La modelización científica como práctica educativa

Despite wide use of physiotherapy and NSAIDs, there is a great interest in non- synthetic, natural medicines derived from herbal sources for the treatment of OA. Many herbal remedies, based on plants or their extracts, are used for the treatment of arthritis and OA. Herbalism is diverse and includes that derived from Greek and Roman sources, the Siddha and Ayurvedic medicine systems from various South- Asian Countries, Chinese herbal medicine, and other forms of herbalism from South America and Africa.(WHO, 2008)

Whilst the gold standard for testing of pharmaceutical drugs is large scale, double blind, randomised controlled trials, many of the studies into herbal medicines have been conducted on a smaller scale. Though there have been positive results demonstrated within in-vitro or small-scale clinical research into herbal remedies, the quality of the studies is highly variable and many have been of poor quality.(Linde et al., 2001) Some of the more popular western herbs and derivatives include ginger extract, avocado-soybean, rose hip, Rosa Canina (cat’s claw), comfrey root, and Boswellia Serrata. One of the main differences between western herbalism and Chinese herbal medicine is that in Chinese medicine, single herbs are rarely used.

4.4.1 Ginger extract

Ginger is the rootstock of a very popular spice Zingiber officinale, with a long

tradition of medical use in Ayurvedic and Chinese medicine.(Ali et al., 2008) Ginger has a complex mixture of compounds and the available ginger extracts for OA treatment are mainly EV.EXT-33 (Eurovita Extract 33) and EV.EXT-77 (combined extracts of Zingiber officinale and Alpinia galangal).(Chrubasik et al., 2005)

A six-week, double-blind, placebo controlled, parallel group trial (Altman and Marcussen, 2001) assessed the efficacy of a concentrated extract (EV.EXT-77) of dried ginger rhizomes and dried galangal rhizomes in the treatment of 247 patients with knee OA grade 2-4 severity according to the Kellgren-Lawrence X-ray ranking system. The results indicated there was a higher rate of responders in the EV.EXT-77 group than in the placebo group (p=0.04) on the WOMAC VAS pain scale. In

72 addition, the greatest improvement in the WOMAC index analysis in patients who received the ginger extract was seen in stiffness rather than pain. In this short-term study, there was no significant difference in the ginger extract and placebo groups in the quality of life (measured by the SF-12) and consumption of acetaminophen (‘rescue medication’). But there were significantly more gastrointestinal (GI) adverse events in the ginger extract group compared with the placebo group, though none of these were considered serious by the investigators.

A cross-over study randomised 75 patients with OA of the hip or knee and radiological ranking of grade 1-4 on the Kellgren-Lawrence scale.(Bliddal et al., 2000) Each patient received three treatment phases of three weeks each with either, 170mg EV.EXT-33, Ibuprofen 400mg or placebo. There was no washout period applied between the three treatment periods except for one week washout before the trial. Acetaminophen was allowed as a rescue medication. This study demonstrated that Ibuprofen was more effective than ginger extract and placebo on pain assessment (as measured on a 100 mm VAS) and global function (Lequesne Index). The same finding was also seen in the consumption of rescue medication, that less acetaminophen were taken in the Ibuprofen group than in the ginger extract group and placebo group (p < 0.01). However, the treatment period of this study may be too short to fully investigate the change in patients’ conditions.

The current studies of ginger extract have not reached a consistent conclusion. Another cross-over trial compared enteric coated ginger extract and placebo in 29 knee OA patients (of Kellgren-Lawrence grade 2-4), each for a 12 week treatment period.(Wigler et al., 2003) During the first 12 weeks (phase one), the difference between groups were not statistically significant though both groups showed a significant decrease in VAS measures of pain and handicap compared with the baseline. However in the second phase, the VAS scores of pain and handicap started to increase in the group who switched from ginger extract to placebo while the scores continued to decrease in the group who switched from placebo to the ginger extract. Furthermore, there was a significant difference between the two groups by the end of 24th week. (p<0.001) This study suggests that ginger extract was effective in the treatment of OA. However, this study had a high drop-out rate (28% and 33%) and a small sample size and there was no wash-out period between the two phases, opening the study to criticism. Therefore, the attitude towards ginger extract for OA treatment

73 in mainstream medicine is still guarded, as it is thought research studies conducted have not met the same standards for efficacy and safety as conventional therapies.(Marcus and Suarez-Almazor, 2001)

4.4.2 Rose hip

Rose hip is the fruit of the rose plant, and certain species, especially Rosa canina, have been used as herbal remedies in the Scandinavian countries. The dried powder of rose hip (Rosa canina) made from the fruit including its seeds and the shells, has been found to reduce chemotaxis of peripheral blood neutrophils and monocytes of healthy subjects in- vitro, and reduce serum C-reactive protein (CRP) levels for healthy volunteers and patients suffering from OA following treatment for 4 weeks.(Winther et al., 1999)

A three month, placebo-controlled, cross-over RCT (Winther et al., 2005) of patients with hip or knee OA found that the WOMAC pain score was significantly reduced in the rose hip group after three weeks treatment compared to placebo group, but there was no significant difference after three months treatment. This result was explained as being consistent with a significant decline in consumption of rescue pain killers after the first three weeks in the rose hip group. On the other hand, the stiffness score and physical activities score of the WOMAC and patients’ global assessment were significantly decreased (improved) compared with placebo after three months treatment (though they were not statistically different at the end of the first three weeks).(Winther et al., 2005). The study also suggested there was a carry-over effect of rose hip powder and its anti-inflammatory action which was not due to its high vitamin C content.(Winther et al., 2005)

The carry-over effect of the powder of Rosa canina fruit was also demonstrated by another three month, cross-over, placebo-controlled RCT.(Rein et al., 2004) The study utilised five-point Likert-scale questionnaires of pain and stiffness as well consumption of rescue medications.(Rein et al., 2004) Group A (placebo first) showed significant difference between the real medicine and placebo in terms of the severity of joint pain and stiffness, and the consumption of concomitant pain-relieving medicine whilst Group B (rose hip first) did not show a significant difference. The study could be criticised for inclusion of patients with OA of various joints instead of confining it to a single joint, given that OA of the hand, hip, knee, neck and shoulder

74 have different impacts on patients’ daily lives which may influenced subjective assessments and the in-take of rescue medication.

4.4.3 Cat’s claw

Cat’s claw is a thick woody vine from the basin of the Amazon rainforest. The bark of the vine has been traditionally prepared as a decoction and drunk as a tea for the treatment of chronic inflammation in South America for over 2000 years.(Erowele and Kalejaiye, 2009) There are two most commonly used species of Cat’s claw, Uncaria tomentosa and Uncaria guianensis. The active chemical constituents from its bark include quinovic acid glycosides, sterols, oxidole and alkaloids contents.(Hardin, 2007) Although Cat’s claw is classified as the same family (Rubiaceae) and genus (Uncaria) as a Chinese herb, Gou Teng (Uncaria rhynchophylla), they are different in the chemical constitutions and medicinal uses. (Heitzman et al., 2005)

The antioxidant and anti-inflammatory properties of its water-soluble extracts are believed to be due to a cytoprotective action against peroxynitrite, thereby preventing the side effects of NSAIDs on the intestine.(Sandoval-Chacón et al., 1998) At the same time the extract of Cat’s claw is an effective inhibitor of inducible nitric oxide synthase gene expression, suppressing the activation of the transcription factor NF- KB.(Sandoval-Chacón et al., 1998) A further experiment indicated the primary mechanism of Cat’s claw anti-inflammatory actions is immunomodulation by suppression of TNF-α synthesis.(Sandoval et al., 2000)

A placebo-controlled, parallel-design RCT (Piscoya et al., 2001) targeting male patients with knee OA found the Cat’s claw group had a significant improvement in the score of pain on activity (measured by a four-point scale), patients’ global assessment and physicians’ global assessment compared to placebo, but there were no significant change in the score of pain at rest and knee circumference in either group. However, caution needs to be taken with respect to the findings of this study. Firstly, the study involved small numbers (30 subjects in the Cat’s claw group, 15 in placebo group) and was of short duration (four weeks). Secondly, there was no information about the number of drop-out patients and no follow-up assessment. Thirdly, the evaluation of knee pain was mainly based on the physicians’ examinations plus patient’s subjective sensations. Further large scale studies are clearly needed in order to reach a definitive conclusion regarding efficacy of Cat’s claw.

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4.4.4 Indian frankincense

Indian Frankincense (Boswellia serrata) is the gum resin from the Boswellia tree grown widely in hilly areas of Northwest India. It has been used as an anti- inflammatory and analgesic drug in Ayuredic medicine.(Basch et al., 2004) It is categorised as the same genus as Boswellia sacra in the Burseraceae family, but the aroma of Boswellia serrata is generally considered to be far inferior compared to Boswellia sacra (as the Chinese herb Ru Xiang). Ru Xiang is used for the treatment of rheumatism, menstrual pain and bruises traditionally in CM.(Basch et al., 2004, Wikipedia) Boswellic acids are the most active component of Boswellia extracts and the major ingredients of Boswellia species, and are potent inhibitors of 5- lipoxygenase, a key enzyme in the cellular inflammatory cascade.(Poeckel and Werz, 2006)

A cross-over, placebo-controlled RCT of Boswellia sacra extracts (Kimmatkar et al., 2003) in patients with knee OA assessed pain, function and swelling on four-point, Likert-like scales. At the end of the first treatment phase (8 weeks), there was a significant decrease in scores relating to pain, function and swelling in the treatment group compared with placebo (p<0.001). After 21 days washout at the end of first treatment period and crossover, scores in those in the placebo group kept relatively stable whilst scores in the treatment group continued to decrease. Boswellia sacra extracts were also well tolerated by the patients except for minor gastrointestinal adverse events. However, there was no change of radiograph signs of the affected knee joint. Another placebo-controlled study (Sengupta et al., 2008) evaluated the clinical efficacy of two different dosages of Boswellia sacra extract, using the WOMAC index visual analogue scale (VAS) and the concentration of matrix metalloproteinase-3 (MMP-3) in synovial fluids of knee joint as the outcome variables. The trial found both dosages of Boswellia sacra extracts significantly reduced the WOMAC pain scores and physical activity scores in OA patients at the end of three months treatment compared with baseline and with the placebo group, and that the MMP-3 concentration had been significantly reduced in the treatment group compared with the placebo group. As for any differences between the high-dose group and low-dose group, differences were observed only for the pain VAS and MMP-3 concentration. This trial was funded by the medicine provider and there was no follow-up assessment. In addition, Boswellia sacra has also been used in the

76 compound of Ayurvedic herbs for OA treatment and preliminary results have demonstrated its potential positive efficacy.(Chopra et al., 2004) Further investigations are needed to establish therapeutic efficacy and safety.

4.4.5 External application of herbs

There are also some herbs which have been applied externally for OA treatment as phytopharmaceutical drugs or homeopathic treatment in Europe. One study showed that 21 days of treatment with comfrey root liquid extract ointment could reduce pain, improve the mobility of the knee and increase the quality of life compared with placebo, as assessed by the WOMAC Index and SF-36 questionnaire respectively.(Grube et al., 2007) There were no reports of serious adverse events associated with this ointment.(Grube et al., 2007) A homeopathic gel which also contains comfrey (Symphytum officinale) has been found to be at least as effective and well-tolerated as the NSAID gel in patients with knee OA after four weeks treatment.(van Haselen and Fisher, 2000) These studies do not provide unequivocal evidence of efficacy and safety of comfrey, however, since they are relatively short in duration and there were difficulties with blinding.(van Haselen and Fisher, 2000) Longer term, rigorous studies are still needed.

4.5 Conclusion

The use of CAM for the treatment of OA has become an important issue for rheumatologists. The data summarised above shows that rigorous trials of CAM have been conducted and there is a growing evidence base to support efficacy of some forms of CAM in the treatment of OA. However, there are concerns regarding the methodological quality of some studies.

Glucosamine and chondroitin are the most studied products amongst these complementary medicines and both have been accepted as safe and effective in comparison to placebo, particularly in certain sub-populations. Although vitamins or mineral supplements are quite popular amongst OA patients, evidence of their clinical efficacy is equivocal. Current research mainly focuses on the links between their anti- oxidant properties and the impact on degeneration of articular cartilage. As for western herbs, the evidence to date in support of clinical efficacy is not convincing though some studies have claimed positive findings. Further large scale trials are

77 required, not only to establish efficacy but also the safety of complementary medicines.

Unlike western herbalism, CM seldom uses single herbs: rather, several herbs are combined in a medicinal formula as described in Chapter 8. Chinese herbal medicine (CHM) formulae target not only the ‘root’ causes of illness but also the symptoms and signs (as described in Chapter 2). Different CHM formulae may be offered at different stages of OA. Combinations of herbs may be chosen to specifically address a particular CM Syndrome or combination of Syndromes, and in accordance with particular theories utilized by the practitioner. The next chapter will discuss how Chinese medicine understands and treats OA.

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Chapter 5 Chinese Medicine Understanding of Osteoarthritis