Osteoarthritis of the knee, hip, and spine as well as non-specific low back pain may be associated with pain, stiffness, limitation of function, and diminished quality of life [25
]. Although treatment guidelines recommend simple analgesics as first-line drugs [26
], surveys indicate that NSAIDs are used in preference to simple analgesics despite the lower safety-margin and the higher cost [11
]. Because of the high incidence of NSAID-related adverse events and complications in the gastrointestinal and cardiovascular systems (especially in the elderly), and the high costs related to adverse events (i.e. gastrointestinal bleeding or perforation), additional medical attendances, diagnostic procedures, treatments and admissions to hospital, alternatives to NSAID therapy should be strongly considered [29
This qualitative analysis of the 12 trials suggests that specific preparations and doses of Harpagophytum procumbens
may be effective in various types of musculoskeletal pain conditions. Statistical pooling was not possible because of a lack of adequate data and clinical heterogeneity. The sensitivity analysis for methodological quality revealed that the trials on low back pain were of high quality, the trials on osteoarthritis were of high quality except one moderate quality study, and the trials on mixed pain conditions were of moderate quality. The quality of reporting in most of these trials was good. In order to increase transparency, trialists should refer to the CONSORT statement in designing and reporting clinical trials of herbal medicinal products [34
One high quality trial indicates that there is moderate evidence of effectiveness for powdered H plant material at a dose equivalent to 60 mg of harpagoside per day for osteoarthritis of the spine, hip, and knee. However, because of the clinical heterogeneity of patients in this trial, a confirmatory study is required to firmly establish efficacy for each location of osteoarthritis. In one high quality study, 4500 mg powder containing 57 mg harpagoside in the daily dosage showed moderate evidence for non-inferiority to diacerhein in patients suffering from acute exacerbations of osteoarthritis in the hip and knee.
Two trials employed an ethanolic extract (solvent 60% ethanol) containing less than 30 mg harpagoside per day in patients with osteoarthritis of the knee [12
] and hip [18
]. Both trials showed statisitically significant favourable results for the H group in terms of percentage of responders. However, the definition of responder in these trials may be questioned because of an allowance of pain increase up to 20% and additional rescue medication in one of the studies [18
]. Therefore, given the low methodological quality of the trials and the lack of clinically significant differences between groups, we conclude there is limited evidence for the use of an ethanolic H extract based on 4500 mg crude plant material per day in patients with osteoarthritis of the knee and hip. Additional high quality trials must be done to determine the efficacy of Harpagophytum procumbens
in osteoathritis. These trials must include homogenous pain conditions and must test H against standard osteoarthitis medications. Additionally, trialists should consider using symptom severity outcome measures that have proven validity and reliability, such as visual analogue scales [35
], osteoarthritis specific outcome measures (e.g. WOMAC, Lequesne Index) [35
], and health-related quality of life instruments (e.g. Medical Outcomes Survey Short-Form 36) [35
A total of four high quality trials tested various dosages of Hextract in acute exacerbations of chronic non-specific low back pain. Two trials with a total of 325 patients showed that an aqueous extract at the equivalent daily dosage of 50 mg harpagoside appears to reduce pain in patients with acute episodes of chronic NSLBP greater than does placebo [14
]. Therefore, the 50 mg harpagoside per dose of an aqueous extract of H can be said to have strong evidence for the treatment of acute episodes of chronic NSLBP in the short term. Additionally, a one year survey indicates that the aqueous extract is well tolerated [38
]. One trial with 197 patients showed that an aqueous H extract at the equivalent daily dose of 100 mg harpagoside appears to reduce pain in patients with acute episodes of chronic NSLBP greater than does placebo [16
]. Therefore, the 100 mg harpagoside per dose of an aqueous H extract has moderate evidence for the treatment of acute episodes of chronic NSLBP in the short term. Superiority of the higher dose was seen in the primary outcome (number of pain-free patients) but not in the secondary outcome measure. Therefore, there is moderate evidence for superiority of the 100 mg H dose to the 50 mg H dose. However, additional trials are required to confirm superiority of 100 mg H over 50 mg H. It is possible that a subgroup of individuals with neurological deficits (e.g. radiation into the leg) may respond well to the 100 mg harpagoside dose, yet more research is required to clarify this.
An aqueous extract of H at the equivalent daily dose of 60 mg harpagoside appears to be equivalent to 12.5 mg Rofecoxib in improving pain in individuals with acute episodes of chronicNSLBP [17
]. Therefore, a 60 mg daily harpagoside dose in aqueous extract of H has moderate evidence for being not inferior to 12.5 mg rofecoxib per day in the treatment of acute episodes of chronic NSLBP in the short term. Additional high quality trials, especially over longer treatment periods, are mandatory. Furthermore, equivalence trials testing Harpagophytum procumbens
against standard treatments will clarify relative efficacy and safety.
The final trials (two of moderate [19
] and of poor quality [20
] included heterogeneous musculoskeletal pain conditions. Therefore, it is difficult to reach any conclusions on the basis of these trials. Future trials should attempt to include homogenous pain conditions.
The results obtained with the proprietary Harpagophytum
products containing aqueous extracts can neither be transferred to an aqueous extract containing less harpagoside in the daily dosage [41
] or to a product containing an ethanolic extract. This can only be done if the ethanolic extract was shown to be essentially similar to aqueous extract, and if both extracts have the same qualitative and quantitative composition of co-active constituents, same pharmaceutical form, and bioequivalence in terms of safety and efficacy [40
]. With 60% ethanol as solvent, only half the amount of harpagoside (and possibly other co-active constituents) is extracted compared to water as solvent [42
]; therefore, it is of great importance that a confirmatory study provide evidence of effectiveness for the ethanolic extract.
Since the "active principle" has not yet been identified for Harpagophytum procumbens,
the constituent harpagoside is used as a marker for standardization of Harpagophytum
preparations. For harpagoside, the dose-dependent absorption into systemic circulation has been shown and may be related to lipoxygenase inhibition [43
]. However, it remains to be established if the inhibitory effect on leukotriene production corresponds to therapeutic efficacy. Future research should attempt to identify the active constituent or profile of constituents that relate to therapeutic efficacy in order to make extract dosing transparent.
There are several drawbacks to the present study. First, this is a qualitative review and as such it does not provide a quantitative summary of results, thus making it difficult to determine the size of effect of each intervention. Secondly, this review includes a small number of trials, often with small sample sizes. This makes it difficult to state definitive conclusions of efficacy and suggests the need for more trials. On the other hand, the trials reviewed were generally of good methodological quality and have several statistically significant and clinically significant effects. Therefore, these trials help us reach some clear conclusions regarding the use of specific preparations and doses of Harpagophytum procumbens for osteoarthritis and non-specific low back pain. Another strength of this study is the comprehensive search strategy, the methodological quality assessment, and the use of an accepted method for a best evidence synthesis. Future reviews may attempt to statistically combine the results of such trials into a meta-analysis.