Sigrun Chrubasik and Elon Eisenberg#
Department of Pharmaceutical Biology, University of Heidelberg, Im Neuenheimer
Feld 364, 69120 Heidelberg; #Pain Unit, Rambam Medical Center, Haifa, Israel
Kampo Medicine for treating rheumatic pain is very popular in Europe. The plants with antirheumatic efficacy 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. This review focuses on Devil's Claw.
Summary
To date there are enough data available to classify preparations from the radix of Harpagophytum procumbens among the rational antirheumatics, but only insofar as the amount of iridoid glycosides in the daily recommended dosage, especially that of harpagoside, is sufficient to alleviate rheumatic pain. Data on the biopharmaceutical quality of the preparations, on their antirheumatic effectiveness as proven in pharmacological and clinical studies, and on their safety in clinical use indicate that the treatment of osteoarthritic pain with Harpagophytum extract should be - together with other rational phytotherapeutics - the first step in the treatment of rheumatic pain. Less adverse effects accompany the Harpagophytum treatment as compared to treatment with NSAIDs. Optimization of the extract and assessment of the optimal daily dosage are now required.
Oral Harpagophytum preparations
Standardized extracts of Harpagophytum procumbens (1) or zeyheri (2) are used to prepare oral medications. The plant grows in the steppes of South and South-West Africa. The drug consists of the cut, dried secondary root tubers. They contain not less than 2.2% of iridoid glycosides or not less than 1.0% harpagoside. Whereas harpagoside dominates within the iridoid glycoside mixture in Harpagophtum procumbens, 8-p-coumaroylharpagide dominates in Harpagophytum zeyheri (Fig. 1 left: harpagoside, right: 8-p-coumaroylharpagide).
Abb1:
Chemical structure of harpagoside (leading compound of Harpagophytum procumbens) and 8-p-coumaroylharpagide (leading compound of Harpagophytum zeyheri)
For the treatment of painful arthrosis or tendinitis, the ESCOP Monograph (1) recommends 1.5 - 3.0 g drug in decoction or equivalent aqueous or hydroalcoholic extracts three times per day. This is double the extract amount recommended by the German Monograph (Bundesanzeiger Nr. 48 March 2, 1989). Unfortunately, there is to date no obligation to declare the amount of iridoidglycosides on Harpagophytum preparations. In 1996, an analysis of the Harpagophytum preparations available in Germany revealed that the mean harpagoside content of tablets varied between 0.5 and 9.3 mg (3) and that the daily consumption of harpagoside varied between 1.5 and 50 mg (Fig. 2). Tea (aqueous extract) of 4.5 g (9 g) crude drug contains a mean of 90 mg (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 (5) provide tablets with 50 mg harpagoside in the daily dosage. 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 Germany in 1996
Characteristics of Harpagophytum tablets and their main ingredient harpagoside (7)
Using the DAB Disintegration Tester, extract WS 1531 containing tablets (batch 9102) were examined. On average, the tablets disintegrated after 18 minutes. The ingredients are highly water-soluble (def. DAB). Both harpagoside and Harpagophytum extract have an octanol-water distribution coefficient of about 4. Using batch 9102 tablets with a mean harpagoside amount of 16.5 mg, release tests were carried out according to DAB 1996 V.5.4. Harpagoside was released in artificial gastric juice (USP XXII) with a mean half-life of t50 = 13.5 min. Harpagoside remained relatively stable for about three hours in artificial gastric juice and for a period of six hours in intestinal juice (USP XXII).
Pharmacological investigations
Harpagoside inhibits both arachidonic metabolism pathways, the cyclo-oxygenase and the lipoxygenase (8) (Fig. 3). 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 (Fig. 3).
Fig. 3
Effect of harpagoside and Harpagophytum extract with harpagoside 2% and 7% on thromboxane B2- and cysteinyl-leukotrien biosynthesis (8)
Surprisingly, 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) (10) or lyphilizised fresh plant, administered i.p. or orally (11), showed a dose-dependent protection, though 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 (12) and by oral administration of aquaeous and methanolic Harpagophytum extracts 200 mg/kg/day (13) was similar to that of phenylbutazon. 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.
Harpagoside bioavailability after oral intake
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, dose-dependent absorption of harpagoside following oral administration of a 20% harpagoside enriched extract was also demonstrated (17). 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 (19)
In a large open study, 630 patients suffering from arthrosis of the hip, knee, fingers and spine, received six months of treatment with aqueous Harpagophytum extract containing 2.5% of iridoid glycosides at a daily dosage of 3 to 9 g powdered drug, divided into three doses. Improvement was demonstrated in 42% to 85% of the patients grouped according to the site of arthrosis (knee 42%; interphalanx 59%, lumbar/cervical spine 54%/85%; hip 70%). No side-effects other than mild gastrointestinal disturbances were reported, even at the highest level.
- a post-marketing surveillance (20)
In a controlled pilot study, 100 patients suffering from various rheumatic pain syndrome randomly received either 2460 mg Harpagophytum extract (drug-extract ratio 2:1) with 30 mg harpagoside per day (3 x 2 capsules) 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.
- double-blind investigations
In a double-blind study (21), 50 volunteers suffering from arthrosis were given three-week courses of capsules containing 400 mg of hydroethanolic Harpagophytum extract with an iridoid glycoside content of 1.5%, at a dosage of two capsules three times daily. 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.
In another double-blind study (22) on 89 ambulant volunteers with articular pain of rheumatic origin, the efficacy and tolerance of capsules containing 335 mg of powdered drug with an iridoid glucusid content of 3% were assessed at a dosage of two capsules three times daily for two months. 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
- double-blind investigations
This study consisted of 118 patients suffering for longer than six months from chronic low back pain not attributable to identifiable causes (23). Upon their written informed consent, they 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 (24) and its scores for pain, invalidity and physical impairment. 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). In patients with pseudoradiating pain into the leg(s), the median effect of Harpagophytum extract was like that of the placebo. However, in patients suffering from pain not pseudoradiating into the leg(s), the pain index decrease was 25% in the Harpagophytum group and zero in the placebo group (Fig. 4). 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. 4
Relative median change of the Arhus low back pain index in patients suffering from local and pseudoradiating low back pain after four weeks with Harpagophytum extract (DoloteffinR) 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, or a placebo (3 x 2 tablets, Batch 9102*) with 50 or 100 mg harpagoside, 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 post-marketing surrveillance (25)
This study was comprised of 102 patients suffering from local (non-pseudoradiating) low back pain that was not attributable to identifiable causes. All patients had suffered from chronic low back pain for more than six months. They received, acording to their physician's decision, either 1800 mg Harpagophytum extract (****drug-extract ratio 2.5:1) with 30 mg harpagoside per day (3 x 2 capsules), as single or co-treatment or as conventional treatment (nonsteroidal anti-inflammatory drugs, physical exercises or paravertebral injections). In order to guarantee careful documentation, physicians from the study group investigated the patients in their consulting rooms. Patients receiving the Harpagophytum treatment were not favoured, 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 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. 5). 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 (Fig. 6). 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.
Fig. 5
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)
Fig. 6
Relative costs of 6 weeks treatment with harpagophytum as single treatment (Group Jmono), as single or co-treatment (Group J), or as conventional treatment (Group C) from the view of social health care and private care (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.
*Schwabe GmbH, Postfach 410925, D 76227 Karlsruhe
**Extrakt Chemie GmbH, Postfach 1212, D 31642 Stadthagen
***Ardeypharm GmbH, Postfach 1153, 58313 Herdecke
**** Strathmann AG, Postfach 610425, 22459 Hamburg
References
1) ESCOP Monographs, Harpagophyti Radix, March 1996, Uiterwaardenstraat 13, NL 8081 HJ Elburg
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6) Chrubasik S, Junck H, Zappe HA. Effectiveness of Harpagophytum extract WS 1531. Unpublished data.
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