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Alternative therapies for musculoskeletalconditions

Luis Vitetta* BSc (Hons), PhD, GradDip IntgrMed, GradDip NutrEnvMed

Associate Professor and Principal Research Fellow

Unit of Health Integration, School of Medicine, University of Queensland, Level 2, Centres for

Health Research, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, Queensland 4102, Australia

Flavia Cicuttini MBBS (Hons), PhD, MSc, DLSHTM, FRACP, FAFPHM

Professor, Monash University, Head, Musculoskeletal Unit DEPM, and Head, Rheumatology Unit

Alfred Hospital, Prahran, Melbourne, Victoria 3181, Australia

Avni Sali MBBS, PhD, FRACS, FACS, FACNEM

Professor and Director

National Institute of Integrative Medicine, 28 Bell St, Heidelberg Heights, Melbourne, Victoria 3081, Australia

The use of complementary and alternative medicine is complex and nuanced. Patterns of use ofcomplementary and alternative medicine differ among racially and ethnically different groups.Multivariate models of utilization indicate that ethnicity plays an independent role in the imple-mentation of these modalities, in seeking practitioners and in health problems for which assis-tance is required. Moreover, there are many reasons why people use complementary andalternative medicine: conventional treatment may not be working as well as they would like;they want greater relief of symptoms and/or disability; they have issues with side-effects of phar-maceutical treatment; they wish to reduce some of the stress that comes from living witha chronic illness and want to cope better; they believe that complementary and alternative ther-apies are safer and ‘natural’; and they are influenced by the widespread advertising and attractiveclaims that are made for many natural products. Although there are more than 150 differentkinds of syndromes and conditions associated with arthritis, this review will focus on currentlyavailable evidence-based medicine for the two most common conditions diagnosed in Westerncountries – osteoarthritis and rheumatoid arthritis – for which people seek and then implementcomplementary and alternative medicine modalitites.

* Corresponding author. Tel.: !61 7 3240 2903; Fax: !61 7 3240 6858.E-mail address: l.vitetta@uq.edu.au (L. Vitetta)

1521-6942/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved.

Best Practice & Research Clinical RheumatologyVol. 22, No. 3, pp. 499–522, 2008

doi:10.1016/j.berh.2007.12.007available online at http://www.sciencedirect.com

Key words: complementary and alternative medicine; rheumatoid arthritis; osteoarthritis;botanicals; supplements; mind body medicine.

Although diseases with the greatest consequent mortality (e.g. cardiovascular disease,cancer) attract much of the public’s attention, musculoskeletal or rheumatic diseasesare the major cause of morbidity throughout the world, having a substantial influenceon health and quality of life, and inflicting a vast burden of cost on health systems.Musculoskeletal disease is a major cause of disability and handicap, and arthritis isthe most prevalent form of musculoskeletal disease.1 Rheumatic diseases includemore than 150 different conditions and syndromes, the common denominators beingpain and inflammation. Five of these account for 90% of the cases – osteoarthritis(OA), rheumatoid arthritis (RA), fibromyalgia, systemic lupus erythematosus (SLE)and gout.1–4

Arthritis is a chronic disease affecting an estimated 43 million (20.8%) adults in theUSA, and is the leading cause of disability in that country3, while OA is reported tobe the most common joint disorder in the world.4 In Western populations it is oneof the most frequent causes of pain, loss of function and disability in adults. Radio-graphic evidence of OA occurs in the majority of people by 65 years of age and inabout 80% of those aged over 75 years. In Australia in 2004, there were 3.4 millionpeople (w17% of the population) suffering from some form of arthritis, with w60%of these being females. Of this total, 1.39 million had OA and more than 438,000 hadRA.5

The associated worldwide trend in morbidity is significant because it often leads toa reduction in quality of life and related conditions such as fatigue, depression and in-somnia. Attendant costs to the health-care system are vast, and current medications,while often effective, are frequently associated with significant side-effects.

In the early 1990s an upsurge in the use of complementary and alternative medicine(CAM) was seen from reports that recognized the extensive use of treatments outsidethe realm of conventional medicine.6,7

A recent review reported that patients with musculoskeletal conditions often em-ploy CAM modalities8 in one form or another. Collectively the evidence demonstratesthat some CAM modalities show significant promise: for example herbal medicines,nutritional supplements, acupuncture, and mind–body medicine.

HERBAL MEDICINES

A number of herbal supplements have been investigated for their efficacy in patientswith OA and RA (Table 1).9–13

Camilla sinensis (green tea)

The anti-inflammatory and pharmacological properties of green-tea extracts have beenattributed to the high content of polyphenols/catechins, of which epigallocatechin-3-gallate (EGCG) predominates.11,14 The emerging molecular evidence thus far givesstrong biological plausability supporting the in-vitro observations that catechinsextracted from green tea can exhibit both anti-inflammatory and chondroprotectiveeffects and hence may be beneficial to arthritis sufferers.14

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Table 1. Botanicals with demonstrated therapeutic anti-inflammatory, analgesic and anti-rheumatic activity.

Herbals/botanicals Actions Indications Dosages Contraindications and cautions

Boswellia/frankincense(Boswellia serrata)

Anti-inflammatoryAnti-arthritic

OARA

600e1200 mg/day extractstandardized to 60% boswellic acids

Occasional mild diarrhoea or urticariaLD50< 2 g/kg

Chilli/cayenne Topical analgesic OARA

0.025e0.075% in a cream baseor plaster

Local adverse effects include rash, swelling

Devil’s claw(Harpogophytumprocumbens)

Anti-inflammatoryAnalgesicChondro-protectiveAnti-rheumatic

OALower-back pain

Liquid extract (1:2) 6e12 mL/dayTrials indicate a need to use extractswith >50 mg harpagoside for pain relief

High doses may increase effects of warfarinTheoretical interaction with anti-arrhythmicdrugs e monitor useNot recommended in pregnancyMay cause gastrointestinal irritation, use withcaution in patients with gastric and duodenalulcers, gallstones and acute diarrhoeaSuspend use 1 week before surgeryLD50< 13.5 g/kg

Ginger Anti-inflammatoryAnalgesic

RAOA

250 mg QID Theoretically may increase bleeding when highdoses taken with anticoagulants andantiplatelet agentsCaution advised in patients with gastric ulcers, reflux

Phytodolor Anti-inflammatoryAnalgesic

OARALower-back pain

20 drops TID1200 mg/day in divided doses

None reported

rose hip Anti-inflammatory OA 5 g/day of powder orally administered None reportedTripterygiumwilfordii Hook F

Anti-inflammatory RA Moderate efficacy reported Up to570 mg/day extract effective

Side-effects reported include vomiting, hair loss,diarrhoea, headaches, dryness, abdominal painand vaginal spottingAmenorrhoea reversible in women <40 yearsof age with short-term use; irreversible inpostmenopausal women

(continued on next page)

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Table 1 (continued )

Herbals/botanicals Actions Indications Dosages Contraindications and cautions

Willow bark(Salix alba)

Anti-inflammatoryAnalgesicAnti-rheumatic

OARALower-back pain

Tincture (1:1) 1e2 mL TIDTrials for OA and lower-back painused preparations standardized to240 mg/day salicin in divided doses

High doses may theoretically increaseeffect of anticoagulantsSalicylate sensitivityLD50 28 mL/kgRequires thorough evaluation for renal,haematological, and hepatic function

OA, osteoarthritis; RA, rheumatoid arthritis.

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Uncaria tomentosa, Uncaria guianensis (cat’s claw)

Extracts of cat’s claw (Figure 1) have been shown to possess antioxidant, anti-inflammatory and immunomodulatory properties.10,11 The most investigated of theactive constituents in Uncaria tomentosa extract for immunomodulatory and anti-inflammatory effects are pentacyclic oxindole alkaloids, which are reported to inducean immune regulating factor.11 Pain associated with activities of daily living was signif-icantly reduced; however, pain at rest or at night was not reduced during the 4-weektrial period. In a further study designed to test the use of an extract of cat’s claw fromthe part of the vine that is rich in pentacyclic alkaloids (roots) versus placebo showeda reduction in the number of painful joints in patients with RA (53.2% versus 24.1%;P< 0.044).15 As no adverse effects were reported, this small preliminary studyshowed the relative safety and modest benefit to the tender joint count of a highlypurified extract from the pentacyclic chemotype of Uncaria tomentosa in patientswith active RA taking sulphasalazine or hydroxychloroquine.15 Other research groupshave documented the safety and pharmacological profile of cat’s claw, which is consid-ered non-toxic, and there are no known contraindications or drug interactions.10,16,17

However, there is a need for rigorous testing of the effectiveness of the recommendeddoses. Until a full pharmacokinetic profile is investigated it would be prudent to avoidits use in women attempting pregnancy, during pregnancy and lactation, and for chil-dren below 3 years of age.10

Figure 1. Uncaria tomentosa, Uncaria guianensis (cat’s claw).

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Harpogophytum procumbens (devil’s claw)

Harpogophytum procumbens (Figure 2) has been shown to be effective for arthritis intwo reviews.17,18 There is little evidence for efficacy of extracts containing <30 mg/day of the active constituent, harpagoside, and that a correct dose is >50 mg/dayfor OA of the knee and hip. Devil’s claw exhibits cellular signalling modulating activitiesthat down-regulate inflammatory markers.19–21 Five randomized clinical trials (RCTs)have reported on the effects of devil’s claw in the treatment of OA.22 Of these, threewere placebo-controlled and two were compared with common pharmaceuticals (di-acerhein and phenylbutazone). Three trials demonstrated significant positive results,while two studies that employed <30 mg harpagoside recorded results that wereless significant. An aqueous extract of devil’s claw (consisting of 60 mg harpagoside)was found to be as effective as 12.5 mg of rofecoxib for the treatment of acutenon-specific lower-back pain in a double-blind pilot RCT.22 Three other trials havealso demonstrated efficacy in lower back pain, with 100 mg of harpagoside consideredsuperior when neurological deficits are present.18,23

Tripterygium wilfordii Hook F

Extracts from the roots of Tripterygium wilfordii Hook F (TwHF) (Figure 3) have beenused for the treatment of various autoimmune and inflammatory diseases, includingRA, SLE, nephritis, psoriasis and asthma.24 An ethanol/ethyl acetate extract has

Figure 2. Harpogophytum procumbens (devil’s claw).

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demonstrated therapeutic benefit in patients with treatment-refractory RA.25 At thedoses of 180 mg/day and 360 mg/day, TwHF extract was of benefit and well toleratedby most patients. A prospective double-blind RCT of TwHF ethanol/ethyl acetateextracts in RA patients has also been reported.25 With a two-dose regimen for 20weeks, patients at the higher dose achieved a rapid ACR-20 response, with 50% of pa-tients improving during the first 4 weeks of treatment. Both treatment groups showeda significant decrease in the number of tender and swollen joints and improvement inthe physician’s global assessment. In a further phase-I study, eight out of nine patientstreated with TwHF extract (>360 mg per day) showed improvements in both clinicalmanifestations and laboratory findings.26 It was concluded that the extract of TwHF atdosages up to 570 mg/day appeared to be safe, and doses >360 mg/day were associ-ated with clinical benefit in patients with RA. In both of these studies, no toxic oradverse effects other than diarrhoea were observed in patients receiving the highestdose. An RCT of a topical application of TwHF in 61 patients with RA demonstratedefficacy in improving ACR-20 score.27

Curcuma longa (turmeric)

Turmeric (Figure 4) has been used for centuries in Ayurvedic medicine as a treatmentfor inflammatory disorders, including arthritis.28,29 The major chemical constituent ofturmeric is curcumin (diferuloylmethane), which constitutes up to about 90% of thetotal curcuminoid content, with the remaining 10% consisting of demethoxycurcuminand bis-demethoxycurcumin.28 Animal studies have demonstrated that oral adminis-tration of curcumin to rats decreased the levels of inflammatory glycoprotein,GpA-72, with a concomitant reduction in paw inflammation.30 Curcumin has alsobeen shown to inhibit the carrageenin-induced paw oedema in mice and rats, withan ED50 dose of 48 and 100.2 mg/kg, respectively.30,31 In a double-blind cross-over

Figure 3. Tripterygium wilfordii Hook F.

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clinical trial of 18 patients with RA given curcumin (1200 mg/day) for 2 weeks followedby 300 mg/day of phenylbutazone for another 2 weeks, respondents showed a signifi-cant improvement in morning stiffness, walking time, and reduction in joint swelling.32

Zingiber officinale (ginger)

The fresh/dried roots of Zingiber officinale (Figure 5) is reported to possess anti-inflam-matory, antiseptic and carminative properties and has been used to treat inflammatoryand rheumatic diseases.33 The pungent phenolic constituent of ginger, 6-gingerol, hasbeen shown to inhibit lipopolysaccharide- (LPS-) induced nitric oxide synthase (iNOS)expression and production of NO in macrophages and to block peroxynitrite-inducedoxidation and nitration reactions in vitro.33–35 Cumulative laboratory animal datasuggest that 6-gingerol is a potent inhibitor of NO synthesis and effective in inhibitingproduction of prostaglandin E2 (PGE2) and tumour necrosis factor a (TNF-a) andcyclo-oxygenase 2 (COX-2) expression in human synoviocytes by regulating nuclearfactor kB (NFkB) activation and degradation of its inhibitor IkBa subunit.33

A recent RCT employing Zingiber officinale and Alpinia galanga (Eurovita Holding,Denmark) comprising 255 mg extracted from 2500–4000 mg ginger and 500–1500 mggalanga rhizome, demonstrated a positive effect on knee OA. Clinical trial participantsin the ginger-extract group experienced a 63% reduction in knee pain on standing versus50% in the placebo group.36 A highly purified and standardized ginger extract had a sta-tistically significant effect on reducing symptoms of OA of the knee with a high safetyprofile and mild adverse gastrointestinal events in the ginger-extract group. In a furthercross-over RCT, in patients with OA the ginger extract showed statistically significantefficacy in the first period of treatment before cross-over; however, a significant

Figure 4. Curcuma longa (turmeric).

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difference was not observed in the study overall.37 In a limited study with RA patients38

ginger was effective in relieving pain and swelling in the joints of seven RA patients. Basedon this limited information, recommendation for it use is difficult and limited in treatingOA or RA.

Capsicum spp (chilli/cayenne)

Capsicum spp (Figure 6) are commonly used topically in a cream base for the relief oflower-back pain.39 A recent systematic review included four studies on cayenne andconcluded that there is evidence that it reduces lower-back pain more than placebo.20

An early review analysed three RCTs and reported that cayenne had poor tomoderate efficacy for the treatment of chronic musculoskeletal or neurologicalpain.39 Cayenne was responsible for a higher rate of side-effects than was placebo;given that the action of chilli is to increase blood circulation, it is prudent to enquirewhether it is the heat generated that alleviates the pain.

Gaultheria yunnanensis (wintergreen)

Topical natural products containing wintergreen (Figure 7) include liniments, balms,creams, gels, oils, lotions, patches, ointments and other products that are applied tothe skin, and these are often sought with the intention of providing relief of mild ar-thritis pain that affects only a few joints, as well as to ease sore muscles, back painand OA.40,41 No clinical trials evaluating these effects are currently available. However,

Figure 5. Zingiber officinale (ginger).

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in-vivo studies have shown that a salicylate fraction isolated from wintergreen hasanalgesic and anti-inflammatory properties.42 Caution, even with topical products, isrequired in patients receiving warfarin, as adverse interactions and bleeding havebeen reported to be a risk with its use.43

Figure 6. Capsicum spp (chilli/cayenne).

Figure 7. Gaultheria yunnanensis (wintergreen).

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Phytodolor

Phytodolor (Steigerwald Arzeimittelwerk GmbH, Germany) is a herbal proprietaryproduct that includes aspen (Populus tremula), golden rod (Solidago virgaurea) andgolden ash (Fraxinus excelsior). Although most of the available literature is German,a recent systematic review of six RCTs concluded that Phytodolor reduced the painassociated with rheumatic disorders.43 The dose administered was 30 drops threetimes a day for three of the trials and 40 drops three times a day for the remainder,with duration ranging from 2 to 4 weeks.

Boswellia serrata (boswellia/frankincense)

Boswellia serrata (Figure 8) is a popular Ayurvedic herb that is purported to exhibit ef-fective analgesic, anti-inflammatory and anti-arthritic activity.44–47 Pilot studies indicatethat boswellia may be an effective intervention for rheumatoid arthritis because of itsanti-inflammatory properties.44,45

A recent RCT assessed its efficacy, safety and tolerability in 30 patients with OA ofknee over a 16-week period.46 Patients receiving 333 mg of boswellia extract contain-ing 40% BA three times a day reported a significant decrease in knee pain and swelling,and an associated increase in movement. A further RCT compared the same extractwith valdecoxib in 66 patients with knee OA over 6 months. This study has a slower

Figure 8. Boswellia serrata (boswellia/frankincense).

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onset of action with pain relief persisting for 1 month after ceasing treatment, whilevaldecoxib acted faster but lasted only for the duration of therapy.47

Willow bark

There is a resurgence of interest in willow bark (Figure 9) as a treatment for chronicpain syndromes that include RA and OA. While white willow (Salix alba) is the willowspecies most commonly used for medicinal purposes; crack willow (Salix fragilis),purple willow (Salix purpurea), and violet willow (Salix daphnoides) are all salicin-richspecies and are available under the label of willow bark. Randomized clinical trials ofshort duration have provided evidence of efficacy.48

Rose hip (rose haw)

Recent systematic searches of the literatures49,50 have demonstrated that rosehippowder or the seeds of the Rosa canina subspecies (Figure 10) had a moderate effectin patients with osteoarthritis. In a study that enrolled 94 patients with osteoarthritisof the hip or knee in a double-blind placebo-controlled cross-over trial51 reported thatthe 47 patients that were given 5 g/day of the herbal remedy for a period of 3 monthsresulted in a significant reduction in WOMAC (Western Ontario and McMasterUniversities) pain (P< 0.014) as compared to placebo when tested after 3 weeks oftreatment. Furthermore, the clinical data suggested that the herbal remedy not onlyalleviated symptoms but also reduced the consumption of ‘rescue medication’.

Figure 9. Willow (Salix spp).

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NUTRITIONAL MEDICINE

Supplements

Various nutritional products are commonly used for pain control for rheumatic prob-lems (Table 2). Most reduce pain via their anti-inflammatory effects. Nutrition is in-creasingly linked to a range of degenerative and developmental disorders. Nutritionaldeficiencies and imbalances can result in metabolic and systemic disturbances thatmay increase susceptibility to joint disease.

Glucosamine

The therapeutic effectiveness of glucosamine treatment on OA has been demon-strated by improved mobility and relief of pain in animal models as well as inRCTs.52 A recent meta-analysis concluded that the evidence for efficacy in improvingsymptoms in OA was conflicting, and that glucosamine hydrocholoride was noteffective.53

A Cochrane review concluded that a specific type of glucosamine supplement (fromDona, Rotta Pharmaceuticals Inc) was superior to placebo in the treatment of pain andfunctional impairment resulting from symptomatic OA.54 Results for the non-Rottapreparation were not statistically significant. The review analysed data from 20RCTs involving 2570 participants, of which ten RCTs used the Rotta preparation. Asecond systematic review reviewed RCTs of at least 1 year’s duration.55 It was re-ported that glucosamine sulphate may be effective and safe in delaying the progressionand improving the symptoms of knee OA. A previous Cochrane review of 16 RCTshad found that glucosamine was effective; however, these included smaller trialswith less methodological rigor.56

Figure 10. Rose hip (rose haw; Rosa canina).

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Table 2. Supplements with demonstrated therapeutic anti-inflammatory, analgesic and anti-rheumatic activity.

Supplements Actions Indications Dosages Contraindications and cautions

Glucosamine sulphateGlucosamine hydrochloride

Anti-inflammatoryChondro-protective

OA 1500 mg/day usually individed dosesMost research has beenconducted on glucosaminesulphate

Occasional mild digestive problems,headache, drowsiness and skin reactionsShellfish allergy e glucosamine is notextracted from the protein componentof shellfish, however caution advised

Chondroitin Chondro-protective OA 1200 mg/day usually individed doses

Collagen hydroly Chondro-protective OA 10 g/dayLipids (avocado/soybeanunsaponifiables)

Chondro-protective OA 300e600 mg/day

Methylsulphonylmethane Chondro-protective OA 500 mg TID alone or incombination withglucosamine

New Zealand green-lippedmussel

Anti-inflammatory OARAResults for bothconditions stillremain inconclusive

1050e1150 mg/day offreeze-dried powder

Gastrointestinal discomfort, gout, skinrashes and one case of granulomatoushepatitis have been reported in trialsContraindicated in people withshellfish allergiesTheoretical caution with hypertensiondue to sodium content

SAMe Anti-inflammatory OAFibromyalgia

A lower dose of 400 mg/daymay be used as a maintenancedose once a response occurs

Tricyclic and SSRI antidepressants asserotonin syndrome theoreticallypossibleThyroxine e monitorBetaine e monitorExtreme caution in bipolar disorder,schizophrenia, schizoaffective disorderand Parkinson’s disease

OA, osteoarthritis; RA, rheumatoid arthritis; SSRI, selective serotonin reuptake inhibitor.

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A concern with most trials of glucosamine sulphate, glucosamine hydrochlorideand chondroitin sulphate in the treatment of OA is weak research design.57 The Glu-cosamine/chondroitin Arthritis Intervention Trial (GAIT) was designed to address theseinconsistencies and provide some clarity on the effectiveness of glucosamine(1500 g/day) and chondroitin (1200 mg/day) for the treatment of knee pain in OAby employing a rigorous research design.57,58 The GAIT found that glucosamineand chondroitin sulphate, alone or in combination, did not significantly reduce OAknee pain more than did placebo.58 A combination of glucosamine and chondroitinsulphate was found to be effective in a subgroup of patients with moderate to severeknee pain (79.2% versus 54.3% for placebo).59 The combined emerging data suggeststhat glucosamine has a structure-modifying effect. However, debate remains regardingthis, largely in relation to methodological issues surrounding outcome measures usedin the positive studies.

Chondroitin

An RCT employing galactosaminoglucuronoglycan sulphate (GS) on 40 patients withtibiofibular OA of the knee were allocated to receive 50 intramuscular injections(one injection twice weekly) for 25 weeks. GS had a significant therapeutic effecton all symptoms evaluated. No important local or systemic side-effects were noted.60

Favourable effects have been reported in pain reduction and improvement in mobilitywhen GS was given either intra-articularly or orally to elderly patients with jointdegeneration.61

A double-blind RCT with 104 patients receiving oral chondroitin 4-sulphate andchondroitin 6-sulphate (CS4 and CS6) at a dose of 800 mg/day or placebo for 1 yearshowed that CS4 and CS6 had a beneficial effect in terms of both clinical manifestationsand anatomical progression in patients with OA of the knee. The main efficacy criterionwas the Lequesne functional score. Functional impairment was reduced by approxi-mately 50%, with a significant improvement over placebo for all clinical criteria.Tolerance was excellent or good in more than 90% of cases. This study suggests thatCS acts as a structure modulator as illustrated by improvement in the inter-articularspace visualized on x-rays of patients treated with CS4 and CS6.62

A double-blind RCTof 46 patients with symptomatic OA of the knee examined theeffect of 400 mg chondroitin sulphate twice a day for 1 year. After 3 months, joint painwas significantly reduced in the chondroitin sulphate group compared to the placebogroup. This difference became more pronounced after 12 months. The increase inoverall mobility capacity was significantly greater at 6 and 12 months in the CS groupthan in the placebo group. After 1 year, the mean width of the medial femorotibial jointwas unchanged from baseline in the CS group, but had decreased significantly in theplacebo group. Although no statistical comparison was presented for the change injoint-space width between the two groups, the finding suggests the possibility thatCS treatment may slow the progression of OA.63 A proprietary CS was studied ina double-blind RCTof 85 patients with OA of the knee. Participants received Condro-sulf! at a dose of 400 mg TID or placebo for 6 months. Lequesne’s index, spontaneousjoint pain, and walking time all decreased progressively in the CS group, with a signif-icant difference in favour of the CS group for each of these parameters.64 In a double-blind RCT parallel-group study using either CS 1 g/day or placebo on 130 patients for3 months, followed by a 3-month post-treatment period, the CS group experiencedgreater but non-significant improvement than the placebo group at the treatment

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endpoint, as measured by the Lequesne index. Improvement became significant in thecompleter population. In the intention-to-treat population, all variables tended towardgreater improvement in the CS group than the placebo group. One month after treat-ment, CS had a significantly higher persistent effect than placebo on the Lequesneindex, pain with activity, and other efficacy criteria. Adverse event rates did not differsignificantly.65

To assess the clinical efficacy of CS in comparison with the non-steroidal anti-inflammatory drug (NSAID) diclofenac sodium, a multicentre double-blind RCT dou-ble-dummy study of 146 patients for 6 months was conducted.66 Patients treated withdiclofenac showed prompt reduction of clinical symptoms that reappeared, however,after the end of treatment. In the CS group, the therapeutic response appeared laterbut lasted up to 3 months after the end of treatment. It was concluded that CS hasslow but gradually increasing clinical activity in OA, and that these benefits last fora long period after the end of treatment. Shortcomings in these studies were thatonly a relatively small number of patients were involved, and that no dose-findinginvestigations for CS could be found.

A double-blind prospective RCT study of 300 patients given Condrosulf! 800 mgdaily or placebo for 2 years investigated the structure-modulating properties of CSin gonarthrosis by measuring the modifications in minimum joint space width, meanthickness, and mean surface of the cartilage in internal femorotibial function. Therewas a significant difference, with worsening of the affection, in the placebo groupcompared to the CS group. In the group treated with CS, there were no significant var-iations in any radiological parameters, which remained remarkably stable. The statisticalanalysis revealed a significant difference in the CS group compared to the placebo groupwith regard to maintenance of the cartilage analysed, in both the intention-to-treatanalysis (the accepted manner of analysis of clinical trials, where subjects are analysedwhether or not they complete the study protocol) and also in the per protocol analysis(when only subjects who completed the study protocol are examined). It was shownthat CS was superior to placebo with regard to stabilization of minimum joint spacewidth of the internal femorotibial articular space, the mean thickness, and the surface.67

Hence there are sufficient controlled trial data to support the use of CS in symptomaticOA, CS having fewer side-effects than currently used NSAIDs.

Chondroitin sulphates appear to have a role in prevention of disease progression.The requisite is that CS be further evaluated in studies of longer treatment duration,with larger numbers of patients, and using well-established measures of function andprogression.

A recent meta-analysis of a set of poor- to moderate-quality trials that were largelyheterogeneous in methodology, making interpretation of the data difficult, concludedthat the results were unreliable. Furthermore, the authors concluded that – sincelarge-scale and methodologically sound trials indicate that the symptomatic benefitof chondroitin is minimal or non-existent – chondroitin cannot be recommended.68

Collagen hydrolysate

Four open-label and three double-blind trials have been reported.69 In a 24-weekmultinational double-blind RCT on knee OA, 10 g/day did not improve the WOMACindex.70 Post-study analysis suggested that the hydrolysate could be more efficient insevere OA. A 60-day cross-over double-blind RCT on knee and hip OA compared10 g/day of collagen hydrolysate, gelatin, gelatin! glycin! calcium phosphate, or egg

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albumin.71 The gelatin preparations were not significantly different from each otherand were superior to egg albumin in reducing pain as assessed by a patient question-naire. According to the best-evidence synthesis, evidence of efficacy for collagen hy-drolysate is equivocal. However, a growing body of evidence provides a rationalefor the use of collagen hydrolysate for patients with OA.69

Methylsulphonylmethane (MSM)

In a 12-week double-blind RCTon knee OA, 500 mg of MSM three times a day – usedalone or in combination with 500 mg of glucosamine hydrochloride three times a day –significantly improved a Likert scale of pain and Lequesne’s functional index (LFI).72

The combination of both ingredients was not more efficacious than each ingredientused alone. A further 12-week double-blind RCTon knee OA, 3 g of MSM given twicea day was more efficient than placebo in decreasing WOMAC pain and functionalscores.73 According to the best-evidence synthesis, MSM provides moderate evidenceof efficacy for knee OA.

S-Adenosyl methionine (SAMe)

A practical amount of research evidence exists to support the use of SAMe for thetreatment of pain associated with OA.74 A meta-analysis of 11 RCTs comprising1442 participants with an average age of 60.3 years from 2002 demonstrated thatSAMe is as effective as NSAIDs in reducing the pain of OA, with significantly fewerside-effects.75,76

New Zealand green-lipped mussel

The reported incidence of arthritis in coastal-dwelling Maoris is low, and it has beensuggested that this is possibly due to their high consumption of green-lipped mussels.76

However, results from clinical trials have been inconsistent, with a recent reviewconcluding that ‘there is little consistent and compelling evidence, to date, in the ther-apeutic use of freeze-dried green-lipped mussel powder products for RA and OAtreatment’ but that further investigations are warranted.77

Lipids (avocado/soybean unsaponifiables, ASUs)

Four double-blind RCTs and one systematic review have evaluated ASUs on knee andhip OA.78–83 In two 3-month RCTs, one on knee and hip OA78 and one on knee OAonly79, 300 mg once a day decreased NSAID intake. No statistical differences in anyprimary or secondary endpoints were detected at 300–600 mg once a day.78 Ina 6-month RCT on knee and hip OA, 300 mg once a day resulted in an improvedLFI compared with placebo.78 ASUs had a 2-month delayed onset of action as wellas residual symptomatic effects 2 months after the end of treatment.79 In a 2-yearRCT on hip OA, 300 mg once a day did not slow down narrowing of joint-spacewidth.80 In addition, none of the secondary endpoints – LFI, visual analogue scale(VAS) of pain, NSAID intake, and patients’ and investigators’ global assessments –was statistically different from placebo after 1 year. However, a post-hoc analysis sug-gested that ASUs might decrease narrowing of joint space width in patients with themost severe hip OA.

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Table 3. Mind–body medicine modalities purported to ameliorate symptoms of osteoarthritis (OA) and rheumatoid arthritis (RA).

Intervention Actions Indications Outcome measures Pain effect sizes/quality grade

Relaxation PMR ! imagery versususual care e 10 sessions

RA AIMS 2 mobility arm function (SS)AIMS 2 pain

Low

Meditation MBSR programme versuswaiting-list control e 8sessions

Chroniclow-back pain

CPAQSFe36 physical function

Moderate32% attrition in intervention group, 6%attrition from controlIncluded 3-month follow-up

Guidedimagery

Guided imagery! PMRversus usual care e 12 sessions

OA AIMS 2 painSelf-reported mobility

Low4% attrition rate

Hypnosis PMR versus hypnosis versususual care e 8 sessions

OA Pain VASPain medication (for hypnosisand relaxation groups comparedwith usual care)

Moderate12% attritionPain reduction most rapid in hypnosis group,study included 6-month follow-upNo instructions for home practicePain medications decreased in hypnosisand relaxation groups

Tai chi Tai chi versus meeting andtelephone control e briefcontact:e 5 weeks contacte 12 weeks contact

OALower-extremityRA

Satisfaction with healthArthritis self-efficacyPain and functional measuresJoint pain and stiffness,physical function (KWOMAC)Joint tenderness, swollen joint count50-foot walkGrip strength

Moderate6e50% attrition rate in both groups

Yoga Yoga ! exercise ORYoga ! relaxation ! educationversus self care or waiting-liste 8 sessionse 12 sessions

OALower-extremity

Pain and physical function(WOMAC)

Moderate overall4e20% attrition rate in both groups

a PMR, progressive muscle relaxation; AIMS 2, Arthritis Impact Measurement Scales – 2; SS, statistically significant; CPAQ, Chronic Pain Acceptance Questionnaire;SF-36, Short Form 36-item Health Survey; VAS, Visual Analogue Scale.

516L.

Vitetta

etal

Although ASUs might display medium-term symptom-modifying effects on knee andhip OA, their symptom-modifying effects in the long term (>1 year) have not beenconfirmed. Based on the best-evidence synthesis, ASUs are good for symptom-mod-ifying effects in knee and hip OA with some evidence of absence of structure-modifyingeffects. A recent systematic review on ASUs recommended further investigationbecause three of the four rigorous RCTs suggest that ASUs are effective symptomatictreatment, but the long-term study was largely negative.81,82

ACUPUNCTURE

Non-pharmacological treatments such as acupuncture are attractive because of theirsafety profiles and lack of the adverse events that have been well documented with theuse of pharmaceuticals, especially when considering elderly populations.

Table 4. Levels of evidence currently available for herbal medicines and nutritional supplements andother modalities for the treatment of osteoarthritis (OA) and rheumatoid arthritis (RA).

Level I Level II Level IIIa Level IIIb Level IIIc Level IV Level V

Catechins from green tea x xUncaria tomentosa xHarpogophytum procumbens x x xTripterygium wilfordii Hook F x xCurcuma longa xZingiber officinale xCapsicum spp. x xGaultheria yunnanensis x xPhytodolor x xBoswellia serrata x xWillow bark x xRose hip xGlucosamine x x x x xChondroitin x x xCollagen hydrolysate x x xMethylsulphonylmethane x xS-adenosyl methionine x x x xNew Zealandgreen-lipped mussel

x x

Lipids (avocado/soybeanunsaponifiables)

x x x

Acupuncture x x x xMindebody medicine x x

Level I, from a systematic review of all relevant randomized controlled trials (RCTs) – meta-analyses;Level II, from at least one properly designed RCT; Level IIIa, from well-designed pseudorandomized con-trolled trials (alternate allocation or some other method); Level IIIb, from comparative studies (includingsystematic reviews of such studies) with concurrent controls and allocation not randomized, cohortstudies, case–control studies, or interrupted time series with a parallel control group; Level IIIc, fromcomparative studies with historical control, two or more single-arm studies, or interrupted time serieswithout a parallel control group; Level IV, opinions of respected authorities based on clinical experience,descriptive studies or reports of expert committees; Level V, minimal evidence that representstestimonials.

Alternative therapies 517

A recent meta-analysis and systematic review concluded that acupuncture proce-dures that meet criteria for adequate treatment were significantly better than shamacupuncture or no additional intervention in improving pain and function in patientswith chronic knee pain due to OA.83,84 These recent studies confirm an earlier sys-tematic review and meta-analysis which concluded that: (1) acupuncture is oftenused for treating and relieving chronic pain due to OA; (2) the meta-analysis of threetrials showed a significant effect of manual acupuncture compared to a sham acupunc-ture procedure; and that (3) there were confirmed beneficial effects for amelioratingpain for peripheral-joint OA.85 However, due to the nature of the heterogeneity in theresults, there is a need for further research to confirm these findings and providemore information on long-term effects.83

MIND–BODY MEDICINE

Multimodal cognitive-behavioural/mind–body therapies (Table 3), in combination witheducational/information components (such as patient education/self-management pro-grammes), may be appropriate adjunctive treatments in the management of rheuma-toid arthritis and osteoarthritis.86,87

SUMMARY (TABLE 4: LEVELS OF EVIDENCE)

Patients expect – and should obtain – advice from their general practitioners regardingdietary/supplement therapies for which there is a high level of evidence, as conclusionsabout efficacy should fit into clinical practice. There is a strong scientific rationale forthe use of an integrative approach to the management of OA and RA (see Practicepoints).

Practice points

For the management of OA and RA pain and attendant psychological distress:

" stress management techniques (e.g. meditation, relaxation therapies)" acupuncture

For improved mobility and relief of pain of OA:

" glucosamine sulphate

To maintain viscosity in joints and stimulate cartilage repair in OA:

" chondroitin sulphate" collagen hydrolysate" lipids (avocado/soybean unsaponifiables)

To alleviate OA- and RA-associated inflammation and pain:

" various herbal medicines (Table 1)

518 L. Vitetta et al

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