COMMENTARY Drug Safety 13 (2), 81 -93,1 995 o 114-5916/95/CXXl8-G08 1/SQ6,5Q/O

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Health Risks of Herbal Remedies Peter A.G.M. De Smet Drug Information Center, Royal Dutch Association for the Advancement of Pharmacy, The Hague, The Netherlands

Contents Summary , , , , , , 1, Indirect Health Risks 2, Direct Health Risks ,

2,1 Different Types of Adverse Reactions 2,2 Limitations of Traditional Experience 2,3 Modification of Herbal Toxicity

81 82 82 83 83 85 86 86 87 88

3. Recommendations , , , , , , , , , 3,1 Availability of Existing Data , 3.2 Application of Existing Data , 3,3 Collection of New Data , , ,

Summary Herbal remedies can result in indirect health risks when they delay or replace a more effective form of conventional treatment or when they compromise the efficacy of conventional medicines. Herbal remedies can also be associated with direct health risks, Long-standing traditional experience may tell much about striking and predictable symptoms of acute toxicity but it is a less reliable tool for the detection of reactions which are inconspicuous, develop gradually or have a prolonged latency period, or which occur uncommonly. Another reason why safety claims cannot always be based on traditional empiricism is that not all herbal remedies are firmly rooted in traditional medicine.

The risk of a herbal remedy producing an adverse reaction depends not only on the remedy and its dosage but also on consumer-related parameters, such as age, genetics, concomitant diseases and concurrent use of other drugs. Another important determinant of the toxicity of herbal remedies is their quality.

What is already known about the risks of herbal remedies must be systemati­cally collected, disseminated and acted upon. What is yet unknown must be found out by herbal postmarketing surveillance and experimental research.

Before the health risks of herbal remedies are out­lined, it is useful to note that there is a whole range of herbal remedies, from self-made teas prepared from self-collected herbs to officially approved medicinal products which have passed through the same rigid registration procedures as synthetic medicines (table I). Unfortunately, it may be diffi-

cult to classify a particular herb in its most appro­priate category. The same botanical product that is an approved medicine in one country, may be a dietary supplement or recreational herb (i.e used for hedonistic purposes) in the next,[ll and in one country the same herb may be available as an official medicine, health food preparation and raw ingredient.

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Table I. Different types of herbal remedies

Raw materials for self-preparation:

by self-collection

through commercial channels

(Semi)-finished nonmedicinal and medicine-like products, e.g.:

dietary supplements

health foods

recreational herbs

Licensed medicines:

by special procedure

by regular procedure

It is important to keep these different categories in mind when the risks of herbal remedies are reviewed, because the nature and magnitude of these risks may vary with the specific type of product. For in­stance, a consumer of a licensed herbal medicine should not have to worry about the correct identity of the ingredients, whereas this should be a primary concern for an individual who goes out into the field to collect his or her own herbal materials.

1. Indirect Health Risks

There are not only different types of herbal remedies, but also different types of herb-related health risks. In addition to adverse reactions and the potentiation of conventional medicines, which will be discussed later, there is the indirect risk that a herbal remedy with unproven therapeutic poten­tial delays or replaces an effective form of conven­tional treatment. This may happen not only when a herbal practitioner is overoptimistic about his or her diagnostic or therapeutic abilities, but also when a headstrong or naive patient puts too much trust in the healing powers of nature. We were recently confronted with the case of an elderly woman with hypertension and non-insulin-dependent diabetes who had been successfully treated for years, but discontinued her conventional medicines of her own accord after she learnt from acquaintances and through the press that such medicines could be dangerous. She started to use alternative medicines from a health food store instead, and this switch was followed by hypertension, elevated blood glu-

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De Smet

cose levels and a cascade of complications which eventually ended in her death.l21

Scientific information about the extent of indi­rect risks is hard to find, and more research in this area is warranted. Of particular concern would seem to be the phenomenon of non-Western patients seeking refuge in the traditional medicine of their homeland. According to Belgian researchers, for instance, serious problems can arise in Moroccan migrants with asthma or diabetes, who swap their Western medicines for local herbs when returning to their homeland for a holiday,l3.41

Certain herbal remedies can reduce the efficacy of concurrently used conventional medicines. For instance, co-administration of phenytoin with an Ayurvedic syrup called 'Shankhapushpi' (prepared from Centella asiatica, Convolvulus pluricaulis, Nardostachys jatamansi, Nepeta elliptica, Nepeta hindostana and Onosma bracteatum) was reported to result in reduced plasma concentrations of phenytoin and loss of seizure controIJ51 More stud­ies on the interactions between traditional and mod­em medicines would certainly be welcome. It would be interesting to establish, for instance, whether herbal bulk-forming agents can interfere with the absorption of low dose oral contraceptives in the same way in which they compromise the absorp­tion of certain other orthodox medicines.[6-81 This research question seems relevant because herbal bulk-formers are often found in alternative slim­ming aids, which are likely to be purchased more often by women in the fertile age.

2. Direct Health Risks

Herbal remedies can also be associated with direct health risks. In principle, their bioactive constitu­ents are capable of producing the same types of adverse reactions that are seen with synthetic drug compounds. This applies not only to alkaloids and cardiac glycosides, the toxicity of which has been recognised long ago, but also to other classes of herbal constituents, such as the flavonoids, which have long been considered to be devoid of signifi­cant toxicity (table II) . Since the drug receptors in our body cannot distinguish whether a molecule

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comes from the plant kingdom or from the chemi­cal laboratory, naturalness does not, by definition, guarantee harmlessness. The toxic potential of a herbal remedy does not depend on its natural origin but on the pharmacological characteristics and dose levels of its bioactive constituents. The toxic­ity of an individual herbal constituent can be mod­ified, of course, by one or more of the other con­stituents. A complex composition will not always reduce toxicity, however, and may also result in a more toxic remedy.

2.1 Different Types of Adverse Reactions

Just as for adverse effects of synthetic medi­cines,[22] adverse reactions to herbal remedies can be classified into different categories: • Type A reactions, which are pharmacologically

predictable and usually dose-dependent. Such reactions should be anticipated, and can often be prevented by dose reduction. An example is the induction of hypertension and anxiety by yohimbine, the major alkaloid in yohimbe bark preparationsJ23]

• Type B reactions, or idiosyncratic reactions, which cannot be predicted on the basis of the principal pharmacological properties and which do not show a correlation between dose level and risk of toxicity. These reactions occur in only a mi­nority of the population, but they are often serious and potentially fatal. For example, normal doses of yohimbine have recently been associated with bronchospasm and increased mucus secre­tion in 1 patient,[24] and with allergic dermatitis, progressive renal failure and a lupus-like syndrome in another.[25]

• Type C reactions, which develop during long term therapy. These reactions are well described and could be anticipated. An example is the occur­rence of muscular weakness due to hypokalae­mia in long term users of herbal anthranoid laxatives.[26]

• Type D reactions, which consist of delayed effects, such as carcinogenicity and teratogenicity. It is now well established that certain herbs have

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Table II. Adverse reactions to pure flavonoids and flavonoid­containing herbs, as described in recent case reports

Blood disturbances Haemolytic anaemia(9.13J

Thrombocytopenia(9,12J

Gastrointestinal disorders Chronic diarrhoeal14,15J

Lymphocytic colitis(161

Liver disorders Hepatitisl9.13,17J

Psychic disturbances Somnolence(18J

Skin disorders

Allergic contact dermatitisl19J

Urticaria or exantheml10J

Urinary tract disorders Acute renal failurel9,l1 ,13,151

Other effects

Anaphylactic shockl2oJ

Drug feverPO,13,21J

carcinogenic and/or teratogenic potential (see table III for examples). As herbal drugs have not been evaluated system­

atically to exclude type D reactions, it is likely that new examples will be discovered in the future. For instance, the reported carcinogenicity of hydroqui­none following prolonged administration of high doses to rats or mice[28,29] raises a question about the long term safety of Arctostaphylos uva-ursi and other medicinal herbs containing arbutin. Arbutin is the monoglucoside of hydroquinone, and when it is administered orally to humans it is hydrolysed to hydroquinone and finally excreted in the urine as hydroquinone glucuronide and sulphatePO] These conjugates are also the major urinary metabolites when rats are treated orally with hydroquinonePI]

2.2 Limitations of Traditional Experience

While herbal healers and consumers will readily recognise type A reactions, it may be less easy for them to identify all type C problems, and it will even be more difficult to detect type B or D reactions. This is particularly so when the signs and symptoms

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84 DeSmet

Table III. Examples of teratogenic and/or carcinogenic herbsl271

Herbs Comments

Acorus calamus The Jammu variety of calamus oil has been shown to be carcinogenic in rats; as studies on the calamus constituent ~-asarone have revealed similar activities, this compound is considered to be the causative agent

Aristolochia species

Blighia sapida

Many Aristolochia species contain carcinogenic aristolochic acids

The unripe fruit of this tree has high levels of a potent hypoglycaemic amino acid, known as hypoglycin A, which is teratogenic in animal experiments

Gonium macula tum Contains the poisonous piperidine alkaloid coniine and related alkaloids. It has well established teratogenic activity in certain animal species

Groton tiglium

Genista tinctoria

Croton oil contains tumour-promoting phorbol diesters

Sassafras albidum

Contains toxic quinolizidine alkaloids, such as anagyrine, cytisine and N-methylcytisine. Anagyrine is a suspected animal teratogen, whereas cytisine has been shown to have teratogenic activity in rabbits

The wood of sassafras root contains 1 to 2% of volatile oil, which in turn consists largely of safrole. This constituent is hepatocarcinogenic in laboratory animals. Experiments in mice suggest the possibility of transplacental carcinogenesis

Symphytum officinale and other herbs containing pyrrolizidine alkaloids

Hepatocarcinogenic pyrrolizidine alkaloids occur in a large number of medicinal plants, which occur notably in the genera of Grotalaria, Gynoglossum, Heliotropium, Petasites, Senecio and Symphytum. Animal studies have also shown that transplacental passage is possible, and there is a human case of fatal neonatal liver injury, in which the mother had used a herbal cough tea containing pyrrolizidine alkaloids throughout her pregnancy

are not unusual in the population and could thus also be ascribed to alternative causes. In other words, long-standing experience may tell much about striking and predictable acute toxicity, but it is a less reliable tool for the detection of reactions which are inconspicuous, develop very gradually or need a prolonged latency period, or which occur uncommonly.

The phenomenon of unobtrusive problems re­maining undetected can be denoted as the 'Aje­imutin' trap. 'Aje-imutin' is the native name which the Nigerian Yoruba people use for an African relative of the ink-cap mushroom. The literal translation of the term is 'eat-without-drinking-alcohol' P2] which shows that the Yoruba have learnt that ingestion of Coprinus mushrooms can induce a disulfiram-like sensitivity to alcohol. Yet the same Yoruba employ herbal enemas to treat diarrhoea and dysentery, apparently without realising that this can exacerbate the dehydration produced by the diarrhoea, reduc­ing the patient's chance of recovery instead of in­creasing itJ33]

The risk that rare adverse reactions to herbal remedies remain unnoticed can be illustrated by the statistical 'rule of 3', which dictates that the number of studied patients must be 3 times as high as the

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frequency of an adverse reaction to have a 95 % chance that the reaction will actually occur in the studied population. When an adverse reaction to a herbal remedy occurs with a clinically relevant fre­quency of 1 in 1000, a healer treating 1000 patients with this remedy still has a 37% chance that he or she will not observe the reaction at all. To be 95 % certain that the reaction will be seen, he or she would have to treat at least 3000 patients (table IV). The healer may need to see more than 1 reaction, however, before a mental connection with the rem­edy is made. To have a 95% chance of observing the reaction 3 times, the healer would have to treat 6500 patients, that is 1 patient every working day for almost 25 years.[34] Such calculations make it clear that personal experience is not a reliable basis for the exclusion of uncommon reactions to herbal remedies.

Another reason why safety claims cannot always be based on traditional empiricism is that not all herbal remedies are firmly rooted in traditional medicine. The method of extraction and further processing, the route of administration and the dose level may be different from those used in a tradi­tional setting, and sometimes the herb may have no medicinal tradition at all. Some years ago, for in-

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Table IV. Number of persons who need to be exposed to a drug to have a 95% chance of detecting an adverse drug reaction (ADR) occurring with a particular frequency at least once, twice or 3 timesl34)

ADR frequency Number of ADR cases

2 3 1 out of 100 300 480 650

1 out of 200 600 960 1300

1 out of 1000 3000 4800 6500

1 out of 2000 6000 9600 13000

1 out of 10000 30000 48000 65000

stance, the expressed sap of a fly-catching plant (Dionaea muscipula) was introduced in Germany as a herbal anti tumour product. The promotion of this nontraditional herb seems to have arisen from the unproven hope that its carnivorous properties would extend from insect tissues to human tumours. The herb was sold not only as oral drops but also in the form of an intramuscular injection. This non­traditional dosage form soon had to be banned from the market, however, after it had become ap­parent that it could produce serious anaphylactic reactionsp5]

2.3 Modification of Herbal Toxicity

The risk of a herbal remedy producing an adverse reaction depends not only on the remedy and its

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dosage, but also on consumer-related parameters, such as age, genetics, concomitant diseases and concurrent use of other drugs. For instance, patients with autonomic failure or with bipolar depression are more sensitive than healthy volunteers to the autonomic and central adverse effects of yohim­bine.[36,37] Patients on tricyclic antidepressants or phenothiazines are also more sensitive to the ef­fects of this alkaloid. [23,38] Some other examples of adverse drug interactions between herbal remedies and conventional medicines are presented in table V. While it is sometimes the conventional medicine which increases the toxicity of a herbal compound, the reverse is also possible (i.e. enhancement of the effects of a conventional drug by a herbal product).

Another important determinant of the toxicity of herbal remedies is their quality. It is a well known problem that herbal preparations, which are not officially approved as medicines, do not always have the composition which is declared on their label. For instance, when we recently analysed a yohimbe tablet on the Dutch market, we found caffeine without any yohimbine, even though the label claimed that O.5g of yohimbe bark extract was present in each tablet.£53] In this particular case, the toxic potential of the product was less than its label suggested, but it also occurs that a herbal ingredient is substituted by a more toxic

Table V. Examp)es of increased toxicity due to interactions between herbal preparations and conventional medicines

Drug Herb(al compound) Comment

Increased toxicity of the herbal compound

Pipemidic acid Caffeine in Co/a, flex and Ciprofloxacin Pauffinia preparations Enoxacin

Quinidine Haloperidol Moclobemide

Sparteine in Cytisus scoparius

The antibacterial quinolones pipemidic acid, ciprofloxacin and enoxacin inhibit the hepatic metabolism of caffeine.139-421 As a result, users of caffeine-containing Co/a, flex and Pauffinia preparations may have an increased risk of adverse effects, such as tremors or tachycardia

The antiarrhy1hmic drug quinidine is a potent inhibitor of the oxidative metabolism of sparteine,143) and a similar effect has been observed with haloperidoll441 and moclobemide.(45) Sparteine is a quinolizidine alkaloid from Cytisus scoparius which was recently found in a herbal slimming remedy on the UK market. Substantial doses in slow metabolisers could be expected to be associated with various adverse reactions, such as circulatory collapse(46)

Increased toxicity of the conventional medicine Theophylline Piperine in Piper spp. Piperine, a major alkaloid of Piper /ongum and Piper nigrum (both of which occur in Pheny10in Ayurvedic formulations) can enhance the bioavailability of conventional drugs, such

as theophylline and pheny1oinI47-51)

Calcium antagonists Grapefruit juice

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Grapefruit juice increases the bioavailability of certain calcium antagonists and might interact in a similar way with certain other conventional drugs(52)

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Table VI. Some toxicologically interesting examples of botanical substitutions in Oriental remedies

According to a Chinese textbook, 'Guanmutong' (the vines of Aristolochia manshuriensis) may be used to substitute 'Mutong' (the stem of Akebia quinata).I56] Such a switch is not without toxicological relevance, since Aristofochia manshuriensis contains carcinogenic and potentially nephrotoxic aristolochic acidsl571

Several cases of herbal poisoning were observed in the Far East, as a result of the substitution of Gentiana or Clematis roots by the roots of Podophyllum emodi. These latter roots contain podophyllotoxin and their use can result in serious neuropathyl58]

An analgesic and hypnotic herbal Chinese tablet available on the Dutch market purportedly contained material from Polygala chinensis, but we showed by chemical analysis the presence of L·tetrahydropalmatine.159] Analgesic tablets containing this alkaloid are indeed used in Chinese medicine, but come from Stephania species.1601 The toxicological relevance of our analytical finding was highlighted by subsequent reports from the US of life-threatening bradycardia and respiratory depression in small children following unintentional overdosingl611 and acute hepatitis in adult users(62]

botanical. One of the most tragic examples in re­cent years was the outbreak of fibrosing interstitial nephritis in 70 Belgian individuals who had been treated with a slimming preparation which suppos­edly included the Chinese herbs Stephania tetrandra and Magnolia officinalis. Analysis of the prepara­tion brought to light that the root of Stephania tetrandra (Chinese name 'Fangji') was in all prob­ability substituted or contaminated with the root of Aristolochiafangchi (Chinese name 'Guang fangji'), which contains potentially nephrotoxic aristolochic acids.[54,55] A few other toxicologically interesting examples of Oriental substitutions are given in table VI.

The risk of botanical substitution also occurs in Western phytotherapy. Dr Linda Anderson of the British Medicines Control Agency (personal com­munication, 1994) observed that the American germander (Teucrium canadense) has been widely used in the UK to replace Scutellaria lateriflora in commercial skullcap materials and products. This substitution could have toxicological significance, since skullcap preparations have been repeatedly associated with hepatotoxicity.l63] Dr Anderson

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DeSmet

personally examined skullcap material that was as­sociated with a UK case of hepatotoxicity, and found that it came from Teucrium canadense. This raises the possibility that other cases of skullcap toxicity may also have involved Teucrium rather than Scutellaria.

Herbal remedies will also show unexpected tox­icity when they are contaminated, intentionally or accidentally, with poisonous nonherbal substances.[64] Of particular concern is the presence of poison­ous metals (lead, arsenic, mercury, cadmium and thallium)[65-79] and conventional pharmaceuticals (e.g. corticosteroids, nonsteroidal anti-inflammatory agents, benzodiazepines)[69,80-92] in herbal and other ethnic remedies of Asian origin.

3. Recommendations

So far, this article has explained that there are different types of herbal remedies and different herb-related health risks, ranging from delay in consulting a doctor to adverse reactions, and from adverse interactions with conventional drugs to contamination with toxic materials or substances. It has also explained that there are certain limita­tions when traditional experiences with herbal remedies are put forward as a basis for safety claims. Rather than continuing with additional examples, it appears more useful to take a look at some conclusions that can be drawn from these observations.

3.1 Availability of Existing Data

First of all, it is important to establish what is already known and to make this information readily available. Systematic efforts to collect, evaluate and disseminate scientific data about the risks of herbal remedies[27,93-( (6] should be contin­ued and expanded. Herbal data collections must also include non-Western herbs, not only because Western doctors are increasingly confronted with non-Western patients who seek refuge in the tradi­tional remedies of their homeland, but even more so because herbal therapy plays a vital role in the healthcare of developing countries.

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The key word here is differentiation: instead of getting involved in an 'all or nothing' discussion about the pros and cons of phytotherapy, herbs which have a favourable benefit/risk ratio should be discriminated, by careful analysis, from those that do not. It should be taken into account that this ratio depends not only on the crude herb as such but also on the way in which it is prepared and applied. For instance, when the internal use of a herb is hazardous, this does not necessarily mean that its external use on the intact skin is equally dangerous.

3.2 Application of Existing Data

It is necessary to act upon what is already known. Nobody deserves a remedy which is worse than the disease being treated, so the herbal market should be actively improved by banning unsafe remedies and by discouraging unsafe practices. The least that should be done is to draw up a list of dangerous herbs and to prohibit the incorporation of these herbs in preparations for internal use. Hereby, it is necessary to be aware that familiar toxic agents may be hidden behind unfamiliar names (see table VII for examples). Lists of prohibited herbs should be continuously adjusted as a result of new find­ings. It is remarkable, for instance, that the Belgian tragedy with StephanialAristolochia did not im­mediately result in a worldwide wave of restrictive measures and that 2 additional cases in France were reported 16 months after the first publication in Lancet.[120,121]

In this connection, it seems worthwhile to para­phrase Michel Auriche and Elisabeth Loupi,[122] who published a general paper about the difficulty in establishing, beyond all scientific doubt, a causal relationship between a drug and an adverse event. They argued that, because of this, a high

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degree of suspicion may be all that is necessary to withdraw a drug from the market. When a drug is repeatedly associated with a serious adverse event, withdrawal may well be the most prudent course of action, rather than wasting time in endless investi­gations to find more definite proof of causality.[I22] If such prudence is called for in the case of drugs with well established efficacy, it would be even more appropriate to prohibit a highly suspected herbal remedy for which there is no convincing evidence of efficacy.

In various countries, the introduction of herbal remedies into the commercial market is not ade­quately monitored. While conventional pharma­ceuticals are only admitted after careful screening of their efficacy, safety and quality has resulted in a marketing authorisation, many herbal remedies escape such evaluation before they are marketed. The consequences are that the burden of providing toxicological data shifts from the vendor to the health authorities, and that numerous consumers may already be exposed to a product before an in­dependent risk assessment becomes available. Such undesirable situations could be prevented by setting up a special licensing procedure for herbal remedies. From the point of view of safety, such a licensing system would offer several advantages. First of all, it would no longer be possible to waive toxicological requirements by self-determination of the vendor but only at the discretion of the reg­istration authorities. Secondly, it would become possible to provide commercial herbal prepara­tions with a licence number. This administrative earmark would facilitate postmarketing surveil­lance and recall procedures, and its presence on the label would make clear to retail dealers and users that the product has been submitted to a premarket­ing safety check.l 123]

Table VII. Examples of familiar toxic agents hidden behind unfamiliar Chinese names

Chinese name

Bajiaolian

Shancigu

Zangqie

Latin binomial

Dysosma pleianthum

Iphigenia indica

Anisodus tanguticus

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Toxic constituent(s) Podophyllotoxin[1171

Colchicine[1181

Hyoscyamine, scopolamine and related alkaloids[1191

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88 DeSmet

Table VIII. Symptoms and/or circumstances in cases of fever requiring attention by a conventional medical practitioner'291

Potential risk Symptoms/circumstancesa

Acute infection of kidney or bladder Pain in the small of the back, abnormally frequent urination, pain when passing urine, pink or cloudy urine

Pneumonia

Meningitis

Cough with shortness of breath and/or coughing up of brownish phlegm

Severe headache, pain when head is bent forwards, nausea or vomiting, aversion to bright light, drowsiness or confusion

Puerperal infection Delivery of baby within past 2 weeks

Tropical disease (e.g. malaria) Recent return from a stay in a tropical country

a A doctor should also be called without delay if temperature remains elevated for longer than 48 hours, rises above 40°C and/or recurs in bouts.

A licensing system also opens up the possibility of demanding proof of product quality. This is partic­ularly relevant, because herbal poisonings are all too often due to a lack of stringent quality assurance rather than to the declared ingredients. The need for better quality control applies not only to the prod­ucts themselves (i.e. the appropriate identity, quan­tity and purity of the herbal ingredients) but also to the consumer information about the products. Us­ers have a basic right to be informed in a reliable way about composition, directions and instructions for use, storage life and conditions. Such information is, in a manner of speaking, the software needed to make the hardware (i.e. the product itself) perform in the way it should perform. Comprehendible warnings would help to reduce the risk of inappro­priate use and adverse reactions. For instance, it would be commendable for Spirulina products to carry a warning about the inappropriateness of pro­motional claims that Spirulina is a good source of vitamin BI2 for vegetarians.1124-1271

Quality control is not only needed to guarantee the quality of herbal products and herbal product leaflets, it is also of importance at the prescribing level. Herbal practitioners should receive adequate training and continuous education to reach and maintain a high standard of operation,[1281 and this should be visible for their clients by an appropriate licensing system. Herbal prescribers need to know which herbs can be toxic and under which circum­stances this toxicity is most likely to manifest itself. They should also have suffkient medical knowledge to distinguish minor illnesses from major disorders so that they can refer patients with a se-

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rious disorder in time for appropriate treatment. In cases of fever, for instance, herbal practitioners should know which symptoms and/or circumstan­ces raise the possibility of a serious disease which requires the immediate attention of a conventional medical practitioner (table VIII).

3.3 Collection of New Data

In addition to establishing what is already known and acting upon the basis of this knowledge, it is important to find out what is not yet known about the adverse reaction potential of herbal remedies. Instead of mistaking the absence of reli­able evidence of risk for reliable evidence of the absence of risk, experimental studies in this field should continue and should be complemented with the new concept of herbal postmarketing surveil­lance. By analogy with conventional postmarket­ing surveillance, herbal postmarketing surveil­lance aims to detect serious adverse reactions, quantify their incidence and identify contributive and modifying factors,!341

The most classical tool of postmarketing sur­veillance is so-called spontaneous reporting, on a voluntary basis, by health professionals, users or other parties who observe or experience a sus­pected or possible adverse reaction during daily practice. The collection and maintenance of such reports is relatively inexpensive, and the system can cover entire countries or large fractions thereof. The major strength of this approach lies in its ability to serve as a warning mechanism that can signal the potential existence of hitherto unknown adverse reactions. A good example is the recent

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Health Risks of Herbal Remedies

characterisation of acute hepatitis associated with the use of wall germander (Teucrium chamaedrys), which almost fully depended on spontaneous re­porting to regional French pharmacovigilance cen­tres)130] Thus, there is much to be said for inclusion of herbal remedies in national and regional post­marketing schemes which are aimed at the col­lection and screening of adverse drug reactions in general. Not only does this have the advantage of obtaining data on the adverse reaction potential of herbal remedies, it also offers the possibility that potential confounding of synthetic drug reactions by herbal remedies can be detected and accounted for.

As many herbal remedies are sold and used out­side the realm of conventional medicine, herbal postmarketing surveillance should not only involve orthodox healthcare providers but should also be of interest to herbal suppliers and prescribers. One obvious measure in this area would be to make suppliers of herbal remedies legally bound (just as suppliers of conventional medicines are) to report to the health authorities any suspicious adverse event during the use of their products which comes to their attention.

Spontaneous reporting of individual cases has its limitations, and it can be useful to supplement this approach with epidemiological studies that look at associations between drug exposure and adverse events at the population level. Epidemio­logical studies may help to detect unrecognised phenomena, and strengthen hypotheses that have been generated from spontaneous reporting or from experimental research. In addition, they can provide essential information about the incidence rate of an adverse effect, something which sponta­neous reporting cannot do. Specific epidemiologi­cal studies can take either the adverse event or the drug exposure as their starting points, i.e. case­control and cohort studies, respectively)I22]

An example of the latter approach was recently reported by Siegers and coworkers,[I31] who eval­uated the relationship between colorectal cancer and abuse of anthranoid-containing laxatives (such as aloe, cascara, frangula and rhubarb). This study

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Table IX. Occurrence of pseudomelanosis coli (an indicator of anthranoid laxative abuse) in a prospective study of 1095 patients undergoing diagnostic colorectal endoscopyl1311

Number of Number with patients pseudomelanosis coli

(percentage)

No abnormalities 537 37 (6.9%)

Colitis 221 5 (2.3%)

Diverticulosis 110 10(9.1%)

Adenoma 225 22 (9.8%)

Carcinoma 59 11 (18.6%)

Total 1095 n!7.0%l

was prompted because certain anthranoids show genotoxic potential in bacterial and mammalian test systems[132-I34] and because 2 anthranoid com­pounds (the synthetic laxative dantron and the nat­urally occurring I-hydroxyanthraquinone) have shown carcinogenic activity in rodents) 135-137] As patient's recall of drug exposure over the years was considered an unreliable method for establishing anthranoid laxative abuse, Siegers and his associ­ates took pseudomelanosis coli as a more reliable indicator. In a prospective study of 1095 patients undergoing diagnostic colorectal endoscopy, they found that the incidence of pseudomelanosis coli was 6.9% in patients without abnormalities of the colorectal mucosa compared with 18.6% in pa­tients with colorectal carcinoma (table IX). They calculated that long term abusers of anthranoid lax­atives had an increased relative risk of 3.04 (95% confidence interval of 1.18 to 4.90) for colorectal cancer. More studies are needed to clarify this is­sue, if only to exclude the possibility that chronic constipation per se might increase the risk for colo­rectal cancer and would thus act as a confounding factor. Pending the results of additional studies, however, it would seem prudent to discourage long term use of those herbal anthranoid laxatives which show genotoxic potential.

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Correspondence and reprints: Dr Peter AGM De Smet, Drug Information Center, Royal Dutch Association for the Advancement of Pharmacy, Alexanderstraat 11, 2514 JL The Hague, The Netherlands.

Drug Safety 13 (2) 1995