Harpagophytum – Devil’s Claw Root (Harpagophyti radix)
|Latin name of the genus:||Harpagophytum|
|Latin name of herbal substance:||Harpagophyti radix|
|Botanical name of plant:||Harpagophytum procumbens dc.; harpagophytum zeyheri decne|
|English common name of herbal substance:||Devil’s claw root|
Latin name of the genus: Harpagophytum
Latin name of herbal substance: Harpagophyti radix
Botanical name of plant: Harpagophytum procumbens DC.; Harpagophytum zeyheri Decne
English common name of herbal substance: Devil’s Claw Root
MA: Marketing Authorisation;
TRAD: Traditional Use Registration;
Other TRAD: Other national Traditional systems of registration;
Other: If known, it should be specified or otherwise add ‘Not Known’
ON HERBAL SUBSTANCE(S), HERBAL PREPARATION(S) OR COMBINATIONS THEREOF WITH TRADITIONAL USE
DC. and/or Harpagophytum zeheyri
BASED ON ARTICLE 16D(1) AND ARTICLE 16F AND 16H OF DIRECTIVE 2001/83/EC AS
II.1.1 Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Herbal substance(s)2,3: Cut dried tuberous secondary root of Harpagophytum procumbens DC. and/or Harpagophytum zeyheri Decne
Herbal preparation(s)1,2: Powdered herbal substance, comminuted herbal substance, liquid extract (1 : 1 ; 30% V/V ethanol), soft extract
The characteristic constituents are iridoid glucosides (0.5 – 3 %): harpagoside, harpagide,
The other constituents are principally sugars (stachyose, raffinose and monosaccharides) and phenolic glycosides (verbascoside and isoacteoside).
II.1.2 Information on period of medicinal use in the Community regarding the specified indication
The first herbal medicinal product has been authorized in Germany in 1978. Some products are marketed also in Belgium, in Denmark, in France, in Hungary and in Malta.
The different herbal medicinal products on the market are prepared with powder, aqueous extract or ethanolic extracts (30 – 40% V/V, and 60 – 90% V/V)
Harpagophytum procumbens belongs to the Pedaliacea family. This perennial herbaceous plant grows naturally in the Kalahari desert and Namibian steppes region of
2According to “Guideline on quality of herbal medicinal products/traditional herbal medicinal products” (CPMP/QWP/2819/00 Rev. 1)
3According to “Guideline on specifications: test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products/traditional herbal medicinal products” (CPMP/QWP/2820/00Rev.1)
traditional medicine for various indications. In Europe, it is used for painful arthritis, tendinitis, loss of appetite and dyspeptic complaint [
Studies quoted in this document were not performed in compliance with GLPs. Most of them were conducted to evaluate the pharmacodynamics of Harpagophytum procumbens secondary roots extracts referred to as “Harpagophytum procumbens extracts” in the following pages. Other
II.2.2.1 Primary pharmacodynamics
II.220.127.116.11 Analgesic effect
An aqueous extract of Harpagophytum procumbens (containing 2.2% harpagoside) was tested for its analgesic activity in the writhing test. It was administered intraperitoneally to male Swiss mice at the following dose levels: 100, 400, 800 and 1200 mg/kg [
1997]. Acetylsalicylic acid (Aspegic®) was used as a reference peripheral analgesic compound at the dose of 68 mg/kg. Control animals received 0.9% NaCl solution under the same experimental conditions. Thirty minutes after these administrations, the animals were injected a 1.2% acetic acid solution by intraperitoneal route. Each animal was then isolated and observed for 30 minutes. During this period, the number of writhings and stretchings was recorded. The percentage of protection against the acetic acid algic effect was then calculated for each group.
The results indicated that Harpagophytum procumbens
Another experiment was performed according to the same protocol, to study the analgesic activity of a standardized aqueous extract of Harpagophytum procumbens containing 1.8% harpagoside (50, 100, 200 and 400 mg/kg) and harpagoside (5 and 10 mg/kg). Acetylsalicylic acid (68 mg/kg) and morphine sulphate (1.15 mg/kg) were used as reference peripheral/central analgesic compounds. The results indicated that Harpagophytum procumbens
The acid treatment of the extract and harpagoside (HCl 0.1 N (pH 1) during 3 hours at 38°C), performed to reproduce the
Hot plate test
The same authors evaluated the protection potential of the extract and harpagoside against heat- induced pain [
1994]. Male Swiss mice were placed in a glass flack bathing in water whose temperature was maintained at 56°C. Reaction times of mice before any treatment were recorded – time to obtain a response to heat stimuli, e.g. licking of the forepaws, jumping. Then, mice were intraperitoneally injected the extract (200 and 400 mg/kg) or harpagoside (10 mg/kg). Acetylsalicylic acid (68 mg/kg) and morphine sulphate (4.6 mg/kg) were used as reference substances. The procedure to measure time reactions was repeated after 30 minutes. Each animal was its own control.
In this test, Harpagophytum procumbens, harpagoside and acetylsalicylic acid did not increase the reaction time of mice. On the contrary, morphine sulphate (4.6 mg/kg) exerted a significant protective effect on
Analgesic activity of Harpagophytum procumbens and harpagoside was evaluated in two murine models. In these models, pain was induced either chemically by intraperitoneal injection of acetic acid (writhing test), or thermally (hot plate test). In these experiments, test articles were administered by intraperitoneal route.
Harpagophytum procumbens had a
In the same animal model, harpagoside was only effective at the dose of 10 mg/kg, which represents twice the harpagoside dose contained in 400 mg of the extract effective at 100 mg/kg. Therefore, the authors concluded that other substances (than harpagoside) are involved in the analgesic activity of Harpagophytum procumbens [
1994]. However, these substances remain unknown.
Moreover, the extract and harpagoside were submitted to an acid treatment whose aim was to mimic the
In the hot plate test, like acetylsalicylic acid, but contrary to morphine sulphate, Harpagophytum procumbens was ineffective. Therefore, it does not possess any central analgesic properties.
In summary, Harpagophytum procumbens possesses peripheral analgesic properties after intraperitoneal administration, as shown in the writhing test in mice. Studies performed with harpagoside suggest that other unidentified substances are involved in this analgesic effect, but these active substances remain unknown. Effective doses are not accurately defined, as they can change according to the extract used. A study performed after the acid treatment of an extract suggested that Harpagophytum procumbens could be ineffective by oral route in terms of analgesia.
II.18.104.22.168.1 Isolated substances (harpagoside, harpagogenin)
Three animal models of inflammation were used:
–the granuloma pouch test [
Eichler and Koch 1970].
This study was designed to evaluate the
One hour after these administrations, each mouse was injected a 3% w/v suspension of carrageenan in its right hind paw to induce oedema. The volumes of the injected and
The values of the oedema volume and the oedema inhibition percentage were calculated for each group. The authors considered that harpagoside administered orally did not exert a notable protective effect in this test.
Male OFA rats were administered harpagoside by intraperitoneal route at the doses of 5 and 10 mg/kg. In the same conditions, indomethacin (2.5, 5 and 10 mg/kg) was used at a reference product and the controls received 0.9% NaCl solution. Twelve rats per harpagoside group were used, as well as
13 control rats and 10 rats per indomethacin group. Thirty minutes after these administrations, each rat received a subplantar injection of a 1% carrageenan suspension in its right back paw.
The average volume of the back paws of each animal were measured before any treatment and at different time points after the injection of the carrageenan suspension (30 min, 1, 2, 3, 4, 5, 6 and 24 hours). For each group, the following data were then calculated: average volumes of the back paws before treatment and at the different time points, and percentages of variation (percentages of oedema).
In control animals, a local oedema was observed 30 minutes after the injection of the carrageenan suspension, and reached a maximal intensity after 3 or 4 hours (% of oedema = 56 to 67%). Then, the oedema progressively decreased but still remained obvious after 24 hours. The intraperitoneal pre- treatment with harpagoside did not induce an inhibitory effect on
Application of a single dose of
Then, harpagoside was administered topically at the dose of 1 mg (right ear). The reference substance was indomethacin, 0.5 mg (right ear). Left ears of the animals served as controls, and were applied vehicle (EtOH) or acetone, which was used to dissolve TPA or harpagoside. After 4 hours, animals were sacrificed and the swelling induced by TPA was assessed in terms of the increase in the weight of the right ear biopsy over that of the left ear.
The results indicate that harpagoside 1 mg/kg induced an inhibition of 36.2 % of the oedema, as compared to controls. This oedema inhibition percentage amounted to 87.1% with indomethacin 0.5 mg/kg. Therefore, it was concluded that harpagoside did not exert
∙Granuloma pouch test [Eichler and Koch 1970]
In this test, an aseptic inflammation with large volumes of haemorrhage is induced. Here, croton oil (0.5 ml, 0.5%) was used as irritant in Wistar rats. Harpagoside (20 mg/kg) and harpagogenin (20 mg/kg) were tested following daily intraperitoneal administration for 12 days. Phenylbutazone (40 mg/kg) was used as a reference substance.
The results indicated that harpagoside and harpagogenin induced a significant inhibition of exudate production (respective values of 33.8% and 28.9%), of granuloma weight (respective values of 29.9% and 24.5%) and of tissue granulation (respective values of 19.2% and 14.6%).
II.22.214.171.124.2 Aqueous extracts of Harpagophytum procumbens (secondary roots)
Various aqueous extracts of Harpagophytum procumbens have been evaluated for their anti- inflammatory activity in mice and rats. Three main animal models of inflammation were used:
McLeod et al. 1979, Whitehouse et al. 1983, Soulimani et al. 1983].
Jadot and Lecomte 1992].
–the granuloma pouch test [
Aqueous extracts of Harpagophytum procumbens were tested in this model by intraperitoneal and oral routes. Due to conflicting results, another study was undertaken to compare directly the anti- inflammatory activity of Harpagophytum procumbens by intraperitoneal, oral and intraduodenal routes.
– Intraperitoneal route
A standardised aqueous extract of Harpagophytum procumbens (containing 1.8% harpagoside) was administered to rats (15 per group) at the following dose levels: 100, 200 and 400 mg/kg – doses expressed in terms of dried plant material [
1994]. As precised in the protocol described above, a carrageenan suspension was injected thirty minutes after in the right back paw of each animal. The average back paw volume of each rat was measured before any treatment and at different time points after the injection of the inflammatory agent (up to 24 hours).
The results showed that the local oedema induced by the carrageenan suspension was reduced dose- dependently by a
The same test was performed to study the influence of acid treatment on the
Another aqueous extract of Harpagophytum procumbens (containing 2.2% harpagoside) was administered to rats at doses of 400, 800 and 1200 mg/kg – doses expressed in terms of dried plant material [
1997]. Control animals received a 0.9% NaCl solution, and the reference substance used was indomethacin 10 mg/kg. As in the previous study, a 1% carrageenan suspension was injected in the right back paw (subplantar route) 30 minutes after these administrations. The average volumes of each rat back paws were measured before any treatment and at different time points after the injection of the inflammatory agent (up to 24 hours).
In controls, a local oedema was observed 1 hour after the injection of the carrageenan suspension, and reached a maximal intensity after 3 or 4 hours and still remained obvious after 24 hours. The
– Oral route
Thirty male Wistar rats were administered either an aqueous extract of Harpagophytum procumbens (1 g/kg), indomethacin as a reference substance (5 mg/kg), or 0.5% tragacanth. One hour after these administrations, carrageenin 0.1% was injected into the rear right foot of each animal, and volumes of both rear feet were then measured at hourly intervals. The peak reaction was observed 4 hours after the injection of the phlogistic agent. At this time point, the
An extract of Harpagophytum procumbens was compared to acetylsalicylic acid (ASA) in terms of inhibition of the oedema induced in male
6000 mg/kg did not reduce the oedema consecutive to carrageenan injection (max. 20.3% inhibition, 2000 mg/kg) contrary to ASA (51.9% inhibition) [
– Intraperitoneal/oral/intraduodenal routes
Harpagophytum procumbens exerts an
The extracts prepared had a total glucoiridoid content 2.72%, and an harpagoside content of 0.44%. Extracts intended to be administered orally and intraduodenally were lyophilized with
–IP route: administration of the extract (100, 200 and 400 mg/kg in terms of dry material) or NaCl 0.9% (controls) followed after 30 minutes by an injection of a 1% carrageenan suspension into the back paw of each animal.
–Oral route: administration of the extract (200, 400, 800, 1600 mg/kg in terms of dry material) or water (controls) followed after 60 minutes by an injection of a 1% carrageenan suspension into the back paw of each animal.
–Intraduodenal route: ketamine anaesthesia followed by the administration of the extract (200, 400, 800, 1600 mg/kg in terms of dry material) or water (controls) and, after 60 minutes, by an injection of a 1% carrageenan suspension into the back paw of each animal.
In control animals belonging to intraperitoneal and oral groups, a local oedema appeared 1 hour after carrageenan injection; its intensity increased to reach a maximum at 3 hours. In control animals of the intraduodenal groups, the local oedema was observed 2 to 3 hours after the injection of carrageenan and reached a maximal intensity at
Three hours after intraperitoneal administration of the extract, significant inhibition of the
Harpagophytum procumbens (powder in suspension in arabic gum, 3% glucoiridoids) was administered daily for 5 days to male Wistar rats by oral gavage (0, 37, 370 and 3700 mg/kg/d). Then, all animals were injected in the left hind paw (subplantar injection) 0.2 ml of a solution of adriamycine chlorhydrate (0.5 mg). The volumes of the injected paw were measured before any administration, 1 hour and 5 days after administration of the inflammatory agent.
In a previous study, the authors showed that the injection of adriamycine chlorhydrate in the same conditions caused, after 1 hour, a release of serotonin and histamine. After 5 days, lipid peroxidation and free radicals were identified.
In the present study, one hour after having induced inflammation, the injected paw volume was decreased in all treated groups, but the effect was maximal in the 37 mg/kg dose group
Jadot and Lecomte 1992].
1979]. Then, the following drugs were administered orally daily for 21 days: Harpagophytum procumbens dried aqueous extract (100 mg/kg – 1 g/kg), indomethacin (3 mg/kg, used as a reference substance), or tap water (controls). The number of animals involved in this experiment totalled 40. During the administration period, the following parameters were measured: body weight and rear foot volumes.
The results of the study indicated that contrary to indomethacin, Harpagophytum procumbens administered orally did not produce a significant effect on either the primary or secondary inflammatory reaction. Moreover, when given in the
In another experiment [
–Water (2 ml/kg).
–Harpagophytum procumbens extract (2 g/kg).
–Indomethacin (3 mg/kg), reference substance.
Volumes of the feet were monitored on days 11, 15 and 17 and mean foot volumes were then calculated. The results indicate that Harpagophytum procumbens was ineffective in this model of inflammation after 6 days of treatment, whereas indomethacin completely alleviated the adjuvant- induced arthritis after 4 days of treatment (day 15 of the experiment) [
∙Granuloma pouch test
An experiment similar to the one described above was performed with an aqueous extract containing 2.7% harpagoside given orally and daily for 11 days at the doses of 20 and 200 mg/kg. At the higher
Aqueous extracts of Harpagophytum procumbens showed
By oral route, Harpagophytum did not exert any
The inefficacy of Harpagophytum procumbens in these models when administered orally, compared to its efficacy in the
amazing. Some studies have shown that this discrepancy could result from the gastric passage of the extract. First, some authors showed that an extract submitted to an acid treatment whose aims was to mimic the
Moreover, in rats injected a suspension of Mycobacterium butyricum to induce arthritis, Harpagophytum procumbens was ineffective but authors evoked its ability to potentiate adjuvant arthritis in a manner similar to that seen with levamisole and penicillamine.
Only two isolated studies reported an
In summary, several points remain unresolved/unclear:
–Isolated compounds (mainly harpagoside) were not or were slightly, effective in animal model of inflammation, whereas Harpagophytum extracts have shown
–The influence of the gastric passage on Harpagophytum procumbens’s
should be clarified; presently, available preclinical studies do not support its potential to induce anti- inflammatory effects after oral administration.
–The lowest effective dose should be accurately precised, as it varied according to the extract used (intraperitoneal studies).
–The ability of Harpagophytum procumbens to potentiate adjuvant arthritis in a manner similar to that seen with levamisole and penicillamine should be taken into consideration.
II.126.96.36.199 Mechanism of action
Four mechanisms of action were investigated either in in vitro or in in vivo studies in order to explain the analgesic and
∙Influence on arachidonic acid pathway
The effects of Harpagophytum procumbens on prostaglandin synthetase were examined in vitro. Radiolabelled arachidonic acid and prostaglandin synthetase were incubated at 37°C for 4 minutes with various concentrations of indomethacin, acetylsalicylic acid or Harpagophytum procumbens extract. The percentage of inhibition of the enzyme was then determined. IC50 were then calculated and amounted to 0.376 μg/ml for indomethacin and 437 μg/ml for acetylsalicylic acid. In comparison, the concentration of Harpagophytum procumbens causing 50% inhibition of prostaglandin synthetase was superior to 105 μg/ml. Therefore, it was concluded that the claimed
Other authors have investigated the effects of Harpagophytum procumbens (aqueous extract) against
2003]. The following parameters were measured:
–Cell viability (MTT assay).
–PGE2 biosynthesis (commercial competitive enzyme immunoassay kit).
–NO biosynthesis (commercial NO detection kit).
The results obtained did not indicate any cytotoxic effect of the extract tested towards L929 cells at concentrations up to 1 mg/ml. In
As shown by Salvemini et al (1993), NO modulates the activity of
This possible inhibitory potential of
Figure 1: Proposed molecular mechanism of
[Kundu et al. 2005].
The methanol extract of
Harpagophytum procumbens inhibited
The effects of different fractions of Harpagophytum procumbens extracts on ecosanoid biosynthesis were evaluated on human whole blood in vitro [
2001]. A crude aqueous ethanolic extract (80% wt/wt), extract fractions prepared by liquid/liquid extraction with solvent of increasing polarity and 2 other extracts were tested. These extracts were
samples were not
The results obtained with different fractions of the extract showed that the inhibition of A23187- stimulated
Table 1: Effect of different Harpagophytum extracts and extract fractions on the ionophore
A23187-stimulated biosynthesis of Cys-LT and TXB2 in vitro in human whole blood [Loew et al. 2001].
This study also showed that the different extract fractions have different pharmacological properties. For example, fraction E stimulates the synthesis of
This potential mechanism of action has been investigated by Fiebich et al 2001. A Harpagophytum procumbens extract was obtained after aqueous ethanolic extraction (60% v/v) and labelled SteiHap69 (Steiner Harpagophytum procumbens 69). This extract was then purified from lipopolysaccharides of bacterial origin to obtain PSH69 extract (Purified SteiHap 69). Studies were also conducted with
Human monocytes were incubated with either PSH69, harpagide or harpagoside and then LPS 10 ng/ml were added in the culture medium. After 24 hours,
The results show that the
Therefore, PSH69 inhibits inflammatory processes by preventing the release of
∙Inhibition of human leukocyte elastase
Boje et al. performed an in vitro study to evaluate the inhibiting activity of Harpagophytum procumbens towards the elastase from human leukocytes [
An aqueous extract (2.35% harpagoside) or 5 of the main components of Harpagophytum procumbens were incubated with human neutrophile elastase for 1 hour. At the end of the enzymatic reaction, inhibition rates were calculated and corresponding IC50 were then determined.
IC50 of the aqueous extract was 542 μg/ml. The more potent active substances in this test were 6
The elastase inhibiting potency of the aqueous extract Harpagophytum procumbens and its main components, with IC50 > 50 μM, is mediocre [
An ethanolic extract (53% w/v) of Harpagophytum procumbens was administered to male Wistar rats by intraperitoneal route for 1, 7 or 14 days in doses of 100 and 200 mg/kg. Control animals received NaCl 0.9% in the same conditions. Selegiline (Deprenyl ) 2 mg/kg was used intraperitoneally as a reference substance.
At the end of the treatment period, the frontal cortex and the striatum were dissected out and the following parameters were measured:
–Catalase (CAT) activity.
–Glutathione peroxidase (GPX) activity.
Bhattacharya and Bhattacharya 1998].
Several in vitro and in vivo studies were conducted to investigate, on a mechanistic basis, the analgesic and
A first series of experiments explored its influence on the arachidonic acid pathway. Two studies showed that Harpagophytum procumbens can interfere with arachidonic acid metabolism by acting on the
In an in vitro model of
In rats, an ethanolic extract administered by intraperitoneal route exerted an
Therefore, some points remain unresolved/ unclear:
–Mechanistic studies were performed with aqueous, aqueous alcoholic or alcoholic extracts of Harpagophytum procumbens. As qualitative and quantitative composition of the extracts differs according to the extraction process, the relevance of these data is uncertain. For example, although
a crude ethanolic extract exerted
II.2.2.2 Other studies
∙Cardiovascular activity [Circosta et al. 1984]
The cardiovascular activity of Harpagophytum procumbens and harpagoside was evaluated in rats, and in Langendorff preparations of rabbit heart.
Single doses of a methanolic extract (2.09% total glucoiridoids/1.70% harpagoside) or harpagoside were administered either orally or intraperitoneally to conscious normotensive rats (5 per group). By i.p. route, the extract was administered from 25 to 100 mg/kg and harpagoside at 5 and 10 mg/kg. By oral route, the extract was administered from 100 to 400 mg/kg and harpagoside at 20 and 30 mg/kg. Controls received water in the same experimental conditions. Sixty minutes after these administrations (30 minutes for i.p. route), anesthetized rats were injected a
Single doses of either the methanolic extract of Harpagophytum procumbens, harpagoside or harpagide, were injected in the coronary circulation of rabbit hearts – Langendorff preparations.
The results indicate that in this model, Harpagophytum procumbens caused a mild positive inotropic effect at lower doses but a marked negative inotropic effect at higher dose, with a concomitant decrease in coronary flow. A mild decrease in heart rate was also reported. In the same model, the negative chronotropic and positive inotropic effects of harpagoside were comparatively higher than that of the extract. Harpagide had slight negative chronotropic and considerable negative inotropic effects. A protective effect of the extract against
From this study, it is concluded that the extract of Harpagophytum procumbens might interfere with penetration of calcium into the myocardial cells – protection against arrhytmias induced by calcium chloride. This could explain the
∙Effects on hyperkinetic ventricular arrhythmias (HVA) by reperfusion [de Pasquale et al. 1985]
A methanolic extract of Harpagophytum procumbens (2.09% total glucoiridoids/1.70% harpagoside) was evaluated for its protective potential against ischemic
Isolated rat hearts were perfused by Langedorff method up to stabilization of ECG. Then, the coronary flow was reduced to provoke an ischemic perfusion. After 30 minutes, the perfusion was brought to basal conditions. In the same time, the extract and harpagoside were added to the perfusion medium through a cannula connected to the aorta. Seven rat hearts per
In control hearts, polytope extrasystoles occurred 1 minute after the reperfusion. One minute later (2nd minute of reperfusion), ventricular tachycardia occurred. The treatment with Harpagophytum
procumbens extract reduced the HVA observed in control animals from 1 mg (= 0.085 mg harpagoside) but this protective effect was improved at the dose of 2 mg. With harpagoside, a protective effect was reported too, at 0.170 mg. However, its intensity was lower than that of the extract containing corresponding quantities of harpagoside (2 mg of extract).
The methanolic extract (2 mg) and harpagoside (0.170 mg) impeded the insurgence of hyperkinetic arrhythmia set off by 100 μg digitoxin, limiting this latter’s toxic effects to disturbances of conduction and of the repolarisation phase. It is hypothesized by the authors that Harpagophytum procumbens might inhibit HVA due to a
These studies were conducted in the same laboratory and most of their authors took part in both studies. Therefore, the methanolic extracts used, containing the same amount of total glucoiridoids and harpagoside, are supposed to be identical.
This methanolic extract of Harpagophytum procumbens exerts hypotensive and bradycardic effects in conscious rats. In isolated rabbit heart a marked negative inotropic effect with a concomitant decrease in coronary flow was reported at the higher dose tested. Moreover, this extract had a protective effect against
From the results of these studies, it is also concluded that Harpagophytum procumbens could have a
– Decreased heart rate and arterial blood pressure were reported in exposed conscious rats, and marked negative inotropic effect with a concomitant decrease in coronary flow was noted in a model of isolated rabbit heart. The authors hypothesized that it might have a
–The potential of Harpagophytum procumbens to induce QT prolongation is unknown.
–Potential pharmacodynamic interactions have not been investigated.
–Therefore, Harpagophytum procumbens should not be administered to patients affected by or treated for cardiovascular disorders.
Van Haelen conducted in vitro studies with harpagoside and harpagide to obtain the corresponding genin resulting form acid hydrolysis (harpagogenin). Optimal conditions were: pH 2 and 6 hours incubation in a saturated
van Haelen 1983].
Another study was performed to study the metabolism of 3 iridoid glycosids from Harpagophytum procumbens by human intestinal bacteria: harpagoside, harpagide and
the 3 iridoids, the amount recovered being higher with human intestinal bacteria than with
Information about the pharmacokinetics of Harpagophytum procumbens is scarce. In vitro studies showed that harpagoside and harpagide can be transformed into harpagogenin in
–The pharmacokinetic profile of Harpagophytum procumbens or its main constituents has not been established.
–In particular, the outcome of the gastric passage could be of interest as pharmacodynamics studies have shown that Harpagophytum procumbens extract exerts
The acute oral LD0 and intravenous LD0 in mice of aqueous, methanolic and butanolic extracts of Harpagophytum procumbens were greater than 4.6 g/kg and 1.0 g/kg, respectively. A purified extract containing 85% harpagoside showed an acute oral LD0 greater than 4.6 g/kg and acute and LD50 of 395 mg/kg and 511 mg/kg, respectively [
1978]. The intraperitoneal LD50 of harpagoside in mice amounted to 1 g/kg, whereas the LD50 of harpagide was greater than 3.2 g/kg in the same conditions [
van Haelen 1983].
In another study, the LD0 of an extract of Harpagophytum procumbens was superior to 13.5 g/kg. However, the mode of extraction was not described by the authors [
Oral LD0 of Harpagophytum procumbens were determined in mice with extracts obtained by various modes of extraction. The results show that their acute toxicity in mice is low.
In male Wistar rats, no significant haematological or gross pathological findings were evident following 21 days of
The relevance of this study remains uncertain. Indeed, it is briefly described in the publication of Whitehouse et al. 1983. The aim of this paper was to report studies exploring the
II 2.4.4 Carcinogenicity
II 2.4.5 Reproduction toxicity
II.2.4.6 Local tolerance
II.2.4.7 Other studies
Assessor’s comments on toxicology
Harpagophytum procumbens has a low toxic potential after a single administration in mice. However, its toxicological profile after repeated administrations is not established, as studies are lacking. Moreover, its genotoxic potential has not been investigated and its toxic potential to reproduction has not been studied.
Therefore, in view of the toxicological data available, the safety of Harpagophytum procumbens in human is not guaranteed.
’S OVERALL CONCLUSIONS ON
Harpagophytum procumbens is claimed to exert analgesic and
In the writhing test, Harpagophytum procumbens showed peripheral analgesic properties after intraperitoneal administration. Unfortunately, similar studies were not performed by the oral route.
In various animal models of inflammation
Most of these studies included the testing of the supposed active substances of Harpagophytum procumbens, harpagoside or harpagide. Harpagoside exerted a peripheral analgesic activity (i.p. route) at a dose level representing twice the harpagoside dose contained in the dose of extract needed to obtain a maximal analgesic effect. Therefore, the authors concluded that other substances are involved in the analgesic activity of Harpagophytum procumbens. In the
inflammatory effect when tested in the
Several in vitro and in vivo studies were conducted to investigate, on a mechanistic basis, the analgesic and
Studies conducted with a methanolic extract have shown that Harpagophytum procumbens could have a
Scarce information is available on the pharmacokinetics and toxicology of Harpagophytum procumbens.
Therefore, the assessor’s current opinion on the subject is:
1.Toxicological data available do not guarantee the safety of Harpagophytum procumbens in humans. In particular, adequately conducted
repeated-dose toxicity studies, genotoxicity studies and reproduction toxicity studies are lacking.
2.Decreased heart rate and arterial blood pressure were reported in exposed conscious rats, and a marked negative inotropic effect with a concomitant decrease in coronary flow was noted in a model of isolated rabbit heart. It has been hypothesized that Harpagophytum procumbens might have a
3.Available studies were performed with extracts differing in their mode of preparation, qualitative and quantitative composition. Extracts are not adequately standardised.
4.Harpagophytum procumbens has been shown to possess peripheral analgesic and anti-
inflammatory properties after intraperitoneal administration. However, effective dose (i.p. route) differs from one study to another and is not accurately defined.
5.When administered intraperitoneally, harpagoside exerted analgesic effects at
6.Neither Harpagophytum procumbens, nor harpagoside, possessed any analgesic or anti- inflammatory activity by oral route in animal models of inflammation. It seems that the gastric passage inactivates some compounds present in the extract. However, pharmacokinetic data are lacking and the influence of the gastric passage on Harpagophytum procumbens activity is not clarified.
7.The ability of Harpagophytum procumbens to potentiate adjuvant arthritis in a manner similar to that seen with levamisole and penicillamine should be taken into consideration
8.Mechanistic studies were performed with aqueous, aqueous alcoholic or alcoholic extracts of Harpagophytum procumbens. As the qualitative and quantitative composition of the extracts differs according to the extraction process, the relevance of these data is uncertain. For example,
although a crude ethanolic extract exerted
The assessment is based on the documentation provided by the European Scientific Cooperative on Phytotherapy (ESCOP) and the Association of the European
The monograph of the ESCOP recommends Harpagophytum procumbens preparation for painful osteoarthritis and low back pain. The assessment is therefore focused on the potential effectiveness of Harpagophytum products in both pathologies. No other rheumatic disease has been examined.
For Harpagophytum products, the ESCOP monograph recommends that the daily dose should contain up to 100 mg of the coactive constituent harpagoside, twice the dose recommended by the German Monograph.
Based on the empirical recommendations of the ESCOP monograph for Harpagophytum clinical use, study selection was made in the field of osteoarthritis and low back pain. In order to establish a sufficient scientific basis, clinical trials should met criteria of randomisation. For safety, open label studies are acceptable.
II.3.2 ASSESSMENT OF EFFICACY AND SAFETY
II.3.2.1 Dose finding studies
The recommended daily dose of harpagoside is not supported by clinical evidence.
According to the provided literature references, no
It should be mentioned that a detailed clinical trial by Chrubasik et al. 1999 compares two doses of Harpagophytum (600 mg and 1200 mg, containing 50 and 100 mg of harpagoside, respectively) but no conclusion about a dose related effect resulted.
II.3.2.2 Randomised Controlled clinical trials
Effectiveness of Harpagophytum procumbens in treatment of acute low back pain.[Chrubasik et al. 1996]
This trial can be considered as a starting point in the assessment of the efficacy of Harpagophytum in patients with low back pain and it was a
The only rescue medication allowed was tramadol. In fact, cumulative requirements for tramadol, over the last three weeks of the study period, were taken as the principal outcome measure of efficacy. Secondary
No difference was observed in the analgesic rescue medication sparing measurement between placebo and treatment groups. A greater number of
Overall, negative clinical results as compared to placebo were observed in this clinical study.
The conclusion of the authors, was the need of further clinical trials. Future studies may also assess the effect of dose in order to obtain clinical
Effectiveness of Harpagophytum extract WS 1531 in the treatment of exacerbation of low back pain: a randomised,
placebo-controlled, double-blind study. [Chrubasik et al. 1999]
This second trial is in direct line with the previous one. The design of the study is identical, but two doses of Harpagophytum (600 and 1200 mg daily containing 50 and 100 mg of harpagoside, respectively) were assessed versus placebo. The principal outcome measure was the proportion of patients free of pain, without rescue medication (tramadol) for at least 5 days, in the fourth week. Secondary outcome measure use Arhus Index to assess pain and functional disability. Of the 197 included patients, 183 completed the trial.
The number of patients free of pain in the last week of treatment (primary analysis) was small. A greater number of responders was significantly observed (p = 0.027) in the treatment groups (9% and 15% for 600 mg and 1200 mg respectively) than in the placebo group (5%) However, inconsistency in the direction of any dose related effect was observed between primary and secondary analyses, in particular for the pain component. Stratification tends to indicate that only some subgroups (shorter exacerbations, less pain, no radiation) could be improved by the treatment. Due to the contradictory results, no clear conclusion could be drawn regarding the efficacy of Harpagophytum in the treatment of low back pain.
Efficacy and tolerance of Harpagophytum procumbens versus Diacerhein in treatment of osteoarthritis. [Chantre et al. 2000]
Harpagophytum procumbens in the treatment of knee and hip osteoarthritis.
A four month clinical trial, published two times in different journals but in similar terms, assessed the efficacy of Harpagophytum in the symptomatic treatment of osteoarthritis. This was a double blind, randomised, parallel group, multicentre trial. Patients were recruited with radiologically proven osteoarthritis of the knee or the hip; the clinical criteria of the activity of the disease was a spontaneous pain of at least 50 mm on a 100 mm Visual Analogue Scale (VAS). The Lequesne Index was also used to assess activity.
The clinical study compared the efficacy of Harpagophytum capsule (435 mg of powder containing 50 mg of harpagoside) to another active medication, diacerrhein, considered as a symptomatic slow acting drug for osteoarthritis. There was no placebo group. Rescue medications allowed were acetaminophen associated with caffeine and, if response was inadequate, diclofenac.
Primary efficacy endpoint was defined by the level of spontaneous pain using VAS. Primary analysis was to demonstrate the
Lequesne Index, functional disability of movement assessed on a VAS, amount of taken rescue medication were used as secondary efficacy endpoints. Overall 122 patients were randomised and 92 patients completed the trial in accordance with the protocol. No differences were found between both treatment in terms of pain relief and
double-blind pilot study comparing Doloteffin® and Vioxx® in the treatment of low back pain. [Chrubasik et al. 2003]
1-year follow-up after a pilot study with Doloteffin® for low back pain [Chrubasik et al. 2005]
The initial clinical trial is a
No statistically significant difference was observed between the two treatments neither for
The interest for this clinical trial is very limited, in particular for efficacy assessment. The absence of a placebo group is questionable as for the choice of active comparator. Rofecoxib can not be considered as a reference in the treatment of chronic low back pain. In the European Union, rofecoxib was principally indicated for symptomatic relief in osteoarthritis and rheumatoid arthritis, and for some countries in the relief of pain and the treatment of dysmenorrhoea. Furthermore, the number of patients was small. No definitive clinical conclusions can be drawn from this study.
Remaining patients from the pilot study (79 of the initial 88 patients) were invited to participate in a
active-controlled, mono-centric study of the herbal drug Devil’s claw (Harpagophytum procumbens) (ALLYA® tablets), Voltaren® and Vioxx® indicates equal efficacy in the treatment of patients with unspecific lumbar pain.
[Lienert A et al. 2005]
There is only a meeting abstract of the 54th annual conference of the north German orthopaedic organisation available with poor information. This study does not seem to have been published. The authors themselves conclude to an equivalent efficacy of the three treatments (ethanolic extract of devil’s claw, Voltaren, Vioxx), but small sample size and data variability make a definitive interpretation difficult. Furthermore, it is not sure whether the North American Spine Society (NASS) Instrument (German version) is valid to show change for the factor “impairment” for a study duration of six weeks.
A stepweise scheme in coxarthrosis:
Double-blind study with Harpagophytum. [Frerick et al. 2001]
In this randomised
regarded as a clinically relevant response) was fulfilled by 70.8% of patients of the Harpagophytum group, but by only 40.9% of patients in the placebo group. This paper gives some suggestions on a possible mild therapeutic effect of Harpagophytum in coxarthrosis patients, however the low number of patients (22 to 24 per group) and the study design in which Harpagophytum was given just as an
II.3.2.3 Open Studies
Efficacy and tolerance of Harpagophytum Extract LI 174 in patients with chronic
non-radicular back pain [Laudahn and Walper, 2001]
Comparison of outcome measures during treatment with the proprietary Harpagophytum Extract Doloteffin® in patients with pain in the lower back, knee or hip. [Chrubasik et al. 2002]
This open study was conducted to examine various outcome measures of effect during treatment with aqueous extract of Harpagophytum (containing 60 mg of harpagoside). Patients were recruited on the basis of non specific low back pain or osteoarthritic pain in the knee or hip with current exacerbations, requiring at least 8 weeks of symptomatic treatment. Patients were allowed to continue their concomitant treatments and to supplement Harpagophytum with other analgesics as necessary.
Assessment of pain and disability included established instruments (Arhus Low Back Pain Index, WOMAC,) and other
Harpagophytum-Extrakt LI 174 (Teufelskralle) bei der Behandlung unspezifischer Rûckenschmerzen. [Göbel et al. 2001]
The study population was an inhomogeneous group. Subpopulations were not evaluated. The results show a significant improvement of muscle pain in the verum group in comparison to the placebo group, but the results of the placebo group are not in accordance with other references and therefore these results seem to be doubtful. In summary, the study is insufficient to prove the efficacy of devil’s claw (ethanolic extract) in the treatment of low back pain.
Therapie der unspezifischen Lumbalgie mit Teufelskrallenwurzelextrakt – Ergebnisse einer klinischen Studie. Effectiveness of Harpagophytum procumbens in treatment of unspecific low back pain. [Schmidt et al. 2005]
This open prospective study shows no significant advantage of a mono therapy or a combination therapy of Harpagophytum procumbens (ethanolic extract) with conventional therapy. Without further information these data are insufficient to support a
Treatment of patients with arthrosis of hip or knee with an aqueous extract of Devil’s Claw (Harpagophytum procumbens DC).[Wegener and Lüpke 2003]
The aim of this open study is to assess the efficacy of a coated tablet containing 400 mg of an aqueous extract in the osteoarthritis of the knee or hip. However, the results of this study can not support a well- established indication.
Patient-perceived benefit during one year of treatment with Doloteffin [Chrubasik et al. 2007]
This open study was conducted to examine various outcome measures of effect during treatment with aqueous extract of Harpagophytum (containing a daily dose of 60 mg of harpagoside). 114 patients were recruited on the basis of
This trial could only be supportive of safety due to its open design. As there was no placebo control group, the documented improvements cannot be attributed confidently to the designated treatment Doloteffin.
Rivoltan (Li 174) zur Behandlung von Patienten mit degenerativen Erkrankungen des Bewegungsapparates [Engel 2000]
This open study was conducted to assess the clinical effectiveness and safety of Harpagophythum extract (480 mg twice/day) on a period of 6 weeks.
Patients with degenerative disease of the musculoskeletal system were recruited. Rescue medications (analgesics) and physical therapies were allowed. Pain and mobility improvement were observed during the overall period of the study.
This study could only be supportive for safety due to its open design and absence of control group.
Harpagophytum procumbens ist effizient bei degenerativen Erkrankungen des Bewegungsapparates [Müller et al. 2000]
This open prospective study aimed to assess the clinical effectiveness of Harpagophythum extract (400 mg 3 times/day) on a period of 4 weeks.
Patients with non acute diseases of the musculoskeletal system were enrolled.
An average improvement of symptoms was reported to be 45% but only minor
This open study with no control group is insufficient to prove the efficacy of Harpagophytum extract.
Behandlung chronisch aktivierter Schmerzen am Bewegungsapparat [Ribbat and. Schakau 2001]
The study population was an inhomogeneous group. The results of the treatment (480 mg of Harpagophytum dry extract once or twice/day up to 8 weeks) show an improvement in the examined parameters of all symptoms. Five treatments were stopped because of adverse events.
This open study is insufficient to prove the efficacy of Harpagophytum extract due to the absence of a control group and to the subjective estimation of the degree of the pain and of the efficacy by the patients and the physicians.
Arthrose-Therapie: Verträglich geht es auch [Schendel 2001]
This open prospective study was conducted with patients suffering from arthrosis of the knee or the hip. A twice daily dose of 480 mg of Harpagophytum extract was tested over a period of 8 weeks.
The aim of the study was to examine whether
Therefore patients were told that they will be able to and should reduce or even discontinue the intake of NSAR.
At the end of the study 27.9% of the patients had reduced their daily intake of NSAR while 61.4% of the patients had discontinued the treatment with NSAR. An improvement of 52.5% in the intensity of pain and an improvement of 49.68% in the rigidity was reported.
Six cases of adverse events were reported. No severe adverse events occurred.
This study is not conclusive due to its open design and the absence of a control group.
Analgetische Wirkung eines Teufelskrallenwurzel [Schmelz et al. 1997]
Wirksamkeit und Wirtschaftlichkeit von Teufelskrallenwurzelextrakt bei Rückenschmerzen: Erste Ergebnisse einer therapeutischen Kohortenstudie [Chrubasik et al. 1997]
This open prospective study was conducted to evaluate the effectiveness and economy of Harpagophytum extract (equivalent to 30 mg harpagoside/day) in the treatment of acute low back pain.
The results of this study cannot support a
Harpagophytum procumbens for osteoarthritis and low back pain: a systematic review [Gagnier et al. 2004]
The quality of twenty studies of treatment with various Harpagophytum products for exacerbations of chronic musculoskeletal pain was examined.
Among the twenty, ten were
II.3.2.4 Other properties
Like other bitter herbals, Harpagophytum is used for loss of appetite and mild digestive disorders. Several EU Member States validate such indications for Harpagophytum based on the
Schilcher H 1999;
Braun and Frohne 1987;
CONCLUSION ON CLINICAL DATA
There is not sufficient evidence of any consistent clinically relevant effect, especially pain relief, as can be judged from selected studies. The provided evidence of efficacy and safety in osteoarthritis and
low back pain is thus insufficient to implement marketing authorisations for a
Despite the lack of adequately conducted toxicological studies the safety of the use of Harpagophytum products is, however, reassuring based on safety data in the clinical trials and lack of serious signals on pharmacovigilance. No clear conclusion of efficacy in osteoarthritis and low back pain can be drawn from the varying doses and kind of Harpagophytum extract.
This is based on the following considerations:
•The numbers of patients included in randomised clinical trials were too small for any definitive conclusion about clinical significant efficacy in the treatment of osteoarthritis or low back pain and the safety.
•The studied populations and the chosen endpoints are variable from one study to another, which makes comparison difficult. Endpoints are generally not in line with those used at present time for assessing clinical efficacy in the treatment of osteoarthritis or low back pain,
•Information on the safety of Harpagohytum product is very sparse and limited, in particular for
•There are inconsistent results when Harpagohytum is compared with placebo. For some comparative clinical trials, the absence of placebo group is highly questionable.
•Therapeutic effects are very doubtful as there is no direct comparison between Harpagophytum products and the known reference therapy (NSAIDs, acetaminophen) in the symptomatic treatment of osteoarthritis or low back pain.
•Analysis of therapeutic efficacy over time (during the first days/weeks) is not presented, therefore, the onset of response cannot be assessed (all studies). This is especially relevant for the target population that needs rather quick pain relief.
Based on the requirements given in the clinical guidance for the treatment of osteoarthritis, there is no sufficient scientific basis to recommend a
II.3.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE
During some clinical studies, data on gastric or duodenal side effects have been reported [
2001]. Harpagophyti radix is contraindicated in case of gastric or duodenal ulcer in the British Herbal Compendium, in the ESCOP monograph and by the German Commission E [
On the basis of non clinical data, Harpagophytum might have a
II.3.5 DRUG INTERACTIONS
Among clinical data available for Harpagophytum, we could not find any study or reported cases suggesting an interaction between Harpagophytum and oral anticoagulants, or sulfonylureas for instance.
Harpagophutym was sometimes quoted as part of phytotherapy in general reviews but no specific publications examined its interactive potential so far. Additionally, no signal, even weak, has emerged from the literature to date [
The clinical data are not sufficient to support a