, and patients had been attending the clinic for a mean of 5 years. Most of the patients had
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rheumatoid arthritis (41%) and systemic lupus erythematosus (SLE) (27%). Two hundred fifty patients (83%) had a lifetime use of 1386 CAM remedies (mean, 5.5; range, 1-19 remedies), and 203 (68%)patients had used CAM in the previous 12 months (mean, 3.5; range, 1-15 remedies). Sixty-one percent of these patients had received at least one CAM treatment before the first rheumatology consultation, but an additional 18%initiated these treatments after their initial contact with a rheumatologist. Of note is the fact that 14% of the interviewed patients discontinued conventional treatment on at least one occasion in order to receive CAM treatments. Patients claimed that CAM practitioners recommended discontinuation of conventional therapy on 57% of the occasions when conventional treatments were discontinued.48 The same group conducted a face-to-face interview with 107 consecutive patients with SLE attending the same clinics.47The mean age of these patients was 33 years, the mean disease duration was 8 +- 6 years, and the mean follow-up interval in the clinics was 6 years. Seventy patients (65%) had used CAM for a total of 121 remedies, which is equivalent to 14 new remedies per 100 person years. There were 52 discontinuations of treatments prescribed by rheumatologists in 33 (31%) patients (1.6 per patient). Of the 33 patients who had used CAM, 28 (85%)discontinued conventional treatment during the period when they used CAM compared with 42 of 74 (60%)who never used CAM (OR = 4.3; 95% CI, 1.5-12.3). Previous hospitalizations as a result of severity of their disease or complications were more frequent in users of CAM (0.83 per patient vs 0.32 per patient in nonusers; P = 0.008)!7 In Australia, Kestin et aPOinterviewed 90 consecutive patients with rheumatoid arthritis attending a rheumatology clinic at a teaching hospital. They found that 8ZYo had used more than one CAM modality or remedy since the diagnosis of rheumatoid arthritis was made and that 52% were currently using a CAM treatment. In all, 352 CAM modalities were used, with a mean of 4 modalities per patient.3O More recently, V e c ~ h i ohas ~ ~reported on a self-administered questionnaire distributed to 314 rheumatology outpatients of a teaching hospital in Woolloongabba, Australia. The response rate was 89%.Forty percent of the respondents had accessed CAM at some stage of their rheumatic illness.55 The prevalence of CAM use by German rheumatic disease patients is similar (78Y0).~~ Complementary and Alternative Medicine Use by Health Professionals
The common assumption that Western physicians discourage the use of both CAM practices and providers is not supported by the
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recently published data on referral patterns of general practitioners and some specialists. For instance, the Kaiser Permanente study cited abovezs also surveyed primary care physicians, obstetricians, and nurse practitioners. The response rate was 61% (N = 624) for the adult primary care physicians and 70.4% (N = 157) for obstetricians and nurse practitioners. Overall, 89% of both adult primary care physicians and obstetricians had used or recommended to patients at least 1 of the 20 CAM practices listed in the survey during the previous 12 months, excluding psychological counseling, prayer, or special diet. Worthy of note is the fact that 40% of those physicians interested in CAM were motivated by uncontrolled observations or anecdotal experiences, whereas only 5% were motivated by articles read in professional A 1992 survey of community physicians in Washington State, New Mexico, and southern Israel, with a 50% response rate, found that more than 60% had referred at least one patient for CAM techniques in the past year (mean number of referrals, 3.7 per year). Twelve percent of the respondents incorporated CAM techniques into their practice, and 47% had used CAM for themselves, family members, or both. Primary care physicians were more likely than specialist to make referrals for CAM treatment^.^ In Canada and some European countries, similar referral patterns can be observed. For instance, in a recent survey of general practitioners in the provinces of Ontario and Alberta, 54% of the 200 respondents (52% response rate) indicated that they refer patients to CAM practitioners, and 16% indicated they practiced some form of CAM.56In another study, 76% of 200 general practitioners in both rural and urban sites in Britain had referred patients to CAM providers during the year preceding the investigation.60Their views about the efficacy of different therapies were influenced primarily by either uncontrolled observations or personal experiences (79%) and the media (14%).60In the district of Kassel, Germany, 95% of the general practitioners who replied to a mail survey (56% response rate) occasionally used at least some form of CAM, most commonly herbal medicine, neural therapy, or homeopathy.26Emst and Kaptchuk19cited that 67% of local health authorities in the United Kingdom purchase at least one form of CAM. PATTERNS OF COMPLEMENTARY AND ALTERNATIVE MEDICINE CONSUMERS
In general, people who use CAM come from all social classes but tend to be overrepresented in the middle and upper classes, whether class is measured by income or level of education.2,*, 17, 36, 38 They are more likely to be women, who are also more likely than men to use
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CAM services, and to be middle-aged rather than under 25 years or over 50 years of age.4,36,38,57 Many use CAM for mild, chronic, and musculoskeletal conditions.2,4, l7 It appears that many patients concurrently use physicians and CAM treatments or providers for the same medical condition2,4, l7 but that a minority of patients rely primarily on CAM to treat a medical condition?, l7 A significant portion of patients do not tell their physician that they are using CAM.17 Rheumatic disease patients who use CAM also come from all social classes, but an association with income or level of education has not been consistent?, 32, 44, 4648 It seems that CAM users are slightly more disabled than nonusers,46,48 but associations with other disease characteristics have not been found. More patients used more CAM remedies 48 This pattern could after their first rheumatology perhaps be explained by longer disease duration with more opportunity to use CAM remedies or a discrepancy between patient expectations of conventional treatment and actual response to therapy. Another CAM-related pattern emerges regarding health care use. As shown in population studies, most of the rheumatic disease patients who use CAM concurrently use conventional therapies and do not inform their attending physicians of its use. It appears that CAM users tend to be more frequent users of health care than non-CAM users and that those users of CAM tend to visit CAM providers more frequently than general practitioners or rheumatologists.44,46, 48 Moreover, several studies have identified a particular subgroup of frequent CAM users at around 5% of their samples.32,44,46, 48 463
GENERAL CONSIDERATIONS ON THE USE AND SAFETY PROFILE OF TREATMENTS AND PROVIDERS OF COMPLEMENTARY AND ALTERNATIVE MEDICINE
There is a growing knowledge about the use of CAM by both the general population and rheumatic disease patients. Interpretation of the medical literature should be made with caution, however. The prevalence of CAM users largely rests on the definition of CAM and on what is listed as CAM treatments in the surveys. For instance, nonprescribed vitamins were considered to be a CAM treatment in the Australian survey,36and their inclusion contributed up to 50% of the prevalence of CAM use; others studies have specifically excluded vitamins. The crosssectional design of most studies precludes cause and effect inferences on the explanatory models for CAM use. In the same way, cross-sectional surveys of rheumatic disease patients attending rheumatology clinics prevent assumptions on efficacy, satisfaction, and safety of different CAM modalities and remedies. The safety profile of each CAM modality
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should be a primary concern; however, most of the literature on CAMrelated side effects are case reports, where publication bias should be considered. Over 130 nonconventional modalities and more than 500 remedies to treat patients with diverse diseases have been described. Some of them are harmless, others are mysterious, but some may have significant toxicity. It seems that for Europeans, the most popular applications of CAM are those for acupuncture, homeopathy, reflexology, and manipulaThe Dutch use acupunction (including osteopathy and ture, homeopathy, and hand healing, and the English use herbalists and homeopaths. People living in Canada and the United States more frequently use chiropractic, massage, acupuncture, relaxation techniques, imagery, and spiritual healing? l7 but homeopathy is employed less frequently. The Australians prefer chiropractic and naturopathy? Rheumatic disease patients use more CAM products than CAM providers. Differences among countries depend mainly on the characteristics of the ”folk” medicine, “faddish” CAM practices, and availability of CAM providers rather than on geographic, ethnic, or disease characteristics. For instance, the products used by Australians include nonprescribed vitamins and herbs; in the United States, topical remedies such as alcohol, whiskey, peanut oil, snake oil, gasoline, kerosene, motor oil, and copper or other jewelry are used*1,32; in Canada, chiropractic, deep heat rubs, fish oil, and acupuncture are used4; and in Mexico, local herbs, homeopathy, topical marijuana diluted in alcohol, and snake pills are used.48Overall, the CAM treatments most used by rheumatic disease patients are chiropractic, acupuncture, massage, and homeopathy.
Safety Considerations
There is growing evidence that the use of CAM modalities and remedies can be a morbid factor even if they are “natural.” Safety concerns related to the use of CAM treatments include the following: Direct toxicity Undeclared addition of prescribed drugs Nonsteroidal anti-inflammatory drugs Analgesics Steroids Others Contamination Heavy metals Microorganisms Additives
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Authenticity and adulterants Pharmacologic interactions between CAM and prescription drugs Behavioral patterns Conventional treatment discontinuations Frequent CAM users CAM users under no professional supervision Low willingness to report CAM-associated adverse reactions In many instances, CAM products have flooded the international market without any monitoring on safety. CAM market products may contain the substances listed on the label in the amounts claimed, but they need not. By way of illustration, the remedy itself may prove to be directly harmful6,15, 29, 33, 34, 39 or harmful through the undeclared addition of drugs such as NSAIDs, benzodiazepines, ephedrine, or ster0ids.2~. 24, 27, 49 In a recent study, 23% of the 2609 samples of traditional Chinese medicines were adulterated, largely those claimed to be effective for rheumatic diseases or to have analgesic or anti-inflammatory activity. More than half of the adulterated samples contained two or more adulterants such as caffeine, analgesics, NSAIDs, and p r e d n i ~ o n e .In ~ ~a recent review of Chinese medicinal herbs available in the United Kingdom, it was estimated that 10% to 25% were of doubtful authenticity.61 In another review of 50 commercial ginseng preparations sold in 11 countries, 12% did not contain ginseng, 1 contained ephedrine, and in 44 of these preparations, the concentration of ginseng varied from 1.9% to 9.9Y0.l~Asian patent medicines were recently screened for adulterants in California; of the 260 products, 83 (32%) contained undeclared pharmaceutic agents or heavy metals, and 23 had more than one a d ~ l t e r a n t . ~ ~ Another source of CAM-associated morbidity is contamination with arsenic, mercury, microorganisms? 14,21, 41, 51 or additives such as those in the myalgia-eosinophilia syndrome.28Drug interactions between conventional and CAM therapy are another potential concern.16,50 Some specific practices related to CAM use deserve further comment. A 1982 survey in the United Kingdom identified a total of 30,000 CAM practitioners of one variety or an0ther.4~The majority of CAM providers in Britain and the United States are nonmedically trained practitioners.%On the other hand, approximately 50% of the individuals who used CAM for a medical condition do so on their own without any supervision, that is, without either visiting a provider of CAM or discussing their CAM use with their medical doctor.17 In the United States, less than 10% of the rheumatic disease patients are attended by rheumatologists." Extrapolation of the above data suggests that many rheumatic disease patients are without any supervision at all. Patients may discontinue conventional treatment to use CAM. In one series, 5% of the cancer patients did and in another series,
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14% of the rheumatic disease patients discontinued conventional treatment.48This practice has been identified as a leading contributing cause of death in patients with SLE.47One concern relates to those patients who use CAM treatments above the mean (>6 treatments). This subgroup of frequent CAM users has been identified in several reports at a prevalence around 5%. For instance, one study found that patients at the upper limits of CAM use received up to 19 remedies, discontinued their conventional treatment 11 times, visited CAM providers up to 180 times, and spent the equivalent of 1333 days’ wages on CAM, all of these in 1 year.48 Those patients who are exposed to more CAM modalities consequently have a higher risk of side effects. Another concern is related to secondary prevention. Patients may use CAM at the beginning of their disease, delaying proper diagnosis and timely treatment.I2As discussed previously, many individuals with chronic diseases use CAM without the knowledge of their attending physician, and in one study, 26% of the CAM users would not consult their physician in case of presenting an adverse reaction associated with CAM? EXTRAPOLATIONS, PROJECTIONS, EXPENDITURES, AND MARKETING CONSIDERATIONS
The market for the use of CAM is substantial and growing rapidly worldwide. The reported prevalence rates of CAM use by the general population range from 30% to 50% in countries such as Australia, Belgium, France, Germany, the United Kingdom, Canada, and the United States. Expenditures associated with the use of CAM are rated in the billions. For instance, extrapolations suggest that in 1990, the US population made an estimated 425 million visits to providers of CAM. This number exceeds the number of visits to all US primary care physicians (388 million). The average charge per visit to CAM providers was $27.60 US and the overall estimated expenditure associated with CAM use in that year amounted to $13.7 billion US.17 The Australian survey estimates a natural expenditure of $930 million AU for CAM items and providers in 1993.36In 1990, sales in the European Union totaled 1billion pounds, with sales in the United Kingdom estimated at 200 million pounds.8 The high prevalence of CAM use among patients with rheumatic diseases is not a surprise. In spite of the disparity in the prevalence rates, 2 of 10 for rheumatic disease patients in the general population and 9 of 10 for clinic-based populations, which is likely the result of methodology issues, these figures are impressive. The reported prevalence rate of CAM provider consultation, which ranges from 12% to 33%, with an average of 4 to 9 visits per year, is superior to the reported
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rheumatology care prevalence rate. In Canada, the reported expenditures are $489.00 C for CAM providers and $133.00 C for CAM products per patient, per year.5,44 In Mexico, the mean expenditure per patient for fees to CAM providers is equivalent to 28 days of the official minimum daily wage, and for the remedies themselves, it is equivalent to 13 days of the official minimum daily In order to better appreciate the potential market for CAM use by rheumatic disease patients, the following presents some extrapolations from known data. The Americas are composed of approximately 35 independent countries, with a reported population of 774,221,000 inhabitants in 1996.' If we accept that the prevalence of CAM use is at least 22% of the general population, including children, the potential market for CAM modalities and remedies in Pan-America would be 174 million people in 1 year. Knowing that 15% of the general population suffers from some form of arthritis or rheumatic condition34and that the prevalence of CAM use by these patients would be 209'0, around 23 million rheumatic disease patients living in the Americas are users of CAM. Given that the prevalence of rheumatoid arthritis is 1% of the general populations and that the prevalence of CAM use by these patients would be 6070, it can be deduced that around 4.6 million patients with rheumatoid arthritis are using CAM. The same extrapolation can be done for patients with SLE. Given that the prevalence of SLE is 0.04% of the general populationMand that 65% of these individuals use CAM, there would be 300,000 SLE patients using CAM. If we accept that there are at least 23 million patients with rheumatic diseases in the Americas who used at least one CAM in 1996 and that the mean expenditure for CAM items is $lOO.OO.US per patient, per year (some reported expenditures exceed this amount even in developing countries), the potential market for CAM products alone used by rheumatic disease patients would be $23 billion US per year. This figure would certainly provide significant relief to the already limited health care budgets of many countries. CONCLUSIONS
The evidence is clear that the use of CAM by sufferers of rheumatic diseases is highly prevalent. Furthermore, not withstanding the significant advances in our understanding and in conventional treatment programs for these diseases, the evidence would suggest that the use of alternative therapies is increasing. In many cases, patients combine conventional therapies prescribed by their physician with those provided by alternative practitioners. It is therefore judicious for physicians and rheumatologists alike to ensure that they are not only acquainted with
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the alternative therapies that their patients may be taking but that they also have some insight into the nature of these remedies, as they may have a significant impact on patient management. Although many patients appear to successfully blend conventional and alternative treatment programs, it is of particular concern that some patients clearly stop physician-prescribed treatments and replace them exclusively with alternative remedies. These issues need to be clearly understood and dealt with both sensitively and insightfully by physicians. It is clear that a need to prove or disprove the potential efficacy of these therapies is an important issue. Physicians can no longer ”bury their head in the sand” but must be prepared to address as scientifically and as accurately as possible any claims for traditional therapies in the same way that they would approach new prescription medications. It is only in this way that they are likely to gain the confidence of their patients when addressing these issues openly with them. It is also clear that such alternative therapies may not be without toxicity; consequently, physicians are obliged to understand the nature of these alternative therapies such that they can appropriately deal with problems that may result from CAM use in exactly the same way as with what is considered to be conventional therapies. Finally, there is clearly a huge market for the use of these alternative therapies, which has a significant socioeconomic impact on individual patient and societal finances. It would certainly be an attractive goal to be able to capture some of the monies that are being spent on this type of therapy and redirect them to the use of more evidence-based treatments. This goal, however, is unlikely to be achieved unless the medical profession actively addresses the issue of the potential effectiveness and toxicity of these therapies in the management of commonly treated diseases. The epidemiological evidence would suggest that this issue in the management of patients with rheumatic diseases is unlikely to disappear and indeed continues to increasingly command our attention.
References 1. Almanaque mundial 1998: Editorial Televisa, Mexico, 1998 2. Astin J A Why patients use alternative medicine. JAMA 279:1548-1553, 1998 3. Barnes J, Mills SY, Abbot NC, et al: Different standards for reporting AD& to herbal remedies and conventional OTC medicines: Face-to-face interviews with 515 users of herbal remedies. Br J Clin Pharmacol45:496-500, 1998 4. Bemstein JH, Shuval JF Nonconventional medicine in Israel: Consultation patterns of the Israeli population and attitudes of primary care physicians. SOCSci Med 44:13411348, 1997 5. Boisset M, Fittzcharles MA: Alternative medicine use by rheumatic patients in a universal health care setting. J Rheumatol21:14&152, 1994 6. Borins M: The dangers of using herbs. Postgrad Med 104:91-100, 1998 7. Borkan J, Neher J, Anson 0, et al: Referrals for alternative therapies. J Fam Pract 39:545-550, 1994
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8. British Medical Association: Complementary Medicine: New Approaches to Good Practice. Oxford, Oxford University Press, 1993 9. But PP: Herbal poisoning caused by adulterants or erroneous substitutes. J Trop Med Hyg 97371-374,1994 10. Cohen CJ, Eisenberg DM, Mayer KH, et a1 Prevalence of alternative medical treatments in HIV-infected patients: Implications for primary care [abstract]. Clin Res 38:692, 1990 11. Cook Ch, Baisden D Ancillary use of folk medicine by patients in primary care clinics in southwestem West Virginia. South Med J 79:1098-1101,1986 12. Coppes MJ, Anderson RA, Egeler Rh4, et a1 Alternative therapies for the treatment of childhood cancer [letter]. N Engl J Med 339896447, 1998 13. Cronan TA, Kaplan RM, Kozin F Factors affecting unprescribed remedy use among people with self-reported arthritis. Arthritis Care Research 6149-155,1993 14. Cui J, Garle M, Eneroth P, et a1 What d o commercial ginseng preparations contain [Letter]? Lancet 344.134, 1994 15. Davis C: Risks of manipulation. J R SOCMed 87182, 1994 16. DiPaola RS,Zhang H, Lambert GH, et a1 Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. N Engl J Med 339:785-791,1998 17. Eisenberg DM, Kessler RC, Foster C, et al: Unconventional medicine in the United States. N Engl J Med 328246-252, 1993 18. Emst E Harmless herbs? A review of the recent literature. Am J Med 104:170-178,1998 19. Emst E, Kaptchuk TJ: Complementary medicine-the case for dialogue. J R C Physicians Lond 30410412,1996 20. Emst E, Cassileth BR The prevalence of complementary/altemative medicine in cancer. Cancer 83:777-782, 1998 21. Espinoza EO, Mann M-J: Arsenic and mercury in traditional Chinese herbal balls. N Engl J Med 33803-804, 1995 22. Fisher P, Ward A: Complementary medicine in Europe. BMJ 309107-110,1994 23. Gertner E, Marshall PS, Filandrinos D, et a1 Complications resulting from the use of Chinese herbal medications containing undeclared prescription drugs. Arthritis Rheum 38:614417, 1995 24. Goldman J A Chinese herbal medicine: Camouflaged prescription antiinflammatory drugs, corticosteroids, and lead [letter]. Arthritis Rheum X1207, 1991 25. Gordon NP, Sobel DS, Tarazona E Z Use of and interest in alternative therapies among adult primary care clinicians and adult members in a large health maintenance organization. West J Med 169:153-161,1998 26. Himmel W, Schulte M, ICochen MM. Complementary medicine: Are patients’ expectations being met by their general practitioners? Br J Gen Pract 43232-235,1993 27. Huang WF, Wen K-Ch, Hsiao M-L Adulteration by synthetic therapeutic substances of traditional Chinese medicines in Taiwan. J Clin Pharmacol37344-350,1997 28. Kamb ML, Murphy JJ,Jones JL, et a1 Eosinophilia-myalgia syndrome in L-tryptophan exposed patients. JAMA 26777-82, 1992 29. Katz M, Saibil F Herbal hepatitis: Subacute hepatic necrosis secondary to chaparral leaf. J Clin Gastroenterol 12203-206, 1990 30. Kestin M, Miller L, Littlejohn G, et a 1 The use of unproven remedies for rheumatoid arthritis in Australia. Med J Aust 143516-518,1985 31. KO RJ: Adulterants in Asian patent medicines [letter]. N Engl J Med 339:847, 1998 32. Kronenfeld JJ, Wasner C: The use of unorthodox therapies and marginal practitioners. SOCSci Med 16:1119-1125,1982 33. Larrey D, Vial T, Pauwels A, et a 1 Hepatitis after germander (Teucrium chamaedtys) administration: Another instance of herbal medicine hepatotoxicity. Ann Intern Med 117129-132, 1992 34. Lawrence RC, Helmick Ch G, Arnett F, et a1 Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 41:778799, 1998 35. MacGregor FB, Abernethy VE, Dahabra S, et a1 Hepatotoxicity of herbal remedies. BMJ 299:1156-1157, 1989 36. MacLennan AH, Wilson DH, Taylor AW. Prevalence and cost of alternative medicine in Australia. Lancet 347569-573,1996 37. McGinnis LS: Alternative therapies, 1990 An overview. Cancer 671788-1792,1991 38. Millar WJ: Revue Canadienne de Sant6 Publique 88:154-158,1997
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39. Mohabbat 0, Younos MS, Merzad AA, et al: An outbreak of hepatic veno-occlusive disease in north-western Afghanistan. Lancet 2269-271, 1976 40. Moody GA, Eaden JA, Bhakta P, et a1 The role of complementary medicine in European and Asian patients with inflammatory bowel disease. Public Health 112269-271, 1998 41. Obt AB, Oh JY, Huntington RA, et a1 Chinese herbal medicine induces acute renal failure. Arch Intern Med 155911-212, 1995 42. Panush Rs: Reflections on unproven remedies. Rheum Dis Clin North Am 19:201206, 1993 43. Pietroni PC: Beyond the boundaries: Relationship between general practice and complementary medicine. BMJ 305:564-566, 1992 44. Pioro-Boisset M, Esdaile JM, Fitzcharles MA: Alternative medicine use in fibromyalgia syndrome. Arthritis Care Research 9:13-17, 1996 45. Rainer F, Ulreich A, Pfeiffer KP: Art und ausmai3 der selbstmedikation mit sogenannten "hausmitteln" bei patienten mit rheumatischen erkrankungen. Z Rheumatol 41:276279, 1982 46. Ramos-Remus C, Watters CA, Dyke L, et al: Prevalence and health locus of control in the use of non-conventional remedies by patients with rheumatic diseases. J Rheumatol, 1998 47. Ramos-Remus C, Gamez-Nava JI, Gonzalez-Lopez L, et a1 Use of alternative medicine in a consecutive sample of patients with systemic lupus erythematosus. J Rheumatol 242490-2491, 1997 48. Ramos-Remus C, Gamez-Nava JI, Gonzalez-Lopez L, et al: Use of non-conventional therapies by patients with rheumatic diseases in Guadalajara, Mexico: Prevalence, beliefs and expectations. Arthritis Care Research 11:411-418, 1998 49. Ries CA, Sahud MA: Agranulocytosis caused by Chinese herbal medicines. Dangers of medications containing aminopyrine and phenylbutazone. JAMA 231:352-355, 1975 50. Shaw D, Leon Ch, Kolev S, et al: Traditional remedies and food supplements. A 5-year toxicological study (1991-1995). Drug Safety 17342-356, 1997 51. Slifman N, Obermeyer WR, Aloi BK, et a1 Contamination of botanical dietary supplements by digitalis lanata. N Engl J Med 339:806-811, 1998 52. Smart HLA, Maybemy JT,Atkinson M. Alternative medicine consultations and remedies in patients with the irritable bowel syndrome. Gut 27826-828, 1986 53. Spigelblatt L, Lain&-Ammara G, Pless IB, et al: The use of alternative medicine by children. Pediatrics 94:811-814, 1994 54. Thomas KJ, Carr J, Westlake L, et al: Use of non-orthodox and conventional healthcare in Britain. BMJ 302:207-210, 1991 55. Vecchio PC: Attitudes to alternative medicine by rheumatology outpatient attenders. J Rheumatol21:14.5147, 1994 * 56. Verhoef MJ, Sutherland L R Alternative medicine and general practitioners. Can Fam Physician 41:1005-1011, 1995 57. Verhoef MJ, Russell ML, Love EJ: Alternative medicine use in rural Alberta. Revue Canadienne de Santt? Publique 85:308-309,1994 58. Verhoef MJ, Sutherland LR, Brkich L: Use of alternative medicine by patients attending a gastroenterology clinic. Can Med Assoc J 142:121-125, 1990 59. Wainapel SF, Thomas AD, Kahan B: Use of alternative therapies by rehabilitation outpatients. Arch Phys Med Rehabil 79:1003-1005, 1998 60. Wharton R, Lewith G: Complementary medicine and the general practitioner. BMJ 292:1498-1500,1986 61. Yu H, Zhong S, Chan K, et al: Pharmacognostical investigations on traditional Chinese medicinal herbs. J Pharm Pharmacol47:1129-1131, 1995
Address reprint requests to Paul Davis, FRCPC, FRCP(UK) Division of Rheumatology 562 Heritage Medical Research Centre University of Alberta Edmonton, Alberta Canada, T6G 2S2