A comparison of the efficacy and safety of nonsteroidal antiinflammatory agents versus acetaminophen in the treatment of osteoarthritis: A meta-analysis

Authors

  • Chin Lee,

    Corresponding author
    1. Northwestern University, The Feinberg School of Medicine, Chicago, Illinois
    • Northwestern University, The Feinberg School of Medicine, Division of Rheumatology, McGaw Pavilion, 240 East Huron St., 2300, Chicago, IL 60611
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  • Walter L. Straus,

    1. Health Dialog Data Services; West Point, Pennsylvania
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    • Dr. Schnitzer is a consultant for AstraZeneca Pharmaceuticals (London, UK), Glaxo SmithKline (London, UK), Mc-Neil Consumer (Raritan, NJ), Merck & Co., Inc. (West Point, PA), and Norvartis (East Hanover, NJ); he has received clinical research support from AstraZenecea, Merck & Co., Inc., and Novartis; and is on the Speakers' Bureau for Merck & Co., Inc. and Ortho-McNeil Pharmaceutical (Raritan, NJ). Drs. Straus and Barlas are currently employed by Merck & Co., Inc. (West Point, PA). Ms. Vogel was formerly employed by Merck & Co., Inc. (West Point, PA).

  • Robert Balshaw,

    1. Simon Fraser University, Burnaby, British Columbia, Canada
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  • Suna Barlas,

    1. Health Dialog Data Services; West Point, Pennsylvania
    Search for more papers by this author
    • Dr. Schnitzer is a consultant for AstraZeneca Pharmaceuticals (London, UK), Glaxo SmithKline (London, UK), Mc-Neil Consumer (Raritan, NJ), Merck & Co., Inc. (West Point, PA), and Norvartis (East Hanover, NJ); he has received clinical research support from AstraZenecea, Merck & Co., Inc., and Novartis; and is on the Speakers' Bureau for Merck & Co., Inc. and Ortho-McNeil Pharmaceutical (Raritan, NJ). Drs. Straus and Barlas are currently employed by Merck & Co., Inc. (West Point, PA). Ms. Vogel was formerly employed by Merck & Co., Inc. (West Point, PA).

  • Suzanne Vogel,

    1. Health Dialog Data Services; West Point, Pennsylvania
    Search for more papers by this author
    • Dr. Schnitzer is a consultant for AstraZeneca Pharmaceuticals (London, UK), Glaxo SmithKline (London, UK), Mc-Neil Consumer (Raritan, NJ), Merck & Co., Inc. (West Point, PA), and Norvartis (East Hanover, NJ); he has received clinical research support from AstraZenecea, Merck & Co., Inc., and Novartis; and is on the Speakers' Bureau for Merck & Co., Inc. and Ortho-McNeil Pharmaceutical (Raritan, NJ). Drs. Straus and Barlas are currently employed by Merck & Co., Inc. (West Point, PA). Ms. Vogel was formerly employed by Merck & Co., Inc. (West Point, PA).

  • Thomas J. Schnitzer

    1. Northwestern University, The Feinberg School of Medicine, Chicago, Illinois
    Search for more papers by this author
    • Dr. Schnitzer is a consultant for AstraZeneca Pharmaceuticals (London, UK), Glaxo SmithKline (London, UK), Mc-Neil Consumer (Raritan, NJ), Merck & Co., Inc. (West Point, PA), and Norvartis (East Hanover, NJ); he has received clinical research support from AstraZenecea, Merck & Co., Inc., and Novartis; and is on the Speakers' Bureau for Merck & Co., Inc. and Ortho-McNeil Pharmaceutical (Raritan, NJ). Drs. Straus and Barlas are currently employed by Merck & Co., Inc. (West Point, PA). Ms. Vogel was formerly employed by Merck & Co., Inc. (West Point, PA).


Abstract

Objective

To perform a meta-analysis comparing the efficacy and safety of recommended dosages of nonsteroidal antiinflammatory drugs (NSAIDs), including cyclooxygenase 2 inhibitors, versus acetaminophen in the treatment of symptomatic hip and knee osteoarthritis.

Methods

Medline and EMBASE searches were performed for original clinical trials directly comparing NSAIDs with acetaminophen. A standardized form was used to abstract all data, including outcome measures of pain at rest, walking pain, and dropouts due to adverse effects. Inverse-variance-weighted mean differences (WMDs) and 95% confidence intervals (95% CI) for pain measures were determined for treatment groups. Odds ratios (ORs) and 95% CIs were calculated for withdrawals due to adverse events. Results were compared using a random effects model.

Results

Seven articles met inclusion criteria with sufficient data for analysis. Participants had a mean age of 61.1 years and 71.1% were women. Test of heterogeneity was not significant for either rest (P = 0.73) or walking (P = 0.76) pain. The scores for overall pain at rest (WMD −6.33 mm on a 100-mm visual analog scale [VAS], 95% CI −9.24, −3.41) and walking pain (WMD –5.76 mm on a 100-mm VAS, 95% CI –8.99, –2.52) favored the NSAID-treated group. Although NSAIDs elevated the risk of withdrawals due to adverse events, the difference was not statistically significant (OR 1.45, 95% CI 0.93, 2.27).

Conclusion

NSAIDs are statistically superior in reducing rest and walking pain compared with acetaminophen for symptomatic osteoarthritis. Safety, measured by discontinuation due to adverse events, was not statistically different between NSAID- and acetaminophen-treated groups.

INTRODUCTION

The current American College of Rheumatology (ACR) guidelines for the management of osteoarthritis (OA) recommends using acetaminophen as first-line oral pharmacotherapy for treating OA pain (1). The recommendation is based on studies showing comparable efficacy of acetaminophen to nonsteroidal antiinflammatory drugs (NSAIDs) in short-term, symptomatic treatment of mild-to-moderate joint pain due to OA, in addition to its more favorable safety profile (2, 3). However, recent clinical trials have found NSAIDs to be more efficacious than acetaminophen in some groups of patients with OA (4, 5). Moreover, there is evidence suggesting OA patients have greater preference for NSAIDs compared with acetaminophen (6). In the past several years, a new class of NSAIDs, cyclooxygenase 2-selective inhibitors (coxibs), have been introduced. Coxibs offer improved gastrointestinal safety profiles (7–13) and possess comparable efficacy to traditional nonselective NSAIDs. The emergence of coxibs has raised debate over the most appropriate role of NSAIDs in the OA treatment paradigm (14–16).

A previous meta-analysis by Eccles et al compared NSAIDs with acetaminophen using data from 3 clinical trials (17). All included trials evaluated only traditional nonselective NSAIDs because they were completed prior to publication of trials assessing the clinical efficacy of coxibs. Furthermore, in one of the included trials, diclofenac was compared with acetaminophen combined with dextropropoxyphene in subjects from a general practice population with arthralgia, but not necessarily with OA of the hip or knee (18). Since the publication of this meta-analysis, additional clinical trials assessing efficacy of NSAIDs, both nonselective NSAIDs and coxibs, as compared with acetaminophen have been reported.

We conducted a meta-analysis to compare the reported efficacy and safety of recommended dosages of NSAIDs, including coxibs, versus acetaminophen in the treatment of symptomatic hip and knee osteoarthritis.

METHODS

A search of Medline (1966 to February 2003) via PubMed and EMBASE Drugs and Pharmacology database (1991 to first quarter 2003) via Ovid was performed to identify original clinical trials directly comparing NSAIDs with acetaminophen in the treatment of symptomatic hip or knee OA. PubMed is a service of the National Library of Medicine providing access to >12 million Medline citations (19). Ovid is a literature search engine that allows search of multiple databases, including EMBASE Drugs and Pharmacology database, a subset of Excerpta Medica containing >1,560,000 abstracts and citations of drug and pharmacology literature (20).

Search strategy

Medline was searched using the following combinations of broad Major Exploded Subject Headings (MesH) terms or text words: “Osteoarthritis” and “anti-inflammatory agents, nonsteroidal” or “NSAIDs” and “acetaminophen” or “paracetamol.” The EMBASE Drugs and Pharmacology search strategy applied the following combinations of MesH terms or key words: “Osteoarthritis” and “nonsteroidal anti-inflammatory agent” or “nsaids” and “paracetamol” or “acetaminophen.” The search was not restricted by language or study design.

All articles in English underwent duplicate review by 2 authors (CHL and WLS). All non-English articles were reviewed by an investigator fluent in the language of the publication. Bibliographies from all identified full-text articles were screened for any additional relevant articles suitable for inclusion in the study not found by systematic search of Medline and EMBASE Drug and Pharmacology databases. A search of unpublished studies via contact with expert informants knowledgeable in OA therapeutic research and through review of personal files (TJS) was completed to obtain data or results from existing unpublished studies not identified from the formal search of the literature.

Selection criteria

Exclusion criteria for titles.

Titles identified from an initial review of the literature were excluded if the following criteria were met: 1) identified as a review in the title, 2) article title pertained to an animal study, 3) article title did not pertain to OA, or 4) study title pertained to nonoral pharmacologic therapy of OA (e.g., intraarticular injections or topical therapies).

Exclusion criteria for abstracts

Abstracts passing title screening were rejected from further review if any of the following criteria were met: 1) review or summary article, 2) letter, 3) survey, 4) commentary, 5) editorial, 6) note, 7) conference paper, 8) case report, 9) case series, 10) case study, 11) basic science, 12) clinical practice guideline, 13) ad-hoc analysis of previously published data, 14) no direct comparison of an NSAID with acetaminophen or paracetamol, or 15) a study comparing an NSAID with acetaminophen or paracetamol combined with a nonnarcotic analgesic or narcotic agent.

Exclusion criteria for articles

Full-text articles for abstracts not explicitly meeting abstract exclusion criteria were reviewed. Articles found to meet any prior exclusion criteria applicable to abstracts or fulfilling any of the following criteria were excluded from our analysis: 1) a meta-analysis, 2) a single patient trial or “n-of-1” trial, 3) lack of sufficient analyzable data, 4) trial assessing OA in joints other than hips or knees, or 5) duration of exposure to the NSAID in the study was <7 days.

Data abstraction

A standardized form was used to abstract all data, including information on study design; study duration; number of subjects and their demographic data (sex and age); joint sites of OA involvement; information on prior NSAIDs or acetaminophen used by study participants; inclusion of a washout period; incorporation of a flare design; type of outcome measures used, including outcome measures of pain at rest and walking pain as measured by a visual analog scale (VAS); and dropouts due to adverse events. To standardize abstracted data, outcome measures of pain using a 10-cm VAS were collected and converted to a 100-mm scale. All NSAID and acetaminophen dosages utilized in the identified studies were within the range of therapeutic dosages used in clinical practice.

The authors of the identified studies for inclusion were contacted when further clarification of original study data or if additional information was necessary. In the study by Pincus et al, the authors provided baseline, 6-week followup, and mean difference in pain data for the rest and walking pain components of the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) target joint outcome measures reported in the original study (4). Case et al supplied baseline, 6-week, and 12-week efficacy data for WOMAC rest and walking pain scores (21). Williams et al provided 6-week data on dropouts due to adverse events (22).

Variables

Our overall measure of efficacy was the inverse-variance-weighted mean difference (WMD) of rest and walking pain measures derived from pooled pain data (in the form of pain scores as measured by or converted to a 100-mm VAS) across included studies. Our safety measure was based on number of subject withdrawals due to adverse events (AEs) from either the NSAID or acetaminophen groups.

Study quality assessment

We applied the Jadad criteria, an accepted measure of evaluating clinical trial quality, to determine the methodologic quality of the included studies (23). The Jadad criteria were developed using actual published clinical trial data. They assess details of 3 items directly related to reduction of bias: blinding, randomization, and subject dropouts or withdrawals. The quality of a study was scored on a scale of 0–5, with a score of 3 or greater indicating a high-quality study. Articles having a Jadad score ≥ 2 were included for review due to the limited number of existing studies comparing NSAIDs with acetaminophen.

Statistical analysis

Abstracted information on number of subjects in each treatment group, data on pain levels at baseline and at the end of a study period measured on a 100-mm VAS, and accompanying standard deviations were used to determine mean change in pain level. All rest and walking pain data were entered into Review Manager (RevMan), Version 4.1 (The Cochrane Collaboration, Oxford, England) for analysis. In studies that did not explicitly provide standard deviations for rest and walking pain scores, the standard deviations using the square roots of the simple averages of within-study variances were calculated. Difference in mean change in pain level from baseline to the end of a study period, and the provided or calculated standard deviations were used to determine point estimates for rest and walking pain data for NSAID and acetaminophen treatment groups.

The presence of heterogeneity was explored using a random effects model (DerSimonian and Laird's Q-test) (24). Pain data were pooled across all NSAID groups in studies with multiple NSAID treatment arms to derive point estimates for pain scores in the absence of any significant heterogeneity. An inverse variance method was employed to combine point estimates for rest and walking pain scores from across all studies to derive an overall efficacy as represented by the WMD expressed using a 100-mm VAS for NSAID and acetaminophen groups. The 95% confidence intervals (95% CIs) for WMD of rest and walking pain measures were determined for NSAID and acetaminophen groups in each of the individual studies, and an overall WMD was calculated using pooled pain data from across the studies. Cohen's effect sizes (ESs) were determined using the mean improvement in pain scores and the reported or calculated standard deviations (25, 26).

Odds ratios (ORs) and 95% CIs were calculated for the safety measure as indicated by withdrawals due to AEs in all identified studies with sufficient analyzable data. An analysis comparing safety measures after excluding low-dose NSAID treatment arms was performed to compare high-dose NSAID with acetaminophen groups. In this study, for trials including more than one NSAID dosage, total daily doses of rofecoxib of 12.5 mg, celecoxib of 200 mg, and ibuprofen of <2,400 mg were categorized as low-dose NSAID arms, whereas total daily doses of ibuprofen of 2,400 mg and rofecoxib of 25 mg were considered high-dose NSAID arms. Analyses of available efficacy and safety data from all included trials and subanalyses of these data from high-quality studies (Jadad score ≥ 3) were performed.

RESULTS

A total of 25 articles were identified following application of exclusion criteria for titles and abstracts from the search of Medline and EMBASE Drug and Pharmacology databases (Figure 1). Fourteen articles, 2 of which were duplicate studies, were rejected based on the predetermined exclusion criteria (Table 1) (17, 27–37). Of the 10 remaining articles, 3 were redundant publications referenced in both literature databases, resulting in 7 nonduplicate trials containing sufficient data for analysis (Figure 1) (4, 22, 38–41).

Figure 1.

Results of Medline and EMBASE Drug and Pharmacology database search.

Table 1. Excluded studies or articles identified from a computerized search of Medline and EMBASE Drug and Pharmacology databases*
StudyReason for exclusion
  • *

    NSAID = nonsteroidal antiinflammatory drug; OA = osteoarthritis.

  • Study or article identified in Medline.

  • Study or article identified in EMBASE Drug and Pharmacology database.

  • §

    Duplicate articles identified in both Medline and EMBASE Drug and Pharmacology databases.

Seideman, 1993No direct comparison between NSAID and acetaminophen
Brooks, 1982No direct comparison between NSAID and acetaminophen
Solomon, 1974Insufficient data for analysis
Wojtulewski, 1974Insufficient data for analysis
Wojtulewski, 1974Insufficient data for analysis
Maneksha, 1973Insufficient data for analysis
Eccles, 1998Meta-analysis
Wegman, 2003Single-patient trial
Rovetta, 2001Trial involving OA of sites other than hip or knees
Whitehead, 1997Insufficient data for analysis
Hackenthal, 1997Review
Nikles, 2000§Single-patient trial
March, 1994§Single-patient trial

Study characteristics

The 7 studies included for analysis were composed of the following study designs: 2 randomized active comparator trials, which did not include placebo arms; 2 randomized parallel-group double-blinded trials; 2 randomized crossover trials; and 1 randomized placebo-controlled double-blinded trial (Table 2). A total of 1,252 subjects were randomized, with 752 subjects in the NSAID groups and 500 subjects placed in the acetaminophen groups. All studies included subjects with knee OA, but only the trials by Pincus et al and Lequesne et al included individuals with hip OA (4, 39). Seven different types of NSAIDs, including 2 coxibs, within recommended dose ranges were compared with acetaminophen with total daily doses ranging from 2,600 mg to 4,000 mg depending on the study. The mean ± SD duration of trial period providing data for analysis was 49.4 ± 24.7 days (range 24–84 days). Of the 7 clinical trials included for review, 5 were of high methodologic quality based on a Jadad score ≥ 3 (4, 21, 22, 38, 41).

Table 2. Characteristics of trials comparing efficacy of nonsteroidal antiinflammatory drug(s) to acetaminophen in treatment of osteoarthritis*
Study, yearnStudy designNSAID; total dosage, mg/day; no.Acetaminophen total dosage, mg/day; no.Duration, daysQuality score
  • *

    NSAID = nonsteroidal antiinflammatory drug.

  • Quality score as per Jadad criteria.

  • Sponsored by National Institutes of Health.

  • §

    Sponsorship not stated.

  • Sponsored by Merck & Co. Inc.

  • #

    Sponsored by Diamant Pharmaceuticals.

  • **

    Pre- and postcrossover data included.

  • ††

    Sponsored by Pharmacia.

  • ‡‡, ‡

    Outcome data for 106 participants available.

  • §§

    Outcome data for 112 participants available.

  • ¶¶

    Only precrossover data included because flare status of participants was unclear prior to crossover.

  • ##

    Intent-to-treat data from first 42 days analyzed.

Bradley, 1991184Randomized comparator without placeboIbuprofen; 2,400; 614,000; 61284
   Ibuprofen; 1,200; 62   
Case, 200382Randomized placebo controlled double blindedDiclofenac; 150; 254,000; 29844
Erturk, 1998§35Randomized comparator without placeboAcemetacin; 90; 202,000; 15842
Geba, 2002382Randomized parallel group double blindedCelecoxib; 200; 974,000; 94425
   Rofecoxib; 12.5; 96   
   Rofecoxib; 25; 95   
Lesquesne, 1997#192Randomized crossoverFloctafenin; 800; 943,000; 9824**2
Pincus, 2001††227Randomized crossoverDiclofenac; 150; 112‡‡4,000; 115§§42¶¶4
Williams, 1993178Randomized parallel group double blindedNaproxen; 750; 902,600; 88730##5

Study participants

Overall, the mean age of the study participants was 61.1 years and most (71.1%) were women with OA involving the hip or knee. Subjects randomized into NSAID and acetaminophen arms were similar as regard to age and sex. Information on duration of OA in subjects prior to study enrollment was not uniformly available from all studies.

Outcome variables

Two of the identified studies provided usable pain data for either rest or walking pain exclusively. The study by Erturk et al (40) contained outcome measures only for walking pain scores, whereas the trial performed by Lequesne et al (39) provided outcome results for only rest pain data. A total of 726 subjects from the NSAID groups versus 482 subjects in the acetaminophen groups from 5 of the original 7 studies contributed analyzable data for rest pain. In comparison, a total of 652 subjects from the NSAID groups versus 399 subjects in the acetaminophen groups from 6 of 7 identified studies contributed analyzable data for walking pain.

Analysis of outcome variables

The test of heterogeneity was not statistically significant for either rest pain (χ2 = 2.81, degrees of freedom [df] = 5, P = 0.73) or walking pain (χ2 = 2.60, df = 5, P = 0.76), thus allowing us to pool data across included studies. Point estimates for rest pain improvement as indicated by the WMD revealed improvement favoring the NSAID-treated groups in 5 of the 6 studies (Figure 2). There was a statistically significant reduction in rest pain (P < 0.05) favoring the NSAID groups in 3 of the 6 studies. Overall improvement in rest pain using pooled data across all 6 studies showed a WMD of −6.33 (95% CI –9.24, –3.41; Figure 2) and an average ES of 0.23 favoring NSAID-treated groups. A subanalysis of improvement in rest pain for 5 of the 6 studies meeting criteria for high methodologic quality showed similar results (WMD = –6.01; 95% CI –9.21, –2.81; ES = 0.22).

Figure 2.

Forest plots of weighted mean differences for rest and walking pain improvement in nonsteroidal antiinflammatory drug (NSAID)– versus acetaminophen-treated groups. 95% CI = 95% confidence interval.

Similarly, point estimates for walking pain (as indicated by the WMD) showed improvement in 5 of 6 studies favoring the NSAID-treated groups, however, in only 2 of the 6 studies did this difference reach statistical significance. As in the case for rest pain, the overall improvement in walking pain using pooled data from all 6 studies demonstrated a WMD of –5.76 (95% CI –8.99, –2.52; Figure 2) and an average ES of 0.23 favoring the NSAID-treated groups. A subanalysis of improvement in walking pain for 5 of the 6 studies meeting criteria for high methodologic quality showed similar results (WMD = –5.67; 95% CI –8.97, –2.38; ES = 0.22).

Results for safety showed the NSAID-treated groups as having a numerically higher number of dropouts due to AEs (n = 63) than the acetaminophen-treated groups (n = 32) (Table 3). Of the 7 identified studies, the ORs for 6 trials were estimable to determine safety. The OR was not estimable for the study by Erturk et al (40) because there were no withdrawals due to AEs. The 6 studies contributing AE data demonstrated a 95% CI that included 1 indicating no statistically significant difference in any individual study favoring either the NSAID- or acetaminophen-treated groups. Similarly, the overall safety measure derived from the pooled data for dropouts due to AEs showed no statistically significant difference between the NSAID- and acetaminophen-treated groups (OR 1.45; 95% CI 0.93, 2.27), as shown in Figure 3. However, the overall trend for safety favored the acetaminophen-treated groups. A subanalysis with exclusion of low-dose NSAID arms, thus comparing the high-dose NSAID- versus acetaminophen-treated groups (Table 3), revealed no statistically significant difference favoring either group, yet the general trend for safety further favored the acetaminophen-treated groups (OR 1.59; 95% CI 0.99, 2.54), as shown in Figure 4. An analysis of dropouts due to AEs of high-dose NSAID compared with acetaminophen among the 5 studies meeting criteria for high methodologic quality showed similar findings (OR 1.52; 95% CI 0.88, 2.62). The specific types of AEs resulting in withdrawal for all included studies were not discernible because of the 6 studies reporting withdrawals due to AEs, 1 study reported AEs for all subjects without specifying the number of withdrawals due AEs. In the remaining 5 studies, specific types of AEs leading to subject withdrawal were clearly discernable in only 2 of the publications.

Table 3. Comparison of dropouts due to adverse events in NSAID-, high-dose NSAID-, and acetaminophen-treated groups*
Study, yearAll NSAID groupsHigh-dose NSAID groups only*Acetaminophen
DropoutsSubjects%DropoutsSubjects%DropoutsSubjects%
  • *

    High-dose nonsteroidal antiinflammatory drug (NSAID)–treated groups excluded low-dose NSAID arms (total daily doses of ibuprofen <2,400 mg, rofecoxib dose of 12.5 mg, and celecoxib dose of 200 mg).

  • High-dose NSAID-treated group consisted of ibuprofen 2,400 mg/day arm.

  • High-dose NSAID-treated group consisted of rofecoxib 25 mg/day arm.

Bradley, 1991101238.16619.85618.2
Case, 200332512.032512.02296.9
Erturk, 19980200.00200.00150.0
Geba, 2002172885.96956.36946.4
Lequesne, 1997139413.8139413.88988.2
Pincus, 20011211210.71211210.761155.2
Williams, 19938908.98908.95885.7
Total637528.4484979.7325006.4
Figure 3.

Dropouts due to adverse events as a measure of safety in nonsteroial antiinflammatory drug (NSAID)– versus acetaminophen-treated groups. 95% CI = 95% confidence interval.

Figure 4.

Dropouts due to adverse events as a measure of safety in high-dose nonsteroidal antiinflammatory drug (NSAID)– versus acetaminophen-treated groups.

DISCUSSION

Our results indicate a statistically significant improvement of rest and walking pain favoring NSAID- versus acetaminophen-treated groups in studies with subjects having symptomatic hip or knee OA. Of particular note is the consistency of this finding across the evaluated studies, with all of the trials demonstrating point estimates favoring NSAIDs over acetaminophen. In terms of safety, there was an absence of any statistically significant difference in AE-associated withdrawals between NSAIDs and acetaminophen groups across studies, but there was a trend for improved safety favoring acetaminophen. We observed similar efficacy and safety results in our analysis of only those studies with Jadad scores ≥3, therefore, inclusion of studies having lower Jadad scores had minimal impact on the findings.

A prior meta-analysis by Eccles et al comparing NSAID and acetaminophen consisted of 3 trials, 1 of which included acetaminophen in combination with propoxyphene as a direct comparator to the diclofenac; furthermore, the trial participants had arthralgias but did not have to meet predefined OA criteria for study enrollment (17, 18). The current meta-analysis includes 5 additional trials not evaluated in the meta-analysis by Eccles et al. Additionally, all trials in the present meta-analysis assessed individuals having predefined OA of the hip or knee. With the exception of 2 studies (4, 38), which allowed use of propoxyphene as rescue therapy during the trial, either a traditional NSAID or coxib was compared with acetaminophen alone, thus optimizing comparability between NSAIDs and acetaminophen.

Meta-analysis provides a systematic approach to compare results across similar trials (42). The improvements in pain outcome reported by the WMDs are consistent with previously reported findings in all individual trials identified for analysis, with the exception of those observed by Bradley et al (38). The Bradley trial found statistically similar improvement in walking pain scores in both the acetaminophen and NSAID groups, whereas NSAIDs were found to be superior to acetaminophen alone for rest pain scores. In contrast, analysis of the reported Bradley data in this study shows NSAIDs to be statistically superior to acetaminophen in reduction of both rest and walking pain measures. The observed discrepancy may be accounted for by our approach of pooling data across the 2 NSAID groups from the Bradley trial that permitted a more precise estimate of the WMD between NSAIDs and acetaminophen groups; additionally, the Bradley trial was not designed or powered as an equivalency study. The failure to show superiority of NSAIDs to acetaminophen for walking pain in the original study may have been a function of the relatively small sample size.

Despite the consistent superiority for OA symptom improvement favoring NSAIDs in all but 1 of the included studies, there are limited data to correlate these results with clinical significance. A recent study determined that differences of 9–12 mm on a normalized 100-mm VAS pain scale were required to achieve minimal perceptible clinical improvement in pain among patients with knee or hip OA (43). Similarly, estimation of Cohen's effect sizes to determine the standardized mean difference for improvement in rest and walking pain between NSAIDs and acetaminophen in the analyzed studies are approximately between 0.2 and 0.3, a range generally considered to reflect a small effect size (5, 25). Thus, the additional clinical benefit in reduction of rest or walking pain with relatively short-term (4 of the studies were ≤ 6 weeks in duration) use of NSAIDs compared with acetaminophen may be limited. However, additional study is needed to better interpret the clinical significance of these differences.

Various factors may impact the results from individual studies, and hence our overall analysis. First, at least 2 of the larger studies, specifically the trials by Bradley et al (38) and Geba et al (41) included in this meta-analysis were evaluated under clinical trial conditions that required a flare of OA pain after discontinuation of any prior medication. With the incorporation of a flare design, these 2 higher-weighted trials contributing to our meta-analysis focused on relief of moderate-to-severe levels of pain. It has been proposed that NSAIDs are more effective than acetaminophen at higher pain levels (5), which would be consistent with findings from these 2 trials. The relative efficacy of NSAIDs and acetaminophen to relieve mild pain may differ from what is reported in such trials. Because data were not available at an individual subject level from most of these studies, the question of heterogeneity in pain relief with different baseline pain levels could not be investigated.

In addition, data were unavailable regarding patients' prior experience with acetaminophen or NSAIDs. There is the possibility that some of these trials were undertaken in populations enriched with subjects who were nonresponders or underresponders to acetaminophen or NSAIDs. Such data would have been useful to address possible selection bias. These points are important to keep in mind when attempting to extrapolate the results to the clinical setting.

Two of the 7 studies (4, 38) clearly indicated the use of rescue medication during the trial. Propoxyphene was employed in both studies, however, the frequency of use by either treatment group was unavailable from either publication. One study (41) allowed acetaminophen as rescue therapy, but only during the washout period. The remaining studies included in our analysis did not indicate if rescue medication was utilized. Individuals with greater baseline level of OA pain or use of a limited form of treatment, whether an NSAID or acetaminophen, would be more likely to utilize rescue therapy. However, without data on active use of rescue medication from any of the studies, conclusions in regard to this issue would be speculative.

A formal test of heterogeneity based on dosage of either NSAID or acetaminophen failed to demonstrate significance, thus allowing comparison of the different treatment groups. However, reasonable exploration of any underlying differences in efficacy based on varying NSAID dosages (i.e., high versus low) among the included treatment groups was limited by the small number of studies with different dosage levels of NSAIDs examined. In general, previous investigations have failed to demonstrate clinically meaningful differences between varying dosage levels of NSAIDs for the treatment of OA pain (26, 44).

Although the absolute number of withdrawals due to AEs was greater in the NSAID- than acetaminophen-treated groups, this finding did not reach statistical significance. The trend for higher withdrawals in the NSAID arms due to AEs was accentuated with elimination of low-dose NSAIDs, suggesting an overall tolerability/safety advantage for the tested acetaminophen regimens. However, the significance of this finding is limited by the relatively small number of high-dose NSAID groups assessed, along with the lower daily dosages of acetaminophen used in 3 of the comparator groups. Finally, only 1 study employing a high-dose coxib (i.e., rofecoxib 25 mg/day) was included in analysis of high-dose NSAID arms; however, there were insufficient data to specifically address the safety of coxibs versus acetaminophen.

The included studies offered limited uniform data on specific types of treatment- associated AEs leading to withdrawal; thus, our safety variable served as a relatively crude means of evaluating overall drug safety. Because these trials were primarily designed to assess efficacy, there were less systematically recorded safety data available. It is likely that other clinical trials would be needed to more satisfactorily address the types and frequencies of specific AEs associated with NSAIDs versus acetaminophen, and in turn allow a more precise assessment of risk–benefit ratio of either therapy in the treatment of symptomatic OA.

There are inherent limitations in most meta-analyses. One of these is publication bias, which refers to the tendency for authors and peer-refereed journals to preferentially publish studies that report positive results. Studies that report null or nonsignificant conclusions are less likely to be published (42), and this may be applicable to industry-supported trials (45). In a study reviewing published randomized controlled trials of NSAIDs for treatment of osteoarthritis and rheumatoid arthritis, Rochon et al (46) reported that industry-associated NSAIDs were often equal or superior in efficacy and safety to the comparison drug in industry-supported trials (46). Not all of the trials examined in this study had industry sponsorship. Two of the 3 studies undertaken without industry support (22, 38) demonstrated improvement for rest pain favoring NSAIDs, and 1 (38) showed NSAIDs to be superior compared with acetaminophen for walking pain. In contrast, industry-supported trials demonstrated less robust findings favoring NSAID efficacy. Regardless of sponsorship, there was a consistent, but not statistically significant, trend for greater AE-associated withdrawal across all studies for the NSAID groups. These observations suggest an absence of sponsorship influence on outcomes among the identified trials analyzed in this meta-analysis.

Despite assiduous efforts to obtain data from known studies relevant to the issue of publication bias, we were unable to obtain data from investigators of at least 3 previously completed OA trials containing data directly comparing NSAIDs with acetaminophen. We cannot draw any additional conclusions on the effect of not having included these data. Additionally, due to the limited number of identified articles and the familiarity of the studies by the investigators, the abstraction process was not blinded, potentially introducing further bias during data collection. However, utilization of standardized data abstraction forms and the use of multiple data extractors were designed to minimize bias in the data abstraction process.

The findings of this study can be used to generate further discussion regarding the current ACR guidelines recommending the use of acetaminophen as first-line oral pharmacologic treatment of symptomatic hip and knee OA. Acetaminophen has been favored as first-line OA therapy by the ACR because of its analgesic efficacy, favorable safety profile, and relatively low cost. In this meta-analysis, NSAID therapy was consistently associated with statistically superior efficacy in relief of resting and walking pain. In aggregate, the efficacy advantages were relatively modest in effect and were accompanied by a trend for higher AE risk in the NSAID-treated subjects. The small number of available studies did not allow us to address several outstanding questions, including the efficacy of high-dose nonselective NSAIDs or different coxibs versus high-dose acetaminophen (i.e., 4,000 mg per day) nor to fully characterize the associated safety and tolerability differences.

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