Best Practice & Research Clinical RheumatologyVol. 20, No. 1, pp. 117–129, 2006

8

Acetaminophen or NSAIDs for the treatment

of osteoarthritis

Bernard Bannwarth* MD

Professor of Therapeutics

Department of Rheumatology, University Hospital Pellegrin & Division of Therapeutics, EA 525, Victor Segalen

University, 33076 Bordeaux, France

Although non-pharmacological interventions are the cornerstone of osteoarthritis management,analgesics are an important component of treatment during the symptomatic periods of thedisease. In this respect, current practice guidelines advocate the use of a simple analgesic,acetaminophen, or a non-steroidal anti-inflammatory drug (NSAID), given either systemically ortopically as first-line or second-line drug therapies. The present paper aims first to assess theevidence for the efficacy and safety of these medications. Given the increasing importance ofpatient involvement in decision-making, the following key practical issue regarding acetaminophenand NSAIDs will then be addressed: ‘which drug do patients prefer?’ Regarding NSAIDs, a furtherquestion concerns the place for non-selective agents and cyclo-oxygenase-2 (COX-2) selectiveinhibitors (coxibs) in the light of new warnings and contraindications concerning coxibs inpatients with increased risk of cardiovascular thrombotic events.

Keywords: osteoarthritis; pain; non-steroidal anti-inflammatory drugs; coxibs; topicaltreatment; acetaminophen.

Osteoarthritis (OA) is a leading cause of pain and disability, especially in the elderly.Although non-pharmacological interventions are the cornerstone of OA management,analgesics play a central role during the painful periods of the condition.1–3 In thisrespect, current practice guidelines advocate the use of a simple analgesic,acetaminophen (paracetamol), or a non-steroidal anti-inflammatory drug (NSAID),given either systemically or topically as first-line or second-line therapies in patientswith symptomatic OA.1–3 The present paper aims first to assess the evidence for theefficacy and safety of these drug treatment modalities. Given the increasing importanceof patient involvement in decision-making, the following key practical issue regardingacetaminophen and NSAIDs will then be addressed: ‘which drug do patients prefer?’ In

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E-mail address: bernard.bannwarth@u-bordeaux2.fr.

118 B. Bannwarth

fact, patients’ preferences may differ from those of their doctors or evidence-basedguidelines.4 Regarding NSAIDs, a further question concerns the place for non-selectiveagents and cyclo-oxygenase-2 (COX-2) selective inhibitors (coxibs) in the light of newwarnings and contraindications concerning coxibs in patients with increased risk ofcardiovascular thrombotic events.

WHAT IS THE EVIDENCE FOR THE EFFICACY OF ACETAMINOPHENAND NSAIDS?

The question of whether acetaminophen is more effective than placebo for OA has beenconsidered in the meta-analysis by Zhang et al.5 The literature search identified fourplacebo-controlled randomized clinical trials published to July 2003. The two earliesttrials were available for the assessment of clinical response rate, defined as thepercentage of patients reporting at least moderate to excellent or O50% pain relief orsymptomatic improvement. As such, acetaminophen had a higher response rate thanplacebo in both studies.5 However, the results were heterogeneous and not relevant forpooling.5 The two latest trials allowed the effect size (ES) to be calculated. There is nocurrent operational definition for what constitutes a sufficiently large ES for a therapeuticintervention to be considered useful, but a value of 0.2 is considered clinically small, 0.5 ismoderate (and would be recognized clinically), and O0.8 is large.2,6 The pooled ES forpain reduction (primary outcome measure) was 0.21 (95% confidence interval [CI]:0.02–0.41), whereas the pooled ES for the total WOMAC (Western Ontario andMcMaster Universities) OA index score was 0.14 (95% CI: K0.06 to 0.34).5 It should beremembered that the WOMAC inquires about the three domains of pain, stiffness, andfunction, but that most of its 24 questions relate to function.

Two further placebo-controlled trials of acetaminophen in large-joint OA have beenreported after July 2003.7,8 In the first one, the proportions of patients with knee OAmeeting the primary endpoint (30% decrease in global knee pain during physical activityin the past 24 hours) were the same for acetaminophen (52.6%) and placebo (51.9%) atthe end of the 6-week study period.7 However, this negative result might be ascribableto several unusual features and caveats, especially selection bias, unexpectedly highplacebo response, and high drop-out rate.9 When the data from the second study,namely PACES-b7, were included in the above-mentioned meta-analysis, the ES for bothpain relief (0.23; 95% CI: 0.13–0.34) and changes in overall WOMAC index (0.16; 95%CI: 0.06–0.28)9 were very similar to those reported by Zhang et al.5

Numerous studies have shown the efficacy of oral NSAIDs in the management ofsymptomatic OA. A meta-analysis of published randomized placebo-controlled trialsconcluded that NSAIDs—including coxibs—can reduce pain and functional disability inknee OA better than placebo (ES: 0.32, 95% CI: 0.24–0.39, and 0.29, 95% CI: 0.18–0.40,respectively).6 However, the current analysis did not support the long-term use ofNSAIDs for this condition.6 NSAIDs might be more effective in hip OA; based on asystematic review of non-aspirin placebo-controlled trials, the ES for pain relief was0.69 (95% CI: 0.12–1.26).3

Taken together, these data indicate that acetaminophen is slightly better thanplacebo in relieving pain while having limited effects, if any, on other aspects of OAsymptomatology, especially disability. On the other hand, oral NSAIDs provide small tomoderate beneficial effects on pain as well stiffness and function. Interestingly, the meta-analysis by Zhang et al5, which included eight trials directly comparing acetaminophen

Acetaminophen or NSAIDs for osteoarthritis treatment 119

and NSAIDs, showed an aggregated ES of 0.20 (95% CI: 0.10–0.30) and 0.30 (95% CI:0.17–0.44) for pain relief and overall WOMAC index, respectively, in favour of oralNSAIDs. It should be stressed that there is high inter-individual variability in patientresponse to both acetaminophen and NSAIDs, and that there are no recognized clinicalpredictors of response to these drugs.2

WHAT IS THE EVIDENCE OF SIDE-EFFECTS OF ACETAMINOPHENAND NSAIDS?

Treatment with NSAIDs is associated with a variety of adverse effects, which mainlyinvolve the gastrointestinal (GI) tract, kidney, cardiovascular system, skin andrespiratory tract. NSAIDs-related side effects are thought to be primarily due totheir mechanism of action: namely, the inhibition of cyclo-oxygenase-1 (COX-1) and/orCOX-2 isoenzymes. Experimental studies support the view that acetaminophen mayalso decrease prostaglandin synthesis, albeit its capacity to inhibit COX isoforms washighly variable among tissues.10,11 Thus, the key question is whether or notacetaminophen shares the toxicity profile of NSAIDs.

Gastrointestinal safety

According to the meta-analysis of randomized controlled trials by Zhang et al5,acetaminophen has a similar safety profile to that of placebo, whereas conventionalNSAIDs—unlike coxibs—cause more GI discomfort (i.e. abdominal pain, GI distress,nausea, vomiting, dyspepsia, or diarrhoea) than acetaminophen (relative risk: 1.39, 95%CI: 1.07–1.80). However, these data derived from relatively small and short-termstudies were conducted on selected patients, and hence they may not be generalizableto the actual OA population. It is acknowledged that patients receiving acetaminophenmay experience dyspeptic symptoms.12 Two epidemiological studies suggested thatacetaminophen, at daily doses O213 or 2.6 g14, increased the risk of severe upper GIside effects, including GI bleeding or perforation. However, in addition to inherentbiases and limitations of such studies, both lacked information on true consumption ofdrugs because they used computerized prescription data.12 Furthermore, their findingsare counter to endoscopic studies and earlier epidemiological studies, including a meta-analysis of individual patient data from three case–control studies in which informationabout drug exposure was obtained by direct questioning of cases and controls.15 Thus,acetaminophen should still be regarded as free of major GI toxicity.12,16,17 Never-theless, a large-scale randomized clinical trial should be carried out to ascertain the GIrisk in patients with OA receiving long-term acetaminophen.5,17

Conversely, GI complications are the most common adverse events of NSAIDs.They range from dyspepsia, the primary cause of discontinuation of NSAID therapy, toserious, possibly life-threatening complications, such as GI perforation, symptomaticulcers and bleeding (PUB). Both clinical trials and observational studies support a strongassociation between the use of conventional NSAIDs and PUB.18 Large GI outcometrials indicated an annual incidence of PUB of approximately 2.5–4.5% in patientsreceiving non-selective NSAIDs.19 The pooled relative risk of PUB derived from ninecohort studies was 2.7 (95% CI: 2.1–3.5).18 This figure was assumed to be the mostrelevant estimate for clinical practice because cohort studies, unlike controlled clinicaltrials, reflect the ‘real world’.18

120 B. Bannwarth

Renal tolerability

All NSAIDs can precipitate acute renal failure under conditions of reduced renalperfusion. Accordingly, predisposing factors include pre-existing compromised renalfunction, congestive heart failure, volume contraction due to concurrent diuretictherapy or an intercurrent disease resulting in dehydration, or old age.20 Simultaneoususe of angiotensin-converting enzyme (ACE) inhibitors may exacerbate this detrimentaleffect by inhibiting the counteracting effect of angiotensin II on the afferent arterioles.21

Furthermore, all NSAIDs are capable of inducing renal sodium retention, which may leadto peripheral oedema and/or cardiac decompensation in patients with pre-existing heartfailure.20 No such adverse events have been reported in patients receiving therapeuticdoses of acetaminophen (%4 g daily).17

Finally, all NSAIDs may increase blood pressure, especially systolic blood pressure,and attenuate the effects of antihypertensive medications through the inhibition ofCOX-1- and/or COX-2-dependent prostaglandins in the kidney and possibly additionalmechanisms.20,22,23 This increase, albeit usually modest (a few mmHg on average), mayhave significant cardiovascular risk implications (ischaemic heart disease, stroke) inpatients given prolonged NSAID therapy, especially those with pre-existinghypertension or other cardiovascular risk factors.22–24 Regarding the effects ofacetaminophen on blood pressure, short-term studies yielded inconsistent results.17,25

In contrast, two prospective cohort studies found that regular consumption ofacetaminophen was associated with a significantly higher risk for development ofhypertension compared with no use.26,27 The relative risk of incident hypertension wasthe most elevated in middle-aged healthy women taking acetaminophen R22 days permonth.26 In this population, the relative risk was similar to that of those taking NSAIDsR22 days per month (2.00, 95% CI: 1.52–2.62, and 1.86, 95% CI: 1.51–2.28,respectively).26 Whilst being worth considering, these findings should be regarded withcaution because of the limitations and potential biases of both cohort studies.25 Thus,from a blood pressure perspective, the available evidence favours the use ofacetaminophen over NSAIDs in treated hypertensive patients requiring analgesics.25

The renal toxicity of acetaminophen has mainly been examined in terms ofdevelopment of chronic renal failure, particularly that resulting from analgesicnephropathy.17 In that respect, some observational studies found an associationbetween habitual use of acetaminophen and chronic renal impairment.17,28 Of note, long-term use of non-aspirin NSAIDs was also reported to lead to irreversible chronic renalimpairment.28,29 For practical purposes, it should be remembered that acetaminophen isusually recommended as the preferred non-opiate analgesic in patients with renalimpairment.30,31

Hypersensitivity reactions

Dermatological adverse events are the second most common side effects of NSAIDs.However, they are usually mild and include pruritus, urticaria, morbilliform rashes, andpseudoporphyria.32 On the other hand, allergic skin reactions to paracetamol areextremely rare.17

Aspirin-induced asthma is a distinct entity that is potentially life-threatening. Itsprevalence is 21% (95% CI: 14–29%) for adults and around 5% (95% CI: 0–14%) forchildren according to a recently published systematic review.33 Cross-reactivity toconventional NSAIDs occurs in most of these patients, whereas cross-sensitivity to

Acetaminophen or NSAIDs for osteoarthritis treatment 121

acetaminophen is only 7%.33 Furthermore, the asthmatic reaction to acetaminophen issignificantly shorter and milder than that to aspirin.17,33 COX-1 inhibition appears toplay a pivotal role in the pathogenesis of aspirin-induced asthma. In fact, selective COX-2 inhibitors have been shown to be well tolerated in most patients with documentedNSAID hypersensitivity.34,35 Unfortunately, detecting the few patients with cross-reactivity between acetaminophen or coxibs and the traditional NSAIDs can only beachieved with provocation tests.17,34,35

A case–control study reported a graded association between acetaminophen andasthma, with daily users of acetaminophen having an odds ratio for asthma of 2.38 (95%CI: 1.22–4.64). In view of the flaws and biases of this study, a causal link is, however,debatable.17,30

Hepatotoxicity

Although several NSAIDs have been withdrawn from the market because of anunacceptable hepatic hazard, it is well appreciated that symptomatic hepatic effectsattributable to NSAIDs are extremely rare and usually mild.36 In contrast, thehepatotoxicity of overdoses of acetaminophen is the most worrisome aspect of its useowing to the narrow therapeutic/toxicity range of this compound.17,30 Fortunately,therapeutic doses of acetaminophen very rarely produce liver damage.17 Whetheralcohol potentiates the hepatotoxicity of acetaminophen sufficiently to maketherapeutic doses hepatotoxic is a controversial issue.17 Of note, acetaminophen hasbeen recommended as the optimal analgesic in patients with stable chronic liverdiseases.17 However, it is prudent to monitor liver function in alcoholics and patientswith liver diseases receiving acetaminophen.17

In summary, the weight of clinical evidence continues to support the superior overallsafety profile of acetaminophen compared with NSAIDs. It should be added that unlikethe latter, the former is virtually devoid of drug–drug interactions of clinicalsignificance.31 Nevertheless, acetaminophen may potentiate the activity of warfarin,so patients taking oral anticoagulants must have their international normalized ratiomonitored closely and their anti-vitamin K drug dose adjusted if necessary.31

WHICH DRUG DO PATIENTS PREFER?

Preferring one drug to another is the result of several factors, including treatmentefficacy, time and chance to benefit, actual or potential side effects, ease ofadministration, out-of-pocket cost, doctor or patient beliefs and interactions, severityof disease, and health status.37–39

Patients’ preferences for either acetaminophen or NSAIDs have been assessed in6-week randomized, double-blind, crossover clinical trials of patients with OA of theknee or hip.7,38 In one study, 57% of the patients found a diclofenac/misoprostolformulation to be ‘better’ or ‘much better’ than acetaminophen, while acetaminophenwas rated ‘better’ or ‘much better’ by 20% of the patients; an additional 22% reported nodifference between the two drugs.38 In two further studies, celecoxib was preferred byabout 50% of the completers, whereas around 20% had no preference, and 24 or 32%preferred acetaminophen.7 Two surveys in which patients with OA were asked to ratemedications based on their previous experiences provided similar results.40,41 One wascarried out in patients, who were participating in a long-term outcome study.40 When

122 B. Bannwarth

both the effectiveness and side effects were considered, more than 50% of patientsreported acetaminophen to be less satisfactory than NSAIDs, while 16% reported theopposite, and around one third found that both types of drug provided about the sameoverall satisfaction.40 Of note, the preference for NSAIDs decreased slightly with age.40

The second survey included 300 patients who were identified in rheumatology treatmentsettings so that their findings are probably not generalizable to people with OA in thegeneral population.41 Among 67% of patients who identified a drug as the ‘most helpful’for OA, 80% named an NSAID, compared to 20% who named acetaminophen (16%) oranother analgesic (4%) as the ‘most helpful’drug.41 It should be underlined that the majordeterminant for patients’ preferences in these studies was the combined efficacy andtolerability of acetaminophen versus NSAID. The larger number of tablets per day whenusing acetaminophen may have been perceived as bothersome, and may also havefavoured NSAIDs, many of which have once- or twice-daily dosing schedules.37 Althoughno study has assessed the compliance to acetaminophen in patients with OA, it is likelythat the four-times-daily dosing regimen, which is the most effective dose regimen ofacetaminophen, hampers adherence to its use in routine clinical practice.42

It can be concluded from the aforementioned studies that a majority of patients withOA preferred NSAID to acetaminophen. Nevertheless, acetaminophen appeared to bean appropriate choice for a significant proportion of them. This is supported byindividualized medication effectiveness tests or n of 1 trials, i.e. within-patient,randomized, double-blind, crossover trials.43,44 Individual patient responses toacetaminophen (1 g twice daily) and diclofenac (50 mg twice daily) were evaluated in25 patients with OA who were treated over three 4-week cycles.43 Eight of the 20patients whose results could be analysed found no clear difference between the twodrugs, symptoms being adequately controlled by acetaminophen; five indicated a clearpreference for diclofenac, two showed control of symptoms after their initial 2 weeks ofthe NSAID which continued throughout subsequent treatment changes, and in fivediclofenac may have been better but neither agent gave satisfactory control. Finally, at 3months, equal numbers were taking diclofenac (nZ9) and acetaminophen (nZ9).43 Ofnote, 16 of the 20 patients were taking NSAIDs before the study. Of these, ninecontinued after the study and seven changed to acetaminophen.43 Another series of n of1 trials investigated whether acetaminophen (3 g/d) was as effective as NSAIDs(diclofenac 75–100 mg/d, ibuprofen 1.2–1.6 g/d, or naproxen 750 mg/d) in 13 patientswith OA of the hip or knee who had been using NSAIDs regularly.44 Each patient receivedfive pairs of treatments comprising 2 weeks of an NSAID and 2 weeks of acetaminophen.Seven patients completed the study. In five of these patients, little or no difference wasfound between NSAIDs and acetaminophen, and in one there was no associationbetween outcome and type of drug.44 Thus, six patients were recommended to changeto acetaminophen at the end of the study. Three months later, four of these six patientswere taking NSAIDs for practical reasons or perceived lack of efficacy.44

In summary, individual patient responses to acetaminophen and NSAIDs vary widelyand are largely unpredictable. It should be borne in mind that some patients with OAcan be switched from NSAID to acetaminophen for a variable period, thereby avoidingunnecessary use of NSAID and averting NSAID-associated side-effects.

CONVENTIONAL NSAIDS VERSUS COXIBS

COX-1-sparing NSAIDs or coxibs has been shown to be as effective as conventionalnon-selective NSAIDs in patients with OA.45 Meta-analyses of randomized controlled

Acetaminophen or NSAIDs for osteoarthritis treatment 123

clinical trials along with epidemiological studies and large GI outcome studies providedevidence that coxibs are associated with significantly fewer upper GI complications(PUB), at least in patients not taking low-dose aspirin, and slightly less dyspepsia,compared with conventional NSAIDs.45,46 As already mentioned, coxibs, unlikeconventional NSAIDs, are well tolerated in most patients with aspirin-induced asthma.On the other hand, coxibs have a pattern of nephrotoxicity and drug interactionssimilar to those of conventional NSAIDs.20,47 Furthermore, there is no evidence thatcoxibs are less toxic to the GI tract than conventional NSAIDs combined with agastroprotective agent such as a proton pump inhibitor, especially in patients at high riskof developing GI adverse events.48,49

Finally, several coxibs were shown to increase the risk of myocardial infarction andstroke compared with placebo.23 Thus, rofecoxib was withdrawn from the market inSeptember 2004 as earlier studies had already raised concerns about its increasedcardiovascular hazard relative to conventional NSAIDs.23 Valdecoxib has recently beentaken off the market because of an increased cardiovascular risk as well as reports ofsevere cutaneous reactions. In a long-term placebo-controlled trial on colorectaladenoma prevention, celecoxib too was found to increase the risk of cardiovascularthrombotic events in a dose-related fashion.23 Although these findings conflicted with alarge body of data showing no cardiovascular signal for celecoxib23, most regulatoryagencies—including the US Food and Drug Administration (FDA) and the EuropeanMedicines Agency (EMEA)—formally recognized the cardiovascular adverse events ofcoxibs as a class effect. Interestingly, the mechanism of action of coxibs provides aplausible biological explanation for their prothrombotic potential.50 Mature humanplatelets uniquely express COX-1, the source of thromboxane A2 (TX A2) whereasCOX-2 is a major source of endothelial-cell-derived prostacyclin (PGI2). Thus, coxibsmay affect the balance between prothrombotic (TX A2) and antithrombotic (PGI2)eicosanoids, thereby promoting cardiovascular events in predisposed patients.Whether this mechanism applies to all coxibs is, however, much debated.23 Anyhow,new warnings have been issued over currently available coxibs, and their use has beenrestricted.51 For instance, the EMEA issued a statement in February 2005 contra-indicating all coxibs for patients with ischaemic heart disease or stroke, and urgingcaution for patients with risk factors such as hypertension, hyperlipidaemia, diabetes,heart disease, smoking or peripheral vascular disease.51

In the light of all these data, a cost-effective analysis was performed to reappraise theinitial NSAID treatment of choice for the management of chronic arthritis in patientswith varying risk factors.49 The use of a generic conventional NSAID appeared to beoptimally cost-effective in patients at low risk for an NSAID-related GI complication.49

The addition of a proton pump inhibitor to a conventional NSAID is the most cost-effective option in patients taking low-dose aspirin or otherwise at high risk for a GI orcardiovascular adverse event, and hence this strategy is preferable to the use of a coxib.49

In summary, a conventional NSAID combined with a gastroprotective agent wouldbe the most appropriate first-line NSAID therapy in many patients with OA. However,it should be remembered that conventional NSAIDs, like coxibs, are capable of inducingan increase in systolic blood pressure in a dose-related way.23 Accordingly, conventionalNSAIDs too have the potential for causing cardiovascular thrombotic effects,particularly myocardial infarction as suggested by a recently published population-based case-control study.52 It ensues that: (1) all NSAIDs should be prescribed at thelowest effective dose for the minimal requisite period of time, and (2) long-term use ofany NSAID, if needed, requires regular blood pressure monitoring.23

124 B. Bannwarth

WHAT IS THE EVIDENCE FOR THE EFFICACY AND SAFETY OFTOPICAL NSAIDS?

Since the analgesic and anti-inflammatory properties of NSAIDs are assumed to beprimarily related to their capacity to inhibit prostaglandin synthesis within the damagedtissues, topical administration of these compounds might offer the advantage ofrelieving the symptoms of OA with reduced incidence of systemic adverse effects.53 Infact, NSAIDs administered topically in the form of creams, gels or patches were shownto produce significant concentrations in the adjacent tissues and synovial fluid whilstpenetrating poorly into the systemic circulation.53 Bioavailability studies suggested thatNSAIDs administered topically achieve only 3–5% of the total systemic absorptionwhen compared with oral administration.53

Several short-term clinical trials indicated that topical NSAIDs were superior toplacebo and possibly as efficacious as oral NSAIDs in the treatment of symptomaticOA.53 Accordingly, current guidelines from Europe and America recommendtopical NSAIDs as effective treatment for OA of the knee.1,2 However, they havebeen challenged by a meta-analysis, which included 13 trials that were identifiedthrough a systematic search of the literature from 1966 to 31 October 2003.54

Most trials lasted 2 weeks, and none went beyond 4 weeks. Topical NSAIDs weremore effective than placebo in relieving pain due to OA only in the first 2 weeksof treatment, whereas no benefit was observed over placebo in weeks 3 and 4.54

The corresponding ES for weeks 1 and 2 were 0.41 (95% CI: 0.16–0.66) and 0.40(95% CI: 0.15–0.65), respectively.54 A similar pattern was observed for function,stiffness and clinical response rate, defined as the percentage of patients reportingat least moderate to excellent or greater than 50% pain relief or improvement insymptoms.54 Thus, the authors of the meta-analysis concluded that ‘researchevidence to support long-term use (more than 1 month) of topical NSAID in OAis absent’.54 Furthermore, topical NSAIDs were less effective than oral NSAIDsnumerically at any week and statistically in the first week.54 Of note, markedheterogeneity became obvious in the results of this meta-analysis, with thelikelihood that publication bias would have acted to overestimate the benefits oftopical NSAIDs.54,55

The molecule and/or formulation used may influence the effects of topicalNSAIDs.53,55 In this respect, a 12-week randomized double-blind clinical trial thatwas not included in the meta-analysis showed that a topical 1.5% diclofenac sodiumsolution in a carrier containing the penetration enhancer dimethyl sulphoxide wassignificantly more effective than the vehicle control solution for all outcomemeasures, including pain, physical function, stiffness, and patient global assessmentin patients with documented OA of the knee.56 However, it seems premature toinfer from this study that this particular topical formulation of diclofenac wouldexert a more prolonged therapeutic effect than others.

Topical NSAIDs are usually well tolerated. Adverse events occur in approximately 10–15% of patients, the vast majority being localized pruritus, itching, burning and/or rash atthe site of administration that resolves quickly upon discontinuation of the drug.53,54

Topical preparations of ketoprofen were reported to be the most frequently involved inphotosensitivity reactions.57 This feature might be ascribed to the chemical structure ofthe compound.57 On the other hand, systemic adverse effects are very uncommon, andno association was found between topical NSAIDs and upper GI bleeding orperforation.53 Nevertheless, there have been case reports of serious systemic reactions

Acetaminophen or NSAIDs for osteoarthritis treatment 125

such as GI and renal toxicities, abnormal hepatic function, haematopoietic disorders andasthma in patients treated with topical NSAIDs.53

In summary, there is reasonable evidence to support the use of topical NSAIDs inOA. Since their efficacy in hip OA is questionable because of the depth of that joint,topical NSAIDs are appropriate as an adjunct to systemic analgesia or monotherapy inpatients with OA of the hand or knee. However, a recent meta-analysis brought out thewaning effectiveness over 4 weeks, implying that topical NSAIDs would be best used forshort periods during flare-ups in the disease.55 It may be anticipated that thisrecommendation will not be followed in practice. As a matter of fact, topical NSAIDsare available without prescription in many countries and they are liked by patients,probably because of their good safety record and marked placebo effect.2,53

CONCLUSION

Goals in managing OA include controlling pain and improving functional impairment. Inthis respect, non-pharmacological interventions are central to any long-termmanagement plan.1–3,30 However, analgesics are an essential component of thetreatment of symptomatic OA. In view of its reasonable efficacy, good safety record andlow cost, acetaminophen is the most cost-effective option in many patients with OA.According to current guidelines, this drug is the oral analgesic to try first and, ifsuccessful, the preferred long-term oral analgesic.1–3 Topical NSAIDs may be used overthe short term as an adjunct to systemic analgesia or monotherapy, especially inpatients with OA of the hand or knee. Finally, systemic NSAIDs should be considered inpatients unresponsive to acetaminophen and/or topical NSAIDs. Available data supportthe use of a conventional NSAID, alone or in combination with a gastroprotectiveagent, rather than that of a coxib.

Practice points

† both acetaminophen and systemic NSAIDs are evidence-based drugs forsymptom relief in OA

† there are no recognized clinical predictors of response to acetaminophen orNSAIDs

† acetaminophen is less effective but also less toxic than systemic NSAIDs, andhence acetaminophen is the most appropriate first-line oral analgesic

† since the overall toxicity of systemic NSAIDs depends on the dosage andduration of exposure, these drugs should be prescribed at the lowest effectivedose for the shortest possible duration

† coxibs are less cost-effective than conventional NSAIDs, alone or combinedwith a gastroprotective agent (depending on whether the patient is a high riskor not)

† short-term use of topical NSAIDs is safe and effective in osteoarthritis of thehand and knee

Research agenda

† there is a need for more randomized clinical trials of acetaminophen andNSAIDs that give outcomes specific to hand and hip OA

† well-designed studies should be carried out to evaluate the gastrointestinalsafety of acetaminophen over the long term

† whether the combination of acetaminophen with an NSAID may provideenhanced analgesic efficacy compared to an NSAID alone needs to beascertained in patients with OA

† whether the molecule and/or formulation used may influence the effectivenessof topical NSAIDs should be examined

126 B. Bannwarth

SUMMARY

Osteoarthritis is a major cause of pain and disability. Its management requires acombination of non-pharmacological and pharmacological interventions. In this respect,acetaminophen and NSAIDs are evidence-based drugs for symptom relief inosteoarthritis. Both conventional NSAIDs and coxibs reduce pain and functionaldisability better than acetaminophen. However, the former carry a greater risk ofserious adverse events than the latter. Although patient preference favours NSAIDs,about 40% of the patients find acetaminophen better than or equally satisfactory toNSAIDs. In view of its reasonable efficacy, good safety record and low cost, currentguidelines recommend acetaminophen as the oral analgesic of first choice in patientswith symptomatic osteoarthritis. In addition to the withdrawals of rofecoxib andvaldecoxib, the benefit/risk ratio of the remaining selective COX-2 inhibitors has beenreassessed recently in such a way that the use of a conventional NSAID alone orcombined with a gastroprotective agent appears to be preferable to that of a coxib. Inany case, NSAIDs should be used at the lowest effective dose for the shortest possibleduration of treatment. Finally, current evidence supports the use of topical NSAIDs,especially in osteoarthritis of the hand and knee. Given the waning effectiveness oftopical NSAIDs with time, they would be best used for short periods during flare-ups inthe disease.

REFERENCES

1. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Recommendations for

the medical management of osteoarthritis of the hip and knee. 2000 update. Arthritis and Rheumatism

2000; 43: 1905–1915.

2. Jordan KM, Arden NK, Doherty M et al. EULAR recommendations 2003: an evidenced based approach to

the management of knee osteoarthritis: report of a Task Force of the standing committee for

international clinical studies including therapeutic trials (ESCISIT). Annals of the Rheumatic Diseases 2003;

62: 1145–1155.

3. Zhang W, Doherty M, Arden N et al. EULAR evidence based recommendations for the management of

hip osteoarthritis: report of a task force of the EULAR standing committee for international clinical

studies including therapeutics (ESCISIT). Annals of the Rheumatic Diseases 2005; 64: 669–681.

4. Say RE & Thomson R. The importance of patient preferences in treatment decisions–challenges for

doctors. British Medical Journal 2003; 327: 542–545.

Acetaminophen or NSAIDs for osteoarthritis treatment 127

5. Zhang W, Jones A & Doherty M. Does paracetamol (acetaminophen) reduce the pain of osteoarthritis?: a

meta-analysis of randomized controlled trials. Annals of the Rheumatic Diseases 2004; 63: 901–907.

6. Bjordal JM, Ljunggren AE, Klovning A & Slordal S. Non-steroidal anti-inflammatory drugs, including cyclo-

oxygenase-2 inhibitors, in osteoarthritis knee pain: meta-analysis of randomized placebo-controlled trials.

British Medical Journal 2004; 329: 1317–1320.

7. Pincus T, Koch G, Lei H et al. Patient preference for placebo, acetaminophen (paracetamol) or celecoxib

efficacy studies (PACES): two randomized, double blind, placebo-controlled, crossover clinical trials in

patients with knee or hip osteoarthritis. Annals of the Rheumatic Diseases 2004; 63: 931–939.

8. Miceli-Richard C, Le Bars M, Schmidely N & Dougados M. Paracetamol in osteoarthritis of the knee.

Annals of the Rheumatic Diseases 2004; 63: 923–930.

9. Neame R, Zhang W & Doherty M. A historic issue of the Annals: three papers examine paracetamol in

osteoarthritis. Annals of the Rheumatic Diseases 2004; 63: 897–900.

10. Graham GG & Scott KF. Mechanisms of action of paracetamol and related analgesics. Inflammopharma-

cology 2003; 11: 401–413.

11. Warner TD, Vojnovic I, Giuliano F et al. Cyclooxygenases 1, 2 and 3 and the production of prostaglandin

I2: investigating the activities of acetaminophen and cyclooxygenase-2-selective inhibitors in rat tissues.

The Journal of Pharmacology and Experimental Therapeutics 2004; 310: 642–647.

12. Bannwarth B. Gastrointestinal safety of paracetamol: is there any cause for concern? Expert Opinion on

Drug Safety 2004; 3: 269–272.

13. Garcia-Rodriguez LA & Hernandez-Dias S. Relative risk of upper gastrointestinal complications among

users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology 2001; 12: 570–576.

14. Rahme E, Pettitt D & LeLorier J. Determinants and sequelae associated with utilization of acetaminophen

versus traditional nonsteroidal anti-inflammatory drugs in an elderly population. Arthritis and Rheumatism

2002; 46: 3046–3054.

15. Lewis SC, Langman MJ, Laporte JR et al. Dose-response relationships between individual nonaspirin

nonsteroidal anti-inflammatory drugs (NANSAIDs) and serious gastrointestinal bleeding: a meta-analysis

based on individual patient data. British Journal of Clinical Pharmacology 2002; 54: 320–326.

16. Abramson SB. Et tu, acetaminophen? Arthritis and Rheumatism 2002; 46: 2831–2835.

17. Graham GG, Scott KF & Day RO. Tolerability of paracetamol. Drug Safety 2005; 28: 227–240.

18. Ofman JJ, Maclean CH, Straus WL et al. A metaanalysis of severe upper gastrointestinal complications of

nonsteroidal anti-inflammatory drugs. The Journal of Rheumatology 2002; 29: 804–812.

19. Laine L. Gastrointestinal effects of NSAIDs and coxibs. Journal of Pain and Symptom Management 2003;

25(supplement): S32–S40.

20. Perazella MA. COX-2 selective inhibitors: analysis of the renal effect. Expert Opinion on Drug Safety 2002;

1: 53–64.

21. Bouvy ML, Heerdink ER, Hoes AW & Leufkens HGM. Effects of NSAIDs on the incidence of

hospitalisation for renal dysfunction in users of ACE inhibitors. Drug Safety 2003; 26: 983–989.

22. Aw TJ, Haas SJ, Liew D& Krum H. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood

pressure. Archives of Internal Medicine 2005; 165: 490–496.

23. Bannwarth B. Do selective cyclo-oxygenase-2 inhibitors have a future? Drug Safety 2005; 28: 183–189.

24. Singh G, Miller JD, Huse DM et al. Consequences of increased systolic pressure in patients with

osteoarthritis and rheumatoid arthritis. The Journal of Rheumatology 2003; 30: 714–719.

25. Egan BM. Nonnarcotic analgesic use and the risk of hypertension in US women. Hypertension 2002; 4:

601–603.

26. Curhan GC, Willet WC, Rosner B & Stampfer MJ. Frequency of analgesic use and risk of hypertension in

younger women. Archives of Internal Medicine 2002; 162: 2204–2208.

27. Dedier J, Stampfer MJ, Hankinson SE et al. Nonnarcotic analgesic use and the risk of hypertension in US

women. Hypertension 2002; 40: 604–608.

28. Perneger TV, Whelton PK & Klag MJ. Risk of kidney failure associated with the use of acetaminophen,

aspirin, and nonsteroidal anti-inflammatory drugs. The New England Journal of Medicine 1994; 331: 1675–

1679.

29. Segasothy M, Chin GL, Sia KK et al. Chronic nephrotoxicity of anti-inflammatory drugs used in the

treatment of arthritis. British Journal of Rheumatology 1995; 34: 162–165.

30. Courtney P & Doherty M. Key questions concerning paracetamol and NSAIDs for osteoarthritis. Annals

of the Rheumatic Diseases 2002; 61: 767–773.

128 B. Bannwarth

31. Bannwarth B & Pehourcq F. Pharmacological rationale for the clinical use of paracetamol:

pharmacokinetic and pharmacodynamic issues. Drugs 2003; 63(2): 5–13 [special issue].

32. Svensson CK, Cowen EW & Gaspari AA. Cutaneous drug reactions. Pharmacological Reviews 2001; 53:

357–379.

33. Jenkins C, Costello J & Hodge L. Systematic review of prevalence of aspirin induced asthma and its

implications for clinical practice. British Medical Journal 2004; 328: 434–437.

34. Senna G, Bilo MB, Antonicelli L et al. Tolerability of three selective cyclo-oxygenase-2 inhibitors,

meloxicam, celecoxib and rofecoxib in NSAID-sensitive patients. Allergie et Immunologie (Paris) 2004; 36:

215–218.

35. Sanchez-Borges M, Caballero-Fonseca F & Capriles-Hulett A. Tolerance of nonsteroidal anti-

inflammatory drug-sensitive patients to the highly specific cyclooxygenase-2 inhibitors rofecoxib and

valdecoxib. Annals of Allergy Asthma and Immunology 2005; 94: 34–38.

36. Rubenstein JH & Laine L. Systematic review: the hepatotoxicity of non-steroidal anti-inflammatory drugs.

Alimentary Pharmacology and Therapeutics 2004; 20: 373–380.

37. Wegman A, Van der Windt D, Van Tulder M et al. Nonsteroidal antiinflammatory drugs or acetaminophen

for osteoarthritis of the hip or knee? A systematic review of evidence and guidelines. The Journal of

Rheumatology 2004; 31: 344–354.

38. Pincus T, Koch GG, Sokka T et al. A randomized, double-blind, crossover clinical trial of diclofenac plus

misoprostol versus acetaminophen in patients with osteoarthritis of the hip or knee. Arthritis and

Rheumatism 2001; 44: 1587–1598.

39. Fraenkel L, Bogardus Jr. ST, Concato J & Wittink DR. Treatment options in knee osteoarthritis. The

patient’s perspective. Archives of Internal Medicine 2004; 164: 1299–1304.

40. Wolfe F, Zhao S & Lane N. Preference for nonsteroidal antiinflammatory drugs over acetaminophen by

rheumatic disease patients. A survey of 1,799 patients with osteoarthritis, rheumatoid arthritis, and

fibromyalgia. Arthritis and Rheumatism 2000; 43: 378–385.

41. Pincus T, Swearingen C, Cummings P & Callahan LF. Preference for nonsteroidal antiinflammatory drugs

versus acetaminophen and concomitant use of both types of drugs in patients with osteoarthritis. The

Journal of Rheumatology 2000; 27: 1020–1027.

42. Scott DL & Kingsley G. Translating research into practice: acetaminophen in osteoarthritis revisited. The

Journal of Rheumatology 2003; 30: 199–202.

43. March L, Irwig L, Schwarz J et al. n Of 1 trials comparing non-steroidal anti-inflammatory drug with

paracetamol in osteoarthritis. British Medical Journal 1994; 309: 1041–1045.

44. Wegman ACM, Van der Windt DAWM, de Haan M et al. Switching from NSAIDs to paracetamol: a series

of n of 1 trials for individual patients with osteoarthritis. Annals of the Rheumatic Diseases 2003; 62: 1156–

1161.

45. Hochberg MC. What have we learned from the large outcomes trials of COX-2 selective inhibitors?

The rheumatologist’s perspective. Clinical and Experimental Rheumatology 2001; 19(supplement 25):

S15–S22.

46. Schnitzer TJ, Burmester GR, Mysler E et al. Comparison of lumiracoxib with naproxen and ibuprofen in

the therapeutic arthritis research and gastrointestinal event trial (TARGET), reduction in ulcer

complications: randomized controlled trial. Lancet 2004; 364: 665–674.

47. Mahajan A & Sharma A. COX-2 selective nonsteroidal anti-inflammatory drugs: current status. The

Journal of the Association of Physicians of India 2005; 53: 200–204.

48. Chan FKL, Hung LCT, Suen BYet al. Celecoxib versus diclofenac and omeprazole in reducing the risk of

recurrent ulcer bleeding in patient with arthritis. The New England Journal of Medicine 2002; 347: 2104–

2110.

49. Spiegel BMR, Chiou CF & Ofman JJ. Minimizing complications from nonsteroidal anti-inflammatory drugs:

cost-effectiveness of competing strategies in varying risk groups. Arthritis and Rheumatism 2005; 53: 185–

197.

50. Clark DWJ, Layton D & Shakir SAW. Do some inhibitors of COX-2 increase the risk of thromboembolic

events? Linking pharmacology with pharmacoepidemiology. Drug Safety 2004; 27: 427–456.

51. Lenzer J. FDA advisers warn: COX 2 inhibitors increase risk of heart attack and stroke. British Medical

Journal 2005; 330: 440.

52. Johnsen SP, Larsson H, Tarone RE et al. Risk of hospitalization for myocardial infarction among users of

rofecoxib, celecoxib, and other NSAIDs. Archives of Internal Medicine 2005; 165: 978–984.

Acetaminophen or NSAIDs for osteoarthritis treatment 129

53. Heyneman CA, Lawless-Liday C & Wall GC. Oral versus topical NSAIDs in rheumatic diseases. A

comparison. Drugs 2000; 60: 555–574.

54. Lin J, Zhang W, Jones A & Doherty M. Efficacy of topical non-steroidal anti-inflammatory drugs in the

treatment of osteoarthritis: meta-analysis of randomized controlled trials. British Medical Journal 2004;

329: 324–326.

55. Cooper C. Topical NSAIDs in osteoartritis. Best used for short periods during flare-ups in the disease.

British Medical Journal 2004; 329: 304–305.

56. Roth SH & Shainhouse JZ. Efficacy and safety of a topical diclofenac solution (Pennsaid) in the treatment of

primary osteoarthritis of the knee. A randomized, double-blind, vehicle-controlled clinical trial. Archives of

Internal Medicine 2004; 164: 2017–2023.

57. Bagheri H, Lhiaubet V, Montastruc JL & Chouini-Lalanne N. Phorosensitivity to ketoprofen. Mechanisms

and pharmacoepidemiological data. Drug Safety 2000; 22: 339–349.