Analgesics for Osteoarthritis— An Update Prepared for: Agency for

Analgesics for Osteoarthritis— An Update Prepared for: Agency for Healthcare Research and Quality (AHRQ) www.ahrq.gov

Outline of Material Introduction to osteoarthritis and nonopioid analgesics for osteoarthritic pain Systematic review methods The clinical questions addressed by the comparative effectiveness review Results of studies and evidence-based conclusions on the effectiveness and adverse effects of nonopioid analgesics for osteoarthritic pain Gaps in knowledge and future research needs What to discuss with patients and their caregivers Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Background: Characteristics of Osteoarthritis Osteoarthritis is a chronic condition involving degeneration of cartilage within joints. It is associated with pain, substantial disability, and reduced quality of life. Osteoarthritis is the most common form of arthritis and is more common in older individuals. It affects about 27 million adults in the United States and is a leading cause of disability. Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm. Felson DT, Zhang Y. Arthritis Rheum 1998 Aug 4;41(8):1343-55. PMID: 9704632. Lawrence RC, Felson DT, Helmick CG, et al. Arthritis Rheum 2008 Jan;58(1):26-35. PMID: 18163497.

Background: Nonopioid Analgesics for Osteoarthritis Common oral nonopioid analgesics: Nonsteroidal anti-inflammatory drugs (NSAIDs) Aspirin Salsalate Acetaminophen Over-the-counter supplements (glucosamine and chondroitin) Topical agents (NSAIDs and rubefacients, including capsaicin) Each class of medication or supplement is associated with a unique balance of risks and benefits. Efficacy and safety may also vary for individual drugs within a class. A challenge in treating osteoarthritis is deciding which medications will provide the greatest symptom relief with the least harm. Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm. Zhang W, Doherty M, Leeb BF, et al. Ann Rheum Dis 2007 Mar;66(3):377-88. PMID: 17046965.

Background: Nonsteroidal Anti-inflammatory Drugs NSAIDs block cyclooxygenase (COX) enzymes, particularly COX-1 and COX-2. COX-1 mediates the mucosal protection of the gastrointestinal (GI) mucosa. COX-2 mediates effects on pain and inflammation. By blocking COX-2 enzymes, NSAIDs decrease pain and inflammation. Nonselective NSAIDs block both COX-1 and COX-2. NSAIDs that block COX-1 can cause GI adverse effects, including bleeding. Selective or partially selective (in vitro) NSAIDs block mostly COX2, and thus should be safer with regard to GI adverse effects. However, COX-2 selectivity may be lost at higher doses. All NSAIDs can also cause cardiovascular adverse effects. Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Background: Oral Nonopioid Analgesics Studied COX-2 selective NSAIDs: Celecoxib Partially selective NSAIDs: Etodolac Meloxicam Nabumetone Nonaspirin nonselective NSAIDs: Aspirin Salsalate Acetaminophen Supplements: Chondroitin Glucosamine Diclofenac Ibuprofen Naproxen Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Background: Glucosamine and Chondroitin Glucosamine and chondroitin are natural compounds found in cartilage that are marketed to patients with osteoarthritis. Their precise mechanisms of action are unknown but may involve promotion of maintenance and repair of cartilage. In Europe, glucosamine is available as a prescription drug. In the United States, however, glucosamine and chondroitin are dietary supplements and are not regulated as pharmaceuticals. Thus, adequate standardization of glucosamine and chondroitin preparations is a significant concern. The actual content of different commercial preparations often varies substantially from what is stated on the label, which could affect effectiveness and safety. Adebowale AO, Cox DS, Liang Z, et al. J Am Nutraceutical Assoc 2000;3(1):37-44. Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others. A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment. The results of these reviews are summarized into Clinician Research Summaries and Consumer Research Summaries for use in decisionmaking and in discussions with patients. The summaries and the full report, with references for included and excluded studies, are available at www.effectivehealthcare.ahrq.gov. Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Clinical Questions Addressed by the CER (1 of 2) Key Question (KQ) 1: What are the comparative benefits and adverse effects of treating osteoarthritis with oral medications or supplements? How do these benefits and adverse effects change with dosage and duration of treatment? The only benefits considered here are improvements in osteoarthritic symptoms. KQ 2: Do the comparative benefits and adverse effects of oral treatments for osteoarthritis vary for certain demographic and clinical subgroups of patients? Demographic subgroups: age, sex, and race Coexisting disease: cardiovascular (CV) conditions, such as hypertension, edema, ischemic heart disease, heart failure; peptic ulcer disease; history of previous GI bleeding (any cause); renal disease; hepatic disease; diabetes; and obesity Concomitant medication use: antithrombotics, corticosteroids, antihypertensives, and selective serotonin-reuptake inhibitors (SSRIs) Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Clinical Questions Addressed by the CER (2 of 2) KQ 3: What are the comparative effects of coprescribing H2-receptor antagonists, misoprostol, or proton pump inhibitors (PPIs) on the GI adverse effects associated with NSAID use? KQ 4: What are the comparative benefits and adverse effects of treating osteoarthritis with oral medications as compared with topical preparations, or of different topical medications compared with one another? Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Rating the Strength of Evidence From the CER The strength of evidence was classified into four broad categories: Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Comparative Effectiveness of Oral Agents: NSAIDs versus NSAIDs No difference in efficacy in relieving osteoarthritic pain was found between celecoxib, the partially selective NSAIDs meloxicam and etodolac, and nonselective NSAIDs. Strength of evidence: High No difference in efficacy was found between various nonselective NSAIDs for the relief of osteoarthritic symptoms. Strength of evidence: High Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Comparative Effectiveness of Oral Agents: NSAIDs versus Other Agents Acetaminophen was modestly inferior to NSAIDs in reducing osteoarthritic pain, but was associated with less risk of GI adverse effects than were NSAIDs. Strength of evidence: High No clear difference was found between glucosamine* and oral NSAIDs for pain or function. Evidence from a systematic review of higher quality trials suggests that glucosamine had some small benefits for pain over placebo. Strength of evidence: High *Note: Most trials showing therapeutic benefits from glucosamine were conducted with pharmaceutical-grade glucosamine not available in the United States. Therefore, the findings of these trials may not be applicable to currently available over-the-counter preparations. No clear difference was found between chondroitin and oral NSAIDs for pain or function. Strength of evidence: Low Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Comparative Effectiveness of Oral Agents: Aspirin and Salsalate Salsalate and full-dose aspirin were not compared to NSAIDs but had similar efficacy when compared with each other. Strength of evidence: Low Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Comparative Adverse Effects of Oral Agents: GI Effects (1 of 2) Acetaminophen could cause elevations of liver enzymes at therapeutic doses in healthy people. Strength of evidence: Moderate to Low Selective NSAIDs as a class were associated with less risk of ulcer complications than were the nonselective NSAIDs naproxen, ibuprofen, and diclofenac. Strength of evidence: High Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Comparative Adverse Effects of Oral Agents: GI Effects 2 of 2) The partially selective NSAIDs meloxicam and etodolac were associated with less risk of ulcer complications and symptomatic ulcers than were various nonselective NSAIDs. Strength of evidence: Moderate A higher risk of serious GI adverse effects was found with naproxen than with ibuprofen. Strength of evidence: High Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Comparative Adverse Effects of Oral Agents: CV Effects Celecoxib and the nonselective NSAIDs ibuprofen and diclofenac were associated with an increased risk of cardiovascular (CV) adverse effects when compared with placebo. Strength of evidence: Moderate The nonselective NSAIDs ibuprofen and diclofenac, but not naproxen, were associated with an increased risk of heart attack when compared with placebo. Strength of evidence: Moderate All NSAIDs had deleterious effects on blood pressure, edema, and kidney function. There were no consistent clinically relevant differences between celecoxib, partially selective NSAIDs, and nonselective NSAIDs in the risk of hypertension, heart failure, or impaired kidney function. Strength of evidence: Moderate Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Comparing Dosage and Duration of Treatment Higher doses of NSAIDs were associated with greater efficacy for some measures of pain relief but also with more adverse effects in some cases. Strength of evidence: High Higher doses of celecoxib increased the risk of CV adverse effects; however, there was no clear association between duration of therapy and the risk of CV adverse effects. Strength of evidence: High Higher doses of nonselective NSAIDs increased the risk of GI bleeding; however, there was no clear association between duration of therapy and the risk of GI bleeding. Strength of evidence: High Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Factors Affecting Outcomes: Demographic Subgroups The absolute risk of serious GI and CV complications increased with age. Strength of evidence: Moderate Evidence was insufficient to determine the comparative benefits and adverse effects of different selective and nonselective NSAIDs in men and women or in different racial groups. Strength of evidence: Insufficient Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Factors Affecting Outcomes: Preexisting Disease The risk of GI bleeding was higher in individuals taking NSAIDs who had had previous bleeding than those who had not. Strength of evidence: Moderate Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Factors Affecting Outcomes: Concomitant Medication Use Concomitant use of low-dose aspirin with celecoxib or a nonselective NSAID increased the rate of endoscopic ulcers by about 6 percent. Strength of evidence: High Concomitant use of low-dose aspirin eliminated the GI benefits of selective NSAIDs, resulting in risks similar to those for nonselective NSAIDs. However, adding a PPI could reduce the risk of GI adverse effects associated with the use of either celecoxib or nonselective NSAIDs plus low-dose aspirin. Strength of evidence: High Concomitant use of anticoagulants and nonselective NSAIDs increased the risk of GI bleeding three-fold to sixfold when compared with anticoagulant use without NSAIDs. Strength of evidence: Moderate Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Effects of Adding an H-2 Antagonist, Misoprostol, or a PPI on GI Adverse Effects Associated With NSAIDs (1 of 3) Adding an H-2 antagonist, misoprostol, or a PPI reduced the risk of endoscopically detected gastric and duodenal ulcers in patients prescribed a nonselective NSAID. Strength of evidence: High Misoprostol was the only gastroprotective agent to reduce the risk of ulcer complications versus placebo in individuals with average risk of GI bleeding who were prescribed nonselective NSAIDs. However, individuals could experience other adverse GI symptoms while taking misoprostol. Strength of evidence: High Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Effects of Adding an H-2 Antagonist, Misoprostol, or a PPI on GI Adverse Effects Associated With NSAIDs (2 of 3) In individuals with increased risk of GI bleeding who were prescribed a nonselective NSAID, adding a PPI resulted in: A reduced risk of endoscopically detected duodenal ulcers when compared with misoprostol or H-2 antagonists Strength of evidence: High A lower risk of endoscopically detected gastric ulcers when compared with H-2 antagonists Strength of evidence: High A similar risk of endoscopically detected gastric ulcers when compared with misoprostol Strength of evidence: High Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Effects of Adding an H-2 Antagonist, Misoprostol, or a PPI on GI Adverse Effects Associated With NSAIDs (3 of 3) Celecoxib plus a PPI could reduce the risk of endoscopic ulcers and ulcer complications when compared to celecoxib alone in individuals at average risk. Strength of evidence: Moderate When compared with placebo, double-dose H-2 antagonists could be more effective than standarddose H-2 antagonists for reducing endoscopically detected gastric and duodenal ulcers. Strength of evidence: High Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Topical Analgesics (1 of 2) Topical diclofenac was similar in efficacy to oral NSAIDs for treating localized osteoarthritis. Strength of evidence: Moderate Topical NSAIDs were associated with a lower risk of GI adverse effects but a higher risk of dermatologic adverse effects (dry skin, rash, and itching) when compared to oral NSAIDs. Strength of evidence: Moderate Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Topical Analgesics (2 of 2) Topical salicylates were not effective for patients with osteoarthritis and were associated with increased risk of local adverse effects. Topical salicylates were not compared to NSAIDs. Strength of evidence: Low Topical capsaicin was effective for treating osteoarthritis but was associated with an increase in local adverse effects. Topical capsaicin was not compared to NSAIDs. Strength of evidence: Low Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Conclusions (1 of 2) When analgesics are compared to each other, none appears to offer greater benefits relative to adverse effects at this time. Trade-offs between benefits and adverse effects appear to differ across analgesics, increasing the need to consider individual patient priorities when choosing among these medications. No significant differences were found in the benefits offered by NSAIDs; however, differences in GI adverse effects must be balanced with associated CV risks. Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Conclusions (2 of 2) Evidence suggests that age, comorbid conditions, and concomitant medication are key considerations affecting decisionmaking. The evidence concerning the use of glucosamine and chondroitin appears unresolved and may not directly apply to unregulated products available in the United States. There is evidence that the topical NSAID diclofenac works as effectively as the oral agent. Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Knowledge Gaps and Future Research Needs (1 of 3) Most of the clinical trials reviewed were “efficacy” trials conducted in ideal settings and among selected populations. “Pragmatic” trials that allow flexible dosing or medication switches and other clinical trials of effectiveness would be valuable for learning the outcomes of different analgesic interventions in realworld settings. More evidence is needed to assess the comparative CV risks and GI benefits associated with different COX-2 selective NSAIDs. Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Knowledge Gaps and Future Research Needs (2 of 3) The risks associated with selective COX-2 inhibitors need better assessment for the effects of dose and duration. More evidence is needed to determine the CV safety of nonselective NSAIDs. Evidence is lacking to determine the GI and CV safety of full-dose aspirin, salsalate, or acetaminophen when compared with nonaspirin NSAIDs or placebo. The effects of alternative dosing strategies such as intermittent dosing or drug holidays have not been studied. Chouwell R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

Knowledge Gaps and Future Research Needs (3 of 3) Most trials showing therapeutic benefits from glucosamine were conducted with pharmaceuticalgrade glucosamine not available in the United States and may not be applicable to currently available over-the-counter preparations. More evidence is needed comparing currently available over-the-counter preparations to oral NSAIDs, as these are likely to remain available even if the FDA approves a pharmaceutical-grade glucosamine. More evidence is needed to evaluate the comparative risks of serious CV and GI adverse Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the effects for oral NSAIDs versus topical NSAIDs. 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.

What To Discuss With Your Patients and Their Caregivers The importance of managing osteoarthritis-related pain and inflammation for improving quality of life and function. The potential benefits and adverse effects associated with different types of nonopioid analgesics based on the characteristics of the individual patient. Individual patient values and preferences when considering the trade-offs between benefits and adverse effects of each treatment option. Information on symptoms that indicate GI and/or CV adverse effects, and directions for when these symptoms should be reported. Chou R, McDonagh M, Nakamoto E, et al. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis: An Update of the 2006 Comparative Effectiveness Review, AHRQ Comparative Effectiveness Review No. 38. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/analgesicsupdate.cfm.