7 Pharmacotherapy and osteoarthritis

7

Pharmacotherapy and osteoarthritis

Stephen J. Brady BMed Department of Rheumatology

Peter Brooks MD, FRACP, FAFRM, FAFPHM, MD Hon Causa (Lund) Medical Professorial Unit

Philip Conaghan MBBS, FRACP Department of Rheumatology

Louise M. Kenyon Medical Professorial Unit St Vincents Hospital, Darlinghurst, 2010, NSW, Australia

Therapy for osteoarthritis (OA) is aimed at relieving symptoms and at maximizing function. Therapies can be considered as either symptom modifying OA drugs (SMOADs) or as disease modifying OA drugs (DMOADs). Currently available agents fall into the catagory of SMOADs. Analgesic medications, particularly paracetamol and capsaicin, have proven efficacy in OA and are recommended first line therapies. Non-steroidal anti-inflammatory drugs (NSAIDs) do appear to provide extra symptomatic benefit for some patients but have greater toxicity. Newer generation NSAIDs may have safety advantages which remain to be confirmed in practice. Further therapies are being developed which aim to prevent cartilage damage and/or aid cartilage restoration, but these DMOADs remain in the experimental stage.

Key words: osteoarthritis; management; pharmacotherapy.

The treatment goals in the therapy of osteoarthritis (OA) are to minimize symptoms (pain and stiffness) and loss of function in the affected joint, while preventing further joint damage. To this end treatments used in the pharmacotherapy of OA can be classified as either symptom modifying OA drugs (SMOADs) or disease modifying OA drugs (DMOADs). A further distinction has been proposed in differentiating between two classes of slow acting drugs for the treatment of OA (SADOA) into those which are symptomatic slow acting drugs for the treatment of OA (SYSADOA) and DMOADs (Lequesne et al, 1994) (see Table 1). Effective DMOADs would be expected to have a symptomatic benefit, although in Bailli~re's ClinicalRheumatology-Vol. 11, No. 4, November 1997 ISBN 0-7020-2368-X 0950-3579/97/040749 + 20 $12.00/00

749 Copyright © 1997, by Bailli~re Tindall All rights of reproduction in any form reserved

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Pharmacotherapyand osteoarthritis 751

OA there has been a long recognized discrepancy between structure (radiological change) and symptoms. Clinical trials of therapies for OA have often been subject to methodological problems. No standard set of outcome measures exist and many tools used currently continue to undergo validation. Different classes of OA drugs may require different outcome measures. A number of recent reviews have discussed issues related to the testing of therapies for OA (Paulus and Bulpitt, 1993; Lesquesne et al, 1994; Thieler et al 1994; March and Brooks, 1996).

SMOADs

Currently used therapies for the treatment of OA fall into the symptom modifying category of OA drugs. Pain remains the major indication for treatment in OA and relief of pain the major aim of therapy. The most commonly used agents, non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics, are rapidly acting agents of short duration which are used to provide short term relief of symptoms. NSAIDs do have the potential to alter cartilage metabolism and therefore may be disease modifying, and this will be discussed later in this article. Historically, NSAIDs have been the most frequently used agents in the treatment of OA. Because of the frequency of this disease NSAIDs have become one of the most commonly prescribed drugs worldwide and are available 'over the counter' in many countries. This has led to an increased awareness of their toxicity. The recognition that pain, the most common symptom of OA, is not necessarily due to inflammation and therefore does not require anti-inflammatory therapy has led to an increased awareness of the role of simple analgesics in the treatment of OA. Recently published evidence-based guidelines produced by the American College of Rheumatology (ACR) for the treatment of OA of the hip and knee (Hochberg et at, 1995a,b), emphasize paracetamol as the first line of pharmacotherapy for OA, as do other recent reviews of the treatment of OA (Schnitzer, 1993; Griffen et al, 1995; March, 1997).

Analgesics Paracetamol

Paracetamol is the most commonly used and recommended analgesic for the treatment of OA. Although it is a very weak inhibitor of cyclooxygenase (COX) and has some peripheral anti-inflammatory actions, its major effect is as an analgesic. The analgesic effect is mediated centrally, possibly at the spinal cord level, but the exact mechanism remains to be elucidated. Paracetamol is remarkably free from toxicity but does cause hepatotoxicity in both acute and chronic overdose. Malnutrition and alcoholism are risk

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factors for hepatotoxicity (Benison et al, 1987). The risk of hepatotoxicity is felt to be minimal in chronic ingestion of doses up to 4.5 g daily. Renal toxicity has been reported with chronic ingestion in a retrospective study, but the risk of this occurring is much lower than with NSAIDs (Perneger et al, 1994). Evidence for the effectiveness of analgesics in OA

In a randomized double-blind crossover trial, Amadio and Cummings (1983) showed that paracetamol (4 g/day) significantly improved pain at rest, pain with motion, and tenderness in OA of the knee when compared with placebo. Function also improved with a significant reduction in 50 foot walk time. Other analgesics have also been assessed in the treatment of OA. A trial comparing paracetamol versus paracetamol plus codeine in the treatment of chronic pain due to OA of the hip (Kjaersgaard-Andersen et al, 1990) was terminated before the planned enrolment was completed. This was because of an unexpectedly high rate of dropouts due to adverse drug reactions, particularly nausea and constipation, and constipation in the combination group. However, higher rates of analgesia were achieved with the addition of codeine. Another study compared two analgesics (Lloyd et al, 1992): controlled release dihydrocodeine (CRD) and dextropropoxyphene/paracetamol (DP) in 86 patients with OA of the hip. The CRD group experienced improved analgesia but had a higher rate of withdrawal, particularly early in the study; predominantly because of gastrointestinal side effects, in particular nausea and vomiting. NSAIDs

NSAIDs are a heterogenous group of drugs with the common property of inhibiting COX and as a resul~t have analgesic and anti-inflammatory properties. They have been shown to be effective treatments for OA in placebo controlled trials. Concern has been raised about their toxicity, in particular their gastrointestinal toxicity. Recently two distinct isoenzymes of COX have been characterized: COX1 and COX2. The implications of this will be discussed later in the article. Comparative effectiveness of NSAIDs and analgesics in OA Despite many trials comparing the efficacy of different NSAIDs in the treatment of OA, there have been only a comparatively small number of studies comparing simple analgesics with NSAIDs (Dieppe et al, 1993a; Table 2). In a randomized controlled trial Bradley et al (1991) compared paracetatool with two doses of ibuprofen (1200 and 2400 mg/day) in the treatment of OA of the knee. The 4-week study was completed by 144 subjects. All

Pharmacotherapy and osteoarthritis

753

treatment groups experienced modest benefit with a 10-12% decrease in pain scores. Rest pain and walking pain decreased significantly in both ibuprofen groups, with a larger decrease in the higher dose group suggesting a dose-response relationship, although these differences did not reach statistical significance. The paracetamol group achieved statistically significant improvements in the HAQ disability score and 50 foot walk time. The only between group differences which reached statistical significance was for rest pain, which improved in the ibuprofen groups but not the paracetamol group. Table 2. Trials comparing non-steroidal inflammatory drugs (NSAIDs) with analgesics. Trial

N o f patients

Parr et al (1989)

846

Bradley et al (1991)

144

Williams et al (1993) Dieppe et al (1993b) March et al (1994)

NSAIDs (daily dose)

Analgesic (daily dose)

Comments

Diclofenac SR 100 mg

Paracetamol 1.95 g + Diclofenac superior pain dextropropoxyphene relief and mobility 180 mg Difference between Ibuprofen 1200 mg Paracetamol 4 g groups only for pain at rest or ibuprofen 2400 mg Difference between groups Naproxen 750 mg Paracetamol 3 g only for pain at rest Diclofenac 100 mg Placebo* Diclofenac 100 mg

Paracetamol 2 g

N of 1 trials

9/20 patients controlled on paracetamol 5/20 controlled by NSAIDs but not paracetamol

*All patients were allowed paracetamol.

In a later paper analysing this study, the authors concluded that clinical signs of inflammation did not necessarily predict response to NSAIDs and therefore are not by themselves an indication for NSAID use. Williams et al (1993) compared naproxen (375 mg twice daily) with paracetamol (750 mg four times daily) in the treatment of OA. At 6 weeks, the paracetamol group had experienced significant improvement in pain on motion and physician assessment, while the naproxen group had significant improvement in pain at rest, pain on motion, 50 foot walk time and physician assessment when compared with baseline. In the between groups comparison, the only significant difference was for pain at rest, naproxen being superior to paracetamol. Both groups had high rates of drop-out due to lack of efficacy or side effects. Only 62 out of 178 patients completed the study (35%). The number completing the study was slightly higher in the naproxen group (39%) than in the paracetamol group (31%), although the proportion of patients dropping out because of adverse drug effects was higher in the naproxen group (23% versus 18%). In a general practice based study, Parr et al (1989) compared slow release diclofenac (DSR) 100 mg daily with a combination of dextropropoxyphene and paracetamol (DP) (180 mg and 1.95 g daily) in the treatment of

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S.J. Brady et al

patients with pain in their hip, knee or ankle joints. Patients with rheumatoid arthritis (RA) were excluded so the majority of this large cohort (846) would be likely to have OA. This trial demonstrated superior efficacy of DSR over DP in the reduction of pain on visual analogue scale (VAS). Physical mobility (measured by Nottingham Health Profile) also increased significantly more with DSR than with DE Gastrointestinal symptoms were more common in the DSR group while tiredness or sleep disturbance were more common in the DP group. The large group size of this study may explain why a small (8%) difference in pain scores on VAS was able to reach statistical significance. Bradley et al (1991) calculated their group size to have a 90% power of picking~up a 20% difference in VAS between treatment groups and therefore had limited power to detect this difference. However, despite the small differences in pain scores, it was accompanied by increased mobility and less work time lost. Small improvements in pain control therefore may still be worthwhile. The fixed dose regimen of DP paracetamol also provides for a suboptimal daily dose of paracetamol of <2 g p/day. A greater level of analgesia may have been achieved with a paracetamol dose of 4 g p/day. A placebo controlled trial of a NSAID (diclofenac 100 mg/day) was undertaken over 2 years (Dieppe et al, 1993). Paracetamol was available for escape analgesia to all patients. This trial effectively looked at the continuing need for NSAIDs in a group of patients already on NSAIDs at recruitment, by firstly looking at the withdrawal rate in the group allocated to placebo and at the completion of the 2-year trial, reviewing the recurrence of symptoms in the group who had received NSAID therapy during the trial. The placebo group showed two patterns of response. Twelve of 44 patients withdrew because of lack of efficacy (almost all early in the study period). In those completing the study on diclofenac, 15 out of 31 'flared' on ceasing active therapy. Twenty of the 44 patients allocated to placebo, completed the 2-year period with adequate symptom control. This trial therefore suggests that a subgroup of patients with~.OA respond to NSAIDs whereas another subgroup do not gain extra benefit from NSAIDs above simple analgesia. A short term study (Quiding et al, 1992) compared ibuprofen (200 rag), ibuprofen plus codeine (30 mg) and placebo in a single and multidose (six treatments in 24 hours) crossover trial in patients with persistent pain from hip OA. No difference between treatments was shown after the first dose. In the multidose comparisons (after six doses) a difference was demonstrated with ibuprofen better than placebo and the ibuprofen plus codeine group better than ibuprofen alone. This perhaps demonstrates the importance of regular dosing and achieving steady state plasma and tissue concentrations. The short term nature of this trial does not enable further analysis particularly of long term tolerability of therapy which tends to be poor in studies in OA. This is particularly so for codeine, with one study terminated early because of the high dropout rate (Kjaersgaard-Andersen et al, 1990). However, the study does demonstrate the potential for opiates to have potent analgesic effects in OA and further investigation may be

Pharmacotherapyand osteoarthritis 755

warranted particularly of slow release morphine which has a broader therapeutic range and greater tolerability than codeine. The lack of a codeine only group does not allow us to distinguish between a powerful analgesic effect of codeine alone or an additive or synergistic effect of codeine and ibuprofen. Added analgesic effect has been demonstrated between opiates and paracetamol in other pain models, however. Metaanalysis of trials comparing paracetamol with paracetamol plus codeine in surgical pain (Zhang and Li Wan, 1996) and in postsurgical, postpartum, osteoarthritic and experimental pain (de Craen et al, 1996) do show increased analgesic effect with the combination of codeine, but also increased side effects. Some caution is warranted however as one trial (Mitchell et al, 1984) suggested that the addition of paracetamol to dextropropoxyphene may have had an antagonistic effect, i.e. a negative effect on pain scores and wellbeing. N of 1 trials

The advantage of the N of 1 trial design is that it allows for multiple comparisons of drugs in an individual patient and can assist in making treatment decisions in chronic disease. In a study of pain from OA of the knee, March et al (1994) entered patients to take at least three cycles of 2-week treatment periods of paracetamol (2 g/day) or diclofenac (100 mg/day) in divided doses. Twenty-five patients entered the study, and five dropped out early. Analysis of the results of the 20 patients completing the study demonstrated several patterns of response. Eight of the 20 patients could not differentiate between NSAIDs and paracetamol with adequate control of symptoms on both medications, and five patients indicated a preference for NSAIDs (Figure 1). In two patients, symptoms were controlled by the initial NSAIDs cycle, and remained so throughout the study, while in five patients NSAIDs may have been better but neither treatment afforded adequate symptom control. Interestingly, after 3 months, nine of the 20 patients (all of whom had taken NSAIDs previously) were adequately maintained on paracetamol alone. A slightly different approach was taken by Seideman (1993) who compared naproxen at two different dosages (0.5 and 1.0 g/day) combined with paracetamol (4 g/day) versus naproxen alone in three different dosages (0.5, 1.0 and 1.5 g/day) in a double blind crossover study in 18 subjects with OA. A paracetamol alone group was not included. The combination treatment groups showed improvement in overall pain scores, pain at rest and pain with movement compared with naproxen alone at equivalent dosages of naproxen and equivalent scores when compared with the higher dosages of naproxen alone. A dose response relationship was seen between the different doses of naproxen. The higher dose of naproxen used (1.5 g/day) did not have much greater anti-inflammatory effect than the lower dosages used, and the extra treatment effect may have been due to increased analgesic effect. Paracetamol demonstrated an additive effect to NSAID therapy which can be utilized to minimize NSAID dosage. The paracetamol

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F i g u r e 1. Representative patterns of response in n of 1 trials. Daily visual analogue scores for pain and stiffness. Patient A, good symptom control on both non-steroidal anti-inilammatory drugs (NSAIDs) and

paracetamol; Patient B, initial response to NSAID maintained on either paracetamol or NSAID; patient C, better symptom control on NSAID than paracetamol. Adapted from March et al (1994, British Medical

Journal 309" 1041-1045) with permission. A, diclofenac; rq, paracetamol.

formulation used in this trial was a slow release preparation given as 2 g twice daily. Taken together these trials suggest that a substantial proportion of patients with OA can be controlled with paracetamol alone. A subgroup of Practice points •

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Pharmacotherapy and osteoarthritis

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patients appear to receive added benefit in terms of symptom control from the use of NSAIDs. Adding these to analgesics rather than substituting them may allow a reduced dosage to be used thereby limiting toxicity.

Differences between NSAIDs

Comparative trials of NSAIDs Despite the many comparative trials of the different NSAIDs in the treatment of OA, no consistent differences in efficacy have been demonstrated. A recent (Towheed and Hochberg ,1997) meta-analysis of pharmacological treatments for OA of the hip, was unable to reach a conclusion regarding the rank order of NSAIDs in the treatment of this disorder and highlighted the methodological difficulties of existing studies in this regard. Low back pain is a common condition caused in many patients by OA of the lumbar spine. Recently, a systematic review of the efficacy of NSAIDs in the treatment of low back pain (Koes et al, 1997) has been published. Clinical trials of NSAID against placebo showed a treatment advantage, but only four out of nine trials comparing NSAID with other therapies including simple analgesics showed a treatment advantage for NSAIDs. Only two of these trials showing an advantage of NSAIDs, involved comparison with paracetamol with or without dextropropoxyphene. Of 11 trials comparing NSAIDs only four were only able to demonstrate a difference. All trials had methodological flaws.

Toxicity NSAIDs may however, vary in their toxicity. Meta-analysis of case control studies of gastrointestinal haemorrhage (Henry et al, 1996) have suggested differences in the relative risk of gastrointestinal haemorrhage with different NSAIDs. Azapropazone, tolmetin, ketoprofen and piroxicam appear to provide the highest relative risk and ibuprofen the lowest (Figure 2; Table 3). Risk factors for gastrointestinal toxicity include increased age, previous NSAID gastrointestinal side effects, and concurrent prednisolone use (Fries, 1991). The recent discovery that COX is present as two isoenzymes may provide a partial explanation for this. The two isoenzymes are COX1 which is a constitutive enzyme and COX2 which is inducible at sites of inflammation. The hypothesis has been formulated that adverse effects of NSAIDs are due to inhibition of physiological COX1 particularly in gastrointestinal tract and kidney and the anti-inflammatory effects are due to inhibition of COX2. The relative risk of gastrointestinal toxicity does appear to correlate

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Table 3. Comparison of the COX selectivity of non-steroidal anti-inflammatory drugs with the reported incidence of upper gastrointestinal bleeding derived from two large case-controlled studies and their toxicity index. From Richardson and Emery (1995). Odds ratio (risk) COX1 : COX2 ratio Langman et al Garcia Rodriguez Toxicity index (Mitchell et al, (Englehardt, (1994) and Hick (1994) (Singh et al, 1994) 1994) 1994) Azapropazone Ketoprofen Piroxicam Indomethacin Naproxen Diclofenac Ibuprofen Tenoxicam Meloxicam Aspirin

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reasonably well with the relative selectivity of COX1 and COX2 (as expressed by the ratio of COX1 to COX2 inhibition) (Hayllar and Bjarnason, 1995; Vane, 1995). Other factors appear important however, including the half-life, dose, acidity and presence or absence of enterohepatic circulation for the drug. It is hoped however that if this hypothesis is correct then highly selective COX2 inhibitors would demonstrate the

Pharmacotherapyand osteoarthritis 759

anti-inflammatory and analgesic effects of current NSAIDs but with reduced toxicity. No currently available agents can be said to be COX2 specific and all will inhibit COX1 at concentrations required to inhibit COX2 completely (de Brum-Fernandes, 1997). Some agents do however have properties which make them likely to exhibit advantages over currently used agents. Nebumetone is a non-acidic NSAID which is hepatically metabolized into the active metabolite 6-methoxy-2-napthylacetic acid (6-MNA). 6-MNA undergoes hepatic clearance and does not have biliary excretion or an enterohepatic circulation. Because nabumetone is not acidic, it can not dissociate in solution and anion trapping of drug in the gastric mucosa, which is probably one of the factors favouring toxicity of traditional acidic NSAIDs, does not occur (Richardson and Emery, 1995). Although 6-MNA is only an equipotent inhibitor of COX2 and COX1 (de Brum-Fernandes, 1997) and not a selective COX2 inhibitor, these properties make it less likely to cause gastrointestinal toxicity, and preliminary clinical data do suggest a safety advantage (Richardson and Emery, 1995). Meloxicam is a member of the enolic class of NSAIDs and exhibits a degree of COX2 selectivity. Pooled clinical trials data (Distel et al, 1996) show a tolerance advantage of meloxicam compared with the comparison agents piroxicam, naproxen and diclofenac, with a withdrawal rate approximately half that of the other agents due to gastrointestinal adverse events. A 6-month trial of meloxicam in the treatment of OA of the hip and knee (Hosie et al, 1996) has demonstrated an efficacy at least equivalent to diclofenac (100 rag/day). The new generation of NSAIDs including nebumetone, meloxicam and the highly selective COX2 inhibitors, may therefore present advantages over currently available NSAIDs in terms of adverse reactions. Currently available NSAIDs and an evidence based approach to limiting their toxicity, has recently been reviewed by a task force in Canada (Tannenbaum et al, 1996). These guidelines emphasize the importance of avoiding the use of NSAIDs in high risk patients as well as using the minimal effective dose of NSAIDs. Topical NSAIDs

The rationale for using topical NSAIDs is that adequate local concentrations of drug and therefore effect may be achieved without requiring systemic therapy and therefore with less toxicity. The efficacy of NSAIDs in OA may however be attributable to their analgesic effect as much as their anti-inflammatory effect and this may occur centrally (McCormack and Brune, 1991). Topical NSAIDs would be unlikely to have enough systemic absorption to have a central analgesic effect. However, topical NSAIDs may still be associated with toxicity (Evans and MacDonald, 1996) although mortality has not been reported. The toxicity of topical NSAIDs does appear to be less than oral NSAIDs but the data are derived from postmarketing surveillance and a limited number of case control studies rather than prospective studies.

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There have been no published trials comparing the efficacy of topical NSAIDs versus simple analgesics in the treatment of OA, and no comparative trials with capsaicin or other topical therapies. A randomized controlled trial (Dickson, 1991) compared topical piroxicam gel with ibuprofen (1200 rag) in the treatment of OA of the knee. This general practice based trial involving 235 patients, demonstrated equivalent efficacy between the oral and the topical agents. The criteria used for the diagnosis of OA in this study were not stated.

Capsaicin Capsaicin is derived from capsicum. It has analgesic properties relating to the stimulation of nociceptive neurons resulting in the release of neuropeptides including substance P. This produces a classical flare response but is followed by analgesia due to a depletion of neuropeptides from the nerve fibre which can be maintained with the continued application of capsaicin. The initial flare can be associated with burning and discomfort but tolerance usually develops with continued application. Neuropeptides may have a role in the pathogenesis of arthritis but the result of altering their physiology remains uncertain (Matucci Cerinic, 1995). Topical capsaicin has been shown in several trials to be better than placebo in the symptomatic relief of OA (Table 4). Table 4. Randomized controlled trials of capsaicin in osteoarthritis. Authors

Nof patients

Study length (weeks)

Capsaicin concentration

Deal et al (1991)

70

4

0,025% "7

McCarthy and McCarty (1992)

14

4

0.075%

Altman et al (1994)

113

12

0.025%

9

0.025%

Schnitzer et al (1994) 59

Comments Mean reduction of pain by 33% Significant difference from placebo P = 0.033 Reduction in tenderness and pain compared with placebo P <0,02 Reduction in pain (P = 0.02) tenderness (P = 0.01) at 12 weeks Reduction in pain and tenderness (P < 0.2)

In a trial of capsaicin cream as monotherapy for OA of the knee, ankle, elbow, wrist or shoulder (Altman et al, 1994), a regimen of capsaicin cream (0.025% four times daily) was compared with vehicle cream in a double blind randomized controlled trial. The capsaicin group demonstrated a significant difference in improvement of pain (measured by VAS) after 4 weeks (53% versus 21%) and maintained this difference for the remainder of the trial. At the completion of the 12-week trial, 81% in the treatment

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group versus 54% in the control group showed improvement by physicians global evaluation. Schnitzer et al (1994) looked at the use of capsaicin cream in hand OA and used a treatment regimen decreasing from four to two times daily after 3 weeks. Over half the patients used concomitant NSAIDs. Significant differences were reached for pain and tenderness by 3 weeks. With the decrease to a twice daily regimen, the capsaicin treated group experienced an increase in symptoms, but with continued therapy a trend towards improvement began to occur again, and by 9 weeks there was a significant difference for tenderness and a non-significant improvement in pain in the treatment compared with the control group In all capsaicin studies, local burning was the most common adverse reaction and this tended to regress with continued use. No serious adverse reactions were recorded. Together, these trials suggest that capsaicin is an effective treatment for OA in both small and large joints either as monotherapy or in addition to NSAIDs or analgesic therapy. The lack of systemic toxicity so far would suggest that it may have an increasing role to play in the management of OA, particularly in those at increased risk of toxicity from traditional therapies.

Other treatments Antidepressant medications, in particular the tricyclic antidepressants (TCAs) (McQuay and Andrew Moore, 1997) and more recently the SSRIs and SNRIs, have been used in the management of chronic pain because of their analgesic effect as well as their sleep restoring and mood elevating effects. They may therefore be expected to be beneficial in OA where chronic pain may occur and may co-exist with sleep disturbance. There have not however been controlled trials of the use of TCAs in OA. Recently, Ro 15-8081, a noradrenaline and serotonin reuptake inhibitor was demonstrated in a randomized controlled trial (Bolnot-Delmas et al, 1996) to have an analgesic effect in OA of the hip and knee, with a response comparable to piroxicam when used in a dose of 100 mg/day. Tolerability was however poor. This trial does demonstrate, however, the potential benefit of alternative analgesic therapies in the symptomatic treatment of OA.

Slow acting symptom modifying drugs Drugs which do not demonstrate rapid analgesic effect or protect against cartilage and joint damage but which may modify symptoms of OA over a period of several weeks, have been identified and formerly termed slow acting symptom modifying drugs (SYSDOA). They are now classified with

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other symptom modifying drugs and are in the process of ongoing clinical evaluation. Drugs which may fall into this class include chondroitin sulphate and diacerrhein. The need for this class of drug has been questioned by some authors, and agents in this class would need to demonstrate advantages over NSAIDs and analgesics in terms of efficacy, safety or cost before gaining a place in clinical use.

DMOADs

To be classed as a DMOAD, a drug must demonstrate the ability to prevent, retard progression of, or reverse morphological change (Brandt, 1995). Trials over several years in patients with pre-existing OA or at high risk of developing OA, are required to demonstrate their effectiveness. No drugs have yet reached clinical practice but several drugs have shown promise in animal models and early human trials. Identification of disease in th e early stages may be required for the effective use of these agents even if they live up to their potential. NSAIDs have differing effects on the metabolism of cartilage leading to potential effects on the progression of disease in OA. These effects can be both beneficial and harmful, The possibility that some NSAIDs may have beneficial or 'chondroprotective' effects on cartilage has been raised by some animal models, but no trials exist to show this effect occurring in humans (Bran&, 1995). Some NSAIDs may have deleterious effects on cartilage, hastening joint destruction. The term 'chondroaggressive' has been coined to describe this effect. The idea that NSAIDs, in particular indomethacin, may hasten cartilage destruction has been present since the idea was proposed in the late 1960s as a result of clinical observations and retrospective uncontrolled trials. Two large prospective trials have addressed this issue. In the first (Rashad et al, 1989) 105 patients referre'd for hip prosthesis were randomized to receive either azapropazone or indomethacin, and followed radiologically every 3 months until the time of joint replacement. The time of arthroplasty was decided clinically based upon failure of analgesia, severe restriction of movement or impairment of activities of daily living. The doctor who made this decision was not blinded to treatment group. Arthroplasty was reached after a mean of 10.4 months in the indomethacin group and 15.7 months in the azapropazone group. There was a faster rate of radiological progression in both the index and contralateral hip radiologically in the indomethacin group but this di¬ reach statistical significance. A later study compared the effect of indomethacin (25 mg three times daily), tiaprofenic acid (300 mg twice daily) and placebo in OA of the knee (Huskisson et al, 1995). Patients were removed from the study when a predetermined reduction in radiological grade of the medial tibiofemoral compartment was reached. Multiple interim analysis was performed and at the third analysis 47% of patients in the indomethacin group compared with 22% in the placebo group had reached the radiographic end point. At

Pharmacotherapyand osteoarthritis 763

this stage the indomethacin arm of the study was terminated. The use of multiple interim analysis does increase the odds of a type 2 error but the P value of <0.01 suggests a highly significant result. The study has been criticized for its interval censored survival design among other features (Doherty and Jones, 1995), but does provide the best evidence yet of a chondroaggressive effect of an NSAID. Interestingly, although it was not statistically significant at the final interim analysis (the seventh) there were a higher number of patients on tiaprofenic acid (43%) than in the placebo group (34%) who had reached the radiological end point. A chondroaggressive effect may therefore not be limited to indomethacin and can not be excluded for most NSAIDs on the trials performed to date. In the meantime, given the large numbers of NSAIDs available for use, it would seem prudent to avoid the use of indomethacin for long term use (Hochberg et al, 1995a). Tetracyclines, including currently available antimicrobials doxycycline and minocycline, inhibit matrix metalloproteins (MMPs) including collagenases, gelatinases and stromolysins which are likely to be involved in the breakdown of proteins in the cartilage matrix. Natural inhibitors of MMPs occur, known as tissue inhibitors of matrix metalloproteins (TIMP), and tetracyclines may also increase their production (Ryan et al, 1996). These effects may be chondroprotective and have been shown to have favourable effects on cartilage in animal models including canine models (Brandt, 1995). Human trials are awaited. Tenidap is a novel agent which exhibits inhibition of cyclooxygenase as well as inhibition of several cytokines including interleukin (IL)-I, IL-6 and tumour necrosis factor (TNF)-og and has potential as a DMOAD. In a dog model of OA it has been shown to decrease the rate of progression in both size and grade of existing cartilage lesions (Fernandes et al, 1997). In human studies tenidap has been shown to reduce the level of C-reactive proteins which is marginally elevated in OA, suggesting an anticytokine effect, but the relevance of this to disease modification is not established (Richardson and Emery, 1995). Further clinical trials are in progress. Hyaluronan (HA) is a large, linear glycosaminoglycan made up of repeating units of D-glucuronic acid and N-acetylglucosamine. Synovial fibroblasts are the main producer of HA within the joint. HA is a major non-structural component of both the synovial and cartilage extracellular matrix, and is also found in synovial fluid whereas in normal joints it is present as a polydisperse species with the average molecular weight of 10 × 106 daltons. HA confers viscoelastic and lubricating properties to the joint, depending on its concentration and molecular weight. It helps maintain water and protein homeostasis and also acts to protect cells within its matrix by acting as a sieve and exclusion barrier. In OA, there is reduced concentration of HA and it has lower molecular weight; hence the concept of viscosupplementation in OA with exogenous HA (Balazs and Denlinger, 1993). Intra-articular HA has been used for many years in racehorses and trials have been conducted in humans since the 1970s. There are problems in the interpretation of many of these trials, due to study design, inclusion criteria

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and sample size, which may explain their discordant results (Ghosh et al, 1992, Peyron, 1993). The use of different molecular weight HAs may also have led to different outcomes, with higher molecular weight compounds suggested to be more clinically beneficial. A recent placebo controlled, randomized, multicentre trial looked at the use of intra-articular HA (molecular weight 1000 kDa) in 240 patients with unilateral OA of the knee (Lohmander et al, 1996). At 20 weeks follow-up, there were no differences between HA and placebo groups, although analysis by stratification demonstrated improvement in those over age 60 and those with more severe disease. This again is in conflict with earlier studies suggesting that only patients with mild to moderate OA gained benefits from HA therapy. The same study did confirm a very low level of toxicity for this intra-articular agent. Bryant et al used hydroxychloroquine in the treatment of erosive OA of the DIP and PIP joints and published a retrospective, uncontrolled report (Bryant et al, 1995) on a small group of patients. Interestingly one patient had radiological progression of the disease despite clinical improvement.

ACR guidelines The ACR has issued evidence based guidelines for the management of OA of the hip and knee (Hochberg et al, 1995a,b).The guidelines for treatment of OA emphasize non-pharmacological therapies which are not discussed in this chapter. The emphasis in the pharmacological treatments is on obtaining adequate analgesia and prescribing in order paracetamol, topical therapies and then NSAID therapy with the short term use of less potent opiates if required. Surgical therapy is reserved for those failing this regimen (Figure 3). Non-pharmacological treatment Education-support-exercise-weight loss-joint protection

$

and Paracetamol (up to 4 g/day) for pain control

4.

Add topical capsaicin or anti-inflammatory cream if necessary

$

If pain relief inadequate, use alternative analgesiclow dose ibuprofen (up to400 mg four times daily) -lIf inadequate, use full dose NSAIDs, with gastroprophylaxis (misoprostol, famotine) if high risk If inadequate, consider joint lavage and/or arthroscopic debridement Referral for orthopaedic surgery (osteotomy or joLnt replacement) Figure 3. Steps in the management of osteoarthritis. Adapted from March (1997, Medical Journal of Australia 166" 98-103) with permission.

Pharrnacotherapy and osteoarthritis 765

As shown in this chapter, these guidelines reflect the available evidence and reflect the limited therapeutic options currently available. It is to be hoped that the next generation of therapies, including COX2 inhibitors and DMOADs, live up to their potential and extend these options. Research will need to continue to be targeted at symptom modification, disease modification and early identification of disease and prevention, if the large burden of morbidity from OA is to be eased. I

Research agenda

,

•

ihere should be continued emphasis on both SM(.):\I)S and 1) M ()..\ l) S

I

•

synq)mnl ulodification will remain an inip(Jrtant parr of the management of ():\ and furtl~er improvements arc' needed on current therapies which often provide incomplete pain relief

I

•

IIlOre potent and/or s;lltfr analgesic agClllS ilrt.' iiet'ded

•

agents which prevent and/or rekel'se cal'iiJagc damage are net'dcd

•

there should he early idcritific
patients to facilitate, trials :lnd effcctivc u~v of DMC)A[)S •

i

i !

preverlrion through reduction of environlnenial/behavioural risk factors is needed

Summary Pharmacotherapy of OA currently aims to provide relief of symptoms of which the major one is pain. Currently available agents have a limited ability to achieve this. The appropriate use of paracetamol, topical capsaicin and NSAIDs can, however, safely bring relief to a large number of patients and improve quality of life. Improved symptom relieving agents with greater efficacy and safety are required as well as agents which modify or prevent the progression of OA, to improve the pharmacotherapy of OA.

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