Best Practice & Research Clinical Rheumatology
Volume 17, Issue 1 , Pages 137-150, February 2003

Pharmacotherapy for regional musculoskeletal pain

  • Tore K Kvien, md, phd (Professor Department of Rheumatology)

      Affiliations

    • Corresponding Author InformationCorresponding author. Tel.: +47-22451500; Fax: +47-22451778.

Diakonhjemmet Hospital, Box 23 Vinderen, Oslo N-0319, Norway

Received 1 September 2002; accepted 1 October 2002.

Article Outline

Abstract 

Studies performed on drug therapy in regional musculoskeletal pain conditions are of varying quality, and this is related to several methodological problems. The efficacy of analgesic medications is well established from clinical practice. However, both weak and especially strong opioid analgesics are associated with adverse reactions and also with dependency and abuse. The use of anti-depressants and skeletal muscle relaxants is only weakly supported by results from controlled clinical trials. The efficacy of both systemic and topical non-steroidal anti-inflammatory drugs (NSAIDs) has been examined in several Cochrane reviews of various regional musculoskeletal pain conditions. Studies of COX-2 selective NSAIDs have not been performed in conditions with regional musculoskeletal pain, but it is assumed that COX-2 selective inhibitors will not differ from dual COX inhibitors regarding efficacy. Therefore, some of the recent controversies related to gastrointestinal safety and possible risk of myocardial infarctions are also discussed.

Keywords:  regional musculoskeletal pain, non-opioid analgesics, opioid analgesics, non-steroidal anti-inflammatory drugs, COX-2 selective non-steroidal anti-inflammatory drugs, topical non-steroidal anti-inflammatory drugs, randomized clinical trials, systematic reviews

 

The purpose of this chapter is to review the evidence for therapeutic efficacy of several classes of drugs widely used for treating conditions with regional musculoskeletal pain. The following classes of drugs will be considered: non-opioid and opioid analgesics, systemic and topical non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, tricyclic antidepressant medications and muscle relaxants. This chapter does not discuss local corticosteroid injections, because this topic is dealt with in chapter 10.

Studies performed on drug therapy in regional musculoskeletal pain conditions are of varying quality, and this is probably related to several methodological challenges with these conditions. First of all, regional musculoskeletal pain may originate from a variety of conditions ranging from acute to chronic diseases and from pure non-inflammatory conditions to conditions with an evident inflammatory pathogenesis.

This heterogeneity and general lack of established diagnostic and classificatory criteria naturally lead to an insufficient description of endpoint measures for clinical studies. With a few exceptions1., 2. there is no consensus on which outcome measures are to be used and uniform guidelines for study methodology are generally non-existent. For most conditions there are three key targets for therapy: pain reduction, reduction of inflammation and restoration of function. For acute conditions time to resolution of pain and other symptoms may be relevant issues to be studied. Which endpoints are primary and which secondary are frequently not described. For example, pain relief may be measured in several ways. However, the interpretation of the results based on the statistical analyses may be difficult if the protocol has not pre-defined which pain measure should be considered as the primary. Systematic reviews have also revealed that the methodological quality is very variable and that low-quality study is prevalent in conditions with regional musculoskeletal pain3., 4., 5., 6., 7., 8., 9. (Table 1).

Table 1. Frequent methodological limitations in controlled trials in conditions with regional musculoskeletal pain
PatientsConditions without universally accepted classification criteria
Often small patient numbers in individual trials
Inclusion and exclusion criteria often insufficiently described

Outcome measures

No universally accepted measures of outcome
Primary and secondary endpoints often not explicitly described

Design

Often methodological limitations related to allocation and blinding
Comparators not always given in equipotent doses

Results

Often difficult to know how to interpret findings because pre-defined primary and secondary endpoint not always described

In this chapter we focus on results from controlled clinical trials, and when available, especially focus on Cochrane reviews.

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1. Non-opioid analgesics 

The most widely used non-opioid analgesic drug for conditions with pain in the musculoskeletal system is paracetamol (acetaminophen in the USA). With the exception of osteoarthritis (OA) of the hip and knee, data are nearly non-existent regarding the efficacy of paracetamol in regional musculoskeletal pain. Below, we have, therefore, focused mainly on documentation in OA, also to indicate the therapeutic potential compared to NSAIDs.

The efficacy of paracetamol in knee OA has been established in a placebo-controlled study.10 Individual trials have indicated that NSAIDs and paracetamol have similar efficacy in OA. A pooled analysis published in 199811 indicated that NSAIDs were superior to paracetamol regarding efficacy. However, recent guidelines for the treatment of OA still rank paracetamol as the first treatment choice in OA—which is probably more related to tradition, concerns about safety issues and differences in cost.12., 13. The latter aspect is probably also the dominating concern after the introduction of a new group of NSAIDs, the COX-2 selective NSAIDs or coxibs. A recent study demonstrated that celecoxib 200mg q.d. and especially rofecoxib 25mg q.d. were more effective than 4000mg of paracetamol daily in patients with OA of the hip and/or knee.14 Pincus et al15 recently showed that the combination of diclofenac 150mg and misoprostol was more effective than paracetamol 4000mg. Wolfe et al16 also studied the drug preference of patients who have used both paracetamol and NSAIDs. A majority of patients with OA preferred NSAIDs to paracetamol, both based on an overall evaluation, the efficacy and tolerability. The issue of which drug to be considered as the first drug of choice is still open to debate.17

In summary, paracetamol is a moderately effective analgesic drug which is widely used and also clinically helpful in many situations with regional musculoskeletal pain. It is still ranked as the first drug of choice in OA, but clinical studies have shown that NSAIDs are more effective. Few data are available from conditions other than OA with regional musculoskeletal pain. For clinical practice we assume that clinical inflammation in conditions with regional musculoskeletal pain will influence the probability of achieving therapeutic success with paracetamol alone. In conditions where inflammation is evident NSAIDs are expected to provide better symptomatic relief.

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2. Opioid analgesics 

To this class of drugs belong the weak opioids codeine, dextropropoxyphene and tramadol, and also stronger opioid analgesics such as ketobemidon, morphine and oxykodon.

Codeine remains the most frequently prescribed oral opioid analgesic drug. It is most often used in combination with paracetamol and has been widely used as a comparator for examining pain relief of drugs that have been launched more recently. For example, pain relief with the combination of codeine and paracetamol has been clearly demonstrated in comparative trials with rofecoxib in dental pain models after molar extraction.18 However, codeine, which is converted to morphine in the liver, has frequent side-effects, especially constipation and central nervous system effects, for example, dizziness. Therefore, codeine cannot be recommended for longer-term treatment of chronic pain, especially in elderly patients.19

Dextropropoxyphene is another weak opioid analgesic drug that has frequently been used by clinicians in a fixed combination with paracetamol. The comparative efficacy and tolerability of paracetamol–dextropropoxyphene combination and paracetamol were evaluated through a systematic review of randomized controlled trials comprising 2231 patients with post-surgical pain, arthritis and musculoskeletal pain reported in 26 randomized controlled trials.20 On the basis of data on analgesic efficacy and acute safety in both head-to-head and indirect comparisons, the authors found little objective evidence to support prescribing a combination of paracetamol and dextropropoxyphene in preference to paracetamol alone in moderate pain.20

Tramadol is another analgesic drug with action on the central nervous system that has become more widely prescribed in conditions with regional musculoskeletal pain over the last years. For example, Roth21 has suggested that tramadol may have a role as adjunctive treatment for breakthrough pain in patients receiving NSAID therapy for musculoskeletal pain attributed to OA. The double-blind placebo controlled part of this study was conducted in 42 adults who had experienced breakthrough OA pain while undergoing stable NSAID therapy. The maximal dose of tramadol was 400mg.21 Another study of musculoskeletal pain did not demonstrate any definite difference in efficacy between tramadol and the combination of hydrocodone and paracetamol.22 Other studies have also confirmed that tramadol provides a moderate pain relief in a variety of conditions23, including OA24., 25. and low back pain.26 It has been claimed that tramadol rarely leads to addiction and drug abuse27, but there is also evidence for at least a physical dependence.

During recent years some studies have also been performed to examine the efficacy of stronger opioid analgesic drugs in musculoskeletal pain, particularly oxycodone.28., 29., 30., 31., 32. The number of patients in individual studies has generally been small and there is no evidence supporting the selection of these agents before other weak opioid analgesics.

Addiction to drugs is a concern with opioid analgesics, including codeine and the other drugs in the group of weak opioids. These drugs may produce euphoria, psychological and physical dependence. The addiction liability of oxycodone is greater than for codeine. Caution should be applied when using these drugs also in acute musculoskeletal conditions because transition to chronicity occurs rather often. Psychological factors play a significant role not only in chronic pain but also in the aetiology of acute pain, particularly in the transition to chronic problems.33 It may be assumed that psychosocial factors known to predict transition to chronicity also are risk factors for developing dependency to drugs with actions on the central nervous system.

In summary, opioid analgesics are not the preferred medications for patients with mild to moderate musculoskeletal pain but may be considered as an add-on therapy in patients failing other pharmacological interventions, either non-opioid analgesics or NSAIDs. Doctors prescribing codeine, dextropropoxyphene or tramadol against musculoskeletal pain should remember possible addiction.

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3. Non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of COX-2 

Several controlled clinical trials have examined the efficacy of NSAIDs in a variety of conditions with regional musculoskeletal pain. Cochrane reviews of NSAID therapy are also available in a number of conditions (Table 2)—but these systematic reviews have also highlighted the methodological limitations of many of these individual trials (Table 1). Below, the efficacy of traditional systemic NSAIDs, COX-2-selective NSAIDs and topical NSAIDs is discussed.

Table 2. Cochrane reviews addressing NSAID in conditions with regional musculoskeletal pain
Title of reviewNumber of evaluated trials related to NSAIDSearch completedConclusion
Analgesia and non-aspirin, NSAIDs for OA of the hip4391994NSAID trials in patients with OA of the hip appear to be weakened by the lack of standardization of case definition of OA, and also by the lack of standardization of outcome assessments. No clear recommendations for the choice of specific NSAID therapy in hip OA can be offered at this time based on this analysis

Non-aspirin, NSAIDs for treating OA of the knee5

221995In spite of the large number of publications in this area, there are few randomized controlled trials. Furthermore, most trials comparing two or more NSAIDs suffer from substantial design errors. From the results of this review it is concluded that no substantial evidence is available related to efficacy, to distinguish between equivalent recommended doses of NSAIDs. Had studies employed appropriate doses of comparator drug, most would have been sufficiently powerful to detect clinically important differences in efficacy. As differences in efficacy between NSAIDs have not been recorded, the selection of an NSAID for prescription for OA knee should be based upon relative safety, patient acceptability and cost

Interventions for shoulder pain6

311998There is little evidence to support or refute the efficacy of common interventions for shoulder pain. As well as the need for further well designed clinical trials, more research is needed to establish a uniform method of defining shoulder disorders and developing outcome measures which are valid, reliable and responsive in these study populations

NSAIDs for treating lateral elbow pain in adults7

142001There is some support for the use of topical NSAIDs to relieve lateral elbow pain, at least in the short term. There remains insufficient evidence to recommend or discourage the use of oral NSAIDs. A direct comparison between topical and oral NSAID has not been made so that no conclusions can be drawn regarding the best method of administration

Interventions for treating acute and chronic achilles tendinitis8

72001There is insufficient evidence from randomizedcontrolled trials to determine which method of treatment is the most appropriate for the treatment of acute or chronic achilles tendinitis. Further research is warranted

NSAIDs for low back pain9

511998The evidence from the 51 trials included in this review suggests that NSAIDs are effective for short-term symptomatic relief in patients withacute low back pain. Furthermore, there does not seem to be a specific type of NSAID which is clearly more effective than others. Sufficient evidence on chronic low back pain is still lacking

3.1. Traditional NSAIDs 

Two Cochrane reviews have focused on OA of the hip4 and knee5 (Table 2). However, these reviews searched Medline only up to 1994 and 1995, respectively. The conclusions of the reviews are shown in Table 2. In general, head-to-head comparison of equipotent doses of various NSAIDs has not shown any consistent trend favouring one NSAID to another.

A relevant review studied the efficacy of common interventions for shoulder pain.6 The determinants for inclusion were that the trial included an intervention of interest (NSAID, intra-articular or subacromial glucocorticosteroid injection, physiotherapy, manipulation or surgery), that treatment allocation was randomized and that the outcome assessment was blinded. Thirty-one trials met inclusion criteria. There was no uniformity in outcome measures used and the measurement properties were rarely reported. Out of the 31 trials, 14 focused on the use of NSAIDs. The results suggested that NSAIDs may be superior to placebo in improving the degree of restriction of abduction in rotator cuff tendinitis and pain.6

Another review focused on the effectiveness of NSAIDs (oral or topical) in the treatment of adults with lateral elbow pain with respect to symptom (pain) reduction, improvement in function, grip strength and adverse effects.7 Fourteen trials were included in the review. Few trials used intention-to-treat analysis, and the sample size of most was small. The median follow up was 2 weeks (range 1–12 weeks). Only two placebo-controlled trials assessed the effect of oral NSAIDs compared to placebo. There is some evidence for short-term benefit with respect to pain and function from oral NSAIDs, but this benefit was not sustained.7

Treatment of foot problems has also been addressed in two reviews. Nine trials, involving 697 patients, met the inclusion criteria of the review treating achilles tendinitis.8 Out of these, seven trials involved NSAIDs. Trials comparing different NSAIDs without a placebo group were excluded. Methodological quality was adequate in most of the trials with regard to blinding but the assessment of outcome was incomplete and short-term. There was weak but not robust evidence from three placebo-controlled trials of a modest benefit of NSAIDs for the alleviation of acute symptoms.8 The review focusing on the effectiveness of treatment in treating plantar heel pain included 11 randomized trials involving 465 participants34, but none of these focused on the efficacy of NSAIDs on plantar heel pain.34

Finally, the objective of another systematic review was to assess the effects of NSAIDs in the treatment of non-specific low back pain and to assess which type of NSAID is most effective.9 A total of 51 trials (total number of patients=6057) were included in this review. Sixteen trials (31%) were of high quality. The pooled results indicated a statistically significant effect in favour of NSAIDs compared to placebo. The results showed that there is conflicting evidence that NSAIDs are more effective than paracetamol for acute low back pain, and that there is moderate evidence that NSAIDs are not more effective than other drugs for acute low back pain. There is strong evidence that various types of NSAID are equally effective for acute low back pain.9Box 1

Box 1. Practice points

Recommended drugs for regional musculoskeletal pain

•non-opioid analgesics

•NSAIDs

•topical NSAIDs

Drugs to be avoided for chronic use due to tendency to abuse and dependency

•opioid analgesics (weak and strong)

•skeletal muscle relaxants

3.2. Cox-2-selective NSAIDs 

The discovery of two cyclo-oxygenase isoenzymes, COX-1 and COX-2 in the early 1990s initiated a process of developing new NSAIDs with selective inhibition of COX-2 and no inhibition of COX-1 in therapeutic doses.35., 36. This COX-2 selectivity hypothesis indicates similar clinical efficacy (pain and inflammation) between traditional NSAIDs and COX-2-selective NSAIDs and reduced occurrence of COX-1-mediated adverse reactions, i.e. gastrointestinal side-effects and inhibition of platelet aggregation leading to increased bleeding time. Several studies have proved that the COX-2-selective NSAIDs have improved gastrointestinal tolerability37., 38. and that they do not inhibit thromboxane formation and thus platelet aggregation and bleeding time.39

In general, there are many studies on OA and rheumatoid arthritis supporting that similar COX-2 inhibition is translated into similar efficacy. Based on this mechanism of action it may be expected that COX-2-selective NSAIDs would have the same potential for efficacy in regional musculoskeletal pain as do NSAIDs with dual COX-1/COX-2 inhibition. It is thus relevant to know that the efficacy of COX-2-selective NSAIDs in hip and knee OA has been demonstrated in a large number of trials. Superiority to placebo has been shown for both rofecoxib40., 41., 42., 43., celecoxib44., 45., 46., 47., etoricoxib48 and valdecoxib49, and comparability to widely used NSAIDs such as diclofenac46., 50., ibuprofen40, naproxen45., 48., 49., 51. and nabumetone43 has also been demonstrated.

Fewer data are available to support the efficacy of COX-2-selective NSAIDs in other conditions with regional musculoskeletal pain. Dental pain models (pain after molar extractions) and other regional conditions with acute pain have been used to prove the efficacy concept in acute pain and have shown that COX-2-selective inhibitors give the same extent of pain relief as traditional NSAIDs and also as the combination of codeine and paracetamol.32., 52. Studies have also been performed to demonstrate pain relief after orthopaedic surgery.53

A Medline literature search in August, 2002, did not identify any controlled clinical trial with COX-2-selective NSAIDs examining the efficacy on regional conditions such as, for example, low back pain, heel pain, lateral epicondylitis or shoulder pain.Box 2

Box 2. Practice points

•traditional instead of COX-2-selective NSAIDs for regional musculoskeletal pain?

pros: cheaper

efficacy better documented in regional musculoskeletal pain

cons: COX-2-selective NSAIDs have better gastrointestinal safety

COX-2-selective NSAIDs do not interfere with bleeding time

Are there any concerns with the COX-2-selective NSAIDs? First of all, clinicians should apply the same caution when using COX-2-selective agents as traditional NSAIDs in patients with cardiac failure, arterial hypertension, fluid retention, users of diuretics and in patients with reduced kidney function.54 Further, questions have been raised about gastrointestinal safety since the CLASS study55 failed to demonstrate reduced occurrence of ulcer complications with celecoxib versus diclofenac and ibuprofen when the entire study was analysed.56 However, the VIGOR study57 demonstrated reduced risk of ulcer complications with rofecoxib compared to naproxen with relative risk reductions of about 55%. The CLASS study had several methodological limitations that at least in retrospect had a major impact on the conduct and results of the trial regarding ulcer complications. The major issue was that patients using low-dose aspirin were allowed to enter the study55 leading to an overall inherent increased risk for the occurrence of the gastrointestinal study endpoints, which was unrelated to the study medications.

Another concern is related to the difference in occurrence of myocardial infarctions in the VIGOR trial.57 This finding has led to a lot of debate and considerations about the possible causes of this difference.58., 59. Recent studies suggest that the difference in the VIGOR study may be explained by a cardioprotective effect from naproxen. Pooled data from comparisons with rofecoxib and naproxen have shown a lower cardiovascular event-rate in the naproxen groups60, whereas rofecoxib did not differ from non-naproxen NSAID and placebo60, and there is no evidence for increased occurrence of infarctions with celecoxib.61 Further, recent epidemiological studies have indicated that naproxen is also associated with some cardioprotective effects62., 63., 64., 65. and in vitro studies have shown that naproxen has a strong inhibitory effect on COX-1.40

3.3. Topical NSAIDs 

Several NSAIDs are available in a topical form for cutaneous application. In general, the NSAIDs are absorbed66, but low systemic concentrations are achieved compared to oral or other systemic administration.

These NSAIDs are clinically useful primarily for local inflammatory processes, particularly acute soft-tissue injuries. The evidence for clinical efficacy in the latter condition was reviewed by Heyneman67 who concluded that the empirical evidence supporting the use of topical NSAIDs in soft-tissue injuries is weak. However, patient ratings of improvement consistently favour NSAIDs over placebo.67

The Cochrane review of NSAIDs for treating lateral elbow pain in adults found that topical NSAIDs are significantly more effective than placebo with respect to pain and participant satisfaction in the short term. This finding was robust against the possible bias introduced by the inclusion of unblinded trials and publication bias. The adverse effects reported were minor.7 The Cochrane review of treatment of acute or chronic achilles tendinitis also included one study of topical NSAID. This study on niflumic acid gel indicated a slight superiority over placebo in the improvement of pain on palpation of the tendon.8

These findings support the notion that topical NSAIDs may be used in regional musculoskeletal pain and that the strongest evidence exists for lateral elbow pain. There is a risk for allergic and photoallergic contact dermatitis and photoxicity68., 69., and recent observations also suggest that topical administration may be followed by adverse events seen with oral administration, for example, renal impairment.70

3.4. NSAID summary 

NSAIDs are effective pain-relieving medications in a variety of conditions with regional musculoskeletal pain, including chronic low back pain, OA and tendinitis of various locations. It has been recommended that NSAIDs be used intermittently, guided by the intensity of pain, in patients with OA, and this approach to administration can probably be applied also in other chronic conditions with regional musculoskeletal pain. The new COX-2-selective NSAIDs have fewer gastrointestinal side-effects and do not prolong the bleeding time. However, few data exist from studies in acute and regional conditions with musculoskeletal pain, whereas several well-performed recent studies are available in OA. Topical NSAIDs may have their therapeutic relevance in lateral elbow pain and in other conditions where the musculoskeletal lesion or injury is rather superficial.

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4. Tricyclic medications 

Antidepressive medication has been used primarily in patients with neuropathic pain and chronic widespread pain, in particular, fibromyalgia. However, even in these conditions authors disagree about the efficacy after having reviewed published controlled clinical trials.71., 72., 73. Fishbain74 concludes that antidepressants may have an antinociceptive effect in chronic pain and that these drugs were effective for neuropathic pain. There was also some evidence that these drugs could be effective for psychogenic or somatoform disorder-associated pain. This evidence also strongly suggested that serotonergic–noradrenergic antidepressants may have a more consistent antinociceptive effect than the serotonergic antidepressants.74

The role of antidepressant treatment on chronic low back pain was explored in a recently published systematic review.75 This review concluded that antidepressants were more effective than placebo in reducing pain severity but not functional status in chronic back pain.

No studies have indicated that antidepressant therapy has a role in acute regional musculoskeletal pain.

In summary, antidepressant medications may improve pain in chronic low back pain, but have no clear role in the treatment of other conditions with regional musculoskeletal pain.

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5. Skeletal muscle relaxants 

This group comprises numerous drugs that were widely used one or two decades ago for pain relief in a variety of conditions with regional musculoskeletal pain: carisoprodol, chlophenesin carbamate, chlorzoxazone, cyclobenzaprine hydrochloride, metaxalone, methocarbamol and orphenadrine citrate.76 Few well designed and well conducted controlled clinical trails are available to document the effect of carisoprodol and other muscle relaxants for the treatment of clinical conditions with regional musculoskeletal pain. Some old controlled trials have shown conflicting results in both widespread and regional pain77., 78., 79., 80., but some review articles have concluded with weak evidence of therapeutic efficacy in neck pain and low back pain.71., 81.

The major limitation of these drugs is their adverse effects, especially drowsiness.76 Further, withdrawal symptoms similar to barbiturate or alcohol withdrawal have been reported. During the last decade it has been recognized that skeletal muscle relaxants have the potential for abuse and dependence.76., 82.

In conclusion, few data support that carisoprodol and other muscle relaxants are of any major therapeutic value in patients with regional musculoskeletal pain. In addition, use of these drugs represents a potential for abuse and dependence, which indicates that usage should be limited to short-term treatment.Box 3Box 4

Box 3. Practice points (selection of drugs based on mechanism of action)

•regional musculoskeletal pain without inflammation: prefer non-opioid analgesics

•regional musculoskeletal pain with possible inflammation: prefer non-opioid analgesics, add NSAIDs if insufficient effect

•regional musculoskeletal pain with inflammation: prefer NSAIDs, add non-opioid analgesics if insufficient effect

Box 4. Research agenda

Study methodology

•establish classification criteria and description of disease entities suitable for clinical trials

•define standardized outcome measures for acute and chronic conditions with regional musculoskeletal pain

•develop a standardized design for testing drugs in acute and chronic conditions

Pharmacotherapy

•compare the efficacy of NSAIDs versus non-opioid analgesics versus the combination of both in acute and chronic conditions with regional musculoskeletal pain

•compare the efficacy of non-opioid analgesics and NSAIDs in both acute and chronic conditions

•determine whether specific clinical factors (especially clinical signs of inflammation) predict response to NSAIDs compared to non-opioid analgesics in patients with regional musculoskeletal pain

•examine the efficacy of COX-2-selective NSAIDs in conditions with regional musculoskeletal pain (both chronic and acute)

•determine whether early interventions with analgesics or NSAIDs prevent transition to chronicity in acute regional musculoskeletal pain

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6. General summary 

This review highlights the fact that relatively few randomized controlled clinical trials have been performed in conditions with regional musculoskeletal pain, with the exception of OA and partly of low back pain. Several of the opioid analgesic drugs as well as the skeletal muscle relaxants are associated with a risk of dependency and abuse. Thus, non-opioid analgesics and NSAIDs remain as the recommended medications. For clinical practice it seems reasonable to summarize the recommended use (see Practice points). However, more trials are needed, as indicated in the Research agenda.

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PII: S1521-6942(02)00102-X

doi:10.1016/S1521-6942(02)00102-X

Best Practice & Research Clinical Rheumatology
Volume 17, Issue 1 , Pages 137-150, February 2003

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