* From the Department of Family Medicine, Ben-Gurion University of the Negev, POBox 653, Beer-Sheva 84105, Israel

Standardized extracts of Harpagophytum procumbens secondary roots is used for the treatment of rheumatic pain. The main active principles act via the inhibition of the eicosanoid biosynthesis, as well as the lipoxygenase pathway. If active ingredients are identified, preparations without declaration of the amount of effective compounds should not be used for treatment since, for example, harpagoside consumption in preparations from Harpagophytum procumbens may vary with the daily prescribed medication between 11 and 79 mg. With teas from 9 g crude drug as recommended for the treatment of rheumatic pain, a mean of 180 mg harpagoside is consumed. Antirheumatic efficacy has been proven in 2 double-blind studies for Harpagophytum procumbens extract. A cohort study demonstrated the low costs of this effective herbal treatment compared to conventional therapy.

Plants for oral treatment of rheumatic pain include Harpagophyti radix; Salicis cortex; Urticae folium/herba; a mixture of Fraxinus cortex, Populus cortex and Solidago herba; Betula folium; Guajaci lignum and the gum resin of Boswellia serrata. Compounds of these multicomponent preparations are involved in the inhibition of the arachidonic acid metabolism (cyclooxygenase and or lipoxygenase inhibition), the inhibition of cytokine release and some have antioxidative effect.

Oral medications are prepared from standardized extracts of Harpagophytum procumbens or zeyheri (1, 2). The plant (Fig. 1) grows in the steppes of South and South-West Africa. The drug consists of the cut, dried secondary root tubers which are used for tea preparations. They contain not less than 1.0% harpagoside (2.2% of iridoid glycosides). Whereas harpagoside dominates within the iridoid glycoside mixture in Harpagophytum procumbens, 8-p-coumaroylharpagide dominates in Harpagophytum zeyheri.

Fig. 1 Devil's Claw

For the treatment of painful arthrosis or tendinitis, the European (ESCOP) Monograph recommends up to 9 g drug in decoction or equivalent aqueous or hydroalcoholic extracts three times per day (1). An analysis of the Harpagophytum preparations available in Israel revealed that the mean harpagoside content of tablets varied between 4.3 and 8.8 mg (3) and that the daily consumption of harpagoside varied between 5.4 and 26.4 mg (Fig. 2). Tea (aqueous extract) of 9 g crude drug contains a mean of 180 mg harpagoside, depending on the harpagoside content of the drug, which varied between 1.1 and 3.6% (n=10) (4). Producer extracts with up to 2% harpagoside provide tablets with 50 mg harpagoside in the daily dosage (5). A special Harpagophytum extract, WS 1531* (drug extract ratio 6-9:1, harpagoside enriched, minimum 5 %), is now available. This extract has recently been used for a dose-finding study in film-coated tablets of 200 and 400 mg extract with 18.4 and 37.2 mg harpagoside, respectively (daily dosage 50 mg and 100 mg harpagoside, respectively) (6). Other harpagoside-enriched extracts are under preclinical testing (e.g., by Extrakt Chemie *). In order to guarantee successful treatment, only oral preparations standardized for harpagoside or total iridoid glycosides should be used.

Fig. 2 Harpagoside (mg) per unit and daily harpagoside consumption of various Harpagophytum preparation available in Israel 1998

PHARMACOLOGICAL INVESTIGATIONS

Harpagoside inhibits both arachidonic metabolism pathways, the cyclo-oxygenase and the lipoxygenase (8). This effect was not seen when using simple test procedures (9). The recent in vitro investigations indicate that, depending on the extraction method, Harpagophytum extracts contain at least one or more compound(s) that antagonize the effect on the eicosanoid biosynthesis.

Harpagoside alone seemed not to be involved in reducing the carrageenan-induced edema in rat backpaws. In this test, as well as in the acid-induced writhing test in mice, intraperitoneal pretreatment with aqueous extracts of Harpagophytum procumbens (1.8% harpagoside) or lyophilizised fresh plant, administered i.p. or orally, showed a dose-dependent protection (10, 11). The effect was less pronounced than that of indomethacin or acetylsalicylate. However, in the croton oil-induced granuloma pouch test in rats, the reduction in inflammation produced by a 12-day i.p. administration of harpagoside at a dosage of 20 mg/kg/day and by oral administration of aquaeous and methanolic Harpagophytum extracts 200 mg/kg/day was similar to that of phenylbutazon (12, 13). There is evidence that aquous extracts from Harpagophytum procumbens and Harpagophytum zeyheri produce similar protection against the carrageenan-induced edema in rat backpaws (14). A significant anti-inflammatory effectiveness was also demonstrated in the semichronic granuloma pouch test in rats (13). Numerous pharmacological studies were performed with non-standardized Harpagophytum extracts and unknown reference substances (reviewed in 15). Their results are of little value.

In a pilot investigation, harpagoside 4 ng/ml and 15 ng/ml levels were measured in plasma and blood, 15 minutes and two hours, respectively, after oral intake of 600 mg Harpagophytum extract with 50 mg harpagoside (16). Recently, a dose-dependent absorption of harpagoside following oral administration of a 20% harpagoside enriched extract was also demonstrated (unpublished). After administration of 2 g Harpagophytum extract with 400 mg harpagoside into the stomach of a pig via incision, peak harpagoside concentrations of 52 ng/ml (at 20 min) and 29 ng/ml (at 60 min) were measured in the V. mesenterica and V. femoralis, respectively (18).

CLINICAL STUDIES

1. Effectiveness of oral Harpagophytum preparations in various osteoarthritic pain patients

An open investigation 630 patients suffering from arthrosis of the hip, knee, fingers and spine, received in an open study over six months, aqueous Harpagophytum extract containing 2.5% of iridoid glycosides at a daily dosage of 3 to 9 g powdered drug. Improvement was demonstrated in 42% to 85% of the patients (knee 42%; interphalanx 59%, lumbar/cervical spine 54%/85%; hip 70%). No side-effects other than mild gastrointestinal disturbances were reported (19).

In a randomized controlled study 100 patients suffering from various rheumatic pain syndromes received randomly in a controlled pilot study either 2460 mg Harpagophytum extract (drug-extract ratio 2:1) with 30 mg harpagoside per day or a placebo. After 30 days of treatment, the number of patients complaining of moderate pain was six in the verum group and 32 in the placebo group. Only one of the verum patients still suffered severe pain, in contrast to nine patients of the placebo group. Adverse effects occurred in two patients (verum: n=1, diarrhea; placebo: n=1, mild gastritis) (20).

In a double-blind study, 50 volunteers suffering from arthrosis were given three-week courses of capsules containing 400 mg Harpagophytum extract (iridoid glycoside content 1.5%). After 10 days of treatment, the extract produced a statistically significant decrease in the severity of pain. Improvements were more frequent in moderately invaliding arthrosis than in the more severe cases (21).

In another double-blind study on 89 ambulant volunteers with rheumatic pain, the efficacy and tolerance of capsules containing 335 mg of powdered drug with an iridoid glucusid content of 3% (a total of 2010 mg per day) over eight weeks was investigated (22). The clinical parameters, measured on days 0, 30 and 60, were severity of pain (Scale 0-10) and joint mobility determined by finger-floor distance during anteflexion of the trunk. Results revealed a significant drop in the intensity of pain and a significant increase in spinal and coxofemoral mobility in the treated group. Neither side-effects nor changes in biological parameters (including blood tests) were observed during the two-month study

2. Effectiveness of Harpagophytum procumbens in Treatment of Low Back Pain

A double-blind study included 118 patients suffering for acute low back pain and from chronic low back pain not attributable to identifiable causes longer than six months (23). Upon their written informed consent, patients received, on a random and double-blind basis, either 2400 mg Harpagophytum extract (* drug-extract ratio 2.5:1) with 50 mg harpagoside per day or a placebo (3 x 2 tablets). Prior to treatment, the groups were comparable with regard to their history and biochemical data, circulatory and laboratory parameters, as well as the Arhus low back pain index and its scores for pain, invalidity and physical impairment (24). After four weeks, the median Arhus low back pain index had improved by 20% in the Harpagophytum group and by 8% in the placebo group (p < 0,059). This significant trend of effectiveness was based on a significant decrease in the pain index (p = 0,016) (Fig. 3). Nine of 54 patients receiving Harpagophytum extract (a total of 20%) were completely pain-free in the fourth week of treatment, as compared one patient (2%) in the placebo group (p = 0,008). Only minor and nonspecific adverse effects occurred during the Harpagophytum treatment.

Fig. 3 Relative median change of the components of the Arhus low back pain index in patients suffering from low back pain after four weeks of treatment with Harpagophytum extract (Doloteffin R) or placebo (23).

Another study included 197 patients suffering from chronic low back pain, local as well as pseudoradiating, that was not attributable to identifiable causes (6). All patients had suffered from chronic low back pain for longer than six months. With written informed consent, they received, on a random and double-blind basis identical-looking tablets with Harpagophytum special extract batch 9601* containing either 200 mg or 400 mg harpagoside per day with 50 or 100 mg harpagoside, or a placebo, respectively. The main criterion of the study was fulfilled and showed that in the fourth week of treatment, the number of pain-free patients increased dose-dependently.

A cohort study was comprised of 102 patients suffering from local (non-pseudoradiating) low back pain that was not attributable to identifiable causes (25). All patients had suffered from chronic low back pain for more than six months. They received, according to their physician's decision, either 1800 mg Harpagophytum extract (* drug-extract ratio 2.5:1) with 30 mg harpagoside per day, as single or co-treatment or as conventional treatment (mostly nonsteroidal anti-inflammatory drugs, physical exercises or paravertebral injections). In order to guarantee careful documentation, physicians from the study group investigated the patients in the physician's consulting rooms. Patients receiving the Harpagophytum treatment were not favoured, they were older, multimorbid and suffered longer from low back pain than the patients receiving conventional treatment. However, the duration of local low back pain and the Arhus low back pain index did not differ for the groups prior to treatment. Six weeks later, the Arhus low back pain index had improved in both groups by about 20% (n.s.). The pain index decreased significantly in the course of treatment from the fourth to the sixth week of treatment, showing an improvement of more than 30% (Fig. 4). The number of pain-free patients after four and six weeks was 16 and 20 (Group Harpagophytum) and 12 and 23 (Group Conventional Treatment), respectively (ns). Surprisingly, the relative cost of treatment was 2/3 lower when Harpagophytum extract was included in the low back pain treatment schedule. Only minor adverse effects that did not necessitate discontinuation of the treatment occurred during the Harpagophytum treatment. An equivalence study must be performed in order to confirm these results.

* Ardeypharm GmbH, P. O. Box 1153, 58313 Herdecke, Germany

Fig. 4 Relative median change of the Arhus low back pain index in patients suffering from local low back pain after four and six weeks of treatment with Harpagophytum extract (JucurbaR), as mono- or co-treatment or as conventional treatment (25)

GENERAL CONSIDERATIONS

According to the European Monograph, the duration of treatment with Harpagophyti radix extract should not exceed three months. If symptoms persist, careful observation is required. Administration of extract is contraindicated in patients suffering from gastric or duodenal ulcers. Further special warnings or precautions are not required. Possible interaction with antiarrhythmic drugs cannot be excluded (26, 27). In accordance with general medical practice, the extract should not be used during pregnancy and lactation without medical advice. Mild gastrointestinal disturbances may occur in sensitive individuals, especially at higher dosage levels. No toxic effects have been reported. Preclinical safety data have proven a very low toxicity in rodents during acute and subacute tests. In case of overdose, no toxic effects have been reported.

REFERENCES

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3. Chrubasik S, Sporer F, Wink M. Unpublished data

4. Chrubasik S, Sporer F, Wink M. Zum Wirkstoffgehalt in Teezubereitungen aus Harpagophytum procumbens. Forsch Komplementaermed, 1996, 3: 116-119

5. Chrubasik S, Sporer F, Wink M. Zum Harpagosidgehalt verschiedener Trockenextrakt-pulver aus Harpagophytum procumbens. Forsch Komplementaermed, 1996, 3: 6-11

6. Chrubasik S, Junck H, Zappe HA. Effectiveness of Harpagophytum extract WS 1531. Unpublished data.

7. Chrubasik S, Sporer F, Dillmann-Marschner R, Friedmann A, Wink M. Physikalisch-chemische Eigenschaften von Harpagosid und in-vitro-Freisetzung von Harpagosid aus Harpagophytum-Tabletten. Phytomedicine (1998. in press)

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17. Loew D, Schuster O, Moellerfeld J. unpublished data

18. Sporer F, Chrubasik S. unpublished data

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