Population and Condition of Interest

As specified in the Key Questions, this review focuses on adults with osteoarthritis. We included studies that evaluate the safety, efficacy, or effectiveness of the included medications in adults with any grade of osteoarthritis. We also included studies that report safety in patients with rheumatoid arthritis or who were taking the drug for cancer or Alzheimer’s prevention.

Interventions and Comparators of Interest

We considered studies that compared any of the oral and topical analgesics listed in Table 2 to another included drug, or placebo.

Oral agents include:

• COX-2 selective NSAIDs:
  • celecoxib
• Partially selective NSAIDs:
  • etodolac
  • meloxicam
  • nabumetone
• Non-aspirin, nonselective NSAIDs:
  • diclofenac
  • diflunisal
  • fenoprofen
  • flurbiprofen
  • ibuprofen
  • indomethacin
  • ketoprofen
  • ketorolac
  • meclofenamate sodium
  • mefenamic acid
  • naproxen
  • oxaprozin
  • piroxicam
  • sulindac
  • tolmetin
• Aspirin and salsalate:
  • aspirin
  • salsalate
• Acetaminophen and supplements:
  • acetaminophen
  • chondroitin
  • glucosamine

For this report, we defined the terms “selective nonsteroidal anti-inflammatory drug (NSAID)” or “cyclooxygenase (COX)-2 selective NSAID” as drugs in the “coxib” class (e.g. celecoxib, rofecoxib, and valdecoxib). We grouped etodolac, nabumetone, and meloxicam into a separate category that we referred to as “partially selective NSAIDs,” based on in vitro differences in COX-2 selectivity intermediate between COX-2 selective NSAIDs and nonselective NSAIDs. However, whether partially selective NSAIDs are truly different from nonselective NSAIDs is unclear because COX-2 selectivity may be lost at higher doses and the effects of in vitro COX-2 selectivity on clinical outcomes are uncertain.³⁵ The salicylic acid derivatives aspirin and salsalate were also considered a separate subgroup. We defined “non-aspirin, nonselective NSAIDs” or simply “nonselective NSAIDs” as all other NSAIDs. We excluded evidence on NSAIDs unavailable in the United States, leaving celecoxib as the only COX-2 selective NSAID included in this update.

Outcomes of Interest

We included studies that evaluate the safety, efficacy, or effectiveness of the previously mentioned medications. Outcomes include:

• Improvements in osteoarthritis symptoms
• Adverse events were evaluated from studies of the drugs used for osteoarthritis, rheumatoid arthritis, or cancer treatment
  • Cardiovascular (CV): stroke, myocardial infarction, congestive heart failure, hypertension, and angina
  • Gastrointestinal (GI): perforations, symptomatic gastroduodenal ulcers and upper GI bleeding (PUBs), obstructions, dyspepsia
  • Renal toxicity
  • Hepatotoxicity
• Other outcomes of interest: quality of life, sudden death

We defined “benefits” as relief of pain and osteoarthritic symptoms and improved functional status. The main outcome measures for this review were pain, functional status, and discontinuations due to lack of efficacy. Frequently used outcome measures include visual and categorical pain scales.³⁶

Patients use visual analog scales (VAS) to indicate their level of pain, function, or other outcome by marking a scale labeled with numbers (such as 0 to 100) or descriptions (such as “none” to “worst pain I’ve ever had”). One study found minimum clinically important improvement thresholds of an absolute improvement from baseline for 15 to 20 points on a 0 to 100 VAS scale, or a relative improvement of 30 percent to 40 percent.³⁷

Categorical pain scales consist of several pain category options from which a patient must choose (e.g., no pain, mild, moderate, or severe). A disadvantage of categorical scales is that patients must chose among categories that may not accurately describe their pain. A variety of disease-specific and nonspecific scales are used to assess these outcomes in patients with osteoarthritis. Commonly used categorical pain scales include:

• The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), a 24-item, disease-specific questionnaire used to assess the functional status of patients with osteoarthritis of the knee and hip. Separate scores can be calculated for pain (5 items, scored 0 to 20, 0 to 500, or 0 to 100), functional status (17 items, scored 0 to 68, 0 to 1700, or 0 to 100), and stiffness (2 items, scored 0 to 8, 0 to 200, or 0 to 100). For each subscale, the score is calculated by adding the scores for all the items together (in some cases translating to a 100 point scale). A lower score indicates better function.³⁸ One study found minimum clinically important improvement thresholds of an absolute improvement from baseline in the WOMAC total score of about 10 points (on a 0 to 100 scale) or a relative improvement of 25 percent.³⁷
• The Medical Outcomes Short Form-36 (SF-36) health survey, an 8-item questionnaire for measuring health-related quality of life across different diseases. Each item is score from 0 to 100, with higher scores indicating better health. Physical and mental component summary scores can be calculated by combining results for several subscales.³⁹
• Patient Global Assessment of Disease Status and Investigator Global Assessment of Disease Status. The patient or investigator answers questions about the overall response to treatment, functional status, and pain response, using a VAS or categorical scale. Thresholds for minimum clinically important improvements for global assessment of disease status were similar to those for pain, based on a 0 to 100 VAS.³⁷

Another method for measuring outcomes is classifying patients dichotomously as “responders” or “nonresponders.” Responders are often defined as patients with at least a 50 percent improvement in pain or function. The Outcomes Measures in Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) criteria, for example, were developed through a consensus process and classifies patients as responders if they meet specific predefined criteria (≥50% improvement in pain or function that was ≥20 mm on a 100-mm VAS, or a ≥20% improvement in at least two of pain, function, or patient global assessment that was ≥10 mm on a 100-mm VAS).⁴⁰

“Harms” include tolerability (not having to stop the drug due to adverse effects); CV, hepato-, renal, and GI toxicity; and increased risk for hospitalizations, drug interactions, and death. For GI toxicity, we focused on serious complications associated with NSAIDs including perforation, bleeding ulcer, and gastric outlet obstruction, though we also evaluated other GI side effects (such as nausea, dyspepsia, and GI tolerability). We only considered rates of endoscopic ulcers when data on clinical ulcer complications were incomplete or not available.

Timing

We did not apply a minimum threshold for duration of intervention.

Setting

Studies conducted in primary care and specialty settings were included.

Types of Studies

We included systematic reviews⁴¹ and controlled trials pertinent to the Key Questions. We retrieved and evaluated for inclusion and exclusion any blinded or open, parallel or crossover randomized controlled trial that compared one included drug to another, another active comparator, or placebo. We also included cohort and case-control studies with at least 1,000 cases or participants that evaluated serious GI and CV endpoints that were inadequately addressed by randomized controlled trials. We excluded non-English language studies unless they were included in an English-language systematic review, in which case we relied on the data abstraction and results as reported in the systematic review. A list of excluded studies can be found in Appendix E.

Figure 1 depicts the key questions within the context of the PICOTS described in the previous section. In general, the figure illustrates how the nonopioid oral medications, over-the-counter supplements, and topical agents may result in outcomes such as improvements in osteoarthritis symptoms. Also, adverse events (including, but not limited to, CV, GI, renal and hepatic events) may occur at any point after analgesics are received.

Figure 1

Analytic framework.

Assessing Research Applicability

The applicability of trials and other studies was assessed based on whether the publication adequately described the study population, how similar patients were to the target population in whom the intervention will be applied, whether differences in outcomes were clinically (as well as statistically) significant, and whether the treatment received by the control group was reasonably representative of standard practice.⁴⁸ We also recorded the funding source and role of the sponsor. We did not assign a rating of applicability (such as “high” or “low”) because applicability may differ based on the user of this report.

Evidence Synthesis and Rating the Body of Evidence

We assessed the overall strength of evidence for a body of literature about a particular key question in accordance with AHRQ’s Methods Guide for Comparative Effectiveness Reviews,⁴⁵ based on evidence included in the original CER,³² as well as new evidence identified for this update. We considered the risk of bias (based on the type and quality of studies); the consistency of results within and between study designs; the directness of the evidence linking the intervention and health outcomes; the precision of the estimate of effect (based on the number and size of studies and confidence intervals for the estimates); strength of association (magnitude of effect); and the possibility for publication bias. We did not perform original meta-analyses. Rather, we relied on the results of existing individual studies and systematic reviews (including meta-analyses when available).

We rated the strength of evidence for each Key Question using the four categories recommended in the AHRQ guide:⁴⁵ A “high” grade indicates high confidence that the evidence reflects the true effect and that further research is very unlikely to change our confidence in the estimate of effect. A “moderate” grade indicates moderate confidence that the evidence reflects the true effect and further research may change our confidence in the estimate of effect and may change the estimate. A “low” grade indicates low confidence that the evidence reflects the true effect and further research is likely to change the confidence in the estimate of effect and is likely to change the estimate. An “insufficient” grade indicates evidence either is unavailable or does not permit a conclusion.