PHYTOTHERAPY RESEARCH

Phytother. Res. 18, 187–189 (2004)

Published online in Wiley InterScience (www.interscience.wiley.com).
LETTER TO THE EDITOR DOI: 10.1002/ptr.1416 187

LETTER TO THE EDITOR

Effectiveness of Harpagophytum Extracts and
Clinical Efficacy

Sigrun Chrubasik1,2*, Christian Conradt 3 and Basil D Roufogalis1

1
Herbal Medicines Research and Education Centre, Faculty of Pharmacy, University of Sydney, NSW 2006, Australia
2
Department of Forensic Medicine, University of Freiburg, Albertstr. 9, 79104 Freiburg, Germany
3
Department of Medical Biometry, Im Neuenheimer Feld 305, University of Heidelberg, 69120 Heidelberg, Germany

Various preparations from Harpagophytum procumbens are used for the treatment of pain in the joints and
lower back. Studies published in peer reviewed journals were examined for their clinical evidence. The studies
offering preparations with 50–60 mg harpagoside in the daily dosage are of better quality and provide more
reliable evidence on efficacy than a proprietary ethanol extract with half the amount of harpagoside per day.
However, confirmatory studies are required for all extracts before they can gain a place in treatment guide-
lines. Copyright © 2004 John Wiley & Sons, Ltd.

Keywords: Harpagophytum; analgesia; osteoarthritis; low back pain.

comparability of groups at baselines (sufficient base-

INTRODUCTION
For more than 50 years, various preparations from the
secondary tubers of Harpagophytum procumbens have
been used in Germany by patients with rheumatic
complaints. The German Commission E Monograph
(Blumenthal, 1998) recommends a dose equivalent to a
maximum of 4.5 g of dried tuber per day, half the dose
recommended by the European Scientific Cooperative
on Phytotherapy (Anon., 1996). Here clinical studies
published in peer reviewed journals have been exam-
ined for evidence of their effectiveness in the treatment
of pain.
METHODS
MEDLINE, PUBMED, EMBASE, BIOSIS searches
were used to find clinical studies on Harpagophytum
procumbens published in peer reviewed journals with
an impact factor. Studies were checked according to
the number of centres, the brands examined, the
harpagoside content of the batch consumed, the number
of patients included in the verum and control group (if
any), the duration of the study, the study category
(either open, randomized and/or double-blind), patient
population included, outcome measures employed, hy-
pothesis to be tested, the power for the case calcula-
tion, the analysis (intention-to-treat, meaning inclusion
of drop-outs as non-responders or per protocol and
inclusion of those that finished the study), employment
of adequate test procedures, number of drop-outs,
* Correspondence to: Dr S. Chrubasik, Herbal Medicines Research and
Education Centre, Faculty of Pharmacy, University of Sydney, NSW 2006,
Australia.
E-mail: sigrun.chrubasik@klinikum.uni-freiburg.de
Copyright © 2004 John Wiley & Sons, Ltd.
Copyright © 2004 John Wiley & Sons, Ltd.
line data available), number of adverse events stated
and the effect size over time.
RESULTS AND DISCUSSION
Seven studies were identified (Tables 1, 2). Only two of
the studies were confirmatory (rejecting the prespecified
null hypothesis and having an acceptable power). These
included the study by Chantre et al. (2000) who com-
pared the effectiveness of cryodried pulverized plant
material with diacerhein and demonstrated that
Harpagophytum powder, with 60 mg harpagoside in the
daily dosage, was not inferior to the weak NSAID at
the endpoint after 16 weeks. The other study (Chrubasik
et al., 1999) investigated the proprietary Harpagophytum
extract WS 1502 (not commercially marketed) and dem-
onstrated that extract delivering 100 mg of harpagoside
per day was more effective than half that dose com-
pared with placebo (www.rzuser.uni-heidelberg.de/~cn6/
harpago/). The aqueous Harpagophytum extract
DoloteffinR (daily dose equivalent to a harpagoside
content of 50–60 mg) was (i) superior to placebo in an
exploratory double-blind study in which both groups
were well matched at baselines; nine out of 54 patients
were pain-free after a 4 week course of treatment com-
pared with one patient in the placebo group, p = 0.008
(Chrubasik et al., 1996c), (ii) apparently not inferior
to rofecoxib in a pilot double-blind study (www.ukl.
uni-freiburg.de/rechtmed/harpago-rofecoxib.html;
Chrubasik et al., 2003) and (iii) almost similar in
outcomes in a quasi-randomized study in patients
suffering from pain in the back, hip and knee (with
hip patients if anything responding best) (www.ukl.
uni-freiburg.de/rechtmed/harpagophytum-back/knee/
hip.html; Chrubasik et al., 2002). Taken together, the
studies investigating the aqueous extract do not prove
Phytother. Received 12 March(2004)
Res. 18, 187–189 2003
Accepted 18 March 2003
188 LETTER TO THE EDITOR

Table 1. Studies with Harpagophytum aqueous extracts

Reference Chrubasik et al. (1996) Chrubasik et al. (1999) Chrubasik et al. (2003) Chrubasik et al. (2002)
Impact factor 1.4 1.2 3.3 1.4

Centre n=1 n=1 n=1 n=1

Brand (H) Doloteffin WS1531 Doloteffin Doloteffin
Harpagoside 50 mg 50, 100 mg 60 mg 60 mg
Patients 59 H vs 59 P 66 H100 vs 65 H50 vs 66 P 44 H vs 44 R 104 B vs 61 H vs 85 K
Study period 4 weeks 4 weeks 6 weeks 8 weeks
Randomized Yes Yes Yes No
Double-blind Yes Yes Yes No
Control Placebo (P) Placebo Rofecoxib (R) Noa
Patient Nonspecific low back pain (NSLBP) r+nr NSLBP (B)
population Radiating (r) and non-radiating (nr) pain Hipb(H), Kneeb (K) pain
Outcome Number of pain-free patients (NPP) Visual analogue (0–10)
measures Visual rating scale 0–4, Arhus index and other pain scores
Rescue consumption HAQ HAQ, global assessment
Hypothesis Yes, rational Yes, rational None None
Power 90% 90% No No
Analysis Per protocol Per protocol Intention-to-treat Intention-to-treat
Test(s) Adequate Adequate Adequate Adequate
Drop-outs 5_H, 4_P 3 H100, 8 H50, 2 P 1 H, 8 R 15 B, 2 H, 6 K
Groups Comparable Comparable Comparable Adjusted
Result Exploratoryc Confirmatory Exploratory Exploratory
Adverse events 4 H vs 10 P 17 H100 vs 18 H50 vs 10 P 14 H vs 14 R 16B vs 14K vs 10H
Effect size Relative median improvement of ARI component pain of VAS current pain
Pain 20% H vs 8% P (4 wks) No difference (4 wks) 30% H vs 29% R (6 wks) 55%B vs 60%H vs 50%K
NPP 20% H vs 2% P 18% H100_vs 9% H50_vs 5% P 22% vs 11% (R) (8 wks)

a
Comparison of pain locations.
b
Based on ACR osteoarthritis criteria.
c
Failed to reject null hypothesis. HAQ, health assessment questionnaire; NPP, number of patients free of pain without rescue
analgesic in the final week of treatment.

Table 2. Studies with Harpagophytum ethanol extracts (eE) and Harpagophytum cryodried powder (CP)

Reference Laudahn and Walper (2001) Göbel et al. (2000) Chantre et al. (2000)
Impact factor 0.9 0.7 1.4

Centre n = 13 n=1 n = 30
Brand (H) Rivoltan (eE) Rivoltan (eE) Harpadol (CP)
Harpagoside < 30 mg < 30 mg 60 mg
Patients n = 130 31 H vs 32 P n = 122
Study period 8 weeks 4 weeks 16 weeks
Randomized No Yes Yes
Double-blind No Yes Yes
Control No Placebo (P) Diacerhein (D)
Patient population nr NSLBPb Various syndromesc Hip and Knee paina
Outcome Arhus index, MPSd Visual analogue scale 0–50 Visual analogue scale
measures clinical global impression (CGI) 0–10, Lequesne index
finger-floor distance experimental tests rescue consumption
Hypothesis None None Yes, rational
Power No No 90%
Analysis Per protocol Per protocol Intention-to-treat
Test Adequate Adequate Adequate
Drop-outs 13 eE n = 12, no details 12 CP, 18 D
Group One group Incomplete baseline data Comparable
Result Exploratory Exploratory Confirmatory
Adverse events 3 eE 4 eE vs 2 P 10 CP vs 21 D
Effect size Delta mean improvement
Pain ARlp 64% (wks) 46% eE vs −2% P (4 wks) 51% CP vs 42% D (16 wks)

a
Based on Kellgren’s radiological changes.
b
nr NSLBP, nonradiating non-specific low back pain.
c
mild to moderate pain or muscle tenseness in the shoulder, neck and/or lower back; ARlp, component pain of the Arhus low back
pain index.
d
MPS, multidimensional pain scale.

Copyright © 2004 John Wiley & Sons, Ltd. Phytother. Res. 18, 187–189 (2004)
 LETTER TO THE EDITOR
clinical efficacy but provide reliable information on the
likelihood of effectiveness and are useful for the design
of future confirmatory studies.
The open uncontrolled study by Laudahn and Walper
(2001) does at most indicate a trend of efficacy, poten-
tial confounders were not considered. Clinical efficacy
can only be proven in a confirmatory study. Unfortun-
ately, the controlled study available with the propri-
etary extract LI 174 (Goebel et al., 2000) is exploratory
(no null hypothesis in terms of primary outcome
measure(s), no alternative hypothesis and no priori
power calculations based on the primary outcome
measure(s)) and has the weakness of a lack of trans-
parency in baseline inter-group differences. Although
the higher initial pain scores in the Harpagophytum
group were statistically adjusted, the different distribu-
tion of pain locations (more patients in the Harpa-
gophytum group suffered from neck and shoulder pain
and/or tenseness), the duration of the disease (acute
and/or chronic), the consumption of additional analge-
sics and other factors were not considered as possible
confounders but might have affected the outcome.
A systematic analysis in 1996 demonstrated that the
harpagoside content in the daily dosage of German
Harpagophytum preparations varied by two orders
of magnitude (Chrubasik et al., 1996a). According to
pharmacopoeial requirements the plant material used
for preparing medicinal products from Harpagophytum
procumbens must contain at least 1.2% of the marker
compound harpagoside. An analysis of the crude plant
materials that are marketed as teas (aqueous extracts)
conformed to this requirement (Chrubasik et al., 1996b).
Since iridoid glycosides are soluble in water as well as
in alcohol, the recommended daily dosage of 4.5 to 9 g
REFERENCES
Anon. ESCOP Monograph. Harpagophyti radix, Fascicle 2, 1996,
ISBN 1-901964-01-9. University of Exeter, Exeter.
Blumenthal M. 1998. The Complete German Commission E
Monographs. American Botanical Council: Austin, Texas.
Chantre P, Cappelaere A, Leblan D, Guedon D, Vandermander J,
Fournie B. 2000. Efficacy and tolerability of Harpagophytum
procumbens versus diacerhein in treatment of osteoarthritis.
Phytomedicine 7: 177–183.
Chrubasik S, Junck H, Breitschwerdt H, Conradt C, Zappe H.
1999. Effectiveness of Harpagophytum extract WS 1531
in the treatment of exacerbation of low back pain: a
randomized placebo-controlled double-blind study. Eur J
Anaesthesiol 16: 118–129.
Chrubasik S, Model A, Black A, Pollak S. 2003. A randomized
double-blind pilot study comparing Doloteffin and Vioxx
in the treatment of low back pain. Rheumatology 42: 141–
148.
Chrubasik S, Roufogalis BD. 2001. Issues in quality and com-
parability of herbal medicinal products. Austr J Pharm 82:
444–445, 546–548.
Chrubasik S, Sporer F, Wink M. 1996a. Zum Harpagosidgehalt
in Arzneimitteln aus Harpagophytum procumbens. Forsch
Komplementärmed 3: 57–63.
Chrubasik S, Sporer F, Wink M. 1996b. Zum Wirkstoffgehalt in
Teezubereitungen aus Harpagophytum procumbens. Forsch
Komplementärmed 3: 116 –119.
Copyright © 2004 John Wiley & Sons, Ltd.
189
crude plant material or equivalent preparations
should contain not less than 50 mg of harpagoside
in preparations meeting the pharmacopeia criteria.
The proprietary Harpagophytum extract LI 174
contains, however, only half of that amount in the
daily dosage (Sporer and Chrubasik, 1999). Although
harpagoside is not considered to be ‘the active prin-
ciple’ of Harpagophytum extract, it seems likely from
animal (Lanhers et al., 1992) and human pharmacolog-
ical (Loew et al., 2001) studies that this iridoid glycoside
contributes to the overall clinical efficacy. Data on
Harpagophytum efficacy from other studies can there-
fore not be transferred to extract LI 174 unless its
bioequivalence (through bioavailability) to the extracts
used in those studies has been demonstrated (Chrubasik
and Roufogalis, 2001).
Although presented as a high-dose Harpagophytum
extract (Laudahn and Walper, 2001), extract LI 174
conforms only to the German Commission E Mono-
graph (Blumenthal, 1998), with the daily dose being
equivalent to 4.5 g crude plant material, rather than the
ESCOP monograph, which recommends a higher dose
– up to 9 g per day (Anon., 1996). The drug – LI 174
extract ratio does not reflect the final content of the co-
active compound harpagoside (Sporer and Chrubasik,
1999). It is also possible that other co-active compounds
may not be present in this extract due to the incom-
plete extraction and it remains to be established which
components are enriched in LI 174.
Although the evidence of effectiveness is greater for
the aqueous Harpagophytum extracts compared with
the ethanol extract, appropriate confirmatory studies
are necessary for all extracts before they can be in-
cluded in the treatment guidelines for low back pain.
Chrubasik S, Thanner J, Künzel O, Conradt C, Black A, Pollak S.
2002. Comparison of outcome measures during treatment
with the proprietary Harpagophytum extract Doloteffin
in patients with pain in the lower back, knee or hip.
Phytomedicine 9: 181–194.
Chrubasik S, Zimpfer Ch, Schütt U, Ziegler R. 1996c. Effective-
ness of Harpagophytum procumbens in treatment of acute
low back pain. Phytomedicine 3: 1–10.
Göbel H, Heinze A, Ingwersen M, Niederberger U, Gerber D.
2001. Harpagophytum-Extrakt LI174 (Teufelskralle) bei der
Behandlung unspezifischer Rückenschmerzen. Schmerz 19:
10–19.
Lanhers MC, Fleurentin J, Mortier F, Vinche A, Younos C. 1992.
Antiinflammatory and analgesic effects of an aqueous extract
of Harpagophytum procumbens. Planta Med 58: 117–123.
Laudahn D, Walper A. 2001. Efficacy and tolerance of
Harpagophytum extract Li 174 in patients with non-radicular
back pain. Phytother Res 15: 621–624.
Loew D, Möllerfeld J, Schroedter A, Puttkammer S, Kaszkin M.
2001. Investigations on the pharmacokinetic properties of
Harpagophytum extracts and their effects on eicosanoid
biosynthesis in vitro and ex vivo. Clin Pharmacol Ther
69: 356–364.
Sporer F, Chrubasik S. 1999. Präparate aus der Teufelskralle
(Harpagophytum procumbens). Zschr, Phytotherapie 20:
235–236.
Phytother. Res. 18, 187–189 (2004)